RESUMO
Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean ageâ¯=â¯44.8, pâ¯=â¯0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (ORâ¯=â¯0.93, 95% CI: 0.88-0.99, pâ¯=â¯0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.
Assuntos
Antirreumáticos/efeitos adversos , Líquido Cefalorraquidiano/virologia , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/etiologia , Esclerose Múltipla/tratamento farmacológico , Fatores Etários , Antirreumáticos/uso terapêutico , Avaliação da Deficiência , Progressão da Doença , Doenças Endêmicas , Feminino , Humanos , Hospedeiro Imunocomprometido , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/virologia , Natalizumab/efeitos adversos , Natalizumab/uso terapêutico , Prognóstico , Índice de Gravidade de Doença , Carga ViralRESUMO
OBJECTIVE: We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML). RESULTS: A 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits. DISCUSSION: This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Vírus BK/fisiologia , Leucoencefalopatia Multifocal Progressiva/terapia , Linfócitos T/fisiologia , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is caused by JC virus opportunistic infection in the setting of immunodeficiency. Typical imaging features are multifocal and asymmetric lesions within supratentorial subcortical white matter in parieto-occipital regions. CASE DESCRIPTION: A 47-year-old patient experienced a relapse of acute myeloid leukemia 21 months after hematopoietic stem cell transplantation. He also had visual impairment and magnetic resonance imaging showed an isolated cerebellar lesion without mass effect or enhancement. Common opportunistic infections and leukemic central nervous system involvement were excluded by cerebrospinal fluid (CSF) analysis. Given the worsening clinical and radiologic scenario, PML was suspected, and CSF protein chain reaction analysis was positive for JC virus. CONCLUSIONS: Given its potential curability, PML should be thoroughly investigated in patients with hematologic neoplasms and atypical isolated cerebellar presentation.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucoencefalopatia Multifocal Progressiva/patologia , Imageamento por Ressonância Magnética/métodos , Humanos , Leucemia Mieloide Aguda/patologia , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/etiologia , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML. METHODS: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides. RESULTS: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up. INTERPRETATION: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779.
Assuntos
Transferência Adotiva/métodos , Vírus JC , Leucoencefalopatia Multifocal Progressiva/terapia , Linfócitos T , Adolescente , Transferência Adotiva/efeitos adversos , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically. METHODS: We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups. RESULTS: The PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function. CONCLUSIONS: This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.
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Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/metabolismo , Infecções por HIV/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Adulto , Feminino , Infecções por HIV/complicações , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/etiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Pseudotumor Cerebral/líquido cefalorraquidiano , Estudos RetrospectivosRESUMO
Progressive multifocal leukoencephalopathy (PML) is a serious infective disease of the central nervous system that may occur in case of severe immunosuppression or after some treatment for multiple sclerosis (MS) with natalizumab, dimethyl fumarate, and fingolimod. In these case reports, we highlight the importance of differential diagnosis between PML and MS lesions in order to provide rapidly the best treatment option, by discussing the finding of brain (magnetic resonance imaging) MRI suggestive for PML in 2 MS patients, one treated with dimethyl fumarate and the other during natalizumab withdrawal. In both cases, although brain MRI was highly suggestive for PML, the detection of John Cunningham virus-DNA copies in cerebrospinal fluid resulted in negative result. These case reports illustrate the diagnostic process in case of suspected PML, as both patients were diagnosed with suspected PML during a routine brain MRI control, and highlights the importance of providing a strict brain MRI follow-up during dimethyl fumarate treatment, although only a few cases of PML during this therapy have been detected, and during natalizumab suspension phase. In clinical practice, in case of a radiologically suspected case of PML, although not confirmed by the cerebrospinal fluid analysis, the best approach could be to perform a close radiological and clinical monitoring before starting a new MS therapy.
Assuntos
DNA Viral/líquido cefalorraquidiano , Fatores Imunológicos/efeitos adversos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Líquido Cefalorraquidiano/virologia , Diagnóstico Diferencial , Fumarato de Dimetilo/efeitos adversos , Feminino , Cloridrato de Fingolimode/efeitos adversos , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/etiologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Natalizumab/efeitos adversos , Reação em Cadeia da Polimerase , Carga ViralRESUMO
OBJECTIVE: To define the risk of progressive multifocal leukoencephalopathy (PML) in SLE. METHODS: This is a retrospective observational study to evaluate PML cases in patients with SLE admitted to two large academic hospitals. Using electronic medical record (EMR) data, International Classification of Diseases (ICD) codes identified PML cases among patients with SLE, rheumatoid arthritis (RA) (controls), had renal transplant and with HIV. Medication exposure was reviewed. RESULTS: A total of 5409 Columbia University Medical Center (CUMC) patients and 2046 Northwell Health patients were identified using one ICD code for SLE. Of 7455 patients, three had an ICD code for PML. On EMR review, however, PML was substantiated in only one fatal SLE case with significant immunosuppressant use and severe lymphopenia (<0.5 cells x 109/L); one patient was evaluated for PML but cerebrospinal fluid (CSF) was negative for JC virus and improved with treatment of central nervous system (CNS) lupus. EMR data were very limited for the third patient and diagnosis could not be confirmed. None of the 13 342 patients with RA ICD codes had PML. Of the 5409 patients with an SLE ICD code at CUMC, 212 also had a renal transplant ICD code, and 83 had concomitant HIV/AIDS. Based on inpatient pharmacy records of 5409 hospitalised patients at CUMC, 59.2% were treated with steroids, and 16.09% with immunosuppressants (7.76% mycophenolate, 3.42% cyclophosphamide, 2.88% azathioprine and 2.03% rituximab). No patients with paediatric SLE (pSLE) (n=538) had PML. The combined prevalence of PML in hospitalised patients with SLE at the two hospitals was 13-27/100 000 patients. CONCLUSION: Among 7455 adult patients with SLE ICD codes, there were two PML cases, with only one confirmed case associated with severe lymphopenia and immunosuppressants, corresponding to a prevalence of 13-27 per 100 000 patients. No PML cases in pSLE were found. A high index of suspicion in patients with SLE and CNS manifestations is required for the prompt diagnosis of PML.
Assuntos
Artrite Reumatoide/complicações , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Lúpus Eritematoso Sistêmico/complicações , Adulto , Estudos de Casos e Controles , Viroses do Sistema Nervoso Central/epidemiologia , Viroses do Sistema Nervoso Central/virologia , Criança , Registros Eletrônicos de Saúde , Feminino , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Hospitalização , Humanos , Imunossupressores/uso terapêutico , Vírus JC/isolamento & purificação , Transplante de Rim/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Leucoencefalopatia Multifocal Progressiva/virologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfopenia/complicações , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Medição de RiscoRESUMO
CASE REPORT: an 80-year-old woman presented with rapidly progressive glomerulonephritis and was admitted to our hospital. Myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) was positive. We diagnosed ANCA-associated renal vasculitis (ANCA-RV). Treatment was initiated with intravenous methylprednisolone pulse therapy, followed by prednisolone (PSL) at 30 mg/day. We gradually reduced the PSL dose to 7.5 mg/day over 6 months. At that time, the patient developed disturbances of consciousness which progressed subacutely. MRI revealed regions of patchy white matter with an increased signal on T2-weighted, fluid attenuated inversion recovery (FLAIR) sequences and diffusion-weighted sequences. JC virus DNA was detected in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), leading to a diagnosis of progressive multifocal leukoencephalopathy (PML). PML is a rare infectious demyelinating disease of the central nervous system caused by JC virus infection, occurring in highly immunosuppressed individuals such as HIV-infected patients and patients using some biological agents, and having a very poor prognosis. In the present case, PML may have been associated with steroid use, although there are very few case reports of PML in patients taking only steroids. We report progressive multifocal leukoencephalopathy during steroid treatment of ANCA-RV. When patients show progressive disturbance of consciousness during treatment for ANCA-RV, we need to take PML into consideration for differential diagnosis.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Glomerulonefrite/diagnóstico , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Esteroides/efeitos adversos , Administração Intravenosa , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Glomerulonefrite/imunologia , Humanos , Hospedeiro Imunocomprometido , Vírus JC/genética , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/virologia , Imageamento por Ressonância Magnética/métodos , Peroxidase/metabolismo , Índice de Gravidade de Doença , Esteroides/administração & dosagem , Esteroides/uso terapêuticoAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Rituximab/efeitos adversos , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Encéfalo/diagnóstico por imagem , Infecções por Clostridium/complicações , Evolução Fatal , Feminino , Humanos , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Imageamento por Ressonância Magnética , Rituximab/uso terapêutico , Choque Séptico/etiologiaRESUMO
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by JC virus (JCV). Although detecting JCV DNA in the cerebrospinal fluid (CSF) by real-time polymerase chain reaction (PCR) is useful, diagnosis is difficult when JCV concentrations are low. We therefore aimed to lower the detection limit of real-time PCR testing by enriching JCV in the CSF via ultrafiltration. METHODS: Virus suspensions and CSF specimens from 20 untreated patients with suspected PML were collected and total DNAs were extracted. The JCV large T gene was detected by quantitative real-time PCR under condition with and without prior centrifugal ultrafiltration. RESULTS: The JCV DNA was reliably detected to a lower limit of 10 copies/mL of virus suspension by real-time PCR with ultrafiltration. When using this method, the quantity of JCV DNA per PCR reaction increased 3.2- to 8.7-fold compared with the standard procedure. Seven patients were positive for JCV when using the standard procedure, and an additional patient was positive when using ultrafiltration. All JCV-positive patients had neurological features and magnetic resonance imaging findings compatible with PML. CONCLUSIONS: The detection limit of JCV DNA by real-time PCR can be lowered by viral enrichment using ultrafiltration. Our simple protocol offers a valuable tool for PML diagnosis when extremely low copy numbers of JCV are released into the CSF or when brain biopsy is not feasible.
Assuntos
DNA Viral/líquido cefalorraquidiano , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Ultrafiltração/métodos , Adulto , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Masculino , Pessoa de Meia-IdadeRESUMO
Progressive multifocal leukoencephalopathy (PML), caused by infection with John Cunningham polyoma virus (JCPyV) in immune-compromised patients, is a serious demyelinating disease of the central nervous system. This disease often leads to major neurological impairments and consecutive disability. No effective treatment for PML has been found as yet. As JCPyV-PCR of the cerebrospinal fluid (CSF) may be negative in some cases, a reliable diagnosis might prove to be difficult as well. So far, two case reports suggested CSF-tau to be a promising biomarker for PML. Our study included 10 patients with assured diagnosis of PML and varying underlying diseases. In all but one the CSF-tau concentration was normal. Our results indicate that CSF-tau is not an appropriate biomarker for PML.
Assuntos
Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess the predictive value of JC virus (JCV) PCR in cerebrospinal fluid (CSF) in the diagnosis of progressive multifocal leukoencephalopathy (PML). METHODS: We conducted a retrospective database query to identify patients with positive CSF JCV PCR. Clinical features, final diagnosis and quantitative PCR results were obtained. RESULTS: A positive CSF JCV PCR had a PPV of 10.4% for the diagnosis of PML. A weakly positive PCR had a PPV of 1.6%, whereas a moderately to highly positive PCR had a PPV of 92.3%. A PPV of 0.0% was observed in immunocompetent patients and in patients without compatible clinical or radiological features. CONCLUSIONS: A false-positive CSF JCV PCR is highly prevalent in our clinical practice. This test should be reserved for patients with a clinical suspicion of PML and the quantitative result of the PCR should be taken into account when making the diagnosis of PML.
Assuntos
Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Reação em Cadeia da Polimerase , Carga Viral/métodos , DNA Viral/sangue , DNA Viral/líquido cefalorraquidiano , DNA Viral/urina , Reações Falso-Positivas , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/urina , Infecções por Polyomavirus/líquido cefalorraquidiano , Infecções por Polyomavirus/diagnóstico , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
West Nile virus is a notable cause of neuroinvasive disease, damage to the central nervous system, or even death. In this study, using metagenomics analysis and quantitative real-time PCR validation, we identified a JC virus infection in urine and cerebrospinal fluid samples of a West Nile virus patient with severe neurological symptoms and extended disease. JC virus is known to be involved in neurological complications, especially in immunocompromised individuals thus suggesting that the coinfection with JC virus is involved with the West Nile virus infection persistence and severe symptoms. JC virus was identified in urine samples from additional West Nile virus patients via quantitative real-time PCR, however, JC virus was not found in any cerebrospinal fluid samples of West Nile virus patients, suggesting that JC virus does not regularly infect the central nervous system of WNV patients. Overall, this study highlights the importance of identifying infection by opportunistic viruses in already-diagnosed patients and highlights the advantages of next-generation sequencing and metagenomics for viral diagnosis.
Assuntos
Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/virologia , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Doença Aguda , Coinfecção , DNA Viral/líquido cefalorraquidiano , DNA Viral/genética , DNA Viral/urina , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/urina , Metagenômica , RNA Viral/líquido cefalorraquidiano , RNA Viral/genética , RNA Viral/urina , Reação em Cadeia da Polimerase em Tempo Real , Febre do Nilo Ocidental/líquido cefalorraquidiano , Febre do Nilo Ocidental/diagnóstico , Febre do Nilo Ocidental/urina , Vírus do Nilo Ocidental/isolamento & purificaçãoRESUMO
There are only few documented cases of progressive multifocal leukoencephalopathy (PML) in Africa. Whether this is caused by a lack of JC virus (JCV) spread or alteration in the JCV genome is unknown. We characterized the clinical presentation, laboratory findings, and JCV regulatory region (RR) pattern of the first documented PML cases in Zambia as well as JCV seroprevalence among HIV+ and HIV- Zambians. We identified PML patients with positive JCV DNA PCR in their cerebrospinal fluid (CSF) among subjects enrolled in an ongoing tuberculous meningitis study from 2014 to 2016 in Lusaka. JCV regulatory region was further characterized by duplex PCR in patients' urine and CSF. Of 440 HIV+ patients, 14 (3%) had detectable JCV DNA in their CSF (age 18-50; CD4+ T cells counts 15-155 × 106/µl) vs 0/60 HIV- patients. The main clinical manifestations included altered mental status and impaired consciousness consistent with advanced PML. While prototype JCV was identified by duplex PCR assay in the CSF samples of all 14 PML patients, only archetype JCV was detected in their urine. All PML Zambian patients tested were seropositive for JCV compared to 46% in a control group of HIV+ and HIV- Zambian patients without PML. PML occurs among HIV-infected individuals in Zambia and is caused by CNS infection with prototype JCV, while archetype JCV strains are present in their urine. JCV seroprevalence is comparable in Zambia and the USA, and PML should be included in the differential diagnosis of immunosuppressed individuals presenting with neurological dysfunction in Zambia.
Assuntos
DNA Viral/genética , Infecções por Henipavirus/diagnóstico , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Tuberculose Meníngea/diagnóstico , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Coinfecção , DNA Viral/líquido cefalorraquidiano , DNA Viral/urina , Feminino , Genótipo , HIV/efeitos dos fármacos , HIV/genética , HIV/isolamento & purificação , Infecções por Henipavirus/líquido cefalorraquidiano , Infecções por Henipavirus/tratamento farmacológico , Infecções por Henipavirus/virologia , Humanos , Vírus JC/efeitos dos fármacos , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/virologia , ZâmbiaAssuntos
Fatores Imunológicos/efeitos adversos , Lenalidomida/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Mieloma Múltiplo/tratamento farmacológico , Líquido Cefalorraquidiano/virologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mieloma Múltiplo/cirurgia , Transplante de Células-TroncoRESUMO
OBJECTIVE: To test the current progressive multifocal leukoencephalopathy (PML) diagnostic criteria by applying them to patients previously diagnosed with natalizumab (NTZ)-associated PML in a real-world clinical setting. METHODS: Patients from the Dutch-Belgian NTZ-PML cohort (n=28) were reviewed at the time of first diagnostic work-up and during follow-up, using the PML diagnostic criteria as proposed in a consensus statement from the American Academy of Neurology. RESULTS: At first diagnostic work-up, 18 patients (64.3%) met the criteria for high diagnostic certainty for PML ('definite PML' or 'probable PML'). During follow-up, this increased to 20 patients (71.4%) as JC virus DNA was detected in cerebrospinal fluid of two additional patients. Nonetheless, 28.6% of patients were still classified as 'possible PML' or 'not PML' (6 (21.5%) and 2 (7.1%) patients, respectively) despite a very high suspicion for PML based on lesion evolution and signs of PML-immune reconstitution inflammatory syndrome on MRI, and development of compatible symptoms. CONCLUSIONS: The current case definition of PML has low sensitivity for diagnosis of NTZ-PML in a real-world clinical setting in which MRI is frequently used for PML screening. This may delay diagnosis and appropriate management of PML, and may complicate a valid estimation of PML incidence during NTZ therapy.
Assuntos
Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Adulto , Bélgica , Encéfalo/diagnóstico por imagem , Estudos de Coortes , DNA Viral/líquido cefalorraquidiano , Diagnóstico Precoce , Feminino , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos , Farmacovigilância , Reação em Cadeia da Polimerase , Ativação ViralRESUMO
Importance: The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. Objective: To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. Design, Setting and Participants: This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Main Outcomes and Measures: Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Results: Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Conclusions and Relevance: Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.
Assuntos
DNA Viral/líquido cefalorraquidiano , Fatores Imunológicos/efeitos adversos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Adulto , Líquido Cefalorraquidiano/virologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Carga ViralRESUMO
Progressive multifocal leukoencephalopathy (PML) is a rare, yet typically fatal complication of allogeneic stem cell transplantation. It is caused by reactivation of the John Cunningham (JC) virus in an immunocompromised host. This report describes an unfortunate case of PML in a recipient of an allogeneic stem cell transplant for acute myelogenous leukemia. The JC virus was undetectable in the patient's cerebrospinal fluid by polymerase chain reaction (PCR); however, a positive diagnosis was made after a brain biopsy. This and other published cases demonstrate that recipients of allogeneic stem cells can develop PML. Moreover, early diagnosis of the disease is often difficult and, as demonstrated in this case, screening with PCR does not appear to have strong diagnostic significance. With no effective treatment presently available, restoration of immune function is the only intervention that can affect prognosis. Further prospective studies are needed to understand the pathophysiology and treatment of this disease.