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BACKGROUND: Epidemiological studies on predisposing conditions and outcomes of progressive multifocal leukoencephalopathy (PML) cases have been carried out exclusively in high-income countries. We aim to report and compare the main characteristics and outcomes of patients with PML and several underlying diseases in a referral center in a middle-income country. METHODS: We performed a retrospective cohort study of PML cases admitted to a tertiary care hospital in São Paulo, Brazil during 2000-2022. Demographic and PML-specific variables were recorded. One-year case-fatality rate and factors associated with death were identified using a multivariate Cox proportional hazards regression model. RESULTS: Ninety-nine patients with PML were included. HIV infection (84.8%) and malignancy (14.1%) were the most prevalent underlying conditions. Other predisposing diseases were autoimmune/inflammatory diseases (5.1%) and solid organ transplantation (1.0%). One (1.0%) patient had liver cirrhosis and another (1.0%) patient was previously healthy. Focal motor deficits (64.2%) and gait instability (55.1%) were the most common signs. The one-year case-fatality rate was 52.5% (95% CI 42.2-62.7). The one-year case-fatality rate (95% CI) in patients with or without malignancy (85.7%, 95% CI 57.2-98.2% and 47.1%, 95% CI 36.1-58.2%, respectively) were statistically different (P = 0.009). Crude and adjusted Cox regression models identified malignancy as independently associated with death (adjusted HR = 3.92, 95% CI 1.76-8.73, P = 0.001). CONCLUSIONS: HIV/AIDS was the predisposing condition in 84.8% of PML cases. The one-year case-fatality rate was 52.5% and having a malignancy was independently associated with death. This study reports emerging data on the epidemiology and outcome of PML in a middle-income country.

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Background Epidemiological studies on predisposing conditions and outcomes of progressive multifocal leukoencephalopathy (PML) cases have been carried out exclusively in high-income countries. We aim to report and compare the main characteristics and outcomes of patients with PML and several underlying diseases in a referral center in a middle-income country. Methods We performed a retrospective cohort study of PML cases admitted to a tertiary care hospital in São Paulo, Brazil during 2000–2022. Demographic and PML-specific variables were recorded. One-year case-fatality rate and factors associated with death were identified using a multivariate Cox proportional hazards regression model. Results Ninety-nine patients with PML were included. HIV infection (84.8%) and malignancy (14.1%) were the most prevalent underlying conditions. Other predisposing diseases were autoimmune/inflammatory diseases (5.1%) and solid organ transplantation (1.0%). One (1.0%) patient had liver cirrhosis and another (1.0%) patient was previously healthy. Focal motor deficits (64.2%) and gait instability (55.1%) were the most common signs. The one-year case-fatality rate was 52.5% (95% CI 42.2–62.7). The one-year case-fatality rate (95% CI) in patients with or without malignancy (85.7%, 95% CI 57.2–98.2% and 47.1%, 95% CI 36.1–58.2%, respectively) were statistically different (P = 0.009). Crude and adjusted Cox regression models identified malignancy as independently associated with death (adjusted HR = 3.92, 95% CI 1.76–8.73, P = 0.001). Conclusions HIV/AIDS was the predisposing condition in 84.8% of PML cases. The one-year case-fatality rate was 52.5% and having a malignancy was independently associated with death. This study reports emerging data on the epidemiology and outcome of PML in a middle-income country.

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This report presents the case of a 47-year-old male patient who worked as a mathematics teacher and experienced the sudden onset of disorientation, aphasia, and acalculia during an online class. The current study reveals the first documented case of HIV and progressive multifocal leukoencephalopathy with the detection of SARS-CoV-2 and human polyomavirus 2 (previously known as John Cunningham virus) in the cerebrospinal fluid. Furthermore, serum analysis revealed elevated concentrations of interleukin (IL)-6, IL-17, and IL-8, which are potential factors known to reduce the expression of tight junctions and adhesion molecules in the extracellular matrix, thereby affecting the permeability of the blood-brain barrier. Finally, the study discusses whether SARS-CoV-2 triggers or exacerbates progressive multifocal leukoencephalopathy.

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RESUMEN La leucoencefalopatía multifocal progresiva es una enfermedad desmielinizante del sistema nervioso central producido por un virus del género Polyomavirus. Las manifestaciones clínicas pueden ser motoras, sensitivas o cognitivas. Se presenta el caso de un paciente masculino de 32 años de edad con un cuadro de 24 horas de evolución de debilidad de miembro superior e inferior izquierdos que inició de manera insidiosa y progresiva, acompañada de disartria y confusión. Por sospecha de vasculitis cerebral versus enfermedad desmielinizante se inicia bolos de corticoides con lo cual mejora la debilidad. Se solicita estudios de laboratorio en la que se confirma sida. La resonancia magnética con Gadolinio en el que se observa lesiones compatibles con leucoencefalopatía multifocal progresiva. Se inicia tratamiento antirretroviral y es dado de alta sin otras complicaciones.

ABSTRACT Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by a virus of the Polyomavirus genus. The clinical manifestations can be motor, sensory or cognitive. We present the case of a 32-year-old male patient with a 24-hour evolution of weakness in the left upper and lower limb that began insidiously and progressively, accompanied by dysarthria and confusion. Due to suspicion of cerebral vasculitis versus demyelinating disease, corticosteroid boluses are started, which improves weakness. Laboratory studies are requested in which AIDS is confirmed. Gadolinium magnetic resonance imaging shows lesions compatible with progressive multifocal leukoencephalopathy. Antiretroviral treatment is started and he is discharged without other complications.

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RESUMEN Introducción: La leucoencefalopatía multifocal progresiva es una enfermedad desmielinizante del sistema nervioso central, de etiología viral. Se presenta en pacientes con enfermedades inmunosupresoras y la localización en fosa posterior es rara. Debido a sus formas clínicas inespecíficas se hace infrecuente su diagnóstico lo que conlleva a daño irreversible y/o a la muerte del paciente. Objetivo: Orientar sobre la posibilidad de leucoencefalopatía multifocal progresiva cerebelosa en pacientes inmunodeprimidos con manifestaciones neurológicas de daño en fosa posterior. Caso clínico: Paciente masculino, de 25 años de edad, sin antecedentes de enfermedades aparentes, que comienza con lenguaje escandido, temblor mixto dismetría y ataxia. Se diagnostica leucoencefalopatía multifocal progresiva cerebelosa por cuadro clínico, neuroimagen y presencia de virus JC en líquido cefalorraquídeo, además de una inmunosupresión severa causada por virus de inmunodeficiencia humana diagnosticado por pruebas serológicas. Conclusiones: Considerar leucoencefalopatía multifocal progresiva cerebelosa en todo paciente con manifestaciones neurológicas de afectación en fosa posterior y estudiar causas de inmunosupresión subyacente.

ABSTRACT Introduction: Progressive multifocal leukoencephalopathy is a demyelinating disease of viral etiology that affects the central nervous system. It presents in patients with immunosuppressive conditions and location in the posterior fossa is rare. Due to its unspecific clinical forms, its diagnosis is infrequent, leading to irreversible damage and/or the patient's death. Objective: Instruct about the possibility of cerebellar progressive multifocal leukoencephalopathy in immunocompromised patients with neurological manifestations of posterior fossa damage. Clinical case: A case is presented of a male 25-year-old patient without apparent pathological antecedents who started out with slurred speech, mixed tremor, dysmetria and ataxia. Cerebellar progressive multifocal leukoencephalopathy was diagnosed by clinical picture, neuroimaging and the presence of JC virus in the cerebrospinal fluid, alongside severe immunosuppression caused by human immunodeficiency virus diagnosed by serological testing.

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BACKGROUND: Patients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management. OBJECTIVE: To identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index. METHODS: Eighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples. RESULTS: In MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G â†’ C), leading to an amino acid change (Lys â†’ Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection. CONCLUSIONS: . The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.

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BACKGROUND: Magnetic resonance imaging is essential to diagnose progressive multifocal leukoencephalopathy. The broad radiological spectrum may partially be explained by genetic viral mutations and their differential neurotropism. Recent pharmacovigilance-magnetic resonance imaging studies have provided new insight into pathophysiology and radiological markers of early stages. However, how lesions evolve and why certain anatomical locations are more frequently affected remains unknown. We aim to describe a new sign - T2/fluid-attenutated inversion recovery mismatch - as a complementary marker of cavitated lesions and propose a link with the milky-way appearance, a key early sign. Furthermore, we hypothesise viral dissemination routes. METHODS: We conducted a retrospective longitudinal study from January 2010 to January 2020, to analyse clinical and magnetic resonance imaging features of 13 progressive multifocal leukoencephalopathy individuals at the symptomatic stage (mean age 58.3 years (SD ± 16.8) - 61.5% were women). RESULTS: The most prevalent pathology was HIV (61.5%) and motor deficit prevailed regarding other symptoms (76.9%). Frontal lobes (76.9%), middle cerebellar peduncle (61.5%), cerebellum (61.5%), and pons (53.8%) were most commonly affected, and the cortico-ponto-cerebellar pathway seemed involved in these patients. Five patients had a pure radiological pattern. Milky-way appearance was the most frequent radiological sign (58.3%). Five patients with milky-way appearance had concomitantly T2/fluid-attenuated inversion recovery mismatch (P = 0.02). This sign showed high sensitivity and specificity (100-71%, P = 0.02) to assess evolved lesions besides diffusion. CONCLUSION: The possible tract-dependent spread, as well as clinical and genetic, have implications on the MRI variability of progressive multifocal leukoencephalopathy. The milky-way appearance could reflect a transitional phase towards evolved lesions, the latter demonstrated by T2/fluid-attenuated inversion recovery mismatch. Both could be key magnetic resonance imaging signs to diagnose progressive multifocal leukoencephalopathy at the symptomatic stage.

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Abstract INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV). METHODS: We described the profile of laboratory-confirmed PML cases among AIDS patients. RESULTS: A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³. CONCLUSIONS: Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.

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RESUMEN La leucoencefalopatía multifocal progresiva es una de las diversas entidades clínicas con compromiso del sistema nervioso central causada por el virus JC en pacientes con infección por VIH o en algún otro estado de inmunocompromiso. Es una enfermedad sin tratamiento específico efectivo demostrado. Se presenta el caso de una paciente de 33 años de edad con SIDA que desarrolló esta enfermedad con deterioro progresivo del estado general hasta que se produjo su deceso a los 7 días de internación.

ABSTRACT Progressive multifocal leukoencephalopathy is one of several clinical entities with compromise of the central nervous system caused by the JC virus in patients with HIV infection or in some other state of immunocompromise. It is a disease without proven effective specific treatment. We present the case of a 33-year-old patient with AIDS who developed this disease with progressive deterioration of the general condition until her death occurred 7 days after hospitalization.

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Psychiatric disturbances in Progressive Multifocal Leukoencephalopathy (PML) are rarely adressed and its study can offer insights into the neurobiology of psychosis. The authors report a case of male patient, 42 years old, HIV positive, with PML and psychotic symptoms. The present case shows the need for regular neurological and neuropsychological evaluations of HIV positive patients and the importance of studying diseases that cause lesions in the white matter,such as PML, to elucidate the neurobiology of psychosis.(AU)

Os distúrbios psiquiátricos na Leucoencefalopatia Multifocal Progressiva (LEMP) raramente são abordados e seu estudo pode oferecer insights sobre a neurobiologia da psicose. Os autores relatam caso de paciente do sexo masculino, 42 anos, HIV positivo, com LEMP e sintomas psicóticos. O caso apresentado evidencia a necessidade de realização regular de avaliações neurológicas e neuropsicológicas de pacientes HIV positivos e a importância de se estudar doenças que causam lesões na substância branca, como a LEMP, para elucidar a neurobiologia da psicose.(AU)

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OBJECTIVES: John Cunningham virus (JCV) is a polyoma virus that infects humans, mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies in human serum has been reported to be between 50.0 and 90.0%. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish the rates of JCV seropositivity in these individuals. METHODS: The present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used the following search terms: "JCV" OR "JC virus" AND "multiple sclerosis" OR "MS" OR "NMO" OR "neuromyelitis optica" AND "prevalence." These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, MEDLINE, SciELO, LILACS, Google Scholar, and Embase. RESULTS: After the initial selection, 18 papers were included in the review. These articles reported the prevalence of JCV antibodies in the serum of patients with MS or NMO living in 26 countries. The systematic review identified data on 29,319 patients with MS/NMO and found that 57.1% of them (16,730 individuals) were seropositive for the anti-JCV antibody (range, 40.0 to 69.0%). CONCLUSIONS: The median worldwide prevalence of JCV among adults with MS or NMO was found to be 57.1%.

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Patients undergoing Natalizumab (NTZ) therapy are at risk of progressive multifocal leukoencephalopathy (PML). Besides John Cunningham virus (JCV), BK polyomavirus might represent an additional concern for such patients since it can also infect CNS cells. Currently, data regarding the presence of anti-JCV antibodies added to previous immunosuppressive therapy and prolonged NTZ therapy has been used to classify patients at risk of developing PML. Here, we investigated the profile shedding of JCV and BKV in multiple sclerosis (MS) patients during treatment with NTZ. Serial blood and urine samples from 97 MS patients receiving either NTZ or ß-interferon were investigated for polyomavirus shedding. While all blood samples tested negative, 36% of the patients shed polyomavirus in the urine in at least one time point. From these, 21.7%, 9.3%, and 5.1% shed JCV, BKV, and both polyomavirus, respectively. No difference was observed between the rates of urinary shedding of patients treated with NTZ (38.9%) and patients treated with other drugs (34.5%), also no PML event was diagnosed during the follow-up. Therefore, urinary shedding might not be interfered by therapy condition. In our study, we also observed 14/27 (52%) of anti-JCV antibodies prevalence, and nearly half of them (42%) did not present any event of urinary shedding during the follow-up

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Patients undergoing Natalizumab (NTZ) therapy are at risk of progressive multifocal leukoencephalopathy (PML). Besides John Cunningham virus (JCV), BK polyomavirus might represent an additional concern for such patients since it can also infect CNS cells. Currently, data regarding the presence of anti-JCV antibodies added to previous immunosuppressive therapy and prolonged NTZ therapy has been used to classify patients at risk of developing PML. Here, we investigated the profile shedding of JCV and BKV in multiple sclerosis (MS) patients during treatment with NTZ. Serial blood and urine samples from 97 MS patients receiving either NTZ or ß-interferon were investigated for polyomavirus shedding. While all blood samples tested negative, 36% of the patients shed polyomavirus in the urine in at least one time point. From these, 21.7%, 9.3%, and 5.1% shed JCV, BKV, and both polyomavirus, respectively. No difference was observed between the rates of urinary shedding of patients treated with NTZ (38.9%) and patients treated with other drugs (34.5%), also no PML event was diagnosed during the follow-up. Therefore, urinary shedding might not be interfered by therapy condition. In our study, we also observed 14/27 (52%) of anti-JCV antibodies prevalence, and nearly half of them (42%) did not present any event of urinary shedding during the follow-up. J. Med. Virol. 89:528-534, 2017. © 2016 Wiley Periodicals, Inc.

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Natalizumab is a therapeutic option for treating multiple sclerosis (MS) and is particularly efficacious for patients with highly active disease. A long washout period has been recommended between withdrawal of natalizumab and start of fingolimod (another option for treating MS). This long washout period has been associated with a significant increase in MS activity. In the present study, a group of 96 patients who were switched from natalizumab to fingolimod had short washout periods between drugs, or monthly corticosteroid pulse therapy if longer washout periods were recommended. This therapeutic approach led to the lowest reported relapse rate so far, among patients with MS switching from natalizumab to fingolimod (8.3%). No complications from short withdrawal were observed in this group of patients.

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La Leucoencefalopatía Multifocal Progresiva (LMP) es una condición grave secundaria a la infección por virusJohn Cunningham (VJC) derivada de la deficiencia de inmunidad celular innata o adquirida. Se presenta el primercaso reportado en Latinoamérica de (LMP) asociada a Natalizumab (NZB) en un paciente con diagnóstico deesclerosis múltiple recaída-remisión, quien ingresa a urgencias con cuadro clínico de deterioro cognoscitivo,comportamental, motor y de lenguaje de curso progresivo. Se realizaron neuroimágenes con resonancia magnéticacerebral sugestivas de LMP, estudios de reacción en cadena de polimerasa en líquido cefalorraquídeopara virus JC, que resultaron negativos en dos oportunidades; el diagnóstico se confirmó mediante la técnica dehibridación in situ en biopsia cerebral. Se realiza este reporte con el fin de resaltar la importancia de la vigilanciaclínica y paraclínica en los pacientes con esclerosis múltiple que reciben NZB...

Progressive Multifocal Leukoencephalopathy (PML) is a serious condition secondary to John Cunninghamvirus (JCV) infection derived from an innate or acquired cellular immunity deficiency. We present the firstreported case in Latin America of PML associated with Natalizumab (NZB) in a patient with a diagnostic ofrelapsing – remitting multiple sclerosis, who entered the emergency room with progressive cognitive, behavioral,motor and language impairment. Neuroimaging performed with magnetic resonance imaging was suggestiveof PML. Polymerase chain reactions in cerebrospinal fluid for JC virus were conducted twice with negativeresults. Finally the diagnosis was confirmed by in situ hybridization technique on brain biopsy. This reportis made in order to highlight the importance of clinical and paraclinical monitoring in patients with multiplesclerosis receiving NZB...

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Introducción: La LMP es una enfermedad causada por el virus JC.Afecta la sustancia encefálica provocando desmielinización progresiva. La infección se produce en la infancia y es en general asintomática. En condiciones de inmunosupresión, adquiere potencial neuropatógeno destruyendo los oligodendrocitos. Generalmente se presenta en pacientes bajo tratamiento QMT o personas HIV + CD4<100 mm3. Objetivos:presentación de un caso clínico y revisión bibliográfica. Reporte de caso: Paciente de 37 años, con diagnóstico reciente HIV, en tratamiento con antirretrovirales, inicia cuadro clínico com impotencia funcional en miembro inferior izquierdo. En un mes, el paciente evolucionó con progresión del foco neurológico,desarrollando plejía FBC izquierda + plejía crural derecha, disartria, trastornos deglutorios, desorientación culminando finalmente condeterioro del sensorio. El paciente fallece a los dos meses derealizado el diagnóstico.Discusión: El diagnóstico de LMP debe plantearse ante um paciente inmunodeprimido, que presenta un cuadro de deterioro cognitivo o déficit neurológico de curso progresivo. La mayoría delos casos ocurre en HIV + con recuento de CD4 muy bajos. Aunque no existe tratamiento específico para LMP, las terapias antirretrovirales de alta potencia (HAART) parecen influir en la supervivência.

Introduction: PML is a disease caused by the JC virus. It affects the brain substance causing progressive demyelination. The infection occurs in childhood and is generally asymptomatic. Under conditions of immunosuppression, acquired destroying oligodendrocytes neuropathogenic potential. It usually occurs in patients receiving QMT or HIV + CD4 <100 mm3. Objectives: clinical case report and literature review. Case report: Patient 35 years old, with newly diagnosed HIV in antiretroviral therapy, clinical starts with loss of function of the left lower limb. In one month, the patient developed focal neurologic progression, developing hemiplegia FBC crural left + right crural pegia, dysarthria, swallowing disorders, disorientation, culminating with sensory impairment. The patient died two months after the diagnosis. Discussion: The diagnosis of PML should be raised in an immunocompromised patient, presented symptoms of cognitive decline or neurological deficits progressive course. Most cases occur in HIV + with very low CD4 count. Although there is no specific treatment for PML, antiretroviral.

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En el contexto de una severa inmunodepresión existe una marcada dificultad para hacer diagnóstico definitivo de las infecciones oportunistas que son causa principal de morbilidad y mortalidad. La presencia de infecciones del SNC durante la evolución del paciente con VIH, es frecuente, siendo menos habitual la presencia múltiple y concurrente de éstas, pues tal situación somete a los pacientes a peor pronóstico. Por este motivo se muestra el estudio de un paciente que presentó múltiples infecciones oportunistas en el SNC, quien tras iniciar y continuar el TARGA mostró buena evolución. Caso clínico: varón de 51 años con antecedentes de alcoholismo que acude al hospital con s¡ndrome de hipertensión endocraneana. Es diagnosticado de meningitis criptocócica e infección por VIH estadio C sin TARGA. Durante el tratamiento se evidenci ademas infecciones oportunistas concurrentes, como meningitis tuberculosa, leucoencefalopatia multifocal progresiva y toxoplasmosis cerebral; conjuntamente presentó síndrome inflamatorio de reconstitución inmunológica (IRIS). El paciente al iniciar y mantener el TARGA se recuperó ¡ntegramente y manifestó buena evolución, actualmente es tratado ambulatoriamente y no se ha complicado. Interpretación: los episodios múltiples y concurrentes de infecciones oportunistas del SNC descritos as¡ como el IRIS, generalmente inducen a los pacientes a mal pronóstico, sin embargo, son pocos los casos que se recuperan copiosamente y muestran buen pronóstico. Este es un caso particular de recuperación después de seguir el TARGA correctamente. Se describe este reporte por su importancia para valorar una apropiada adherencia al TARGA.

In the context of severe immunosuppression, there is a marked difficulty in making a definitive diagnosis of opportunistic infections, which are leading causes of morbidity and mortality. The presence of CNS infections during the evolution of HIV patients is common, less common being multiple and concurrent presence of these. This situation undergoes patients with poor prognosis. For this reason we report the case of a patient who developed multiple opportunistic infections in the CNS, who after HAART initiation and continuation showed good performance. Clinical case: 51 year old male with a history of alcoholism, was admitted to hospital with intracranial hypertension syndrome. He was diagnosed with cryptococcal meningitis and HIV infection stage C without HAART. During treatment also showed concurrent opportunistic infections such as TB meningitis, progressive multifocal leukoencephalopathy and cerebral toxoplasmosis, jointly presented immune reconstitution inflammatory syndrome (IRIS). The patient, initiating and maintaining HAART, fully recovered and showed good performance. Currently he is treated as an outpatient and has no complications. Interpretation: The multiple concurrent episodes of opportunistic infections of the CNS described, as well as the IRIS, generally induce poor prognosis in patients. However, there are few cases that improve and show good prognosis. This is a particular case of recovery after HAART follow correctly. We describe this report because of its importance in assessing adherence to HAART.

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