Marco A. Lima

Seizures and their outcome in progressive multifocal leukoencephalopathy

Seizures are not expected in progressive multifocal leukoencephalopathy (PML), a condition considered to be restricted to the white matter. Review of medical records of 89 patients with possible or proven PML showed an 18% prevalence of seizures. Seizures usually responded well to treatment and did not affect survival. The presence of PML lesions immediately adjacent to the hemispheric cortex was the only risk factor associated with seizures in this population.

Frequency and phenotype of JC virus-specific CD8+ T lymphocytes in the peripheral blood of patients with progressive multifocal leukoencephalopathy

ABSTRACT JC virus (JCV)-specific CD8+ cytotoxic T lymphocytes (CTL) are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML) and cross-recognize the polyomavirus BK virus (BKV). We sought to determine the frequency and phenotype in fresh blood of CD8+ T cells specific for two A*0201-restricted JCV epitopes, VP1p36 and VP1p100, and assess their impact on JC and BK viremia and viruria in 15 healthy subjects, eight human immunodeficiency virus-positive (HIV+) individuals, and nine HIV+ patients with PML (HIV+ PML patients) classified as survivors. After magnetic preenrichment of CD8+ T cells, epitope-specific cells ranged from 0.001% to 0.22% by tetramer staining, with no significant difference among the three study groups. By use of seven-color flow cytometry, there was no predominant differentiation phenotype subset among JCV-specific CD8+ T cells in healthy individuals, HIV+ subjects, or HIV+ PML patients. However, in one HIV+ PML patient studied in the acute phase, there was a majority of activated effector memory cells. BKV DNA was undetectable in all blood samples by quantitative PCR, while a low JC viral load was found in the blood of only one HIV+ and two HIV+ PML patients. JCV and BKV DNA were detected in 33.3% and 13.3% of all urine samples, respectively, independent of the presence of JCV-specific CTL. The detection of JCV DNA in the urine was associated with the presence of a JCV VP1p100 CTL response. Immunotherapies aiming at increasing the cellular immune response against JCV may be valuable in the treatment of HIV+ individuals with PML.

Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the polyomavirus JC (JCV) in immunosuppressed people. There is no cure for PML but 1-year survival has increased from 10% to 50% in HIV-infected individuals treated with highly active antiretroviral therapy. We describe herein the clinical outcome of 24 PML patients whose survival exceeded 5u2005years, with a mean follow-up of 94.2u2005months (range, 60–188u2005months). Of all patients, only two were females including one who had non-Hodgkins lymphoma and was HIV negative. All 23 HIV-positive patients received highly active antiretroviral therapy, and additional experimental therapies were not associated with a better clinical outcome. Marked neurological improvement occurred in 4/24 (17%) of patients, while 11/24 (46%) had partial improvement and 9/24 (37%) remained stable. By the end of the period of observation, 8/24 (33%) of patients had no significant disability despite persistent symptoms (modified Rankin disability scale (MRDS) =1), 6/24 (25%) had slight disability and were living independently (MRDS=2), 5/24 (21%) were moderately disabled, requiring some help during activities of daily living (MRDS=3) and 5/24 (21%) had moderately severe disability, requiring constant help or institutionalisation (MRDS=4). Patients with cerebellar lesions tended to have a worse clinical outcome. MRI showed leukomalacia with ventricular enlargement secondary to destruction of the white matter at the site of previous PML lesions, and focal areas of subcortical atrophy with preservation of the cortical ribbon. Of 20 patients tested, 19(95%) had detectable CD8+ cytotoxic T-lymphocytes against JCV in their blood. In absence of a specific treatment, immunotherapies aiming at boosting the cellular immune response against JCV may improve the prognosis of PML.

Sporothrix schenckii meningitis in AIDS during immune reconstitution syndrome

Sporotrichosis is a fungal disease usually restricted to the cutaneous and lymphatic systems. Visceral involvement is unusual. To date, only 21 cases of sporotrichosis meningitis have been reported, some of these associated with immunosuppression. According to the reported cases, difficulty establishing the correct diagnosis is almost the rule which, undoubtedly, is associated with a worse prognosis. In this report, two HIV infected patients are described who developed meningitis due to Sporothrix schenckii associated with immune reconstitution inflammatory syndrome. This is the first report of sporotrichosis meningitis associated with immune reconstitution inflammatory syndrome in AIDS patients.

Efficient in vitro expansion of JC virus-specific CD8+ T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by JC virus (JCV) for which there is no cure. PML patients who have JCV-specific CD8(+) cytotoxic T lymphocytes (CTL) in their blood have a better clinical outcome. We compared JCV-specific CTL responses in vitro elicited either by JCV peptide-loaded dendritic cells (DC) or by direct peptide stimulation of lymphocytes from 20 HLA-A0201(+) healthy controls, HIV(+) and PML patients. JCV peptide-loaded DC elicited a stronger CTL expansion in 13/15 responders. DC can induce a potent JCV-specific CTL response in vitro, and may constitute a promising approach for PML immunotherapy.

New features of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy and natalizumab.

Over the past three decades, progressive multifocal leukoencephalopathy (PML) evolved from being a clinical rarity to become an important cause of neurological complications in acquired immunodeficiency syndrome (AIDS) patients. Recently this disease unexpectedly occurred in patients receiving the novel immunomodulatory medication natalizumab. These changes in the epidemiology of PML also brought new questions with regard to the pathogenesis of this disease. The authors review the current challenges in the diagnosis and management of patients with PML, based on the recent advances in the understanding of the JC virus biology and discuss potential methods to monitor disease evolution and predict outcome.

Atypical radiological presentation of progressive multifocal leukoencephalopathy following liver transplantation

Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by JC virus (JCV), occurs following transplantation and other conditions associated with immunosupression. On magnetic resonance imaging (MRI), PML lesions typically appear as hyperintense signal on T2-weighted and FLAIR images located in the subcortical white matter, which are devoid of contrast enhancement or mass effect. The prognosis is poor, but unusual inflammatory forms of PML characterized by contrast enhancement have been associated with a cellular immune response against JCV and a better prognosis. The authors report an atypical presentation of PML with contrast-enhancing lesions and mass effect on the MRI in a liver transplant recipient, who had a progressive course and fatal outcome.

Sporotrichosis in the Central Nervous System caused by Sporothrix brasiliensis

TO THE EDITOR—The metropolitan region of Rio de Janeiro is hyperendemic for catassociated sporotrichosis, and Sporothrix brasiliensis has been implicated in the majority of cases in this region. A unique clinical profile has been characterized by disseminated cases in nonimmunosuppressed patients, hypersensitivity reactions, and an increase in the number of patients with human immunodeficiency virus (HIV), with a higher incidence of severe disseminated cases, hospitalizations, and deaths [1, 2]. From January 1999 through March 2013, 3618 adult patients were diagnosed with sporotrichosis at the Instituto Nacional de Infectologia Evandro Chagas/ Fundação Oswaldo Cruz, the main referral center for the treatment of this mycosis in Rio de Janeiro State. Among these patients, 48 were coinfected with HIV, and the disseminated or disseminated cutaneous forms were present in the majority of these patients (58.3%), in contrast with the localized forms (lymphocutaneous or fixed cutaneous [41.7%]) [2]. The first patient with sporotrichosis and HIV coinfection had meningitis; since that first diagnosis, all patients with disseminated sporotrichosis have undergone a lumbar puncture to exclude central nervous system (CNS) invasion. Furthermore, the remaining 3 patients had fungus present in the cerebrospinal fluid (CSF). All but 1 patient was male, and the median CD4 cell count was 104/μL. Sporothrix brasiliensis was identified using T3B polymerase chain reaction fingerprinting [3]. Patients had skin lesions and developed subacute meningoencephalitis during the infection. Two patients died due to hydrocephalus complications. One patient presented with Cryptococcus neoformans coinfection of the CNS and died of complications that were not related to sporotrichosis. The first diagnosed patient is still alive 16 years after the onset of sporotrichosis. Three of these cases have been previously reported [4, 5]. CNS involvement in sporotrichosis, although rare, has been previously described in immunosuppressed patients, particularly within recent decades due to the HIV pandemic. When we analyzed this cohort of HIV-infected sporotrichosis patients, we found a considerable number of patients with disseminated forms of the disease, in whom S. brasiliensis was found in the CSF (14.3%). In a murine model, S. brasiliensis was the most virulent member of the Sporothrix schenckii complex, with dissemination to different organs including the CNS [6]. Sporothrix brasiliensis produces large amounts of urease and melanin, which are virulence factors that can promote penetration into tissues and evasion from the immune system [7]. We propose that S. brasiliensis, similar to what has been observed in C. neoformans infection, is neurotropic in humans, although the mechanisms implicated in CNS invasion and persistence are not yet completely understood [8, 9]. These findings highlight the potential aggressiveness of S. brasiliensis in immunosuppressed patients, particularly patients with HIV and advanced disease. CNS involvement is challenging to treat and is associated with a worse prognosis because its sterilization is difficult. In areas where HIV and sporotrichosis overlap, physicians should be aware of this potentially disastrous association and should perform an early lumbar puncture to aggressively treat CNS disease. Close follow-up of patients is necessary in order to document CSF sterilization, and alternative treatment strategies, such as novel azoles and combination therapy, may be considered.