Carlos Otávio Brandão

Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse

The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process.

Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients

Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.

Structural brain abnormalities are related to retinal nerve fiber layer thinning and disease duration in neuromyelitis optica spectrum disorders

Background: Although aquaporin-4 (AQP4) is widely expressed in the human brain cortex, lesions are rare in neuromyelitis optica (NMO) spectrum disorders (NMOSD). Recently, however, several studies have demonstrated occult structural brain atrophy in NMO. Objective: This study aims to investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMOSD and to assess the visual pathway integrity during disease duration correlation of the retinal nerve fiber layer (RNFL) and pericalcarine cortex thickness. Methods: Twenty-one patients with NMOSD and 34 matched healthy controls underwent both high-field MRI (3T) high-resolution T1-weighted and diffusion-tensor MRI. Voxel-based morphometry, cortical analyses (Freesurfer) and diffusion-tensor imaging (DTI) analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, RNFL measurement by optic-coherence tomography (OCT) was performed. Results: We demonstrate that NMOSD is associated with GM and WM atrophy, encompassing more frequently the motor, sensory and visual pathways, and that the extent of GM atrophy correlates with disease duration. Furthermore, we demonstrate for the first time a correlation between RNFL and pericalcarine cortical thickness, with cortical atrophy evolving over the course of disease. Conclusions: Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved.

Prognostic indicators for long-term disability in multiple sclerosis patients

BACKGROUND Daily practice is still faced with uncertainty in predicting the long-term disability of multiple sclerosis (MS). Most information comes from northern hemisphere cohorts, but in South America this information is scarce, and race, genetic and environmental factors could play an important role in the heterogeneity observed in disease outcomes. METHODS We evaluated 197 patients attending our MS Center gathering clinical and demographic information. Outcome measures analyzed were time from first clinical symptom to EDSS of 6, 7 and 8. For survival analysis we employed Cox regression models and the Kaplan-Meier method. RESULTS Time to EDSS 6 was 25.83 years (95% CI 15.36-36.31), and 36.25 years (95% CI 20.72-51.78) for EDSS 7. Male sex was associated with a 4.63 and 4.69 fold increased risk to EDSS 6 and 7, respectively (p<0.001 and p=0.006). Motor and brainstem symptoms at onset were also associated with an 8.1 and 13.1 fold increased risk to EDSS 6, respectively (p=0.04 and p=0.01). The number of relapses in five and ten years of disease onset was associated with a slightly increased risk to EDSS 8 (1.28 and 1.19, respectively; p=0.032 and p=0.015). CONCLUSIONS Male patients presenting with frequent relapses, especially those with motor and brainstem involvement, deserve close observation and should be cautiously monitored to early signs of treatment failure.

Interferon-beta modifies the peripheral blood cell cytokine secretion in patients with multiple sclerosis

Immunotherapy with Interferon-beta (IFNbeta) results in remarkably beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. An investigation was made of the effects of IFNbeta on pro-inflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as in healthy controls. Results show a significant increase in the production of pro-inflammatory cytokines such as TNFalpha, IFNgamma and IL-12 in the plasma and in the supernatant of leukocyte cultures from MS patients with the untreated disease; IFNbeta administration significantly reduced the levels of TNFalpha and IFNgamma, with no changes in the level of IL-12. The Interferon-beta therapy also led to a significant increase in the production of IL-10, as well as a slight increase in that of TGFbeta. The reduction in pro-inflammatory cytokine production in the treated MS patient group, accompanied by a simultaneous increase in the production of anti-inflammatory cytokines and the reduction of relapse rates suggests that the beneficial effects of IFNbeta immunotherapy result, at least in part, from the modulation of cytokine patterns.

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission

Cytokines and intrathecal IgG synthesis were determined in the cerebrospinal fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNFalpha and IFNgamma in the CSF and serum, with no significant changes of IL12 and IL10 production. The changes in the cytokine production patterns were associated with an increase of leukocytes in the CSF, as well as the presence of oligoclonal bands suggesting intrathecal IgG synthesis. These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.

Factors associated to the positive cerebrospinal fuid culture in the tuberculous meningitis

Central nervous system involvement is the most common neurological complication in the course of tuberculosis. The lack of rapid and sensitive tests delays the early diagnosis. Here, we retrospectively reviewed the cerebrospinal fluid (CSF) examination of 30 patients with tuberculous meningitis confirmed by bacteriological tests (culture and/or polymerase chain reaction). The purpose of the present study was to determine the CSF parameters associated to the positive CSF culture for Mycobacterium tuberculosis in tuberculous meningitis. We found higher frequency of positive CSF culture in patients infected with HIV as well in patients with high number of neutrophils and high protein content (characteristic in the early or acute-stage patients), which suggests that the positive culture found in these patients may be associated with the presence of high bacillary load in CSF occurring in these stages.

Impact of electroacupuncture on quality of life for patients with Relapsing-Remitting Multiple Sclerosis under treatment with immunomodulators: A randomized study

BackgroundMultiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS.MethodsThirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients.ResultsElectroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure.ConclusionThis paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly.Trial RegistrationRBR-58yq52

Multiple sclerosis: clinical and laboratorial correlation

The clinical and demographic characteristics of 86 Brazilian patients with clinically definite multiple sclerosis (MS) were compared to the cerebrospinal fluid (CSF) findings. The disease course was relapsing-remitting in 71% and chronic progressive in 29% of the cases. The IgG index was increased in 76% in the chronic progressive status and 46% and 49% during the bout and remission, respectively (p < 0.005). Only 36% of the MS patients using corticosteroids had increased IgG index, in comparison to the 64% of the patients without immunosupressive treatment. Oligoclonal IgG bands were detected in the CSF of 77% and 88% of the MS corticosteroids users and non-users, respectively. The quantitative study of intrathecal synthesis of IgG contributes to demonstrate the immunological differences between the two forms of MS, the relapsing-remitting and the chronic progressive. The treatment with corticosteroids decreases quantitatively the intrathecal synthesis of IgG but not the presence of oligoclonal bands.

Multiple sclerosis in Brazil. Analysis of cerebrospinal fluid by standard methods.

The demonstration of intrathecal IgG synthesis has been used as an important laboratory parameter to support the diagnosis of multiple sclerosis (MS). The Committee for European Concerted Action for Multiple Sclerosis has recommended a protocol for the assessment of intrathecal IgG synthesis. We applied this methodology to determine the cerebrospinal (CSF) profile of 128 Brazilian patients with MS. We detected hypercytosis lower than 35 cells/mm3 in 97%, protein lower than 80 mg/dl in 99%, normal blood-CSF barrier function in 76%, increased IgG local production around 53% and oligoclonal IgG bands by isoelectric focusing in 85% of the definite MS patients. The diagnostic accuracy of the quantitative analysis was lower than the qualitative. The detection of oligoclonal bands was especially important in the cases of normal quantitative assays of IgG. In addition, we found a lower frequency of inflammatory reaction in CSF in our MS cases, in comparison to some European studies.