John A. Lincoln

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study

Background: There are no published MRI studies comparing interferon beta 1b (IFNβ-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). Objective: To compare the efficacy of IFNβ-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI. Methods: A total of 75 patients with relapsing-remitting MS or clinically isolated syndromes were randomized to standard doses of IFNβ-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement. The primary outcome was the number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery (FLAIR) lesions. Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years. Results: Baseline characteristics were similar between the groups. The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1–12, 0.63 (2.76) for IFNβ-1b, and 0.58 (2.45) for GA (p = 0.58). There were no differences in new lesion or clinical relapses for 2 years. Only 4.4% of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions. Conclusion: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity.

Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant, acemannan

Previous studies by these investigators have shown that mannosylated bovine serum albumin (m-BSA) enhances the respiratory burst (RB), phagocytosis, and killing of Candida albicans by resident murine peritoneal macrophages (MO). Upregulation of the above MO functions was associated with binding of m-BSA to the MO-mannose receptor. The present study was done to determine if the immunostimulant, acemannan prepared from aloe vera, could stimulate MO in a similar manner. Resident peritoneal MO collected from C57BL/6 mice were exposed to acemannan for 10 min. The RB was measured using chemiluminescence and demonstrated approximately a two-fold increase above the media controls. In studies involving phagocytosis, MO were exposed to acemannan, washed and exposed to Candida at a ratio of 1:5. The percent phagocytosis and Candida killing were determined using fluorescence microscopy. There was a marked increase in phagocytosis in the treated cultures (45%) compared to controls (25%). Macrophages exposed to acemannan for 10 min resulted in ca 38% killing of Candida albicans compared with 0-5% killing in controls. If MO were incubated with acemannan for 60 min, 98% of the yeast were killed compared to 0-5% in the controls. The results of the present study indicate that short term exposure of MO to acemannan upregulates the RB, phagocytosis and candidicidal activity. Further studies are needed to clarify the potential use of this immunostimulant as an anti-fungal agent.

New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate

Background: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. Methods: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon β-1b (IFNβ1b) in the BECOME study. Findings: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for ⩾1 year, 103 (18.8%) were still visible ⩾12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up ⩾1 year converted to CBH, 9.8% with IFNβ1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNβ1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. Interpretation: Only a minority of new brain lesions in patients with MS treated with GA or IFNβ1b convert to CBH.

Regional cortical thickness in relapsing remitting multiple sclerosis: A multi-center study.

A comprehensive analysis of the global and regional values of cortical thickness based on 3D magnetic resonance images was performed on 250 relapsing remitting multiple sclerosis (MS) patients who participated in a multi-center, randomized, phase III clinical trial (the CombiRx Trial) and 125 normal controls. The MS cohort was characterized by relatively low clinical disability and short disease duration. An automatic pipeline was developed for identifying images with poor quality and artifacts. The global and regional cortical thicknesses were determined using FreeSurfer software. Our results indicate significant cortical thinning in multiple regions in the MS patient cohort relative to the controls. Both global cortical thinning and regional cortical thinning were more prominent in the left hemisphere relative to the right hemisphere. Modest correlation was observed between cortical thickness and clinical measures that included the extended disability status scale and disease duration. Modest correlation was also observed between cortical thickness and T1-hypointense and T2-hyperintense lesions. These correlations were very similar at 1.5 T and 3 T field strengths. A much weaker inverse correlation between cortical thickness and age was observed among the MS subjects compared to normal controls. This age-dependent correlation was also stronger in males than in females. The values of cortical thickness were very similar at 1.5 T and 3 T field strengths. However, the age-dependent changes in both global and regional cortical thicknesses were observed to be stronger at 3 T relative to 1.5 T.

Enhancement of macrophage-mediated bactericidal activity by macrophage-mannose receptor-ligand interaction.

Neutrophils represent one of the hosts primary defenses against invading organisms. These cells often arrive at the site of infection prior to macrophages (MØ). Neutrophils release myeloperoxidase (MPO) into the micro‐environment during phagocytosis. Previous studies by the present investigators have shown that MØ bactericidal activity is enhanced by exposure to MPO. A recent report suggests that as much as 40% of this protein is enzymatically inactive once it is released into the micro‐environment. In the present study, exposure of MØ to an enzymatically inactive form of MPO (iMPO) or another mannosylated protein, mannoslyated bovine serum albumin (mBSA). can induce the same enhanced MØ‐mediated bacterial cell killing observed with the active form of MPO. Furthermore, this phenomenon is limited as galactosylated BSA (gBSA) did not induce enhancement of bacterial killing. The data suggest that interaction of either enzymatically active or inactive mannosylated proteins with the MØ mannose receptor (MMR), is sufficient to enhance MØ bactericidal activity and further underscores the binding of the MMR and resultant responses as a major host defense mechanism.

MACROPHAGE-MEDIATED CANDIDACIDAL ACTIVITY IS AUGMENTED BY EXPOSURE TO EOSINOPHIL PEROXIDASE: A Paradigm for Eosinophil-Macrophage Interaction

Various disease states are associated with eosinophilia and the release of eosinophil peroxidase (EPO) into the microenvironment. The present study targets the effects of low levels of EPO on macrophage (MØ) phagocytosis and intracellular killing of Candida albicans as well as MØ oxidative activity measured as the luminescence product of luminol dioxygenation. Resident murine peritoneal MØ were exposed to various concentrations of EPO. Chemiluminescence data indicate that nanomolar concentrations of EPO markedly enhanced the dioxygenation activity (respiratory burst) of MØ. In other studies, the exposure of MØ to 0.17 μM EPO for 10 min. enhanced MØ-mediated candidacidal activity 10 fold. The above data indicate that EPO enhances certain MØ functions. Also the results illustrate a previously un-recognized interaction between eosinophils and MØ and implicate yet another possible role for EPO in host defenses against disease.

Distinguishing and quantification of the human visual pathways using high-spatial-resolution diffusion tensor tractography.

Quantification of the living human visual system using MRI methods has been challenging, but several applications demand a reliable and time-efficient data acquisition protocol. In this study, we demonstrate the utility of high-spatial-resolution diffusion tensor fiber tractography (DTT) in reconstructing and quantifying the human visual pathways. Five healthy males, age range 24-37years, were studied after approval of the institutional review board (IRB) at The University of Texas Health Science Center at Houston. We acquired diffusion tensor imaging (DTI) data with 1-mm slice thickness on a 3.0-Tesla clinical MRI scanner and analyzed the data using DTT with the fiber assignment by continuous tractography (FACT) algorithm. By utilizing the high-spatial-resolution DTI protocol with FACT algorithm, we were able to reconstruct and quantify bilateral optic pathways including the optic chiasm, optic tract, optic radiations free of contamination from neighboring white matter tracts.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

An overview of gene-epigenetic-environmental contributions to MS causation.

In this paper we review how environmental factors might interact with genes and epigenetic factors to trigger multiple sclerosis (MS), the latter probably by immune-mediated mechanisms.