Is Late-Onset Multiple Sclerosis Associated With A Worse Outcome?
Tremlett H, Devonshire V
Neurology 2006 Sep 26;67(6):954-9
University of British Columbia, Department of Medicine (Neurology), Rm. S159, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
To describe the characteristics of Late-Onset Multiple Sclerosis (MS) (LOMS, 50+ years) vs Adult-Onset MS (AOMS, 16 to < 50 years) and examine prognosis and associated risk factors.
Patients with definite MS, onset prior to July 1988, registered with a BCMS clinic before July 1998, with at least one Expanded Disability Status Scale (EDSS) score, were selected from the longitudinal population-based British Columbian (BC) MS database.
Clinical and demographic characteristics were compared between LO and AOMS. Progression was measured as time to reach sustained EDSS 6 and potential risk factors examined were sex, disease course (Primary/Progressive [PP] vs Relapsing [R]), and onset symptoms.
Of those eligible (n = 2,837), LOMS comprized 132 (4.7%), with PPMS predominating (54.5% vs 10.6% in AOMS, p < 0.0005). Motor onset symptoms were more prevalent in LOMS and Sensory and Optic Neuropathy more prevalent in AOMS (p < 0.0005).
AOMS averaged 27.7 years (95% CI: 26.3 to 29.1) to EDSS 6 from onset vs 16.9 years (95% CI: 9.0 to 24.8) in LOMS, p < 0.0005. However, AOMS was associated with a younger age at EDSS 6 (58.4 years [95% CI: 57.1 to 59.6] vs 71.2 years [95% CI: 65.2 to 77.3] in LOMS, p < 0.0005).
There were no differences in progression between AO or LO for those with PPMS (p = 0.373) or R-MS (p = 0.438), although considerable variation was observed.
Late-Onset Multiple Sclerosis (LOMS) is not necessarily associated with a worse outcome:
First, progression in the Primary/Progressive or Relapsing patients differed little between Late-Onset vs Adult-Onset.
Secondly, those with LOMS were older when reaching Expanded Disability Status Scale 6.
The disease course has a far greater implication for disease prognosis than the presence of LOMS.
Wattjes MP, Lutterbey GG, Gieseke J, Traber F, Klotz L, Schmidt S, Schild HH
AJNR Am J NeuroRadiol 2007 Jan;28(1):54-9
University of Bonn, Departments of Radiology/NeuroRadiology, Bonn, Germany
Background And Purpose
To prospectively determine the sensitivity in the detection of Multiple Sclerosis (MS) lesions by using Double Inversion Recovery (DIR), Fluid-Attenuated Inversion Recovery (FLAIR), and T2-weighted Turbo Spin-Echo (T2 TSE) MR imaging at 3T.
Seventeen patients presenting with a Clinically Isolated Syndrome (CIS) suggestive of MS, 9 patients with definite MS, and 6 healthy control subjects were included. Imaging was performed on a 3T MR system using DIR, FLAIR, and T2 TSE sequences.
Lesions were counted and classified according to 5 anatomic regions: InfraTentorial, PeriVentricular, deep White Matter, JuxtaCortical, and mixed White Matter-Gray Matter.
The sensitivity at DIR was compared with the corresponding sensitivity at FLAIR and T2 TSE sequence. The contrast between lesions and Normal-Appearing Gray Matter, Normal-Appearing White Matter, and CSF was determined for all sequences.
Because of higher lesion-White Matter contrast, the DIR showed a higher number of lesions compared with the FLAIR (7% gain, P = 0.04) and the T2 TSE (15% gain, P = 0.01).
The higher sensitivity was also significant for the InfraTentorial region compared with the FLAIR (56% gain, P = 0.02) and the T2 TSE (44% gain, P = 0.02).
Compared with the FLAIR, no significant changes of the lesion load measurements were observed in the SupraTentorial Brain.
Slightly higher numbers of PeriVentricular and mixed Gray Matter-White Matter lesions on the DIR were counterbalanced by a slightly reduced sensitivity regarding JuxtaCortical lesions.
DIR Brain imaging at 3T provides the highest sensitivity in the detection of MS lesions especially in the InfraTentorial region.
Detection Of Simulated Multiple Sclerosis Lesions On T2-Weighted And FLAIR Images Of The Brain: Observer Performance
Woo JH, Henry LP, Krejza J, Melhem ER
Radiology 2006 Oct;241(1):206-12
Hospital of the University of Pennsylvania, Department of Radiology, Division of NeuroRadiology, 3400 Spruce St, Dulles 2, Philadelphia, PA 19104, USA
To determine observer performance in the detection of Multiple Sclerosis (MS) lesions on Magnetic Resonance (MR) images of the Brain.
And to assess the dependence of observer performance on lesion size, Parenchymal location, pulse sequence, and SupraTentorial versus InfraTentorial level.
Materials And Methods
This HIPAA-compliant protocol was approved by the institutional review board, and previously acquired MR data from a healthy volunteer and a patient with MS were used to derive parameter maps, with waiver of informed consent.
Parameter maps and image simulator software were used to generate 320 phantom brain images with simulated SupraTentorial and InfraTentorial MS lesions.
Images were displayed with T2-weighting or Fluid-Attenuated Inversion Recovery (FLAIR) contrast.
Four readers independently evaluated the images, rating lesions on a five-point certainty scale.
Observer performance was measured by using the area under the alternative free-response receiver operating characteristic curve (A(1)), and significance was determined with the z test.
Pooled A(1) scores were significantly better for FLAIR imaging (0.96 +/- 0.01 [standard error]) than for T2-weighted MR imaging (0.89 +/- 0.04) SupraTentorially (P = .05).
But were similar for FLAIR imaging (0.90 +/- 0.06) and T2-weighted MR imaging (0.88 +/- 0.05) InfraTentorially.
A(1) scores for Cortical, deep White Matter, and PeriVentricular lesions were 0.93 +/- 0.05, 0.97 +/- 0.02, and 0.89 +/- 0.04, respectively, for FLAIR imaging and 0.77 +/- 0.06, 0.99 +/- 0.01, and 0.89 +/- 0.05, respectively, for T2-weighted MR imaging.
FLAIR scores were significantly higher than T2-weighted scores for Cortical lesions. Linear correlation was found between A(1) and lesion size (r = 0.5).
SupraTentorially, performance was better with FLAIR imaging than with T2-weighted MR imaging.
InfraTentorially, performance was moderate with both modalities. Observers did better with FLAIR imaging in the detection of Cortical lesions, and performance improved with increasing lesion size.
(c) RSNA, 2006.
Altered Diffusion Tensor In Multiple Sclerosis Normal-Appearing Brain Tissue: Cortical Diffusion Changes Seem Related To Clinical Deterioration
Vrenken H, Pouwels PJ, Geurts JJ, Knol DL, Polman CH, Barkhof F, Castelijns JA
J Magn Reson Imaging 2006 May;23(5):628-36
VU University Medical Center, MR Center for MS Research, Department of Radiology, Amsterdam, The Netherlands
To investigate Normal-Appearing White (NAWM) and Cortical Gray (NAGM) Matter separately in Multiple Sclerosis (MS) in vivo using Diffusion Tensor Imaging (DTI).
Materials And Methods
In 64 MS patients (12 Primary/Progressive [PP], 38 Relapsing/Remitting [RR], 14 Secondary/Progressive [SP]) and 20 healthy controls, Whole-Brain Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) maps were acquired.
A Stimulated Echo Acquisition Mode (STEAM) DTI sequence was used with minimal geometrical distortion in comparison to Echo-Planar Imaging (EPI).
NAWM and NAGM were identified using conventional Magnetic Resonance (MR) images, allowing a cautious assessment of FA in Cortex.
Histogram analyses showed significant global FA decreases and ADC increases in MS NAWM compared to control WM. MS Cortical NAGM had no significant global ADC increase, but FA was decreased significantly.
In regional analyses, nearly all NAWM Regions-Of-Interest (ROIs) had significantly increased ADC compared to controls, but FA was not changed.
In nearly all Cortical NAGM ROIs, ADC was significantly increased and FA significantly reduced.
In multiple linear regression analyses in RR/SPMS patients, NAGM-ADC Histogram peak height was associated more strongly with clinical disability than T2 lesion load.
Tissue damage occurs in both NAWM and Cortical NAGM. The Cortical damage appears to have more clinical impact than T2 lesions.
Copyright 2006 Wiley-Liss, Inc.
Increased IL-23p19 Expression In Multiple Sclerosis Lesions And Its Induction In Microglia
Li Y, Chu N, Hu A, Gran B, Rostami A, Zhang GX
Brain 2007 Feb;130(Pt 2):490-501
Thomas Jefferson University, Department of Neurology, Philadelphia, PA, USA
IL-12 has long been considered important in the pathogenesis of Multiple Sclerosis, however, evidence from recent studies strongly supports the critical role of IL-12-related Proinflammatory Cytokine IL-23.
But not IL-12, in the development of Experimental Autoimmune Encephalomyelitis (EAE), an animal model of this disease.
The role of IL-23 in the CNS immunity of Multiple Sclerosis patients has not been elucidated; nor is it known whether human Microglia produce this Cytokine.
In this study we investigated the expression of IL-23p19 and p40, with its key subunit p19 as the focus, in histologically characterized CNS specimens from Multiple Sclerosis and control cases using in situ hybridization and ImmunoHistoChemistry.
A significant increase in mRNA expression and protein production of both subunits of IL-23 was found in lesion tissues compared with non-lesion tissues.
Double staining showed that activated Macrophages/Microglia were an important source of IL-23p19 in active and chronic active Multiple Sclerosis lesions.
We also detected IL-23p19 expression in mature Dendritic Cells which were preferentially located in the PeriVascular cuff of active lesions.
The finding that human Microglia produce IL-23 was further confirmed by the inducible production of IL-23p19 and p40 in cultured human Microglia in vitro upon different Toll-like receptor stimulations.
Taken together, these findings on the expression of IL-23p19 in Multiple Sclerosis lesions may lead to a better understanding of the events culminating in human Multiple Sclerosis.
Association Between Parasite Infection And Immune Responses In Multiple Sclerosis
Correale J, Farez M
Ann Neurol 2007 Jan 17
Raul Carrea Institute for Neurological Research (FLENI), Department of Neurology, Buenos Aires, Argentina
To assess whether parasite infection is correlated with a reduced number of exacerbations and altered Immune reactivity in Multiple Sclerosis (MS).
A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated Eosinophilia.
All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the Eosinophilia was not present during the 2 previous years.
Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study.
InterLeukin (IL) IL-4, IL-10 IL-12, Transforming Growth Factor (TGF)-beta, and Interferon-γ production by Myelin Basic Protein-specific Peripheral Blood Mononuclear Cells were studied using Enzyme-Linked Immunospot (ELISPOT).
FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction.
During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer Magnetic Resonance Imaging changes when compared with uninfected MS patients.
Furthermore, Myelin Basic Protein-specific responses in peripheral blood showed a significant increase in IL-10 and TGF-ß and a decrease in IL-12 and Interferon-γ-secreting cells in infected MS patients compared with noninfected patients.
Myelin Basic Protein-specific T-Cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-beta secretion, showing a Cytokine profile similar to the T-Cell subsets Tr1 and Th3.
Moreover, cloning frequency of CD4+CD25+ FoxP3+ T-Cells was substantially increased in infected patients compared with uninfected MS subjects.
Finally, Smad7 messenger RNA was not detected in T-Cells from infected MS patients secreting TGF-beta.
Increased production of IL-10 and TGF-ß, together with induction of CD25+CD4+ FoxP3+ T-Cells, suggests that regulatory T-Cells induced during parasite infections can alter the course of MS.
Ann Neurol 2007.
Induction Of CD4+CD25+ Regulatory T-Cells By Copolymer-I Through Activation Of Transcription Factor Foxp3
Hong J, Li N, Zhang X, Zheng B, Zhang JZ
Proc Natl Acad Sci USA 2005 May 3;102(18):6449-54
Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai 200025, China
Copolymer-1 (Cop-1) has unique Immune regulatory properties and is a treatment option for Multiple Sclerosis (MS).
This study revealed that COP-I induced the conversion of peripheral CD4+CD25- to CD4+CD25+ regulatory T-Cells through the activation of transcription factor Foxp3.
COP-I treatment led to a significant increase in Foxp3 expression in CD4+ T-Cells in MS patients whose Foxp3 expression was reduced at baseline.
CD4+CD25+ T-Cell lines generated by COP-I expressed high levels of Foxp3 that correlated with an increased regulatory potential.
Furthermore, we demonstrated that the induction of Foxp3 in CD4+ T-Cells by Cop-1 was mediated through its ability to produce IFN-γ and, to a lesser degree, TGF-ß1, as shown by antibody blocking and direct Cytokine induction of Foxp3 expression in T-Cells.
It was evident that in vitro treatment and administration with Cop-1 significantly raised the level of Foxp3 expression in CD4+ T-Cells and promoted conversion of CD4+CD25+ regulatory T-Cells in wild-type B6 mice but not in IFN-γ knockout mice.
This study provides evidence for the role and mechanism of action of Cop-1 in the induction of CD4+CD25+ regulatory T-Cells in general and its relevance to the treatment of MS.