A Randomized Controlled Crossover Trial Of Aspirin For Fatigue In Multiple Sclerosis
Wingerchuk DM, Benarroch EE, O'Brien PC, Keegan BM, Lucchinetti CF, Noseworthy JH, Weinshenker BG, Rodriguez M
Neurology 2005 Apr 12;64(7):1267-9
Mayo Clinic, Department of Neurology, Scottsdale, AZ 85259, USA
PharmacoTherapeutic options for Multiple Sclerosis (MS)-related Fatigue are limited.
Thirty patients were randomly assigned to Aspirin (ASA) 1,300 mg/day or placebo in a double-blind crossover study.
Results favored ASA for the main clinical outcomes: Modified Fatigue Impact Scale scores (p = 0.043) and treatment preference (p = 0.012). There were no significant adverse effects.
The results warrant further study and support a role for ASA-influenced mechanisms, perhaps Immunologic, in the generation of MS-related chronic Fatigue.
Altered Functional Connectivity Related To White Matter Changes Inside The Working Memory Network At The Very Early Stage Of MS
Au Duong MV, Audoin B, Boulanouar K, Ibarrola D, Malikova I, Confort-Gouny S, Celsis P, Pelletier J, Cozzone PJ, Ranjeva JP
J Cereb Blood Flow Metab 2005 Apr 20
CRMBM-CNRS, Faculte de Medecine, Centre de Resonance Magnetique Biologique et Medicale, Marseille, France
Functional Magnetic Resonance Imaging (fMRI) using Paced Auditory Serial Addition Test (PASAT) as paradigm was used to study the functional connectivity in 18 patients at the very early stage of Multiple Sclerosis (MS) compared with 18 controls.
To determine the existence of circuitry disturbance inside the Working Memory network and its relationship with White Matter abnormalities assessed by conventional MRI and Magnetization Transfer Ratio (MTR) imaging.
The left BA 45/46 was selected as the seed region to compute correlation maps with other Brain regions.
After obtaining the correlation map for each subject, between-group comparisons were performed using random effect procedure.
Compared with controls, patients did not show any greater functional connectivity between left BA 45/46 and other regions during PASAT.
In contrast, decrease in functional connectivity was observed in patients between left BA 45/46 and left BA 9, right BA 3, and the Anterior Cingulate Cortex (BA 24).
In patients, no correlations were found between altered functional connectivity and clinical data.
However, functional connectivity observed between left BA 45/46 and BA 24 in patients was correlated with the MTR of Normal-Appearing White Matter, and with Brain T2 lesion load.
Altered functional connectivity is present inside the working memory network of patients at the very early stage of MS and is related to the extent of diffuse White Matter changes.
Increasing Normal-Appearing Gray And White Matter Magnetization Transfer Ratio Abnormality In Early Relapsing/Remitting Multiple Sclerosis
Davies GR, Altmann DR, Hadjiprocopis A, Rashid W, Chard DT, Griffin CM, Tofts PS, Barker GJ, Kapoor R, Thompson AJ, Miller DH
J Neurol 2005 Apr 18
NMR Research Unit, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
Abnormalities within Normal-Appearing Gray and White Matter (NAGM and NAWM) occur early in the clinical course of Multiple Sclerosis (MS) and can be detected in-vivo using the Magnetization Transfer Ratio (MTR).
To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early Relapsing/Remitting MS patients, using NAGM and NAWM MTR Histograms.
Twenty-three patients with clinically definite early Relapsing/Remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied.
A Magnetization Transfer Imaging sequence was acquired yearly for two years.
Twenty-one patients and 10 controls completed followup. NAWM and NAGM MTR Histograms were derived and mean MTR calculated.
A hierarchical regression analysis, adjusting for Brain Parenchymal Fraction,was used to assess MTR change over time.
MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow-up: (-0.10pu/year, p = 0.001 and -0.18pu/year, p < 0.001 respectively).
The rate of MTR decrease was significantly greater in NAGM than NAWM (p = 0.004).Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset.
We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of Relapsing/Remitting MS.
It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.
Severe Delayed Heart Failure In Three Multiple Sclerosis Patients Previously Treated With Mitoxantrone
Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ
J Neurol 2005 Apr 18
Service de Neurologie, Cliniques Universitaires Saint Luc, Universite catholique de Louvain, Brussels, Belgium
Mitoxantrone is an approved drug for patients with worsening Relapsing/Remitting, Secondary/Progressive and Progressive/Relapsing Multiple Sclerosis (MS).
From a cohort of 820 MS patients, 52 (6%) were treated with this drug between December 1991 and April 2003.
Mitoxantrone was administered at a dose of 12 mg/m(2) once a month for three months and then at three-month intervals to reach a total cumulative dose of 144 mg/m(2).
The left Ventricular Ejection Fraction was checked by Radionuclide VentriculoGraphy prior to treatment and every six months.
Treatment was stopped if the Ejection Fraction was below 50% in two consecutive VentriculoGraphies performed one to three months apart. Cardiotoxicity during the course of the treatment was not observed.
However, three patients developed Congestive Heart Failure 24, 39 and 80 months after the last dose of Mitoxantrone. Other Cardiac causes were excluded. Two of these patients had been treated previously with Cyclophosphamide.
All patients first recovered on medical treatment, but two worsened a few months later. One patient remained severely symptomatic in spite of optimal medical treatment.
Although Mitoxantrone is generally well tolerated and reduces progression of disability and clinical exacerbations, our observation of a delayed CardioToxicity makes necessary a long-term follow-up of MS patients treated with this drug.
Achiron A, Polliack M, Rao SM, Barak Y, Lavie M, Appelboim N, Harel Y
J Neurol NeuroSurg Psychiatry 2005 May;76(5):744-9
Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, 52621, Israel
Background And Objectives
Rate and pattern of progression of Cognitive decline in Multiple Sclerosis (MS) has not been clearly identified.
The present study aimed to identify correlations between Cognitive tests and disease duration, construct longitudinal Cognitive curves, and assess pattern of change over time.
The NeuroPsychological Screening Battery for Multiple Sclerosis was administered in 150 consecutive MS patients, and tests that correlated with disease duration were identified.
Percentile curves were constructed and the pattern of Cognitive decline over time explored. The Cognitive curves were validated in an additional group of 83 patients with MS.
Three of four measures of the Spatial Recall Test (SPART 7/24), and the Paced Auditory Serial Addition Task for two seconds (PASAT 2'), correlated with disease duration.
These tests were used to construct cross-sectional curves identifying the pattern of Cognitive decline over time in the MS population.
On the basis of this cross-sectional analysis, the earliest Cognitive decline occurred in the SPART 7/24 trials 1-5 between one and three years from onset.
Followed by decline in the SPART delayed recall between three and seven years, and then by decline in the PASAT 2' after seven years from onset.
Verbal Fluency and Verbal Memory appear to be affected earliest in MS.
The pattern of Cognitive decline is further characterized by a decrease in VisuoSpatial Learning, followed by Delayed Recall, and then by Attention and Information Processing Speed.
Cognitive percentile curves can be used to evaluate the pattern of progression and identify patients at increased risk.
The Presence Of Glutamic Acid At Positions 71 Or 74 In Pocket 4 Of The HLA-DRß1 Chain Is Associated With The Clinical Course Of Multiple Sclerosis
Greer JM, Pender MP
J Neurol NeuroSurg Psychiatry 2005 May;76(5):656-662
The University of Queensland, Department of Medicine, Clinical Sciences Building, Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia
Primary/Progressive Multiple Sclerosis (PP-MS) differs from Relapsing/Remitting or Secondary/Progressive MS (RR/SP-MS) in ways suggesting differences in the pathogenic pathways.
Susceptibility to both PP-MS and RR/SP-MS is linked to carriage of the HLA molecule DRB1*1501. Several serologically defined HLA-DR groups (DR1, DR4, DR6, and DR9) occur less often in RR/SP-MS than in controls.
Some or all of the HLA-DR molecules encoded by alleles in these serologically defined groups have a negatively charged Glutamic Acid at residue 71 or 74 of the ß1 chain (ß1(71)/ß1(74)).
Residues at these positions are important in the formation of pocket 4 in the Antigen binding site of the HLA-DR molecule.
To investigate whether the presence of Alleles encoding HLA-DR molecules containing Glutamic Acid at ß1(71)/ß1(74) correlates with the course of MS.
HLA-DR and HLA-DQ alleles and genotypes were analyzed in 121 MS patients (50 with PP-MS) and 109 controls by molecular typing.
Alleles encoding HLA-DR molecules containing a Glutamic Acid at ß1(71)/ß1(74) occurred less often in patients with RR/SP-MS than in those with PP-MS or controls.
In subjects not carrying the DRB1*1501 allele, a much higher proportion of PP-MS patients carried alleles encoding HLA-DR molecules containing a Glutamic Acid at beta1(71)/ß1(74) than did RR/SP-MS patients or controls.
The Amino Acid residues involved in determining the shape and charge of pocket 4 of the HLA-DR ß1 chain could influence the clinical course of MS by determining protection against RR/SP-MS or susceptibility to the development of PP-MS.
Interferon-gamma And Interferon-beta Affect Endogenous Catecholamines In Human Peripheral Blood MonoNuclear Cells: Implications For Multiple Sclerosis
Cosentino M, Zaffaroni M, Ferrari M, Marino F, Bombelli R, Rasini E, Frigo G, Ghezzi A, Comi G, Lecchini S
J NeuroImmunol 2005 May;162(1-2):112-21
University of Insubria, Department of Clinical Medicine, Section of Experimental and Clinical Pharmacology, Via Ottorino Rossi n. 9, 21100 Varese VA, Italy; Center for Research in NeuroScience, University of Insubria, Varese, Italy
Interferon-gamma (IFN-γ) plays a pivotal role in the pathogenesis of Multiple Sclerosis (MS), while IFN-ß may be able to modify the clinical course of the disease, eventually also by counterbalancing IFN-γ-mediated effects.
Catecholamines (CA) exert important effects on the Immune Response, both as transmitters between the Nervous and the Immune System, as well as Autocrine/Paracrine mediators in Immune Cells, and several lines of evidence support their involvement in MS.
In particular, dysregulated production of CA seems to occur in Peripheral Blood MonoNuclear Cells (PBMCs) of MS patients. We assessed the effects of IFN-ß and IFN-γ on endogenous CA in PBMCs.
In cultured PBMCs stimulated with PhytoHaemAgglutinin (PHA), IFN-ß increased CA production and induced CA release in the culture medium.
While IFN-γ decreased both CA production and the expression of mRNA for the CA-synthesizing Enzyme Tyrosine Hydroxylase.
Coincubation with both IFNs prevented the inhibitory effect of IFN-γ, as well as the stimulatory effect of IFN-ß. IFNs are the first physiological compounds shown to affect endogenous CA in PBMCs:
In view of the role of CA-dependent mechanisms in the Immune Response, these findings may help to better understand the mechanisms of action of IFN-ß as an ImmunoModulatory Drug in MS.