Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Miller DH, O'Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA
Neurology 2007 Apr 17;68(16):1299-304
University of Pennsylvania School of Medicine, Department of Neurology, Philadelphia, PA 19104, USA
To examine the effects of Natalizumab on Low-Contrast Letter Acuity as a prespecified tertiary endpoint in two randomized clinical trials.
And, to evaluate the usefulness of Low-Contrast Letter Acuity Testing as a candidate test of visual function in Multiple Sclerosis (MS).
AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of Natalizumab in Relapsing MS.
Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to Interferon-ß-1a in SENTINEL.
Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%).
The risk of clinically significant Visual Loss (predefined as a two-line worsening of Acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the Natalizumab treatment arms by 35%,
In AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models).
Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-Natalizumab groups.
Natalizumab reduces Visual Loss in patients with Relapsing Multiple Sclerosis.
Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of Visual outcomes in future Multiple Sclerosis trials.
Beiske AG, Naess H, Aarseth JH, Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Sandberg-Wollheim M, Sorensen PS, Myhr KM
Mult Scler 2007 May;13(3):386-92
University Hospital of Akershus, Department of Neurology, Lorenskog, Norway
Common disability scales in Multiple Sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as Depression, Fatigue and Pain substantially influence wellbeing in MS.
Health-Related Quality of Life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens.
We analyzed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 Secondary/Progressive MS (SPMS) patients participating in a randomized trial of Interferon-beta-1a (IFN-ß-1a), 22 mug subcutaneously weekly, or matching placebo.
The results did not reveal any beneficial effect of IFN-ß-1a in any outcome measure.
NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables.
SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores.
Increased Fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores.
SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and Fatigue strongly influenced this. MS.
O'rourke K, Walsh C, Antonelli G, Hutchinson M
Mult Scler 2007 May;13(3):336-42
St Vincent's University Hospital, Department of Neurology, Dublin, Ireland
Proposed Interferon-beta (IFN-ß) treatment failure criteria for patients with Relapsing/Remitting Multiple Sclerosis (RRMS) have not been validated in clinical practice.
This study aimed to establish whether:
- IFN-ß attenuated accumulation of fixed disability in comparison to a cohort of matched historical control subjects from the Sylvia Lawry Center for MS research, and
- Relapse-based treatment failure criteria or clinical and demographic variables had predictive value for the accumulation of fixed disability
Of the 175 IFN-ß-treated RRMS patients, 60 (34%) developed accumulation of fixed disability over a median of five years follow-up, which was significantly less than the rate of accumulation of fixed Disability in the control group (P< 0.0001).
Any relapse in the treatment period predicted accumulation of fixed disability with a sensitivity of 80% and specificity of 43%; patients totally relapse free were less likely to develop accumulation of fixed disability (P < 0.002).
Multivariate analysis confirmed that a greater risk of accumulation of fixed disability was conferred by a higher Expanded Disability Status Scale (EDSS) score starting IFN-ß (P=0.02), and by failure of IFN-beta to completely suppress relapses (P=0.004).
In conclusion, IFN-ß therapy reduced the accumulation of fixed disability in a cohort of RRMS patients, followed for a median of five years.
Higher baseline EDSS and failure of complete relapse suppression were associated with a significantly greater likelihood of accumulation of fixed Disability.
Ness JM, Chabas D, Sadovnick AD, Pohl D, Banwell B, Weinstock-Guttman B
Neurology 2007 Apr 17;68(16 Suppl 2):S37-45
Children's Hospital of Alabama, 1600 7th Avenue South, CHB 314, Birmingham, AL 35233-1711
There is increasing appreciation that Multiple Sclerosis (MS) can begin in childhood or adolescence.
But pediatric MS continues to be a rare entity, with an estimated 2 to 5% of patients with MS experiencing their first clinical symptoms before age 16.
A prompt diagnosis of pediatric MS is important to optimize overall management of both the physical and social impact of the disease.
The widespread use of disease-modifying therapies (DMTs) for MS in adults, as early as following an initial isolated episode, has led to the use of DMTs in children and adolescents with MS.
However, it is imperative to distinguish pediatric MS from other childhood CNS Inflammatory DeMyelinating Disorders such as Acute Disseminated EncephaloMyelitis.
Although increasing evidence suggests a slower disease course in children with MS compared to adults, significant disability can still accumulate by early adulthood.
Furthermore, associated NeuroCognitive deficits can impair both academic and PsychoSocial function at a critical juncture in a young person's life.
This article reviews the clinical characteristics, NeuroImaging, ParaClinical findings, disease course, Epidemiology, Genetics, and PathoPhysiology of pediatric MS vis-a-vis adult MS.
Further research of pediatric MS may advance our understanding of MS PathoPhysiology in general, as well as improve the long-term health care outcomes of children and adolescents diagnosed with MS.
Saindane AM, Law M, Ge Y, Johnson G, Babb JS, Grossman RI
AJNR Am J NeuroRadiol 2007 Apr;28(4):767-72
New York University Medical Center, Department of Radiology, New York, NY, USA
Background And Purpose
HypoPerfusion of the Normal-Appearing White Matter in Multiple Sclerosis (MS) may be related to Ischemia or secondary to HypoMetabolism from Wallerian Degeneration (WD).
This study evaluated whether correlating Perfusion and Diffusion Tensor Imaging (DTI) metrics in Normal-Appearing Corpus Callosum could provide support for an Ischemic mechanism for HypoPerfusion.
Materials And Methods
Fourteen patients with Relapsing/Remitting MS (RRMS) and 17 control subjects underwent Perfusion MR imaging and DTI.
Absolute measures of Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), and Mean Transit Time (MTT) were calculated.
Mean Diffusivity (MD) and Fractional Anisotropy (FA) maps were computed from DTI data.
After visual coregistration of Perfusion and DTI images, regions of interest were placed in the Genu, Central Body, and Splenium of Normal-Appearing Corpus Callosum.
Pearson product-moment correlation coefficients were calculated using mean DTI and Perfusion measures in each region.
In the RRMS group, CBF and CBV were significantly correlated with MD in the Splenium (r = 0.83 and r = 0.63, respectively; both P < .001) and in the Central Body (r = 0.86 and r = 0.65, respectively.
Both P < .001), but not in the Genu (r = 0.23 and 0.25, respectively; both P is nonsignificant).
No significant correlations were found between MTT and DTI measures or between FA and any Perfusion measure in the RRMS group.
No significant correlations between Diffusion and Perfusion metrics were found in control subjects.
In the Normal-Appearing Corpus Callosum of patients with RRMS, decreasing perfusion is correlated with decreasing MD.
These findings are more consistent with what would be expected in primary Ischemia than in secondary HypoPerfusion from WD.
Callander M, Haghighi S, Landtblom AM, Ahlgren CE, Nilsson SI, Rydberg L, Al Khoury H, Rosegren L, Andersen O
Mult Scler 2007 May;13(4):441-5
University Hospital, Department of Neurology, Linkoping, Sweden
We analyzed HLA haplotypes in pairs of 78 sporadic Multiple Sclerosis (MS) patients and 78 healthy siblings.
The presence of 2 OligoClonal IgG Bands, detected by Immunoblotting of the CerebroSpinal Fluid in healthy siblings, has previously been defined as MS Immunopathic Trait (MSIT).
Based on a cut-off derived from healthy unrelated volunteers. The frequency of MSIT was 17.9% (n=14/78 siblings).
The HLA-DR(15)2 allelle was present in:
- 21.4% (n=3/14) of the siblings with MSIT
- 40.6% (n =26/64) of the siblings without MSIT
- 59% (n =46/78) of the patients with clinically-definite (CD) MS
The distribution of zero, one or two HLA-DR(2)15 alleles was significantly skewed towards a lower allelle count in the siblings with MSIT.
Compared with the group of unrelated siblings with MS (P=0.002), and also lower than their related siblings with MS (P=0.1).
These results suggest that the MS susceptibility gene, HLA-DR(2)15 type, does not induce MSIT, and conceivably these are two separate risk factors in the development of MS.
The effect of HLA-DR(2)15 and MSIT in sporadic MS appears to be synergistic.
Zivadinov R, Locatelli L, Cookfair D, Srinivasaraghavan B, Bertolotto A, Ukmar M, Bratina A, Maggiore C, Bosco A, Grop A, Catalan M, Zorzon M
Mult Scler 2007 May;13(4):490-501
University at Buffalo, State University of New York, The Jacobs Neurological Institute, Department of Neurology, Buffalo NeuroImaging Analysis Center, Buffalo, NY, USA
Brain Atrophy, as assessed by Magnetic Resonance Imaging (MRI), has been correlated with disability in patients with Multiple Sclerosis (MS).
Recent evidence indicates that both White Matter (WM) and Gray Matter (GM) are subject to Atrophy in patients with MS.
Although Neurological deficiencies in MS are primarily due to loss of WM, the clinical significance of GM Atrophy has not been fully explored in MS.
We have undertaken a three-year, open-label study, comparing 26 patients who elected to receive intramuscular Interferon-beta-1a (IFN-ß ) therapy, with 28 patients who elected not to receive therapy.
Both groups had quantitative Cranial MRI scans at study entry and after three years, and standardized clinical assessments every six months.
Brain Parenchymal Fraction (BPF), GM Fraction (GMF), and WM Fraction (WMF) percent changes were calculated, and T2- and T1-lesion volumes (LVs) assessed.
After three years, mean percent (%) change in BPF favored the IFN-ß-1a treatment group (IFN-ß -1.3% versus the control group -2.5%, P=0.009).
As did the mean percent change in GMF (+0.2 versus -1.4%, P=0.014), and the mean percent change in T1-LV (-9.3 versus +91.6%, P=0.011).
At the end of the study, there was a significant within-patient decrease in BPF for both groups (P=0.02 for the IFN-ß-1a treatment group, and P < 0.001 for the control group).
A significant within-patient decrease in WMF for the IFN-ß-1a treatment group (P=0.01), and a significant decrease in GMF for the control group (P=0.013) when compared with baseline.
Over a three-year period, treatment with IFN-ß significantly slowed the progression of Whole-Brain and GM Atrophy, and of T1-HypoIntense LV accumulation, when compared with the control group.