Evolution Of Different MRI Measures In Patients With Active Relapsing/Remitting Multiple Sclerosis Over 2 And 5 Years. A Case Control Study
Horakova D, Cox JL, Havrdova E, Hussein S, Dolezal O, Cookfair D, Dwyer MG, Seidl Z, Bergsland N, Vaneckova M, Zivadinov R
J Neurol NeuroSurg Psychiatry 2007 Jun 5
Dept. of Neurology, Czech Republic
There is growing evidence for the concept of Multiple Sclerosis (MS) as an Inflammatory-NeuroDegenerative Disease, with a different pattern of Atrophy evolution in Gray Matter (GM) and White Matter (WM) tissue compartments.
We aimed to investigate the evolution of different MRI measures in early Relapsing/Remitting (RR) MS patients and in Normal Controls (NC) over 2 years.
We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years.
Included in this study were one hundred forty-seven (147) patient.
Who participated in the combination ASA (Avonex, Steroids, Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months.
A subgroup of 66 patients was followed for 36 months, 51 for 48 months and 43 for 60 months, respectively.
Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualized relapse rate before study entry was 1.7.
MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years.
In addition to the MS group, 27 NC were examined at months 0, 12 and 24 using the same MRI protocol.
Percent Brain Volume Change (PBVC), GM Volume (GMV), WM Volume (WMV) and Peripheral Gray Volume (PGV) were measured annually using SIENA/X software.
T2-HyperIntense Lesion Volume (LV), Lateral Ventricle Volume (LVV), and Third Ventricle Width (3VW) were also assessed annually.
Over the period of 0-24 months, MS patients lost significantly more GMV (-2.6% vs. -0.72%, p < 0.0001), PGV (-2.4% vs. -1.03%, p < 0.0001).
And PBVC (-1.2% vs. -0.22%, p < 0.0001), and increased in LVV (+16.6% vs. +0.55%, p < 0.003) and 3VW (+9.3% vs. 0, p=0.003), when compared to NC.
Within-person change in MRI measures for MS patients over 5 years was -4.2% for PBVC, -6.2% for GMV, -5.8% for PGV, -0.5% for WMV (all p < 0.0001), +68.7 for LVV (p < 0.00001), +4% for 3VW (p < 0.00001) and +42% for T2-LV (p < 0.0001).
Our study confirmed a different pattern of GM, WM and Central Atrophy progression over 2 years between MS patients and NC.
The study showed a different evolution of tissue compartment Atrophy measures in MS patients, with faster decline in Cortical and deep GM regions, as well as PeriVentricular WM regions over a 5-year period.
Dysregulated T-Cell Expression Of TIM3 In Multiple Sclerosis
Koguchi K, Anderson DE, Yang L, O'Connor KC, Kuchroo VK, Hafler DA
J Exp Med 2006 Jun 12;203(6):1413-8
Brigham and Women's Hospital and Harvard Medical School, Department of Neurology,
Center for Neurologic Diseases, Boston, MA 02115, USA
T-Cell ImmunoGlobulin- and mucin domain-containing molecule (TIM)3 is a T-Helper cell (Th1)-associated cell surface molecule that regulates Th1 responses and promotes Tolerance in mice, but its expression and function in human T-Cells is unknown.
We generated 104 T-Cell clones from the CerebroSpinal Fluid (CSF) of six patients with Multiple Sclerosis (MS) (n = 72) and four control subjects (n = 32) and assessed their Cytokine profiles and expression levels of TIM3 and related molecules.
MS CSF clones secreted higher amounts of Interferon-gamma (IFN-γ) than did those from control subjects, but paradoxically expressed lower levels of TIM3 and T-bet.
InterLeukin-12-mediated polarization of CSF clones induced substantially higher amounts of IFN-γ secretion but lower levels of TIM3 in MS clones relative to control clones, demonstrating that TIM3 expression is dysregulated in MS CSF clones.
Reduced levels of TIM3 on MS CSF clones correlated with resistance to Tolerance induced by costimulatory blockade.
Finally, reduction of TIM3 on ex vivo CD4+ T-Cells using small interfering (si)RNA enhanced proliferation and IFN-γ secretion, directly demonstrating that TIM3 expression on human T-Cells regulates proliferation and IFN-γ secretion.
Failure to up-regulate T-Cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of MS and other human Autoimmune Diseases.
Protective And Therapeutic Role For alphaß-Crystallin In Autoimmune DeMyelination
Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O'conner K, Hafler DA, Sobel RA, Robinson WH, Steinman L
Nature 2007 Jul 26;448(7152):474-9
Stanford University, Department of Neurology and Neurological Sciences, Stanford, California 94305, USA
alphaB-Crystallin (CRYAB) is the most abundant gene transcript present in early active Multiple Sclerosis lesions, whereas such transcripts are absent in normal Brain tissue.
This Crystallin has Anti-Apoptotic and NeuroProtective functions. CRYAB is the major target of CD4+ T-Cell Immunity to the Myelin sheath from Multiple Sclerosis Brain.
The pathophysiological implications of this Immune Response were investigated here.
We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the Immune System and Central Nervous System (CNS).
CRYAB(-/-) mice showed worse Experimental Autoimmune Encephalomyelitis (EAE) at the acute and Progressive phases, with higher Th1 and Th17 Cytokine secretion from T-Cells and Macrophages, and more intense CNS inflammation, compared with their wild-type counterparts.
Furthermore, CRYAB(-/-) Astrocytes showed more cleaved Caspase-3 and more TUNEL staining, indicating an Anti-Apoptotic function of CRYAB.
AntiBody to CRYAB was detected in CerebroSpinal Fluid from Multiple Sclerosis patients and in Sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE.
Thus, the Immune Response against a negative regulator of inflammation, CRYAB, in Multiple Sclerosis, would exacerbate Inflammation and DeMyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease.
Predicting Short-Term Disability In Multiple Sclerosis
Gauthier SA, Mandel M, Guttmann CR, Glanz BI, Khoury SJ, Betensky RA, Weiner HL
Neurology 2007 Jun 12;68(24):2059-65
Brigham and Women's Hospital, Partners Multiple Sclerosis Center, Brookline, MA 02445, USA
To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits.
Semiannual EDSS scores were prospectively collected in 218 Relapsing/Remitting (RR) and Clinically Isolated Syndrome (CIS) patients.
As part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study.
Baseline Brain Parenchymal Fraction (BPF) and T2 lesion volume were available on 205 patients.
A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits.
A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented.
The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS.
Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression.
In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume.
Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with Multiple Sclerosis.
Disparities In The Management Of Multiple Sclerosis-Related Bladder Symptoms
Marrie RA, Cutter G, Tyry T, Vollmer T, Campagnolo D
Neurology 2007 Jun 5;68(23):1971-8
Cleveland Clinic Foundation, Department of Neurology, OH 44195, USA
Participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry report disability status using Performance Scales (PS), a self-report measure.
The bladder/bowel subscale (PSB) of PS has not been validated. It is also unknown whether ethnic or socioeconomic disparities exist in bladder care.
We aimed to validate the bladder/bowel subscale used by the NARCOMS registry and to describe urologic symptoms, investigations, and treatments received by registry participants.
In the Fall 2005 update questionnaire, we collected the Bowel Control Scale (BWCS) and Urogenital Distress Inventory-6 (UDI-6) as criterion measures and urologic investigations and treatments.
We measured associations between investigations, treatments, and symptoms with clinical and sociodemographic variables using chi(2) tests for categorical variables and Kruskal-Wallis tests for continuous variables, followed by multivariable logistic regression.
Nine thousand six hundred eighty-eight participants completed the survey.
For the UDI-6, the median (interquartile range) score was 33.3 (16.7 to 50.0), for the BWCS 3 (1 to 6), and for the PSB 1 (1 to 3).
The correlation between the PSB and the UDI-6 was r = 0.67 and between the PSB and the BWCS r = 0.53 (both p < 0.0001).
Participants had increased odds of receiving medication for bladder symptoms if they had health insurance (odds ratio [OR] 1.90; 1.07 to 3.35).
Participants who were white (OR 1.5; 1.16 to 1.94) and had health insurance (OR 2.0; 1.3 to 3.07) had increased odds of undergoing urologic investigations.
The Performance Scales bladder question has adequate criterion and construct validity in Multiple Sclerosis (MS). There are ethnic and socioeconomic disparities in bladder management in MS.
Natural History Of Multiple Sclerosis With Childhood Onset
Renoux C, Vukusic S, Mikaeloff Y, Edan G, Clanet M, Dubois B, Debouverie M, Brochet B, Lebrun-Frenay C, Pelletier J, Moreau T, Lubetzki C, Vermersch P, Roullet E, Magy L, Tardieu M, Suissa S, Confavreux C
Adult Neurology Departments KIDMUS Study Group
N Engl J Med 2007 Jun 21;356(25):2603-13
Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France
The course and prognosis of Childhood-Onset Multiple Sclerosis have not been well described.
We used data from 13 adult Neurology departments affiliated with the European Database for Multiple Sclerosis (EDMUS) network.
To identify a cohort of 394 patients who had Multiple Sclerosis with an onset at 16 years of age or younger and a comparison group of 1775 patients who had Multiple Sclerosis with an onset after 16 years of age.
We determined the initial clinical features, the dates of disease onset, and the occurrence of outcomes, including relapse, conversion to secondary progression, and irreversible disability as measured by scores of:
- 4 (limited walking ability but ability to walk more than 500 m without aid or rest),
- 6 (ability to walk with unilateral support no more than 100 m without rest), and
- 7 (ability to walk no more than 10 m without rest while using a wall or furniture for support) on the Kurtzke Disability Status Scale (range, 0 to 10; higher scores indicate more severe disability).
For patients with Childhood-Onset Multiple Sclerosis, the estimated median time from onset to Secondary Progression was 28 years, and the median age at conversion to Secondary Progression was 41 years.
The median times from onset to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and 50.5 years.
In comparison with patients with adult-onset disease, those with Childhood-Onset Disease were more likely to be female than male (female:male ratio, 2.8 vs. 1.8), were more likely to have an Exacerbating/Remitting initial course (98% vs. 84%).
Took approximately 10 years longer to reach Secondary Progression and irreversible disability, and reached these landmarks at an age approximately 10 years younger (P < 0.001 for all comparisons).
Patients with Childhood-Onset Multiple Sclerosis take longer to reach states of irreversible disability but do so at a younger age than patients with adult-onset Multiple Sclerosis.
Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B
Ann Neurol 2008 Mar;63(3):303-11
National Institute of Neurology and NeuroSurgery, Center for Research and Advanced Studies, NeuroImmunology Unit, Mexico City, Mexico
Recent studies in Peripheral Blood Mononuclear Cells (PBMCs) have indicated that exacerbations of Multiple Sclerosis (MS) could be associated with the reactivation of latent Varicella-Zoster Virus (VZV).
Ultrastructural observations for Viral particles were made by electron microscopy in CerebroSpinal Fluid (CSF) from 15 MS patients during relapse, 19 MS patients during remission, and 28 control subjects.
Initial findings were reproduced in a confirmation cohort.
In addition, DNA from VZV was quantified by real-time polymerase chain reaction in PBMCs and CSF from a large number of MS patients (n = 78).
We found by electron microscopy the presence of abundant Viral particles identical to VZV in CSF obtained from MS patients within the first few days of an acute relapse.
In contrast, Viral particles were not seen in CSF samples from MS patients in remission or from Neurological control subjects.
Also, DNA from VZV was present in CSF and in PBMCs during relapse, disappearing in most patients during remission.
The mean Viral load was 542 times greater in CSF at relapse than in CSF at remission and 328 times greater in CSF at relapse than in PBMCs at relapse.
The UltraStructural finding of Viral particles identical to VZV, together with the simultaneous presence of large quantities of DNA from VZV in the SubArachnoid Space, almost restricted to the periods of exacerbation.
As well as its steady diminution and eventual disappearance from clinical relapse to clinical remission are surprising and constitute the strongest evidence to support the participation of VZV in the pathogenesis of MS.
Ann Neurol 2008.