Cognitive Impairment And Decline In Different MS Subtypes
Huijbregts SC, Kalkers NF, de Sonneville LM, de Groot V, Polman CH
J Neurol Sci 2006 Jun 15;245(1-2):187-94
University of Southampton, School of Psychology, Highfield, SO17 1BJ, Southampton, UK
This paper presents results of two studies conducted to investigate Cognition in different MS subtypes. First, the results of a study that has previously been published will be discussed.
This was a cross-sectional study with 108 Relapsing/Remitting (RR), 71 Secondary/Progressive (SP), 55 Primary/Progressive (PP) MS patients, and 67 healthy controls:
S.C.J. Huijbregts, N.F. Kalkers, L.M.J. de Sonneville, V. de Groot, I.E.W. Reuling, C.H. Polman, Differences in Cognitive Impairment of Relapsing/Remitting, Secondary and Primary/Progressive MS. Neurology 63 (2004) 335-339.
The second study involved a follow-up assessment after 2 years and included 30 SPMS patients, 25 PPMS patients, and 33 controls.
The Brief Repeatable Battery of NeuroPsychological Tests (BRB-N) was used for all Cognitive assessments. All patient groups demonstrated Cognitive Deficits compared to healthy controls.
RRMS patients were less affected compared to patients with Progressive MS subtypes on the Paced Auditory Serial Addition Task (PASAT) and the Symbol Digit Modalities Test (SDMT).
These differences were attenuated after control for physical disability level as measured by the Expanded Disability Status Scale.
RRMS and SPMS patients were more severely impaired than PPMS patients on the 10/36 Spatial Recall Task and Word List Generation.
Results of the follow-up study indicated that both Progressive MS subtypes showed a lack of improvement compared to controls on the PASAT and the SDMT, but not on the other tasks of the BRB-N.
Indicating that performance on tasks requiring multiple abilities concurrently, i.e. Visuo-Spatial ability and Processing Speed (SDMT) or Working Memory and Processing Speed (PASAT), is most likely to decline across time.
Gaillard N, Fabro-Perray P, Faillie JL, Le Bayon A, Castelnovo G, Dupeyron A, Froger J, Pelissier J, Labauge P
Rev Neurol (Paris) 2007 Jan;163(1):72-81
Service de Neurologie, CHU Carémeau, Nîmes
Rate of relapse occurring during the first 5 years of MS-RR is a prognosis factor of occurrence of disability or Secondary/Progressive (SP) phase.
Progressive phase, related to chronic Axonal Loss, is mainly considered as the principal factor of disability progression.
Influence of acute relapses during the Relapsing/Remitting phase on disability development is not known as a prognosis factor.
To determine the influence of the exacerbations among patients with RR-MS after the second clinical event on the disability occurrence.
Diagnosis of Multiple Sclerosis was established according to Poser's classification. Disability measurement was made with the use of the Expanded Disability Status Scale (EDSS).
The patients included in the study were classified as clinically definite RR-MS, with an EDSS score < or = 3.5.
The Progressive phase was defined as the steady worsening of symptoms and signs for at least 6 months (Schumacher et al., 1965; Lublin and Reingold, 1996).
The exacerbations were quoted and evaluated by a Neurologist and the residual disability lasting at least 6 months after an acute event was measured with the EDSS.
A score of 4.0 corresponds to limited walking ability, but without aid or rest for > 500 m.
The study began at the time of the second clinical event and ended when an EDSS score of 4.0 was reached.
Or when a SP phase was beginning or at the last follow-up visit date if these two stages were not reached.
The primary outcome measure was the comparison of the risk and the average time to reach an EDSS > or = 4.0.
Or a SP form according to the Annual Exacerbation Rate (AER) using Kaplan-Meier survival curve.
Among the 238 MS patients of the database, 136 patients were classified as having a definite RR-MS.
Among these 136 patients, 99 patients could be included in the study according to the inclusion criteria. The median follow up of the patients since the first clinical event was 9.8 years (range 4 to 44).
The average EDSS score was 0.7 at the beginning of the study and 2.3 at the end. 20.2p.cent of patients (n=20) reached an EDSS score of 4.0 or a SP-MS.
The median AER was 0.4 and the average 0.62 (range 0 to 6.1).
The time to reach the primary end point for 25p.cent of the population was 17.8 years in group with an AER < 0.4 (group A) and 6.9 years in group with an AER > 0.4 (group B) (logrank; p < 0.0001).
The relative risk for patients of the group B compared to group A to reach an EDSS of 4.0 or a SP form was 8.01 (IC-95p.cent: 2.74-23.46; p=0.0001).
In spite of a limited number of patients, this study gives evidence:
That a high rate of acute exacerbations in RR-MS patients after the second clinical event may be an independent predictive factor of long-term residual disability progression.
High relapse rate leads to a more frequent and faster SP or EDSS > 4.0 occurrence.
Brown MG, Kirby S, Skedgel C, Fisk JD, Murray TJ, Bhan V, Sketris IS
Neurology 2007 Oct 9;69(15):1498-507
From the Health Outcomes Research Unit (M.G.B.), and Dalhousie University, College of Pharmacy (I.S.S.), Department of Medicine, Neurology (S.K., T.J.M., V.B.) and Department of Medicine (C.S.), Department of Psychiatry (J.D.F.), and Department of Community Health and Epidemiology (M.G.B., T.J.M., I.S.S.), Capital Health District, Nova Scotia; Halifax, Nova Scotia, Canada
Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying Multiple Sclerosis (MS) disability progression in Relapsing-Onset (R-Onset) definite MS patients under "real-world" conditions.
Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history.
A basic model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment.
An expanded model estimated annual EDSS change in pretreatment years, treatment years on first drug, treatment years after drugs were switched, and in years after treatment stopped.
Models were populated with 1980 through 2004 clinical data, including 1988 through 2004 data for all Nova Scotians treated with DMDs.
Estimates were made for Relapsing/Remitting MS (RRMS), Secondary/Progressive MS (SPMS), and R-Onset groups.
Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-Onset group.
Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-Onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%.
Estimated EDSS progression was faster in years after drug switches and treatment stops.
Our estimates of Disease-Modifying Drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance.
DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with Relapsing-Onset definite Multiple Sclerosis (MS) (90%).
Although effectiveness is much better for Relapsing/Remitting MS than for Secondary/Progressive MS groups.
AFFIRM and SENTINEL Investigators
Rudick RA, Miller D, Hass S, Hutchinson M, Calabresi PA, Confavreux C, Galetta SL, Giovannoni G, Havrdova E, Kappos L, Lublin FD, Miller DH, O'connor PW, Phillips JT, Polman CH, Radue EW, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA
Ann Neurol 2007 Oct;62(4):335-46
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Department of Neurology, Cleveland, OH
To report the relationship between disease activity and health-related quality of life (HRQoL) in Relapsing Multiple Sclerosis, and the impact of Natalizumab.
HRQoL data were available from 2,113 Multiple Sclerosis patients in Natalizumab clinical studies.
In the Natalizumab Safety and Efficacy in Relapsing/Remitting Multiple Sclerosis (AFFIRM) study, patients received Natalizumab 300mg (n = 627) or placebo (n = 315).
In the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing/Remitting Multiple Sclerosis (SENTINEL) study, patients received Interferon-beta-1a (IFN-beta-1a) plus Natalizumab 300mg (n = 589), or IFN-beta-1a plus placebo (n = 582).
The Short Form-36 (SF-36) and a subject global assessment Visual Analog Scale were administered at baseline and weeks 24, 52, and 104.
Prespecified analyzes included changes from baseline to week 104 in SF-36 and Visual Analog Scale scores.
Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated.
Mean baseline SF-36 scores were significantly less than the general US population and correlated with:
Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of Brain Magnetic Resonance Imaging lesions.
Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM.
PCS changes were significantly improved by week 24 and at all subsequent time points.
Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS.
The visual analog scale also showed significantly improved HRQoL with Natalizumab.
HRQoL was impaired in Relapsing Multiple Sclerosis patients, correlated with severity of disease as measured by Neurological ratings or Magnetic Resonance Imaging, and improved significantly with Natalizumab.
Ann Neurol 2007.
Bar-Or A, Vollmer T, Antel J, Arnold DL, Bodner CA, Campagnolo D, Gianettoni J, Jalili F, Kachuck N, Lapierre Y, Niino M, Oger J, Price M, Rhodes S, Robinson WH, Shi FD, Utz PJ, Valone F, Weiner L, Steinman L, Garren H
Arch Neurol 2007 Oct;64(10):1407-15
Antel, Lapierre, and Niino and Mss Bodner and Jalili) and NeuroRx Research (Dr Arnold), Montreal, Quebec, Canada; Barrow Neurological Institute, Phoenix, Arizona (Drs Vollmer, Campagnolo, and Shi and Mss Price and Rhodes); Bayhill Therapeutics, Inc, Palo Alto, California (Ms Gianettoni and Drs Valone and Garren); University of Southern California, Los Angeles (Drs Kachuck and Weiner); University of British Columbia, Vancouver, British Columbia, Canada (Dr Oger); and Stanford University, Stanford, California (Drs Robinson, Utz, Steinman, and Garren)
To assess safety and Immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human Myelin Basic Protein, in patients with Multiple Sclerosis (MS).
The study was a randomized, double-blind, placebo-controlled trial.
Subjects receiving placebo were crossed over into an active arm after treatment unblinding.
The trial was conducted at 4 academic institutions within North America.
Patients Thirty patients with Relapsing/Remitting or Secondary/Progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial.
Further, the patients were required to have either 1 to 5 Gadolinium-enhancing lesions on screening Brain Magnetic Resonance Imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years.
BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral AtorvaStatin Calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg).
Main Outcome Measures
The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of Gadolinium-enhanced lesions on MRI, relapses, and analysis of Antigen-specific Immune Responses.
BHT-3009 was safe and well tolerated, provided favorable trends on Brain MRI, and produced beneficial Antigen-specific Immune changes.
These Immune changes consisted of a marked decrease in proliferation of Interferon-gamma-producing, Myelin-reactive CD4+ T-Cells from peripheral blood.
And a reduction in titers of Myelin-specific AutoAntiBodies from Cerebral Spinal Fluid as assessed by protein microarrays.
We did not observe a substantial benefit of the AtorvaStatin combination compared with BHT-3009 alone.
In patients with MS, BHT-3009 is safe and induces Antigen-specific Immune Tolerance with concordant reduction of inflammatory lesions on Brain MRI.
Trial Registration clinicaltrials.gov Identifier: NCT00103974.Published online August 13, 2007 (doi:10.1001/archneur.64.10.nct70002).
Spinal Cord Spectroscopy And Diffusion-Based Tractography To Assess Acute Disability In Multiple Sclerosis
Ciccarelli O, Wheeler-Kingshott CA, McLean MA, Cercignani M, Wimpey K, Miller DH, Thompson AJ
Brain 2007 Aug;130(Pt 8):2220-31
Institute of Neurology, University College London, Department of Brain Repair and Rehabilitation, London, UK
There is a need to assess Spinal Cord involvement in Multiple Sclerosis with new imaging techniques in order to understand better the underlying pathology.
We aimed to evaluate whether quantitative MRI measures, obtained using single-Voxel (1)H-MR Spectroscopy of the Cervical Cord and Diffusion-based Tractography.
Of the major Spinal Cord pathways, in patients with a Cervical Cord relapse, differed from controls and correlated with acute disability.
Fourteen patients at the onset of a Cervical Cord relapse with at least one lesion between C1 and C3 were imaged on a 1.5 T scanner and clinically assessed on the Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9-HPT) and Timed 25-Foot Walk test.
Thirteen age- and gender-matched control subjects were also scanned. Metabolite concentrations, including total N-Acetyl-Aspartate (tNAA), Choline-containing compounds (Cho), Creatine plus PhosphoCreatine (Cr) and myo-Inositol (m-Ins), were quantified at C1-C3.
Probabilistic Tractography was performed at C1-C3 to track the Lateral CorticoSpinal Tracts in:
The Lateral Columns, the Anterior CorticoSpinal Tracts and the Anterior Spino-Thalamic Fasciculi in the Anterior Columns, and the Bilateral Fasciculus Gracilis and Cuneatus in the Posterior Columns.
Diffusion- and Tractography-derived measures of these tracts, including Fractional Anisotropy and Voxel-based connectivity, which reflect fiber integrity, were obtained.
These MRI measures were compared between patients and controls using the Mann-Whitney test. Univariate correlations between MRI measures and disability were assessed using the Spearman's rho correlation coefficient.
Multiple regression analyses were performed to investigate which MRI measures independently correlated with the clinical scores, adjusting also for Cross-Sectional Cord Area, age and gender.
Patients showed lower tNAA of the Cervical Cord, lower connectivity and lower Fractional Anisotropy of the Lateral CorticoSpinal Tracts and Posterior Tracts, than controls.
In patients, there were significant correlations between:
- EDSS and m-Ins, Cho, Cr and Radial Diffusivity of the lateral CorticoSpinal Tracts
- HPT and Cr, Radial Diffusivity of the Lateral CorticoSpinal Tracts, connectivity and Fractional Anisotropy of the Posterior Tracts, and connectivity of the Anterior Tracts
- M-Ins was independently associated with the EDSS, while Cr, tNAA and connectivity of the Posterior Tracts were independently associated with the HPT
MR Spectroscopy and Diffusion-based Tractography of the Cervical Cord provide measures that are sensitive to the tissue damage occurring in this area in patients with a Cervical Cord relapse.
These measures were found to correlate with acute disability.
Our findings suggest that it would be worthwhile performing longitudinal studies and extending these novel techniques to Other Neurological Diseases affecting the Spinal Cord.
Rosen HJ, Cummings J
Ann Neurol 2007 Feb;61(2):92-6
University of California, Department of Neurology, San Francisco 94143, USA
PseudoBulbar Affect (PBA) is a dramatic disorder of Emotional Expression and regulation characterized by uncontrollable episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of life.
The disorder occurs in patients with Brain injury caused by many types of Neurological Disease, Including Stroke, Tumors, and NeuroDegenerative Gray and White Matter Disorders.
Although the pathophysiology is unknown, PBA may relate to release of BrainStem emotional control centers from regulation by the Frontal Lobes.
Diagnosis of PBA can be difficult and relies on careful characterization of episodes and differentiation from Depression.
Although there are no US Food and Drug Administration-approved treatments for PBA, several agents have been shown to be effective, including Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and a new agent containing Dextromethorphan and Quinidine.
The growing number of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder.