MS Abstracts 03b-2g7

Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in NeuroDegenerative Diseases such as Multiple Sclerosis (MS).

We investigated the role of InterLeukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE).

We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells.

We also found that CNS-resident Microglial Cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated Macrophages (aaMphis), in an IL-4-dependent manner.

This aaMphi phenotype extended to the lack of Nitric Oxide (NO) production by activated Microglial Cells, which is a marker of classically activated Macrophages.

We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, Macrophages that migrate into the CNS exhibit a dual phenotype.

These data indicate that IL-4 production in the CNS is essential for controlling Autoimmune Inflammation by inducing a Microglial Cell aaMphi phenotype.

Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for Microglial Cells in the regulation of inflammation in the CNS.

Background
Interferon-beta (IFN-ß)therapy represents an important advance in the management of Relapsing Multiple Sclerosis (MS), but information about the relative benefits and risks of available preparations is limited.

OBJECTIVE
This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study.

Methods
The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-ß dosing regimens.

In the study, patients with Relapsing MS were randomly assigned to SC IFN-ß-1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-ß-la 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years.

The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses.

Secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, respectively.

All clinical and Magnetic Resonance Imaging (MRI) evaluations were performed by blinded assessors.

In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months.

Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase.

Results
A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase.

During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023).

The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002).

MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment.

During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity.

Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001).

Neutralizing AntiBody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001).

Conclusions
The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-ß-1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-ß-la 30 microg QW treatment.

The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.

Involuntary crying or laughing are symptoms of a condition known as Involuntary Emotional Expression Disorder (IEED).

This disorder is common among patients with Stroke and Other Neurological Disorders, such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Traumatic Brain Injury (TBI).

Despite its prevalence, this condition is underrecognized and consequently undertreated in Neurological settings. IEED can become disabling for patients who are not accurately diagnosed and treated.

Differential diagnosis depends on recognition of the condition as an Affective Disorder and on its delineation from Unipolar Depression and other major Psychiatric Disorders.

Clinical evaluation is essential for effective nursing care of this disorder.

When the condition is found to be present, effective management must include education, pharmacological treatment, and teaching of self-care strategies.

As patient advocates, NeuroScience nurses are in a unique position to identify and assess such patients and to effectively guide patients and families in the management of this condition.

To evaluate the progression of Cognitive decline in Multiple Sclerosis (MS) patients and the susceptibility of the Multiple Sclerosis Functional Composite (MSFC) Paced Auditory Serial Addition Test (PASAT) to change:

We conducted a 1-year follow-up with a comprehensive NeuroPsychological examination to 19 initially Cognitively Impaired and 26 Cognitively Intact Relapsing/Remitting MS patients, and to 48 healthy controls.

The results indicated that the Cognitive performance of MS patients remained relatively stable. Healthy controls tended to perform better on most NeuroPsychological measures at follow-up, the same was not observed in the MS groups.

PASAT showed a significant difference between the groups: the Cognitively Impaired group tended to deteriorate, whereas the control group and the Cognitively Intact group improved.

The change in PASAT could not be explained by the background variables, for example, mood, quality of life, or nervousness.

Therefore, the MSFC-PASAT seems to be a sensitive measure to show clinical change in the Cognitive status.

Background
The Ventro-Lateral Thalamus is the stereotactic target of choice for severe Intention Tremor.

Nevertheless, the optimal target area has remained controversial, and targeting of the SubThalamic Area has been suggested to be superior.

Patients and methods
Eleven patients with disabling Intention Tremor of different etiology:

Essential Tremor (n = 8), Multiple Sclerosis (n = 2) and one with, SpinoCerebellar Ataxia were implanted bilaterally with DBS electrodes targeted to the Ventro-Lateral Thalamus using micro-recording and micro-stimulation.

Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation.

Postoperative Tremor suppression elicited by individual electrode contacts was quantified using a lateralised Tremor rating scale at least 3 months (in most patients > 1 year) after implantation.

The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI.

Results
In all patients, DBS suppressed Intention Tremor markedly. On average, Tremor on the left and right side of the body was improved by 68% (+/-19; standard deviation) and 73% (+/-21), respectively.

In most patients, distal electrode contacts located in the SubThalamic Area proved to be more effective than proximal contacts in the Ventro-Lateral Thalamus.

In stereotactic coordinates, the optimal site was located 12.7 mm (+/-1.4; mean +/- standard deviation) lateral, 7.0 (+/-1.6) mm posterior, and 1.5 (+/-2.0) mm Ventral to the Mid-Commissural point.

In general, the best contacts could be selected for permanent stimulation.

Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (Paraesthesiae, Dysarthria, Gait Ataxia) which were more pronounced with bilateral stimulation resulting in slightly less Tremor suppression on the left and right side of body (63 +/- 18 and 68 +/- 19%, respectively).

Conclusion
Direct comparison of different stimulation sites in individual patients revealed that DBS in the SubThalamic Area is more effective in suppressing pharmacoresistant Intention Tremor than the Ventro-Lateral Thalamus proper.

Anatomical structures possibly involved in Tremor suppression include Cerebello-Thalamic projections, the PreLemniscal Radiation, and the Zona Incerta.

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.

Introduction
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.

Objectives
To determine the influence of the exacerbations among patients with RR-MS after the second clinical event on the disability occurrence.

Methods
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.

Results
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).

Conclusions
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.

Objective
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.

Methods
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.

Results
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.

Conclusions
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.

Objective
To report the relationship between disease activity and health-related quality of life (HRQoL) in Relapsing Multiple Sclerosis, and the impact of Natalizumab.

Methods
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.

Results
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.

Interpretation
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.

Objective
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).

Design
The study was a randomized, double-blind, placebo-controlled trial.

Subjects receiving placebo were crossed over into an active arm after treatment unblinding.

Setting
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.

Interventions
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.

Results
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.

Conclusion
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).

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:
1. EDSS and m-Ins, Cho, Cr and Radial Diffusivity of the lateral CorticoSpinal Tracts
2. HPT and Cr, Radial Diffusivity of the Lateral CorticoSpinal Tracts, connectivity and Fractional Anisotropy of the Posterior Tracts, and connectivity of the Anterior Tracts
3. 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.

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.