MS Abstracts 04c-2g7

Motor control demands coordinated excitation and inhibition across distributed Brain Neuronal Networks.

Recent work has suggested that Multiple Sclerosis (MS) may be associated with impairments of Neuronal inhibition as part of more general progressive impairments of connectivity.

Here, we report results from a prospective, multi-center fMRI study designed to characterize the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners.

Brain deactivation during right hand movement was assessed in 56 right-handed patients with Relapsing/Remitting or Secondary/Progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects.

The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the Ipsilateral Hemisphere in the region functionally specialised for hand movement control.

We hypothesise that this impairment of deactivation is related to deficits of TransCallosal connectivity and GABAergic NeuroTransmission occurring with the progression of pathology in the MS patients.

This study has substantially extended previous observations with a well-powered, multicenter study.

The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

Objectives
To study the effect Of Botulinum Toxin A (BoNTA) injections into the Detrusor muscle on the incidence of symptomatic Urinary infections in patients with Neurogenic Detrusor Overactivity.

Methods
Between February 2004 and June 2005, 30 patients (18 men, 12 women), mean age 39.4+/-12.1 yr, with Neurogenic Detrusor Overactivity received an injection of 300 U Botox((R)) (Allergan Inc., Irvine, CA, USA) into the Detrusor.

Fifteen patients had Multiple Sclerosis, 14 had Spinal Cord Injury, and 1 had Myelitis. Twenty-two patients had Urinary Incontinence.

Patients were either resistant to AntiCholinergic medications, had discontinued treatment because of adverse effects, or had contraindications to AntiCholinergic drugs.

Before and 6 wk after injection, each patient kept a bladder diary and underwent Urodynamic investigation, retrograde and voiding cystourethrography, and urine culture.

All symptomatic Urinary infections (Pyelonephritis, Orchitis, Prostatitis) occurring in the 6 mo before and the 6 mo after injection were recorded.

Results
Before injection, the mean number of symptomatic Urinary infections over 6 mo was 1.75+/-1.87. After injection, the mean was 0.2+/-0.41 (p=0.003), and only 3 patients presented symptomatic urinary infections.

These patients were those who showed less improvement in their Urodynamic parameters after injection (volume of the first uninhibited contraction, maximum bladder pressure, and maximum cystometric capacity, respectively; p=0.0037, p=0.0002, p=0.0027, ANOVA).

Conclusions
BoNTA injections into the detrusor muscle significantly decreased the incidence of symptomatic urinary infections.

This effect seems to be related to improvement in urodynamic parameters, reflecting improved reservoir capacity at low pressure.

Background
Multiple Sclerosis (MS) Intention Tremor is a disabling symptom, which is difficult to treat.

Objectives
To investigate the effects of Levetiracetam, an AntiEpileptic drug, on Tremor severity and related functionality in MS.

Methods
A randomized, double-blind, placebo-controlled, cross-over study examined the effects of 6 weeks of oral Levetiracetam administration (starting dose = 250 mg/day, maximal dose = 2000 mg/day) in 18 MS patients with disabling Intention Tremor.

Primary outcome was Fahn's Tremor Rating Scale (FTRS) A&B.

Secondary outcome measures were the Nine-Hole Peg Test, patient's opinion rated with the visual analog scale, FTRS C, and an activities of daily life questionnaire.

And validated Tremor Indexes derived during the performance of a digitized spiral drawing task and a wrist step-tracking task. Repeated measures analysis of variance and Friedman tests were applied.

Results
In all, 14 patients completed the trial. Maximal dose intake ranged from 1000 to most commonly 2000 mg, depending on patients' tolerance level. No significant effects of Levetiracetam were found for any outcome measure.

Further analyses on subgroups with different Tremor severity showed no differential effects. Eight patients reported adverse events such as fatigue and stomach ache.

Conclusions
Levetiracetam intake of 2000 mg/day did not affect Tremor severity or functionality in patients with MS.

Objective
Four different patterns of DeMyelination have been described in active DeMyelinating lesions of Multiple Sclerosis (MS) patients that were biopsied shortly after disease onset.

These patterns were suggested to represent heterogeneity of the underlying pathogenesis.

The aim of this study was to determine whether lesion heterogeneity also exists in an unselected collection of autopsy material from patients with established MS.

Methods
All MS Brain tissue available in the VU Medical Center was assessed for the presence of active DeMyelinating lesions using Magnetic Resonance Imaging-guided sampling and ImmunoHistoChemistry.

Tissue blocks containing active DeMyelinating lesions were evaluated for the presence of Complement and AntiBody deposition, Oligodendrocyte Apoptosis, differential loss of Myelin proteins, and Hypoxia-like damage using histology, ImmunoHistoChemistry, and confocal microscopy.

Blocks with active DeMyelinating lesions were compared with blocks with active (NonDeMyelinating) and inactive lesions.

Results
Complement and AntiBodies were consistently associated with Macrophages in areas of active DeMyelination.

Preferential loss of Myelin proteins, extensive Hypoxia-like damage, and Oligodendrocyte Apoptosis were absent or rare.

This pattern was observed in all tissue blocks containing active DeMyelinating lesions; lesion heterogeneity between patients was not found.

Interpretation
The ImmunoPathological appearance of active DeMyelinating lesions in established MS is uniform.

Initial heterogeneity of DeMyelinating lesions in the earliest phase of MS lesion formation may disappear over time as different pathways converge in one general mechanism of DeMyelination.

Consistent presence of Complement, AntiBodies, and Fc-gamma Receptors in Phagocytic Macrophages suggests that AntiBody- and Complement-mediated Myelin Phagocytosis is the dominant mechanism of DeMyelination in established MS.

Background
Short term high dose CorticoSteroid treatment improves symptoms and short term disability after an acute exacerbation of Multiple Sclerosis (MS) but it is unknown whether its long-term use can reduce the accumulation of disability.

Objectives
To determine the efficacy and safety of long-term CorticoSteroid use in MS.

Search Strategy
We searched the following bibliographic databases: CENTRAL (Issue 1, 2007), MEDLINE (1966 to February 2007) and EMBASE (1980 to February 2007).

In an effort to identify further published, unpublished and ongoing trials we searched reference lists and contacted trial authors and one pharmaceutical company.

Selection Criteria
We considered controlled, randomized trials (RCTs), with or without blinding, of long term treatment (i.e. longer than 6 months) of any type of CorticoSteroid in MS, irrespective of disease course.

Data Collection & Analysis
Reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information.

Main Results
Three trials, all classified at high risk of bias, contributed to this review (Miller 1961; BPSM 1995; Zivadinov 2001) resulting in a total of 183 participants (91 treated).

CorticoSteroid therapy did not reduce the risk of being worse at the end of follow-up (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.26 to 1.02) but there was a substantial heterogeneity between studies (I(2): 78.4%).

IV periodic high dose MethylPrednisolone (IVMP) was associated with a significant reduction in the risk of disability progression at 5 years in Relapsing/Remitting (RR-MS) (OR 0.26, 95% CI 0.10 to 0.66).

While Oral continuous low dose Prednisolone was not associated with any risk reduction in disability progression at 18 months (OR 1.23, 95% CI 0.43 to 3.56).

Risk of experiencing at least one exacerbation at end of follow-up was not significantly reduced with CorticoSteroid treatment (OR 0.36; 95% CI 0.10 to 1.25).

Only one study recorded adverse events: in one patient IVMP was discontinued after the fourth pulse when he developed acute GlomeruloNephritis; a second patient was removed from the study after the fifth IVMP pulse because of severe Osteoporosis.

Authors' Conclusions
There is not enough evidence that long-term CorticoSteroid treatment delays progression of long term disability in patients with MS:

Since one study at high risk of bias showed that the administration of pulsed high dose IVMP is associated with a significant reduction in the risk of long term disability progression in patients with RR MS.

An adequately powered, high quality RCT is needed to investigate this finding.

The classical view of MS as an Inflammatory-DeMyelinating condition affecting the White Matter (WM) of the Central Nervous System (CNS) has recently been challenged by the results of several Magnetic Resonance Imaging (MRI) studies.

These consistently show Gray Matter (GM) involvement, which correlates only moderately with the extent of WM pathology.

Here we summarize how conventional and modern imaging-based techniques have quantified GM damage in MS, in terms of focal lesions, diffuse tissue abnormalities and irreversible tissue loss.

Results from functional MRI studies, together with these new findings, are contributing to a significant change in our MS understanding.

MS is now viewed as a global CNS condition, affecting both WM and GM, which has an early and important NeuroDegenerative component.

Objective
Cortical Lesions in Multiple Sclerosis (MS) are notoriously difficult to visualize with standard MR imaging (MRI) techniques.

However, the use of higher field-strengths with intrinsically higher signal-to-noise, which can partly be used to increase spatial resolution, may improve Cortical lesion detection.

Therefore, in this post mortem study, the sensitivity of high fieldstrength MRI (4.7 T) for Cortical lesions was investigated, and compared to that of standard fieldstrength (1.5 T).

Methods
At 1.5 T, dual-echo T₂-weighted Spin-Echo, as well as 3D-FLAIR images of seventeen formalin-fixed coronal MS and four control Hemispheres were acquired.

At 4.7 T, the same specimens were imaged with a mainly Proton-Density (PD)- weighted sequence.

ProteoLipid Protein (PLP)-stained tissue sections (10 mum) of the same Brain slices were matched to the corresponding MR images, and Cortical Lesions were scored on all three MR sequences (blinded to Histology) and in tissue sections (blinded to MRI).

Sensitivity of the sequences for four Cortical lesion types was calculated. Additionally, an unblinded, retrospective MR scoring was performed.

Results
Sensitivity for purely IntraCortical lesions (histological lesion Types II, III, and IV; n = 128) was below 10 % for both 1.5 T and 4.7 T MRI, while mixed Gray Matter-White Matter (Type I) lesions (n = 5) were detected in four out of five cases.

All lesion counts increased upon retrospective (unblinded) scoring. However, up to 80% of the IntraCortical lesions still remained undetected.

Conclusions
MRI sensitivity for post mortem detection of Cortical lesions is low, even when a higher field-strength was used. It varies, however, for different subtypes of Cortical Lesions.

Several lines of evidence link ImmunoSuppression to inflammation in patients with Multiple Sclerosis (MS) and provide a rationale for the increasing use of ImmunoSuppressive drugs in the treatment of MS.

Treatment-refractory, clinically active MS can quickly lead to devastating and irreversible Neurological disability and treating these patients can be a formidable challenge to the clinician.

Patients with refractory MS have been treated with intense ImmunoSuppression, such as Cyclophosphamide or Mitoxantrone, or with Autologous Haematopoeitic Stem Cell Transplants.

Evidence shows that intense ImmunoSuppression might be effective in patients who are unresponsive to ImmunoModulating Therapy, such as Interferon-ß and Glatiramer Acetate.

Natalizumab, a new addition to the armamentarium for treating MS, might also have a role in the treatment of this MS phenotype.

This Review describes the use of intense ImmunoSuppressant Drugs and Natalizumab in patients with rapidly worsening MS and provides clinicians with guidelines for the use of these drugs in this patient group.

Aggressive forms of Multiple Sclerosis (MS) represent a limited group of DeMyelinating Diseases that rapidly progress to severe disability.

Currently available therapies are poorly effective against these clinical entities.

Recently, it has been demonstrated that intense ImmunoSuppression followed by Autologous Haematopoietic Stem Cell Transplantation (AHSCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by MRI.

We report the result of the Italian phase 2 GITMO study, a multicenter study in which 21 MS patients, who were rapidly deteriorating and not responding to the usual therapeutic strategies, were treated with this procedure.

The clinical effect of the treatment is long lasting, with a striking abrogation of inflammation detected by MRI findings.

These results support a role for intense ImmunoSuppression followed by ASCT as treatment in rapidly evolving MS cases unresponsive to conventional therapies.

Objective
To determine if exercise benefits patients with Multiple Sclerosis.

Design & Settings
A randomized controlled trial, participants exercised at home and also attended exercise classes held in a hospital physiotherapy gym.

Subjects
Thirty patients, diagnosed and independently mobile, were recruited in the Dublin area.

Intervention
For three months, classes were held twice-weekly and participants exercised independently once-weekly. The control group was monitored monthly and management remained unchanged.

Measurements
Measurements were taken at baseline, three and six months.

The Modified Fatigue Impact Scale (MFIS), Multiple Sclerosis Impact Scale-29 (MSIS-29) and Functional Assessment of Multiple Sclerosis (FAMS) were used to measure Fatigue and Quality Of Life (QOL).

Heart Rate (HR) and the Borg's Rating of Perceived Exertion (RPE) were recorded during an incremental exercise test. The change from baseline scores between groups was compared using the Mann-Whitney U-test.

Results
Twenty-four participants completed the program (n = 12 in each group).

Based on the change in scores at three months, the exercise group had significantly greater improvements in exercise capacity (HR: -14 [-18.5, -2.5] versus 0.5 [-4, 5.5], P= 0.009), QOL (FAMS: 23 [9.5, 42.5] versus -3.5 [-16, 5], P=0.006) and Fatigue (MFIS: -13 [-20, -3] versus 1 [-4, 4.5], P=0.02).

At six months, the difference in change scores remained significant for FAMS (19 [14, 31] versus -4.5 [-25, 8], P=0.002) and MFIS (-8.5 [-19.5, -1] versus 0.5 [-2.5, 6.5], P=0.02) only.

Conclusions
A three-month exercise program improved participants' exercise capacity, QOL and Fatigue, with the improvements in QOL and Fatigue lasting beyond the program.

Background
Multiple Sclerosis (MS) is a chronic DeMyelinating Neurological Disease afflicting young and middle-aged adults, resulting in problems with Coordination, Strength, Cognition, Affect, and Sensation.

Objective
The objective of this study was to determine whether a Ginkgo extract (EGb 761) improved functional performance in individuals with MS.

Design
This study used a double-blind, placebo-controlled, parallel group design.

The end point was change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four tablets per day at 60 mg per tablet for four weeks.

Setting
The study was conducted in academic and clinical-based settings.

Patients/
Twenty-two individuals with MS were randomly assigned to either the treatment or control condition. Groups did not differ with respect to age, IQ, and education.

Intervention
Half of the subjects received 240 mg per day of Ginkgo special extract (EGb 761), and the other half received placebo.

Main Outcome Measure
The main outcome measures assessed depression (Center for Epidemiologic Studies of Depression Scale [CES-D]), Anxiety (State-Trait Anxiety Inventory [STAI]), Fatigue (Modified Fatigue Impact Scale [MFIS]); symptom severity (Symptom Inventory [SI]) and functional performance (Functional Assessment of Multiple Sclerosis [FAMS]).

Results
The Ginkgo group had significantly more individuals showing improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of Fatigue, symptom severity, and functionality.

The Ginkgo group also exhibited less Fatigue at follow-up compared with the placebo group.

Conclusions
This exploratory pilot study showed that no adverse events or side effects were reported and that Ginkgo exerted modest beneficial effects on select functional measures (eg, Fatigue) among some individuals with MS.

Objectives
To assess if short-term combination of Glatiramer Acetate (GA) and IV steroid in patients with Relapsing/Remitting Multiple Sclerosis (RRMS) is safe and sustains the effect of GA treatment on MRI-disease activity.

Methods
RRMS patients with >/=2 Gadolinium (Gd)-enhancing lesions on screening MRI and EDSS score < /=4.0 received GA injection (20 mg subcutaneously once daily) and monthly 1 g IV MethylPrednisolone (IVMP) for 6 months.

Afterwards, all subjects received GA injections daily alone for additional 6 months.

Neurological evaluations were performed at screening, baseline and every 3 months. Laboratory tests for safety were performed at screening, baseline, months 1, 6 and 12.

Brain MRIs were performed at screening, baseline, months 5, 6, 11, and 12 to assess the change in the number of Gd-enhancing lesions i) from baseline to month 6, and ii) from baseline to month 12 compared with the change from baseline to month 6.

Results
89 subjects were eligible for the study. In this group, GA in combination with IVMP resulted in 65% (95% CI=0.25-0.49, p < 0.0001) reduction in the number of Gd-enhancing lesions.

This reduction was sustained for additional 6 months when patients received GA alone.

The analysis for change achieved in the second 6 month period showed no difference from the change achieved in the first six months (ratio 0.75, 90% CI=0.468-1.197).

Overall, treatment was well tolerated and adverse events reported were similar to the known safety profile of GA.

Conclusions
Short-term combination of GA with 1 g monthly IVMP, preceding treatment with GA alone, is safe.

MRI data suggest that this combination therapy may result in an early and sustained reduction of disease activity in RRMS patients.