MS Abstracts 03c-2g7

  1. Treatment with Interferon-beta-1b delays conversion to clinically definite and McDonald MS in patients with Clinically Isolated Syndromes
    Neurology 2006 Oct 10;67(7):1242-9

  2. History and prevalence of Involuntary Emotional Expression Disorder
    CNS Spectr 2007 Apr;12(4 Suppl 5):6-10

  3. Role of Mitochondria in Multiple Sclerosis
    Curr Neurol NeuroSci Rep 2006 May;6(3):244-52

  4. MRI to monitor treatment efficacy in Multiple Sclerosis
    J NeuroImaging 2007 Apr;17 Suppl 1:50S-55S

  5. Daclizumab phase II trial in Relapsing and Remitting Multiple Sclerosis: MRI and clinical results
    Neurology 2007 Aug 21;69(8):785-9

  6. Gelsolin concentration in CerebroSpinal Fluid from patients with Multiple Sclerosis and other Neurological Disorders
    Eur J Neurol 2008 Jun;15(6):584-8

  7. Exploring recombinant human Erythropoietin in Chronic/Progressive Multiple Sclerosis
    Brain 2007 Aug 29

  8. InterLeukin-7 receptor alpha chain (IL-7R) shows allelic and functional association with Multiple Sclerosis
    Nat Genet 2007 Sep;39(9):1083-91

  9. Regional Brain Atrophy development is related to specific aspects of clinical dysfunction in Multiple Sclerosis
    NeuroImage 2007 Nov 15;38(3):529-37

  10. The incidence and significance of Anti-Natalizumab AntiBodies. Results from AFFIRM and SENTINEL
    Neurology 2007 Oct 2;69(14):1391-403

  11. Botulinum toxin a improves the quality of life of patients with Neurogenic Urinary Incontinence
    Eur Urol 2007 Sep;52(3):850-9

  12. Prognostic value of high-field proton Magnetic Resonance Spectroscopy in patients presenting with Clinically Isolated Syndromes suggestive of Multiple Sclerosis
    NeuroRadiology 2008 Feb;50(2):123-9


Treatment With Interferon-beta-1b Delays Conversion To Clinically Definite And McDonald MS In Patients With Clinically Isolated Syndromes

Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R
Neurology 2006 Oct 10;67(7):1242-9
University Hospital, Basel, Switzerland
PMID# 16914693

To assess efficacy, safety, and tolerability of every-other-day Interferon-ß-1b treatment in patients with a first clinical event suggestive of Multiple Sclerosis (MS) (Clinically Isolated Syndrome).

We conducted a multicenter, randomized, double-blind, placebo-controlled trial.

Patients with a first clinical DeMyelinating event and at least two clinically silent Brain MRI lesions were randomized to Interferon-ß-1b (IFN-ß-1b) 250 mug subcutaneously (SC) every other day (EOD) (n = 292) or placebo (n = 176), until Clinically Definite MS (CDMS) was diagnosed or they had been followed for 24 months.

After 2 years, 45% of placebo patients had converted to CDMS (Kaplan-Meier estimate; primary outcome measure) and 85% fulfilled the McDonald criteria (co-primary outcome measure).

Overall Interferon-ß-1b delayed the time to diagnosis of CDMS (p < 0.0001) and McDonald MS (p < 0.00001). Hazard ratios (95% CI) were 0.50 (0.36 to 0.70) for CDMS and 0.54 (0.43 to 0.67) for McDonald MS favoring treatment with IFN-ß-1b.

Treatment was well tolerated, as indicated by the low rate of patients dropping out of the study before CDMS was reached (6.6% overall, 7.2% in the IFN-ß-1b group).

Interferon-ß-1b 250 mug subcutaneously every other day delayed conversion to Clinically Definite Multiple Sclerosis, and should be considered as a therapeutic option in patients presenting with a first clinical event suggestive (CIS) of Multiple Sclerosis.


History And Prevalence Of Involuntary Emotional Expression Disorder

Duda JE
CNS Spectr 2007 Apr;12(4 Suppl 5):6-10
Philadelphia VA Medical Center, Education and Clinical Center (PADRECC), Parkinson's Disease Research, Philadelphia, PA, USA
PMID# 17426669

The syndrome now known as Involuntary Emotional Expression Disorder (IEED) is a condition characterized by uncontrollable episodes of laughing and/or crying.

It has been known for more than a century, but confusing and conflicting terminology may have hampered the progress of physicians in recognizing this condition.

IEED is associated with various Neurological Disorders and NeuroDegenerative Diseases, including Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson's Disease, Alzheimer's Disease and other Dementias, and Neurological injuries such as Stroke and Traumatic Brain Injury.

It is hoped that better defined terminology for IEED may help in the future diagnosis of this debilitating condition, the establishment of accurate prevalence rates for IEED in the varying underlying conditions.

And also in removing blame and stigma from sufferers by providing reassurance about the nature of their condition.


Role Of Mitochondria In Multiple Sclerosis

Kalman B
Curr Neurol NeuroSci Rep 2006 May;6(3):244-52
Saint Luke's Roosevelt Hospital Center, Columbia University, Department of Neurology, 432 West 58th Street, Room 226, New York, NY 10019, USA
PMID# 16635434

This review presents inherited and acquired forms of Mitochondrial Dysfunction associated with OligodendroCytopathy and NeuroDegeneration in order to better understand the degenerative features of inflammatory DeMyelination.

The recognition that various Mitochondrial Mechanismsm are involved in the pathogenesis of Multiple Sclerosis leads to therapeutic considerations, re-emphasizing the importance of early NeuroProtection in combination with the approved means of Immune modulation.


MRI To Monitor Treatment Efficacy In Multiple Sclerosis

Fazekas F, Soelberg-Sorensen P, Comi G, Filippi M
J NeuroImaging 2007 Apr;17 Suppl 1:50S-55S
Medical University of Graz, Department of Neurology, Austria
PMID# 17425736

It is the primary goal of Disease Modifying Treatments in Multiple Sclerosis (MS) to prevent the occurrence of new clinical deficits and lessen or prevent accumulation of Disability.

As a consequence, clinical aspects constitute the major outcome variables in treatment trials and are also the leading factor for treatment decisions in individual patients.

However, determining treatment efficacy by clinical evaluation suffers from limited objectivity, sensitivity, and specificity for the underlying pathophysiologic aspects, which may constitute the target of a given therapy.

Magnetic Resonance Imaging (MRI) can partly overcome these limitations by showing Morphologic aspects of the disease with clinical relevance and responsiveness to therapy.

Within the past 10 years sufficient data have been collected to establish the accumulation of new/enlarging T2 lesions and Gadolinium enhancing lesions, T2 lesion load, T1-HypoIntense lesions.

And, Brain Volume changes as reasonably well-defined markers of disease processes, which may serve to monitor treatment efficacy.

Accordingly, these variables have been extensively used for probing the efficacy of Disease Modifying Treatments. In part they are also suited to guide therapeutic decisions in the individual patient.

Further options may come from the use of advanced techniques like Magnetization Transfer MRI, Diffusion-weighted MRI, and Proton Magnetic Resonance Spectroscopy, which detect more subtle MS related tissue abnormalities.

Irrespective of the technique employed, great care has to be given to the standardization and reproducibility of both data acquisition and interpretation when using MRI to monitor treatment efficacy.

For the individual patient therapeutic decisions based on MRI need experience and caution.


Daclizumab Phase II Trial In Relapsing And Remitting Multiple Sclerosis: MRI And Clinical Results

Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG
Neurology 2007 Aug 21;69(8):785-9
Veterans Affairs Salt Lake City Health Care System, NeuroVirology Research Laboratory, Salt Lake City, UT 84148, USA
PMID# 17709711

Daclizumab is an InterLeukin-2 Receptor alpha chain specific humanized MonoClonal AntiBody that has shown promising therapeutic effects in Multiple Sclerosis (MS).

Daclizumab treatment in patients with Relapsing/Remitting MS was administered to determine effects on MRI and clinical outcomes.

Patients with MS on Interferon (IFN) therapy but with continuing relapses and contrast enhancing lesions (CEL) were selected.

Patients were evaluated with monthly MRI scans and clinical rating scales starting 3 months prior to treatment and then at 0.5 to 27.5 months during treatment.

Daclizumab (1 mg/kg IV) was administered twice in the first month (initiated and administered again in 2 weeks), followed by treatments every 4 weeks.

IFN was continued until 5.5 months after Daclizumab was initiated.

Patients were then placed on Daclizumab monotherapy. Patients with recurrent CEL were restarted on IFN with Daclizumab therapy at (1.5 mg/kg IV) every 28 days.

Nine patients qualified for inclusion and completed the trial.

Efficacy measured by both total CEL and new CEL (p < 0.001), relapses, timed ambulation, Expanded Disability Status Scale, and Neurologic Rating Scale (p < 0.05 to p < 0.01) was observed.

Daclizumab was effective in reducing contrast enhancing lesions.

And improving clinical scores in patients with Relapsing/Remitting Multiple Sclerosis with active disease not controlled by Interferon therapy.

These results provide evidence for long-term efficacy and support further clinical development of Daclizumab.


Gelsolin Concentration In CerebroSpinal Fluid From Patients With Multiple Sclerosis And Other Neurological Disorders

Kulakowska A, Drozdowski W, Sadzynski A, Bucki R, Janmey PA
Eur J Neurol 2008 Jun;15(6):584-8
Medical University of Bialystok, Department of Neurology, Bialystok, Poland
PMID# 18474076

Gelsolin is a highly conserved IntraCellular Actin-binding protein with an ExtraCellular isoform, plasma Gelsolin, for which there is not yet a clearly defined function.

Materials And Methods
In this study, we determined gelsolin concentrations in blood and CerebroSpinal Fluid (CSF) obtained from 25 subjects using ImmunoBlotting and a functional assay that quantifies Gelsolin's ability to accelerate Actin polymerization.

The Gelsolin concentration in CSF, determined by quantitative ImmunoBlotting was 1.2-15.9 microg/ml (average 5.9 +/- 3.8 mug/ml).

In samples obtained from patients diagnosed with conditions that do not alter standard CSF clinical tests [(idiopathic Cephalgia, Ischialgia due to Discopathy, and idiopathic (Bell's) Facial Nerve Palsy or Entrapment Radial Neuropathy)], the average Gelsolin concentration was 7.2 +/- 4.3 microg/ml.

In contrast, the Gelsolin concentration in samples obtained from patients diagnosed with Multiple Sclerosis was 2.1 +/- 0.7 microg/ml, and a similar low concentration was found in a patient recovering from a SubArachnoid Hemorrhage.

The range of CSF Gelsolin concentrations determined by the Actin polymerization assay was 0.61-9.97 microg/ml (average 3.6 +/- 2.2 microg/ml).

These lower values compared with those obtained from ImmunoBlotting analysis suggest that CSF Gelsolin may bind other CSF molecules leading to a reduction of its Actin-binding activity.

The results presented here show that CSF Gelsolin concentration is significantly altered in certain Neurological conditions, including Multiple Sclerosis, indicating the possible utility of CSF Gelsolin levels for diagnostic purposes.


Exploring Recombinant Human Erythropoietin In Chronic/Progressive Multiple Sclerosis

Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Sirén AL, Paulus W, Nave KA, Gold R, Bartels C
Brain 2007 Aug 29
Max Planck Institute of Experimental Medicine, Departments of Radiology and Clinical NeuroPhysiology, Georg-August-University and Hertie Institute of Multiple Sclerosis Research, Göttingen, Germany
PMID# 17728357

The NeuroDegenerative aspects of Chronic Progressive Multiple Sclerosis (MS) have received increasing attention in recent years, since Anti-Inflammatory and ImmunoSuppressive treatment strategies have largely failed.

However, successful NeuroProtection and/or NeuroRegeneration in MS have not been demonstrated yet.

Encouraged by the multifaceted NeuroProtective effects of recombinant human Erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with Chronic/Progressive MS.

    Main study objectives were:
  1. Evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and
  2. Collecting first evidence of potential efficacy on clinical outcome parameters

Eight MS patients, five randomly assigned to high-dose (48 000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naďve Parkinson patients (receiving 48 000 IU) were followed over up to 48 weeks:

A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase.

Clinical and ElectroPhysiological improvement of motor function, reflected by a reduction in Expanded Disability Status Scale (EDSS).

And of Cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application.

In contrast, low-dose EPO MS patients and drug-naďve Parkinson patients did not improve in any of the parameters tested.

There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings.

This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in Chronic/Progressive MS.


InterLeukin-7 Receptor Alpha Chain (IL-7R) Shows Allelic And Functional Association With Multiple Sclerosis

The Multiple Sclerosis Genetics Group
Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL
Nat Genet 2007 Sep;39(9):1083-91
Duke University Medical Center, Center for Human Genetics, Department of Molecular Genetics and MicroBiology, Durham, North Carolina 27710, USA
PMID# 17660817

Multiple Sclerosis is a DeMyelinating NeuroDegenerative Disease with a strong genetic component.

Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the Major Histocompatibility Complex on Chromosome 6p.

We describe allelic association of a polymorphism in the gene encoding the InterLeukin-7 Receptor alpha chain (IL-7R) as a significant risk factor for Multiple Sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)).

Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL-7R, has a functional effect on gene expression.

The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.


Regional Brain Atrophy Development Is Related To Specific Aspects Of Clinical Dysfunction In Multiple Sclerosis

Jasperse B, Vrenken H, Sanz-Arigita E, de Groot V, Smith SM, Polman CH, Barkhof F
NeuroImage 2007 Nov 15;38(3):529-37
VU University Medical Center, Department of Neurology, Boelelaan 1117, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
PMID# 17889567

Brain Atrophy in Multiple Sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit.

Little is known about the rate of Atrophy in specific Brain Regions in relation to specific clinical deficits.

We determined the displacement of the Brain surface between two T1-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly Disabed MS patients.

Voxel- and cluster-wise permutation-based statistics were used to identify Brain regions in which Atrophy development was significantly related to:

Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT).

Clusters were considered significant at a corrected cluster-wise p-value of 0.05.

Worse EDSS change-score and worse follow-up EDSS were related to Atrophy development of PeriVentricular and BrainStem regions and right-sided Parietal, Occipital and Temporal regions.

Worse PASAT at follow-up was significantly related to Atrophy of the Ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to Atrophy around the Ventricles and of the BrainStem.

Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the Atrophy of widely distributed peripheral regions, as well as Atrophy of PeriVentricular and BrainStem regions.

Our findings suggest that decline in ambulatory function is related to Atrophy of central Brain regions exclusively.

Whereas decline in Neurologically more complex tasks for coordinated hand function is related to Atrophy of both Central and Peripheral Brain regions.


The Incidence And Significance Of Anti-Natalizumab AntiBodies. Results From AFFIRM And SENTINEL

For the AFFIRM and SENTINEL Investigators
Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O'connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA
Neurology 2007 Oct 2;69(14):1391-403
Johns Hopkins Multiple Sclerosis Center, Baltimore, MD, USA
PMID# 17761550

To determine the incidence and clinical effects of AntiBodies that develop during treatment with Natalizumab.

In two randomized, double-blind, placebo-controlled studies (Natalizumab safety and efficacy in Relapsing/Remitting Multiple Sclerosis [MS, AFFIRM].

And safety and efficacy of Natalizumab in combination with Interferon-beta-1a [INF-ß-1a] in patients with Relapsing/Remitting MS [SENTINEL]) of patients with Relapsing Multiple Sclerosis.

Blood samples were obtained at baseline and every 12 weeks to determine the presence of AntiBodies against Natalizumab. AntiBodies to Natalizumab were measured using an ELISA.

Patients were categorized as "transiently positive" if they had detectable AntiBodies (>/=0.5 microg/mL) at a single time point or "persistently positive" if they had AntiBodies at two or more time points >/=6 weeks apart.

In the AFFIRM study, AntiBodies were detected in 57 of 625 (9%) of Natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive.

Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p < /= 0.05), relapse rate (p = 0.009), and MRI (p < /= 0.05) compared with AntiBody-negative patients.

In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming AntiBody negative.

The incidence of infusion-related adverse events was significantly higher in persistently positive patients.

Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and AntiBody-negative patients were not statistically significant.

The incidence of persistent AntiBody positivity associated with Natalizumab is 6%.

Reduced clinical efficacy is apparent in persistently positive patients.

Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for AntiBody testing.


Botulinum Toxin A Improves The Quality Of Life Of Patients With Neurogenic Urinary Incontinence

Schurch B, Denys P, Kozma CM, Reese PR, Slaton T, Barron RL
Eur Urol 2007 Sep;52(3):850-9
University Hospital Balgrist, Spinal Cord Injury Center, Zurich, Switzerland
PMID# 17467889

To evaluate the impact of Botulinum Toxin Type A (BoNTA) on health-related quality of life in patients with Neurogenic Urinary Incontinence (UI) using the Incontinence Quality of Life questionnaire (I-QOL).

Randomized, double-blind, multicenter, placebo-controlled study involving eight centers across Belgium, France, and Switzerland.

Patients (n=59) with UI due to Neurogenic Detrusor OverActivity (Spinal Cord Injury, n=53; Multiple Sclerosis, n=6) who were inadequately managed on oral AntiCholinergics received a single dose of BoNTA (200U or 300U, Botox((R))) or placebo.

I-QOL scores at screening and after treatment at weeks 2, 6, 12, 18, and 24 were recorded.

Median total and subscale I-QOL scores increased significantly from screening with BoNTA 300U compared with placebo at all time points (p < 0.05) and with BoNTA 200U compared with placebo at all time points for total score.

And the Avoidance Limiting Behavior subscale (p < 0.05), and at weeks 2, 6, 12, and 18 (p < 0.05), but not 24 for the Psychosocial Impact and Social Embarrassment subscales.

Approximately twice as many BoNTA recipients as placebo recipients achieved at least a minimal important difference in total I-QOL score at 2, 6, 12, and 24 wk.

BoNTA significantly improves UI-associated health-related quality of life in patients with Neurogenic UI.


Prognostic Value Of High-Field Proton Magnetic Resonance Spectroscopy In Patients Presenting With Clinically Isolated Syndromes Suggestive Of Multiple Sclerosis

Wattjes MP, Harzheim M, Lutterbey GG, Bogdanow M, Schmidt S, Schild HH, Träber F
NeuroRadiology 2008 Feb;50(2):123-9
University of Bonn, Department of Radiology/NeuroRadiology, Bonn, Germany
PMID# 17982745

The aim of this study was to determine the prognostic value of metabolic alterations in the Normal-Appearing White Matter (NAWM).

Of patients presenting with Clinically Isolated Syndromes (CIS) suggestive of Multiple Sclerosis (MS) with special regard to the prediction of conversion to definite MS.

Using a 3T whole-body MR system, a multi-sequence conventional MRI protocol and single-voxel Proton MR Spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the Parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls.

Absolute concentrations of N-Acetyl-Aspartate (tNAA), myo-Inositol (Ins), Choline (Cho) and Creatine (tCr) as well as metabolite ratios were determined.

Follow-up including Neurological assessment and conventional MRI was performed 3-4 and 6-7 months after the initial event.

Nine patients converted to definite MS during the follow-up period.

Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (-13.4%, P = 0.002) whereas nonconverters (-6.5%, P = 0.052) did not.

The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance.

No significant differences could be observed for tCr and Cho in either patient group.

Axonal Damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS.

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