MS Abstracts: 2c-2g

  1. Gabapentin effect on Spasticity in Multiple Sclerosis
    Arch Phys Med Rehabil 2000 Feb;81(2):164-9

  2. Clinical tests of standing balance in Multiple Sclerosis
    Arch Phys Med Rehabil 2000 Feb;81(2):215-21

  3. Increased numbers of CCR5+ Interferon-gamma- and Tumor Necrosis Factor-alpha-secreting T-Lymphocytes in Multiple Sclerosis
    Ann Neurol 2000 Feb;47(2):269-73

  4. Heterogeneity of T-Lymphocyte function in Primary/Progressive Multiple Sclerosis: relation to Magnetic Resonance Imaging lesion volume
    Ann Neurol 2000 Feb;47(2):234-7

  5. Spinal Cord Magnetic Resonance Imaging in suspected Multiple Sclerosis
    Eur Radiol 2000 Jan 27;10(2):368-376

  6. Inhibition of Th1 development and treatment of Chronic/Relapsing Experimental Allergic EncephaloMyelitis by a non-hypercalcemic analogue of 1,25-Dihydroxyvitamin D(3)
    Eur J Immunol 2000 Feb;30(2):498-508

  7. Managing the adverse effects of Interferon-ß therapy in Multiple Sclerosis
    Drug Saf 2000 Feb;22(2):149-59

  8. Up-regulation of the Hyaluronate receptor CD44 in canine Distemper DeMyelinated plaques
    Acta Neuropathol (Berl) 2000 Feb;99(2):138-46

  9. The contribution of MRI in the differential diagnosis of the damage of the Cerebral Hemispheres
    J Neurol Sci 2000 Jan 15;172 Suppl 1:S57-S62

  10. Assessment of the damage of the Cerebral Hemispheres in MS using NeuroImaging techniques
    J Neurol Sci 2000 Jan 15;172 Suppl 1:S63-S66

  11. Pathologic role and temporal appearance of newly emerging AutoEpitopes in Relapsing Experimental AutoImmune EncephaloMyelitis
    J Immunol 2000 Jan 15;164(2):670-8

  12. Myelin-associated Oligodendrocytic basic protein: identification of an Encephalitogenic Epitope and association with Multiple Sclerosis
    J Immunol 2000 Jan 15;164(2):1103-9





#1

Gabapentin Effect On Spasticity In Multiple Sclerosis: A Placebo-Controlled, Randomized Trial

Cutter NC, Scott DD, Johnson JC, Whiteneck G
Arch Phys Med Rehabil 2000 Feb;81(2):164-9
Univ of Colorado Health Sciences Center, Denver, USA
PMID# 10668769; UI# 20132203
Abstract

Objective
To investigate the effect of Gabapentin on subject self-report and physician-administered Spasticity scales in individuals with Multiple Sclerosis.

Design & Setting
Prospective, double-masked, placebo-controlled, crossover design. The Multiple Sclerosis Center at the Denver Veterans Affairs Medical Center.

Intervention
Subjects were titrated to either 900mg Gabapentin orally three times a day or placebo over a 6-day period.

Subjects underwent a 14-day washout and then were crossed over. No other changes were made to their medication regimen.

Main Outcome Measures
The outcome measures were divided into two categories: subject self-report scales physician-administered scales.

Subject self-report scales included the Spasm Frequency Scale, Spasm Severity Scale, Interference With Function Scale, Painful Spasm Scale, and Global Assessment Scale.

Physician-administered scales included the Modified Ashworth Scale, Clonus Scale, Deep Tendon Reflexes, Plantar Stimulation Response, and the Kurtzke Expanded Disability Status (EDSS) Scale.

Digit Span and Digit Symbol subtests of the WAIS-R Intelligence Scale were administered to assess for possible impaired concentration.

The Fatigue Impact Scale was administered to assess for changes in Fatigue. The adjective generation technique was administered to assess for alterations in mood.

Results
A statistically significant reduction in the impairment of Spasticity was found in the Gabapentin-treated subjects compared with placebo.

As measured by the self-report scales of the Spasm Severity Scale, Interference With Function Scale, Painful Spasm Scale, and Global Assessment Scale and by the Physician-Administered Scales of the Modified Ashworth and plantar stimulation response.

No significant difference was noted in the Digit Span, Digit Symbol, adjective generation technique, and EDSS.

Conclusion
Gabapentin reduces the impairment of Spasticity, compared with placebo, without the side effects of worsening concentration and Fatigue.



#2

Clinical Tests Of Standing Balance
In Multiple Sclerosis

Frzovic D, Morris ME, Vowels L
Arch Phys Med Rehabil 2000 Feb;81(2):215-21
LaTrobe University, School of Physiotherapy, Faculty of Health Sciences, Bundoora, Victoria, Australia
PMID# 10668778; UI# 20132212
Abstract

Objective
To investigate differences in performance between people with Multiple Sclerosis (MS) and control subjects on clinical tests of balance, and to assess performance consistency on balance tests in people with MS from morning to afternoon.

Study Design & Setting
Two factor repeated measures design with a two group sample of convenience. Kingston Centre and the Camberwell Centre of the MS Society of Victoria, Australia.

Subjects
Fourteen people with MS and 14 control subjects matched for age, height, and sex.

Main Outcome Measures
Subjects were measured on their ability to maintain standing balance in steady stance, (feet apart, feet together, stride stance, tandem stance, and single leg stance), during self-generated perturbations (functional reach, arm raise, and step tests) and in response to an external perturbation.

Participants with MS were also asked to rate their Fatigue level in the morning and afternoon.

Results
There were no differences between MS and control groups on the ability to maintain standing balance with feet apart, feet together, or in stride stance.

Participants with MS performed more poorly than control subjects in tandem stance and single leg stance and in the functional reach test, arm raise test, step test, and in response to an external perturbation.

There was little change in balance from morning to afternoon in participants with MS (ICCs (2,1) .70 to .94), despite an increase in self-rated Fatigue (t(14) = -3.14, p = .008).

Conclusion
The ability to maintain balance in standing is a marked problem in people with MS despite the consistency of their performance from morning to afternoon.



#3

Increased Numbers Of CCR5+ Interferon-gamma- And Tumor Necrosis Factor-alpha-Secreting T-Lymphocytes In Multiple Sclerosis

Strunk T, Bubel S, Mascher B, Schlenke P, Kirchner H, Wandinger KP
Ann Neurol 2000 Feb;47(2):269-73
Univ of Lubeck School of Medicine, Institute of Immunology and Transfusion Medicine, Germany
PMID# 10665504; UI# 20127270
Abstract

To determine the frequency of in vivo activated T(H)1 Lymphocytes, T-Cell subsets of 9 Multiple Sclerosis patients with active disease and 17 healthy controls were analyzed by Immunostaining for CCR5, CD26.

And their expression of InterLeukin-2, Interferon-gamma, and Tumor Necrosis Factor-alpha.

The numbers of CCR5+ Interferon-gamma- and Tumor Necrosis Factor-alpha-producing T-Cells were significantly increased in the peripheral blood of Multiple Sclerosis patients.

CCR5 expression may be a useful marker to identify effector cells in Multiple Sclerosis and could be used as a tool for monitoring disease activity.



#4

Heterogeneity Of T-Lymphocyte Function In Primary/Progressive Multiple Sclerosis: Relation To Magnetic Resonance Imaging Lesion Volume

Prat A, Pelletier D, Duquette P, Arnold DL, Antel JP
Ann Neurol 2000 Feb;47(2):234-7
Montreal Neurological Institute, McGill University, NeuroImmunology Unit, Quebec, Canada
PMID# 10665495; UI# 20127261
Abstract

We found that in vitro migration and Interferon-gamma production by Lymphocytes derived from Primary/Progressive Multiple Sclerosis patients preselected on the basis of a high T2-weighted lesion volume (>10 cm3) on Magnetic Resonance Imaging, were increased compared with that in Primary/Progressive Multiple Sclerosis patients with a low T2-weighted lesion volume (<3 cm3) and controls.

Whether the Heterogeneity of Immune function within the Primary/Progressive population will correlate with response to therapy remains to be established.



#5

Spinal Cord Magnetic Resonance Imaging In Suspected Multiple Sclerosis

Lycklama a Nijeholt GJ, Uitdehaag BM, Bergers E, Castelijns JA, Polman CH, Barkhof F
Eur Radiol 2000 Jan 27;10(2):368-376
Dutch MS-MRI Center, Dept of Radiology, Vrije Universiteit Hospital, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
PMID# 10663771
Abstract

We examined the value of Spinal Cord Magnetic Resonance Imaging (MRI) in the diagnostic work-up of Multiple Sclerosis (MS). Forty patients suspected of having MS were examined within 24 months after the start of symptoms.

Disability was assessed, and symptoms were categorized as either Brain or Spinal Cord. Work-up further included CerebroSpinal Fluid analysis and standard proton-density, T2-, and T1-weighted Gadolinium-enhanced Brain and Spinal Cord MRI.

Patients were categorized as either Clinically Definite MS (n = 13), laboratory-supported definite MS (n = 14), or clinically probable MS (n = 4); four patients had clinically probable MS, and in nine MS was suspected.

Spinal Cord abnormalities were found in 35 of 40 patients (87.5 %), consisting of focal lesions in 31, only diffuse abnormalities in two, and both in two. Asymptomatic Spinal Cord lesions occurred in six patients.

All patients with diffuse Spinal Cord abnormality had clear Spinal Cord symptoms and a Primary/Progressive disease course.

In Clinically Definite MS, the inclusion of Spinal imaging increased the sensitivity of MRI to 100 %. Seven patients without a definite diagnosis had Clinically Isolated Syndromes involving the Spinal Cord.

Brain MRI was inconclusive, while all had focal Spinal Cord lesions which explained symptoms and ruled out other causes. Two other patients had atypical Brain abnormalities suggesting Ischemic/Vascular Disease.

No Spinal Cord abnormalities were found, and during follow-up MS was ruled out. Spinal Cord abnormalities are common in suspected MS, and may occur asymptomatic.

Although diagnostic classification is seldom changed, Spinal Cord imaging increases diagnostic sensitivity of MRI in patients with suspected MS.

In addition, patients with Primary/Progressive MS may possibly be earlier diagnosed. Finally, differentiation with atypical lesions may be improved.



#6

Inhibition Of Th1 Development And Treatment Of Chronic/Relapsing Experimental Allergic EncephaloMyelitis By A Non-HyperCalcemic Analogue Of 1,25-Dihydroxyvitamin D(3)

Mattner F, Smiroldo S, Galbiati F, Muller M, Di Lucia P, Poliani PL, Martino G, Panina-Bordignon P, Adorini L
Eur J Immunol 2000 Feb;30(2):498-508
Roche Milano Ricerche, Milano, Italy
PMID# 10671205
Abstract

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits production of IL-12, a Cytokine involved in the development of Th1 cells and in the PathoGenesis of Th1-mediated AutoImmune Diseases.

Here, we show that 1,25(OH)(2)D(3) and a Non-HyperCalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype.

Administration of 1,25(OH)(2)D(3) or its analogue prevents Chronic/Relapsing Experimental Allergic EncephaloMyelitis (CR-EAE) induced by the Myelin Oligodendrocyte Glycoprotein (MOG) peptide 35 - 55 (MOG(35 - 55)) in Biozzi AB / H mice.

The inhibition of EAE induction is associated with a profound reduction of MOG(35 - 55)-specific proliferation and Th1 cell development.

Importantly, the Non-HyperCalcemic analogue also provides long-term protection from EAE relapses induced by immunization with Spinal Cord homogenate when administered for a short time at symptom onset or even after the first peak of disease.

NeuroPathological analysis shows a reduction of inflammatory infiltrates, DeMyelinated areas and Axonal loss in Brains and Spinal Cords of treated mice.

These resuls indicate that inhibition of IL-12-dependent Th1 cell development is associated with effective treatment of CR-EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL-12 production in the treatment of Multiple Sclerosis.



#7

Managing The Adverse Effects Of Interferon-ß Therapy In Multiple Sclerosis

Bayas A, Rieckmann P
Drug Saf 2000 Feb;22(2):149-59
Univ of Wurzburg, GermanyDept of Neurology,
PMID# 10672896; UI# 20135451
Abstract

Interferon-ß is an established therapy in Relapsing/Remitting Multiple Sclerosis. Recently, it has also been shown that Interferon-ß-1b is effective in Secondary/Progressive Multiple Sclerosis.

However, adverse effects of Interferon-ß treatment are common, particularly during the first weeks of treatment, and are a major concern.

Flu-like symptoms, injection site reactions and laboratory abnormalities are the most common adverse effects, and may result in reduced compliance or even discontinuation of treatment in a number of patients.

Therefore, efforts to minimise these reactions, e.g. appropriate comedication with analgesic/antipyretic drugs, use of correct preparation and injection technique and sometimes modification of the dosage of Interferon-ß, are of considerable importance.

This article provides an overview of the management of clinically relevant adverse effects related to treatment with Interferon-ß, based on a literature review and personal experience. Essential aspects of patient information are also stressed.

If these recommendations are followed, adverse effects related to Interferon-ß may be substantially reduced in the majority of patients.



#8

Up-Regulation Of The Hyaluronate Receptor CD44 In Canine Distemper DeMyelinated Plaques

Alldinger S, Fonfara S, Kremmer E, Baumgartner W
Acta NeuroPathol (Berl) 2000 Feb;99(2):138-46
Justus-Liebig-Universitat Giessen, Institut fur Veterinar-Pathologie, Germany
PMID# 10672320; UI# 20136251
Abstract

CD44 Antigen (CD44), the principle Cell Surface Receptor for Hyaluronate, is up-regulated in the human DeMyelinating Disease Multiple Sclerosis on fibrous Astrocytes.

As Astrocytes are the main target cell of Canine Distemper Virus (CDV), the consequences of a CDV infection on the CD44 expression and distribution in Brains with spontaneous DeMyelinating Canine Distemper Encephalitis (CDE) were of interest.

Thirteen acute, 35 subacute, and 11 chronic plaques of nine dogs with ImmunoHistologically confirmed CDE and Brains of control dogs were included in the study.

For light microscopy, 5-micron-thick serial sections were stained with H&E and incubated with MonoClonal AntiBodies (mAbs) against CD44 and Canine Distemper Virus NucleoProtein and PolyClonal AntiBodies (pAbs) against Glial Fibrillary Acidic Protein (GFAP) and Myelin Basic Protein (MBP).

For Immunoelectron microscopy, 90-nm-thick sections were double stained with Anti-GFAP and Anti-CD44 mAbs to specify CD44-expressing structures.

In controls, CD44 was diffusely distributed in the White Matter and single Meningeal Cells exhibited a marginal expression of the Antigen.

In acute and more prominently in SubAcute DeMyelinating Encephalitis, there was a plaque-associated up-regulation of CD44 which paralleled GFAP. In Chronic DeMyelinating lesions, a reduction of CD44 associated with a loss of GFAP-positive Astrocytes was noted.

Additionally, in chronic plaques, CD44 was expressed on the cell membrane of PeriVascular MonoNuclear Cells. Immunoelectron microscopically, in controls, CD44 was rarely demonstrated on Astrocytic Cell Processes.

In contrast, in Brains with CDE, CD44 was found on the Cell Membrane of broadened Astrocytic Cell Processes.

In summary, CD44 is up-regulated on Astrocytes in the early phase of CDE and seems to represent a marker for the activation of Immune Cells in the late phase of the infection.



#9

The contribution of MRI in the differential diagnosis of the damage of the Cerebral Hemispheres

Grossman RI, Kappos L, Wolinsky JS
J Neurol Sci 2000 Jan 15;172 Suppl 1:S57-S62
Univ of Pennsylvania Medical Center, Dept of Radiology, 3400 Spruce Street, Philadelphia, PA, USA
PMID# 10606809
Abstract

There are presently many Magnetic Resonance (MR) measures that can aid the assessment of damage to the Brain. The conventional measures include T2 lesion volume, T1 enhanced lesion volume, and Brain Atrophy.

Newer methodologies include Magnetization Transfer measures and Proton Spectroscopy. These methods have the potential for improving the specificity of MR with respect to the underlying pathology.

MR Spectroscopy offers the ability to quantitate the component of Axonal Loss in Multiple Sclerosis. MR techniques can be implemented to assess the effectiveness of treatment algorithms.



#10

Assessment Of The Damage Of The Cerebral Hemispheres In MS Using NeuroImaging Techniques

Comi G, Rovaris M, Leocani L, Martinelli V, Filippi M
J Neurol Sci 2000 Jan 15;172 Suppl 1:S63-S66
Scientific Institute, Ospedale San Raffaele, Dept of NeuroScience, Via Olgettina 60, 20132, Milan, Italy
PMID# 10606810
Abstract

The pattern of mental dysfunction in Multiple Sclerosis (MS) is characteristic of the so-called SubCortical Dementia.

Cognitive dysfunction results predominantly by the disruption of communication among Cortical and SubCortical Areas, as a consequence of the White Matter damage.

As expected, studies with conventional Magnetic Resonance Imaging (MRI) demonstrated that Cognitive Impairment in MS patients is related to the lesion burden, although the strength of this correlation is weak.

This can be partially explained by the poor pathological specificity of conventional MRI techniques and by the invisible (Silent ) damage in the Normal-Appearing White Matter (NAWM).

Recent studies using non-conventional MRI techniques with a higher specificity for the heterogeneous substrates of MS pathology, such as the assessment of HypoIntense lesion load on T1-weighted scans and the measurement of the Magnetization Transfer Ratio (MTR) of whole Brain, MS lesions and NAWM, support this interpretation.

Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.



#11

Pathologic Role And Temporal Appearance Of Newly Emerging AutoEpitopes in Relapsing Experimental AutoImmune EncephaloMyelitis

Vanderlugt CL, Neville KL, Nikcevich KM, Eagar TN, Bluestone JA, Miller SD
J Immunol 2000 Jan 15;164(2):670-8
Northwestern Univ, Medical School, Dept of MicroBiology-Immunology and Interdepartmental ImmunoBiology Center,Chicago, IL 60611; and
Univ of Chicago
The Ben May Institute for Cancer Research and the Committee for Immunology,
PMID# 10623809; UI# 20090853
Abstract

Relapsing Experimental AutoImmune EncephaloMyelitis (R-EAE) is a CD4+ T-Cell-mediated DeMyelinating Disease model for Multiple Sclerosis.

Myelin destruction during the initial Relapsing phase of R-EAE in SJL mice initiated by immunization with the ProteoLipid Protein (PLP) Epitope PLP139-151 is associated with activation of T-Cells specific for the endogenous, non-cross-reactive PLP178-191 Epitope (intramolecular Epitope spreading).

While relapses in R-EAE induced with the Myelin Basic Protein (MBP) Epitope MBP84-104 are associated with PLP139-151-specific responses (intermolecular Epitope spreading).

Here, we demonstrate that T-Cells specific for endogenous Myelin Epitopes play the major pathologic role in mediating clinical relapses. T-Cells specific for relapse-associated Epitopes can serially transfer disease to naive recipients and are demonstrable in the CNS of mice with Chronic R-EAE.

More importantly, induction of Myelin-specific tolerance to relapse-associated Epitopes, by i.v. injection of Ethylene Carbodiimide-fixed peptide-pulsed APCs, either before disease initiation or during remission from acute disease effectively blocks the expression of the initial disease relapse.

Further, blockade of B7-1-mediated costimulation with Anti-B7-1 F(ab) during disease remission from acute PLP139-151-induced disease prevents clinical relapses by inhibiting activation of PLP178-191-specific T-Cells.

The protective effects of Anti-B7-1 F(ab) treatment are long-lasting and highly effective even when administered following the initial Relapsing episode wherein spreading to a MBP Epitope (MBP84-104) is inhibited.

Collectively, these data indicate that Epitope spreading is B7-1 dependent, plays a major pathologic role in disease progression, and follows a hierarchical order associated with the relative Encephalitogenic dominance of the Myelin Epitopes (PLP139-151 > PLP178-191 > MBP84-104).



#12

Myelin-Associated Oligodendrocytic Basic Protein: Identification Of An Encephalitogenic Epitope And Association With Multiple Sclerosis

Holz A, Bielekova B, Martin R, Oldstone MB
J Immunol 2000 Jan 15;164(2):1103-9
National Institutes of Health
National Institute of Neurologic Disorders and Stroke, NeuroImmunology Branch, and The Scripps Research Institute, Dept of NeuroPharmacology, Division of Virology, Viral-Immunobiology Laboratory, La Jolla, CA 92037
PMID# 10623862; UI# 20090906
Abstract

Myelin-associated Oligodendrocytic Basic Protein (MOBP) is an abundant Myelin constituent expressed exclusively by Oligodendrocytes, the Myelin-forming cells of the CNS.

We report that MOBP causes Experimental Allergic EncephaloMyelitis (EAE) and is associated with Multiple Sclerosis. First, we note that purified recombinant MOBP inoculated into SJL/J mice produces CNS disease.

Tests of overlapping peptides spanning the murine MOBP molecule map the Encephalitogenic site to Amino Acids 37-60.

MOBP-induced Experimental Allergic EncephaloMyelitis shows a severe clinical course and is characterized by a prominent CD4+ T-Lymphocyte infiltration and a lesser presence of CD8+ T-Cells and Microglia/Macrophages around vessels and in the White Matter of the CNS.

Second, PBL obtained from patients with Relapsing/Remitting Multiple Sclerosis mount a proliferative response to human MOBP, especially at Amino Acids 21-39.

This response equals or exceeds the response to Myelin Basic Protein and an Influenza Virus hemagglutinin peptide, both serving as internal controls.

Thus, a novel Myelin Ag, MOBP aa 37-60, plays a role in rodent AutoImmune CNS disease, and its human MOBP counterpart is associated with the human DeMyelinating Disease Multiple Sclerosis.



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