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MS Abstracts: 2d-2g

  1. Assessment of Posterior Fossa damage in MS using MRI
    J Neurol Sci 2000 Jan 15;172 Suppl 1:S50-S53

  2. A Comparison of continuous Thalamic Stimulation and Thalamotomy for Suppression of Severe Tremor
    N Engl J Med 2000 Feb 17;342(7):461-468

  3. Cryoelectron microscopy of protein-Lipid Complexes of human Myelin Basic Protein charge Isomers differing in degree of Citrullination
    J Struct Biol 2000 Feb;129(1):80-95

  4. Genetic analysis of Vitamin D related Genes in Canadian Multiple Sclerosis
    Neurology 2000 Feb 8;54(3):729-32

  5. Identification of HLA-class-II-restricted Epitopes of AutoAntigens in transgenic mice
    Curr Opin Immunol 2000 Feb;12(1):122-129

  6. Soluble and cell surface ICAM-3 in blood and CerebroSpinal Fluid of patients with Multiple Sclerosis: influence of MethylPrednisolone treatment and relevance as markers for disease activity
    Acta Neurol Scand 2000 Feb;101(2):135-9

  7. CerebroSpinal Fluid C3 and C4 indexes in Immunological Disorders of the Central Nervous System
    Acta Neurol Scand 2000 Feb;101(2):116-21

  8. Cerebellar deficit and Respiratory impairment: a strong association in Multiple Sclerosis?
    Acta Neurol Scand 2000 Feb;101(2):98-103

  9. IL-1ra Serum levels in disease stages of MS - a marker for progression?
    Acta Neurol Scand 2000 Feb;101(2):95-7

  10. Cardiovascular dysfunction in Multiple Sclerosis
    Acta Neurol Scand 2000 Feb;101(2):85-8

  11. Analysis of sulfatide from rat Cerebellum and Multiple Sclerosis White Matter by negative ion electrospray mass spectrometry
    Biochim Biophys Acta 2000 Feb 24;1484(1):59-7


Assessment Of Posterior Fossa Damage In MS Using MRI

Yousry TA, Grossman RI, Filippi M
J Neurol Sci 2000 Jan 15;172 Suppl 1:S50-S53
Klinikum Grosshadern Ludwig Maximilian UnivMunich, Dept of NeuroRadiology, Marchioninistr. 15. D-81377, Munich, Germany
PMID# 10606807

In Multiple Sclerosis (MS), BrainStem and Cerebellum are frequent sites of damage in Clinically Isolated Syndromes at presentation and it is likely that lesions located in such structures can have an important impact on the development of disability in the definite forms of the disease.

In patients presented with isolated BrainStem syndromes, the symptomatic lesion was often not detected by Magnetic Resonance (MR) imaging. But patients with asymptomatic InfraTentorial lesions progressed to Clinically Definite MS in 65% of cases.

InfraTentorial lesions are included in various MR criteria designed to assist in the differential diagnosis of MS lesions from incidental lesions, to differentiate MS from SubCortical Encephalopathic Arteriopathy.

The preferred MR sequence to visualize InfraTentorial lesions is the Fast Spin Echo sequence. It is preferred to conventional Spin Echo and Fast Fluid Attenuated Inversion Recovery sequences because of its relatively short acquisition time and good sensitivity.

The correlation between disability and InfraTentorial lesion load on T2 weighted sequences is controversial.

However, it was recently shown that the correlations between clinical measures and T1 lesion load, Histogram Magnetization Transfer Ratio and peak positions, and InfraTentorial volume measurements are strong.

These findings suggest that one of the major factors in the development of disability in patients with MS is the pathological damage in clinically eloquent sites such as the BrainStem and Cerebellum.


A Comparison Of Continuous Thalamic Stimulation And Thalamotomy For Suppression Of Severe Tremor

Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM, Merkus MP, Speelman JD
N Engl J Med 2000 Feb 17;342(7):461-468
Academic Medical Center, Dept of Neurology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
PMID# 10675426

Deep-Brain stimulation through an electrode implanted in the Thalamus was developed as an alternative to Thalamotomy for the treatment of drug-resistant Tremor. Stimulation is thought to be as effective as Thalamotomy but to have fewer complications.

We examined the effects of these two procedures on the functional abilities of patients with drug-resistant Tremor due to Parkinson's Disease, Essential Tremor, or Multiple Sclerosis.

Sixty-eight patients (45 with Parkinson's Disease, 13 with Essential Tremor, and 10 with Multiple Sclerosis) were randomly assigned to undergo Thalamotomy or Thalamic stimulation.

The primary outcome measure was the change in functional abilities six months after surgery, as measured by the Frenchay Activities Index. Scores for this index can range from 0 to 60, with higher scores indicating better function.

Secondary outcome measures were the severity of Tremor, the number of adverse effects, and patients' assessment of the outcome.

Functional status improved more in the Thalamic-Stimulation group than in the Thalamotomy group, as indicated by increases in the score for the Frenchay Activities Index (from 31.4 to 36.3 and from 32.0 to 32.5, respectively; difference between groups, 4.4 points; 95 percent confidence interval, 2.0 to 6.9).

After adjustment for base-line characteristics, multivariate analysis also showed that the Thalamic-Stimulation group had greater improvement (difference between groups, 5.1 points; 95 percent confidence interval, 2.3 to 7.9).

Tremor was suppressed completely or almost completely in 27 of 34 patients in the Thalamotomy group and in 30 of 33 patients in the Thalamic-Stimulation group.

One patient in the Thalamic-Stimulation group died perioperatively after an IntraCerebral Hemorrhage. With the exception of this incident, Thalamic Stimulation was associated with significantly fewer adverse effects than Thalamotomy.

Functional status was reported as improved by 8 patients in the Thalamotomy group, as compared with 18 patients in the Thalamic-Stimulation group (P=0.01).

Thalamic stimulation and Thalamotomy are equally effective for the suppression of drug-resistant Tremor, but Thalamic Stimulation has fewer adverse effects and results in a greater improvement in function.


Cryoelectron Microscopy Of Protein-Lipid Complexes Of Human Myelin Basic Protein Charge Isomers Differing In Degree Of Citrullination

Beniac DR, Wood DD, Palaniyar N, Ottensmeyer FP, Moscarello MA, Harauz G
J Struct Biol 2000 Feb;129(1):80-95
Univ of Guelph, Guelph, Dept of Molecular Biology and Genetics, Ontario, N1G 2W1, Canada

Myelin Basic Protein (MBP) is considered to be essential for the maintenance of stability of the Myelin Sheath.

Reduction in cationicity of MBP, especially due to conversion of positively charged Arginine residues to uncharged Citrulline (Cit), has been found to be associated with Multiple Sclerosis (MS).

The interactions of an anionic Phosphatidylserine/Monosialoganglioside-G (M1) (4:1, w:w) Lipid monolayer with 18.5-kDa MBP preparations from age-matched adult humans without MS (no Cit residues), with Chronic MS (6 Cit), and with Acute Marburg-type MS (18 Cit) were studied by transmission and ultralow dose scanning transmission electron microscopy under cryogenic conditions.

Immunogold labeling and single particle electron crystallography were used to define the nature of the complexes visualized.

These electron microscopical analyzes showed that the three different MBP charge Isomers all formed uniformly sized and regularly shaped Protein-Lipid complexes with G(M1), probably as hexamers, but exhibited differential association with and organization of the Lipid.

The least cationic Marburg MBP-Cit(18) formed the most open Protein-Lipid complex.

The data show a disturbance in lipid-MBP interactions at the ultrastructural level that is related to degree of Citrullination, and which may be involved in Myelin degeneration in Multiple Sclerosis.

Copyright 2000 Academic Press.


Genetic Analysis Of Vitamin D Related Genes In Canadian Multiple Sclerosis

Canadian Collaborative Study Group
Steckley JL, Dyment DA, Sadovnick AD, Risch N, Hayes C, Ebers GC
Neurology 2000 Feb 8;54(3):729-32
Univ of Oxford, Wellcome Trust Centre for Human Genetics, England
PMID# 10680811; UI# 20143004

The objective of this study was to investigate Genes involved in the metabolism and function of Vitamin D as candidate Genes for Genetic susceptibility to MS.

Restriction fragment length polymorphisms and highly polymorphic microsatellite markers within or very close to the 1,25(OH)2D3 receptor (VDR) [12q14], the Vitamin D binding protein (DBP) [4q12], and the 25(OH)D2 1alpha-hydroxylase [12q13] loci were analyzed for linkage or association with MS.

We found no evidence for linkage or association of these candidate Genes with MS in the Canadian population.


Identification Of HLA-Class-II-Restricted Epitopes Of AutoAntigens In Transgenic Mice

Abraham RS, David CS
Curr Opin Immunol 2000 Feb;12(1):122-129
Mayo Medical School, Dept of Immunology, Rochester, MN-55905, USA
PMID# 10679410

The past year has seen a spate of research in the use of HLA transgenic mice in the identification of Self Antigens associated with AutoImmunity.

Dominant T-Cell determinants - and, in a few cases, B-Cell determinants - have been characterized in the context of disease-predisposing HLA DR and DQ Genes for at least three prominent and devastating AutoImmune Diseases: Rheumatoid Arthritis, Multiple Sclerosis and Insulin-dependent Diabetes Mellitus.


Soluble And Cell Surface ICAM-3 In Blood And CerebroSpinal Fluid Of Patients With Multiple Sclerosis: Influence Of MethylPrednisolone Treatment And Relevance As Markers For Disease Activity

Kraus J, Oschmann P, Engelhardt B, Bauer R, Schiel C, Kern A, Stolz E, Traupe A, Dorndorf W
Acta Neurol Scand 2000 Feb;101(2):135-9
Justus-Liebig-Universitat Giessen, Dept of Neurology, Germany
PMID# 10685862; UI# 20148298

The expression of InterCellular Adhesion Molecule-3 (ICAM-3), a member of the Ig supergene family, is restricted to Immune Competent Cells. Expression of soluble and cell surface ICAM-3 (s- and c-ICAM-3) is preferentially seen in the state of low activation of the Immune System.

We studied the relevance of the expression levels of s- and c-ICAM-3 in CerebroSpinal Fluid (CSF) and blood as markers for disease activity as well as the influence of high-dose MethylPrednisolone (MP) treatment upon the expression of s- and c-ICAM-3 in blood of patients with Multiple Sclerosis (MS).

Materials & Methods
A total of 33 patients (relapses n = 25, remission n = 8) with Relapsing/Remitting MS were included into the study. CSF and blood were acquired from all of them. Of the patients 24 were treated with high-dose MP.

In those, blood was additionally collected at the 10th day of the therapy and after 3 months. Expression of c-ICAM-3 was determined by two colour FACS analysis, whereas the concentration levels of s-ICAM-3 were measured by ELISA.

In CSF we detected a significant decrease of the expression levels of c-ICAM-3 on CD3+ T-Cells in 25 patients suffering from an acute relapse in contrast to 8 patients with remission (P= 0.04).

In comparison to the levels before treatment and after 3 months, at the 10th day of MP treatment we obtained highly significant changes of the expression values of c-ICAM-3 both on CD3+ T-Cells (P = 0.0004; P= 0.005) and CD14+ Monocytes/Macrophages (P =0.0006; P=0.008) on the 10th day of high-dose MP treatment from 24 MS patients.

The increase of ICAM-3 levels might indicate the anti-inflammatory effect of the MMP treatment. It could be interesting to search for similar effects investigating the new Immune Modulatoring Therapy forms of MS.


CerebroSpinal Fluid C3 And C4 Indexes In Immunological Disorders Of The Central Nervous System

Jongen PJ, Doesburg WH, Ibrahim-Stappers JL, Lemmens WA, Hommes OR, Lamers KJ
Acta Neurol Scand 2000 Feb;101(2):116-21
Multiple Sclerosis Centre Nijmegen, The Netherlands
PMID# 10685859; UI# 20148295

Validation of CerebroSpinal Fluid (CSF) indexes as a measure for Intrathecal C3 and C4 production. Examination of their role in differential diagnosis of Immunological Disorders of the Central Nervous System (CNS).

Material & Methods
Correlative study in controls (low back pain without Disk Herniation) between the CSF/Serum ratio (Q) for Albumin, and Q C3 and Q C4.

Comparative study of C3 and C4 indexes in patients with CNS Dysfunction due to Relapsing/Remitting (RR) Multiple Sclerosis (MS), Secondary/Progressive (SP) MS, Systemic Lupus Erythematosus (SLE), and Human Immunodeficiency Virus (HIV) infection.

Strong and statistically highly significant correlations between Q Albumin and Q C3 (r=0.89, P=0.0001), and Q C4 (r=0.68, P= 0.0001).

In MS patients decreased mean values for Serum (RR, SP) and CSF (RR) C3, and increased C3 index mean value (RR, SP). In CNS SLE increase of mean C3 and C4 index values.

In CNS HIV increase of mean C3 and C4 index values, and CSF C3 and C4 concentrations. Most individual index values were within the reference range.

CSF index is a valid tool to detect Intrathecal C3 or C4 production. C3 or C4 index contributes little to the differential diagnosis of Immunological CNS Disorders.

C3 might play a Pathogenic role in various Immunological CNS disorders.


Cerebellar Deficit And Respiratory Impairment: A Strong Association In Multiple Sclerosis?

Grasso MG, Lubich S, Guidi L, Rinnenburger D, Paolucci S
Acta Neurol Scand 2000 Feb;101(2):98-103
Rehabilitation Hospital, IRCCS S Lucia, Rome, Italy
PMID# 10685856; UI# 20148292

The aim of the study was to analyze Pulmonary Function and to identify reliable prognostic factors associated with Respiratory abnormalities in a consecutive series of patients with Multiple Sclerosis (MS).

Pulmonary Function was evaluated by means of a battery of measures, including Maximal Voluntary Ventilation, Forced Vital Capacity, Forced Expiratory Volume, in 71 consecutive patients with Primary and Secondary/Progressive MS.

Respiratory Impairment was common in MS patients, occurring in 63.4% of all patients, ranging from 82.9% in non-ambulatory patients (with EDSS score >6.5) to 35.7% in ambulatory patients (with EDSS score <6).

Severity of illness and Cerebellar and Mental Impairment were significantly negatively associated with basal pulmonary function.

Coordination plays an important role in determining Respiratory abnormalities: Respiratory abnormalities were found in 27 out of 32 patients (84.4%) with severe Cerebellar Impairment.

The presence of severe Cerebellar Signs was associated with a very high risk of occurrence of Respiratory Impairment (O.R. = 6.24; 95% C.I. 1.71-22.82).

Other significant variables were severity of illness (EDSS score > 6.5) (O.R. =4.71; 95% C.I. 1.42-15.66) and long disease duration (> 15 years) (O.R. = 3.39; 95% C.I. 1.01-11.42).


IL-1ra Serum Levels In Disease Stages Of MS - A Marker For Progression?

Heesen C, Sieverding F, Buhmann C, Gbadamosi J
Acta Neurol Scand 2000 Feb;101(2):95-7
Univ of Hamburg, Dept of Neurology, Germany
PMID# 10685855; UI# 20148291

InterLeukin-1 (IL-1) is one of the major proinflammatory Cytokines expressed consistently in Multiple Sclerosis (MS) lesions. InterLeukin-1 receptor antagonist (IL-1ra) is the only known naturally occurring specific antagonistic Cytokine counteracting IL-1.

Thus IL-1ra may have a downregulating potential in the disease course of MS. We analyzed if circulating IL-1ra could be associated with different disease stages of MS in Sera of 84 MS patients and 18 controls.

IL-1ra showed considerable variations in MS patients and controls. Nevertheless we found significantly elevated Serum levels in active as well as in stable disease stages compared to controls.

IL-1ra levels were higher in Progressive Disease courses compared to Relapsing/Remitting MS, but not statistically significant (median: 516 versus 434 pg/ml). Further analysis with larger groups of patients and longitudinal studies will clarify if IL-1ra is useful as a prognostic Serum marker in MS.


Cardiovascular Dysfunction In Multiple Sclerosis

Acevedo AR, Nava C, Arriada N, Violante A, Corona T
Acta Neurol Scand 2000 Feb;101(2):85-8
Instituto Nacional de Neurologiay Neurocirugia MVS, Mexico City, Mexico
PMID# 10685853; UI# 20148289

Cardiovascular Dysfunction (CD) in Multiple Sclerosis (MS) is related to involvement of reflex pathways in the BrainStem.

The battery of CD tests was applied to a group of 40 healthy subjects and 40 patients with MS, divided in 2 subgroups according to the Expanded Disability Status Scale (EDSS).

    The tests included:
  1. Postural Blood Pressure changes
  2. Postural Heart Rate changes
  3. Heart Rate changes on Inspiration/forced Expiration
  4. ECG R-R interval measurement on the Valsalva maneuver

Both groups were subjected to the Functional Independence Scale (FIM). Imaging studies were reviewed and Autonomic Dysfunction at other levels was explored. The results showed a statistically significant difference (P < 0.05) in all tests when comparing patients to controls.

Tests 1 and 4 had the highest significance, with findings of more severe involvement in patients with a higher EDSS and lower FIM. A correlation was also found between CD and BrainStem lesions on MRI (P < 0.01).

A significant number of MS patients had evidence of CD. Test 1 may be considered a simple marker, in daily clinical practice, to detect subclinical CD. Subclinical CD is a cause of Disability in this group of patients.


Analysis Of Sulfatide From Rat Cerebellum And Multiple Sclerosis White Matter By Negative Ion Electrospray Mass Spectrometry

Marbois BN, Faull KF, Fluharty AL, Raval-Fernandes S, Rome LH
Biochim Biophys Acta 2000 Feb 24;1484(1):59-7
UCLA School of Medicine, Dept of Biological Chemistry, CHS 33-257, Los Angeles, CA, USA
PMID# 10685031

20:0) are present at day 7 and the ratio of Non-hydroxylated compared to Hydroxylated Sulfatide rises as the amount of non-Hydroxylated Sulfatide increases.

24:1-Sulfatide accumulates at a ratio of about 3:1 over 24:0-Sulfatide during active Myelination. Analyzes of the Sulfatide in human tissue have shown differences between MS plaque tissues, Normal Appearing Adjacent White Matter and control tissues.

The findings show that total Sulfatide is reduced by 60% in the plaque matter and decreased 25% in Adjacent NNormal-Appearing White Matter.

There are significant increases (P=0.05) in the amount of Hydroxylation of Sulfatide, demonstrated by an increase in the percentage of Hydroxylated h24:0-Sulfatide (Hydroxy-Lignoceroyl Sulfatide).

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