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MS Abstracts 10a-2g

  1. Quantitative Ultrastructural Analysis of a Single Spinal Cord DeMyelinated Lesion Predicts Total Lesion Load, Axonal Loss, and Neurological Dysfunction in a Murine Model of Multiple Sclerosis
    Am J Pathol 2000 Oct;157(4):1365-1376

  2. Optic Neuritis in children
    J Pediatr Ophthalmol Strabismus 2000 Sep-Oct;37(5):254-9

  3. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in Multiple Sclerosis
    J Neurol Sci 2000 Sep 15;178(2):132-135

  4. Variations in T1 and T2 relaxation times of Normal-Appearing White Matter and lesions in Multiple Sclerosis
    J Neurol Sci 2000 Sep 15;178(2):81-87

  5. Is fatigue in patients with Multiple Sclerosis related to Autonomic dysfunction?
    Clin Auton Res 2000 Aug;10(4):169-75

  6. A meta-analysis of MethylPrednisolone in recovery from Multiple Sclerosis exacerbations
    Mult Scler 2000 Aug;6(4):267-73

  7. Secondary conditions and women with physical disabilities: a descriptive study
    Arch Phys Med Rehabil 2000 Oct;81(10):1380-7

  8. Cost-utility analysis of Interferon-ß-1b in Secondary/Progressive Multiple Sclerosis
    Int J Technol Assess Health Care 2000 Summer;16(3):768-80


Quantitative Ultrastructural Analysis Of A Single Spinal Cord DeMyelinated Lesion Predicts Total Lesion Load, Axonal Loss, And Neurological Dysfunction In A Murine Model of Multiple Sclerosis

Sathornsumetee S, McGavern DB, Ure DR, Rodriguez M
Am J Pathol 2000 Oct;157(4):1365-1376
Mayo Clinic and Foundation, Depts of Neurology and Immunology, and the Molecular NeuroScience Program, Rochester, Minnesota
PMID# 11021839

Infection of susceptible mice with Theiler's Murine EncephaloMyelitis Virus results in Neurological Dysfunction from Progressive Central Nervous System DeMyelination that is pathologically similar to the human disease, Multiple Sclerosis.

We hypothesized that the development of NeuroPathology proceeds down a final common pathway that can be accurately quantified within a single Spinal Cord lesion.

To test this hypothesis, we conducted quantitative ultrastructural analyzes of individual DeMyelinated Spinal Cord lesions from chronically infected mice to determine whether pathological variables assessed within a single lesion accurately predicted global assessments of morphological and functional disease course.

Within lesions we assessed by electron microscopy the frequencies of normally Myelinated, ReMyelinated, and DeMyelinated Axons, as well as degenerating Axons and Intra-Axonal Mitochondria.

The frequency of medium and large ReMyelinated fibers within a single lesion served as a powerful indicator of Axonal preservation and correlated with preserved Neurological function.

The number of degenerating Axons and increased Intra-Axonal Mitochondria also correlated strongly with global measures of disease course, such as total lesion load, Spinal Cord Atrophy, and Neurological function.

This is the first study to demonstrate that functional severity of disease course is evident within a single DeMyelinated lesion analyzed morphometrically at the ultrastructural level.


Optic Neuritis In Children

Morales DS, Siatkowski RM, Howard CW, Warman R
J Pediatr Ophthalmol Strabismus 2000 Sep-Oct;37(5):254-9
Univ of Miami School of Medicine, Dept of Ophthalmology, Bascom Palmer Eye Institute, Fla, USA
PMID# 11020105; UI# 20470784

To describe the clinical characteristics of Optic Neuritis in children, including final Visual Acuity and development of Multiple Sclerosis (MS).

Charts were reviewed of all patients < 15 years of age who presented with Optic Neuritis to the Bascom Palmer Eye Institute or the Miami Children's Hospital between 1986 and 1998.

Fifteen patients were identified. There was a slight female predilection in the study group (60%), with a mean age of 9.8 years at presentation.

A preceding febrile illness within 2 weeks of Visual symptoms was reported in 66% of patients.

Initial Visual Acuity ranged from 20/15 to no light perception. Involvement was bilateral in 66% of patients, and disc swelling was present in 64% of involved eyes.

Of the patients who underwent Magnetic Resonance Imaging, 33% had focal DeMyelinating lesions in the Brain, and 63% of affected nerves were enlarged or enhanced with Gadolinium.

Eleven patients were treated with intravenous Steroids. Final Visual Acuity was > or = 20/40 in 58.3% of eyes.

Thirty percent of the patients had vision of finger counting or worse. Four (26%) patients developed MS.

The mean age of patients with MS was 12 years, compared with 9 years in children who did not develop MS.

Patients with unilateral involvement had an excellent visual prognosis (100% > 20/40), but a higher rate of development of MS (75%). Two patients had positive serology for Lyme Disease.

Optic Neuritis presents differently in children than in adults. Children typically have bilateral involvement with papillitis following an antecedent Viral illness.

Although Visual prognosis is poorer in children than adults, the development of MS is less common in children.

Children who present with unilateral involvement have a better Visual prognosis; however, they also develop MS at a greater frequency than children with bilateral involvement.

Patients who developed MS were, on average, older at presentation with Optic Neuritis than those who did not develop MS.


Sex And Age At Diagnosis Are Correlated With The HLA-DR2, DQ6 Haplotype In Multiple Sclerosis

Celius EG, Harbo HF, Egeland T, Vartdal F, Vandvik B, Spurkiand A
J Neurol Sci 2000 Sep 15;178(2):132-135
Oslo City Hospitals, Dept of Neurology, Ullevaal Sykehus, 0407, Oslo, Norway
PMID# 11018705

The HLA-DR2, DQ6 (i.e., HLA-DRB1*1501, DQA1*0102, DQB1*0602) haplotype contributes to the risk of developing Multiple Sclerosis (MS) in Caucasoids of Northern European heritage.

A correlation between the clinical expression of MS and the presence of HLA-DR2, DQ6 has, however, not convincingly been shown.

In this study conventional bivariate analysis and logistic regression analysis were used to study the relationship between HLA-DR2, DQ6 and four disease variables in a cohort of 286 Norwegian MS patients from the Oslo area.

Logistic regression analysis showed that HLA-DR2, DQ6 was significantly more frequent among female than male patients (P=0.0251), and was negatively correlated with age at diagnosis regardless of sex (P=0.0254).

No significant correlation was observed between HLA-DR2, DQ6 and type of disease (Relapsing/Remitting versus Primary Chronic/Progressive MS) or presence/absence of OligoClonal Bands in the CerebroSpinal Fluid.


Variations In T1 And T2 Relaxation Times Of Normal-Appearing White Matter And Lesions In Multiple Sclerosis

Stevenson VL, Parker GJ, Barker GJ, Birnie K, Tofts PS, Miller DH, Thompson AJ
J Neurol Sci 2000 Sep 15;178(2):81-87
Institute of Neurology, NMR Research Unit, Queen Square, WC1N 3BG, London, UK
PMID# 11018698

To investigate the variation in T1 and T2 relaxation times of Normal-Appearing White Matter (NAWM) and lesions in Multiple Sclerosis (MS) throughout the Brain.

The Magnetic Resonance Imaging (MRI) sequence fast FLAIR (Fluid Attenuated Inversion Recovery) has demonstrated overall increased lesion detection when compared to conventional or Fast Spin Echo (FSE) but fewer lesions in the Posterior Fossa and Spinal Cord.

The reasons for this are unknown, but may be due to variations in the T1 and T2 relaxation times within NAWM and MS lesions.

Ten patients and 10 controls underwent MRI of the Brain which involved FSE, fast FLAIR and the measurement of T1 and T2 relaxation times.

Of 151 lesions analyzed (22 Infra-Tentorial, 129 Supra-Tentorial), eight were missed by the fast FLAIR sequence.

T1 and T2 relaxation times in normal controls were longer in the Infra-Tentorial, than Supra-Tentorial, region.

Patient NAWM relaxation times were prolonged compared with control values in both regions.

Lesions demonstrated longer relaxation times than either control White Matter or patient NAWM in both regions, however this difference was less marked Infra-Tentorially.

The eight Posterior Fossa lesions not visible on the fast FLAIR sequence were characterized by short T1 and T2 relaxation times which overlapped with the patient NAWM for both T1 and T2 and with control values for T2 relaxation times.

Both lesion and NAWM relaxation time characteristics vary throughout the Brain.

The T1 and T2 relaxation times of Infra-Tentorial lesions are closer to the relaxation times of local NAWM than Supra-Tentorial lesions, resulting in reduced contrast between Posterior Fossa lesions and the background NAWM.

Consequently the characteristics of some lesions overlap with those of NAWM resulting in reduced conspicuity.

By utilising this information, it may be possible to optimise fast FLAIR sequences to improve Infra-Tentorial lesion detection.


Is Fatigue In Patients With Multiple Sclerosis Related To Autonomic Dysfunction?

Keselbrener L, Akselrod S, Ahiron A, Eldar M, Barak Y, Rotstein Z
Clin Auton Res 2000 Aug;10(4):169-75
Tel Aviv University, Abramson Center of Medical Physics, Tel Aviv, Israel
PMID# 11029013; UI# 20479984

Time-dependent frequency decomposition of fluctuations in CardioVascular signals (Heart Rate [HR], blood pressure, and blood flow) provides noninvasive and quantitative evaluation of Autonomic activity during transient and steady-state conditions.

This method was applied during a change of position from supine to standing in patients with Multiple Sclerosis (MS) who experienced unexplained Fatigue and in age-matched control subjects.

No difference in response to standing, as reflected in the time domain parameters (mean HR, mean blood pressure, and mean blood flow), was observed between patients with MS and control subjects.

Moreover, no difference was observed in very-low-frequency and low-frequency (related to Sympathetic activity) content of HR, blood pressure, blood flow, or high-frequency content of HR (related to ParaSympathetic activity).

The only Spectral estimates that showed a significant difference between groups were the ratio of low-frequency to high-frequency content of HR and low-frequency content of HR normalized to total power. Both these parameters provide an estimate of the SymPathoVagal balance.

A significant increase in these two estimates on standing was observed in control subjects only, indicating possible impairment of the SymPathoVagal balance response to standing in patients with MS who experienced Fatigue.

The authors observed a significant age dependence between close age subgroups, which occurred in the MS group only and was observed in some of the investigated Spectral estimates that reflect Vagal activity.

Therefore, the authors assumed that age-related reduction in Vagal activity occurred earlier in patients with MS who experienced Fatigue.

This reduction could also explain the lack of increase in the SymPathoVagal balance on standing.

To validate this enhanced age dependence, further investigation should be performed in a larger group of subjects with a wider age range.


A Meta-Analysis Of MethylPrednisolone In Recovery From Multiple Sclerosis Exacerbations

Miller DM, Weinstock-Guttman B, Bethoux F, Lee JC, Beck G, Block V, Durelli L, LaMantia L, Barnes D, Sellebjerg F, Rudick RA
Mult Scler 2000 Aug;6(4):267-73
Cleveland Clinic Foundation, I.H. Page Center for Health Outcomes Research, Cleveland, Ohio 44195, USA
PMID# 10962547; UI# 20420518

Despite recent advances in Multiple Sclerosis treatment, patients experience relapses for which standard treatment remains GlucoCorticoSteroids (GCS).

However, there is limited information comparing doses or routes of administration for different GCS types or the benefit of GCS compared to natural recovery.

Currently, high dose (HD) MethylPrednisolone (MP) is the preferred therapy.

We conducted meta-analyzes of published studies assessing MP at different doses and in comparison to other steroid products or no treatment.

Relevant studies were identified through predetermined processes and five articles met the inclusion criteria.

Three studies compared HD MP to placebo; two studies compared the effect of HD MP and low dose (LD) MP; only one accepted report compared HD MP to another GCS.

This report could not be included in a meta-analysis.

The meta-analysis of HD MP vsplacebo studies indicated a mean treatment difference of 0.76 in Expanded Disability Status Score (EDSS) changes from baseline.

The meta-analysis of HD and LD MP demonstrated no difference in EDSS change.

Despite these rather obvious findings, these meta-analyzes have been valuable in identifying further research questions.

We recommend studies to determine optimum benefit related to dosage, timing for starting therapy and the most appropriate GCS type.

Given the advances in MS therapeutics, these studies will have to include patients on additional disease modifying therapy.

Multiple Sclerosis (2000) 6 267 - 273


Secondary Conditions And Women With Physical Disabilities: A Descriptive Study

Coyle CP, Santiago MC, Shank JW, Ma GX, Boyd R
Arch Phys Med Rehabil 2000 Oct;81(10):1380-7
Temple University, Dept of Health Studies, Philadelphia, PA 19122, USA
PMID# 11030504; UI# 20483421

To examine secondary conditions and their relationship to life satisfaction in women with physical disabilities.

Design & Setting
Survey research at Metropolitan Philadelphia.

Women aged 18 to 65 years with self-reported functional limitations associated with Neurologic, Neuromuscular, Brain, Sensory, Arthritic, Spinal Cord, Orthopedic, or other chronic conditions.

Main Outcome Measures
Secondary conditions, health status, functional status, and life satisfaction.

In the past year, an average of 12 +/- 6.1 (SD) secondary conditions were experienced.

Fatigue, mobility, physical deconditioning, spasticity, and joint pain were reported most frequently, followed by depression, chronic pain, access problems, weight problems, and isolation.

In comparing women with Multiple Sclerosis (MS) and those with other disabling conditions, women with MS had higher Secondary Conditions Problem Index (SCPI) scores for bladder, bowel, and sexual dysfunction than women in the mixed disability group.

Other secondary conditions with the highest SCPI scores remained similar.

Self-reported emotional health status and SCPI scores were the only significant predictors of life satisfaction.

Secondary conditions influence health status and quality of life for women with physical disabilities.

Despite differences among disability groups in terms of the type of secondary conditions, common secondary conditions experienced by most women may be amenable to non-disability-specific health promotion programs.


Cost-Utility Analysis Of Interferon-ß-1b In Secondary/Progressive Multiple Sclerosis

Kobelt G, Jonsson L, Henriksson F, Fredrikson S, Jonsson B
Int J Technol Assess Health Care 2000 Summer;16(3):768-80
Karolinska Institutet
PMID# 11028132; UI# 20482567

Interferon-ß-1b has recently become available for the treatment of Secondary/Progressive Multiple Sclerosis (SPMS).

This study aims at estimating the cost-effectiveness of this new treatment that has been shown in a clinical trial to reduce the progression of the disease.

Effectiveness is measured as the number of quality-adjusted life-years (QALYs) gained from the reduction in progression.

Because the clinical trial period will only capture part of the treatment's effect in terms of QALYs gained, since benefits achieved during the trial will have an effect beyond it, the cost-effectiveness analysis involves modeling over the longer term using complementary data.

A Markov model with states based on disability expressed by EDSS scores was used.

Transition probabilities were calculated directly from clinical trial data for the first 3 years and then extrapolated to 10 years.

Mean costs and utilities for each Markov state were calculated from a population-based cross-sectional study in Sweden.

The incremental cost per QALY is SEK 342,700 (US $39,250; US $1 = SEK 8.73, March 10, 2000) when all costs (direct, informal care, and indirect) are included (discounted 3%).

When indirect costs are excluded, the cost per QALY is SEK 542,000 ($62,100).

Cost-effectiveness analysis in SPMS requires that the effect of treatment beyond clinical trials be included.

Also, analysis should be done from a societal perspective, since many of the costs occur outside the healthcare system.

The cost-utility ratios estimated in this analysis are at or below the mean threshold value indicated in a recent survey of health economists ($60,000).

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