MS Abstracts: 1c-2g

The question of a connection between vaccination and AutoImmune Illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as Measles and Anti-Hepatits B Virus (HBV), and Multiple Sclerosis (MS).

Brain AntiBodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other AutoImmune Illnesses have been associated with vaccinations.

Tetanus Toxoid, Influenza Vaccines, Polio Vaccine, and others, have been related to phenomena ranging from AutoAntiBodies production to full-blown illness (such as Rheumatoid Arthritis (RA)).

Conflicting data exists regarding also the connection between Autism and Vaccination with Measles Vaccine.

So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and AutoImmune findings has been examined.

In healthy puppies immunized with a variety of commonly given vaccines, a variety of AutoAntiBodies have been documented but no frank AutoImmune Illness was recorded.

The findings could also represent a polyclonal activation (Adjuvant Reaction). The mechanism (or mechanisms) of AutoImmune Reactions following immunization has not yet been elucidated.

One of the possibilities is Molecular Mimicry; when a structural similarity exists between some Viral Antigen (or other component of the vaccine) and a Self-Antigen.

This similarity may be the trigger to the AutoImmune Reaction. Other possible mechanisms are discussed.

Even though the data regarding the relation between vaccination and AutoImmune Disease is conflicting, it seems that some AutoImmune phenomena are clearly related to immunization (e.g. Guillain-Barre Syndrome).

The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for AutoImmune Disease has not been irrevocably proved.

We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).

Copyright 2000 Academic Press.

Objective
Magnetization Transfer Imaging (MTI) provides information about Brain damage with increased pathological specificity over conventional MRI and detects subtle abnormalities in the Normal-Appearing Brain Tissue, which go undetected with conventional scanning.

Brain MRI and MTI findings were compared in patients with Multiple Sclerosis (MS) and Systemic Immune mediated Diseases (SIDs) affecting the CNS to investigate their roles in understanding the nature of Brain damage in these diseases.

Methods
Brain dual echo, T1 weighted and MTI scans were obtained in patients affected by Systemic Lupus Erithematosus (SLE) with (NSLE, n=9) and without clinical CNS involvement (n=15), Behcet's Disease (BD) (n=5), Wegener's Granulomatosis (WG) (n=9), and AntiPhosphoLipid Antibody Syndrome (APLAS) (n=6).

Ten patients with Clinically Definite MS and 15 healthy controls also underwent the same scanning protocol. Brain MRI and MT Ratio (MTR) images of the same subject were coregistered and postprocessed to obtain MTR Histograms of the whole Brain and of the NABT.

Results
Brain HyperIntense lesions were found in all patients with MS and with NSLE and in 5/15 patients with SLE, 5/9 with WG, 1/5 with BD, and 3/6 with APLAS.

The lesion burden in the Brain was significantly higher in patients with MS compared with all the other disease groups. All MTR Histogram parameters were significantly different among patient subgroups.

Patients with MS had significantly lower average MTR than all except patients with NSLE and significantly lower peak height and location than patients with SLE.

Patients with NSLE had significantly lower average MTR than patients with SLE.

Conclusions
Microscopic Brain tissue damage is relevant in patients with MS, but, apart from patients with NSLE, it seems to be absent in Systemic Immune mediated Diseases, even in the presence of macroscopic MRI lesions or clinical evidence of CNS involvement.

Objectives
To assess:

1. Whether the changes in the Normal-Appearing Brain Tissue (NABT), as revealed by Magnetization Transfer (MT) Histogram analysis, correlates with Cognitive dysfunction in patients with Multiple Sclerosis and
2. The relative contribution of these changes by comparison with that of Multiple Sclerosis lesions visible on conventional MRI

Methods
Dual echo, T₁ weighted and MT scans of the Brain were obtained in 12 patients with Multiple Sclerosis with Cognitive Impairment and in seven without Cognitive Impairment. Lesion Loads were assessed from T₂ and T₁ weighted scans.

To create MTR Histograms of the NABT, Multiple Sclerosis Lesion outlines from Dual Echo scans were superimposed automatically and nulled out from the coregistered and scalp stripped MTR maps.

Average lesion MT Ratio (MTR) and Brain size were also measured.

Results
T₂ and T₁ lesion loads were significantly higher and the average lesion MTR and Brain size were significantly lower in the group of Cognitively Impaired patients.

Patients with Cognitive deficits also had significantly lower average MTR and peak location of the NABT Histogram.

Logistic regression analysis showed that 68% of the total variance was explained by average NABT-MTR alone.

A multivariable regression model showed that NABT-MTR was the only factor that significantly correlated with Cognitive Impairment in these patients (p=0.001).

Conclusions
The extent of abnormalities which go undetected when using conventional MRI is relevant in determining Cognitive Impairment in Multiple Sclerosis.

Objectives
Understanding the properties of an outcome measure is essential in choosing the appropriate instrument and interpreting the information it generates.

The MOS 36 item short form health survey questionnaire (SF-36) is widely acknowledged as the gold standard generic measure of health status; few studies however have evaluated its use for clinical trials in Multiple Sclerosis.

Its clinical appropriateness, internal consistency reliability, validity, and responsiveness was investigated across a broad range of patients with Multiple Sclerosis.

Methods
A prospective study in which 150 adults with Clinically Definite Multiple Sclerosis completed a battery of questionnaires evaluating generic health status, disability, handicap, and emotional wellbeing.

Of these, 44 patients undergoing inpatient rehabilitation completed the questionnaires before and after intervention to evaluate responsiveness.

Results
Score distributions demonstrated significant floor and ceiling effects in four of the eight dimensions which were particularly marked when patient selection was restricted to a narrow band of disease severity (as is the case in most clinical trials).

Internal consistency exceeded the standard for group comparisons for all dimensions. Convergent and discriminant construct validity was supported by the direction, magnitude, and pattern of correlations with other health measures.

In comparison with instruments measuring associated constructs, the responsiveness of the SF-36 was poor in evaluating change in moderate to severely disabled patients participating in a programme of inpatient rehabilitation.

Conclusions
The SF-36 has some limitations as an outcome measure in Multiple Sclerosis. The results highlight the need for all instruments to be examined in the specific sample population under question and for the specific research question being investigated.

In Multiple Sclerosis clinical trials, the SF-36 should be supplemented with other relevant measures.

Objective
To evaluate the cost-effectiveness of Interferon beta-1b (IFß-1b) for Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
Construction of a cost-effectiveness model using published data on IFß-1b effectiveness and the natural history of RRMS, and new data on costs and quality of life (QoL) from a sample of 102 patients with RRMS and resident in northern England.

Results
Poorer QoL was found for patients with Multiple Sclerosis compared with the general population; those who had had a relapse; those with worse states identified by a clinical measure (Expanded Disability Status Scale (EDSS)).

Relapses have effects over several months. Health state valuations were higher than in the general population. Costs were higher in relapse than remission and for worse EDSS states.

IFß-1b costs were larger than cost savings. The best cost-effectiveness estimate was pound28 700 per relapse avoided, which is pound809 900 per QALY gained; or pound328 300 per QALY gained allowing for effects of progression over 5 years. Estimates were robust to changes in assumptions.

Conclusions
The impact of Multiple Sclerosis on QoL is substantial. Future trials should base outcomes measurement on QoL and be better linked to natural history and cost data.

IFß-1b produces important occasional short term QoL gains, but small gains in QALYs overall and large additional costs.

Chemokines are secreted proteins that function as ChemoAttractants, mediating the recruitment of specific subsets of Leukocytes to sites of tissue damage and Immunological reactions.

Chemokines may also function as AntiViral agents, since Viruses such as Human Immunodeficiency Virus type 1 (HIV-1) use Chemokine receptors as co-receptors for Viral entry.

This study examines whether Virus-induced Interferon, IFN-ß, or immune-related Interferon, IFN, affects the production of ß-Chemokines by CNS Microglia and Peripheral Monocytes.

When IFN-ß was used as the stimulus, induction of MIP-1, MIP-1ß, MCP-1, and RANTES mRNA and protein was observed within 12 h of stimulation in Microglia.

By contrast, when IFN was used as the stimulus, only MCP-1 was induced. IFN-ß stimulation of blood Monocytes resulted in upregulation of MIP-1, MIP-1ß, and MCP-1.

Thus, type I and II Interferons differentially regulate ß-Chemokines in human fetal Microglia and peripheral blood Monocytes.

These observations may have relevance for the therapeutic activity of IFN-ß in Multiple Sclerosis and for the AntiViral effects of IFN-ß for HIV-1 infection of Monocytes and Microglia.

Copyright 2000 Wiley-Liss, Inc.