The mechanisms by which Type I Interferons (IFN) reduce the rate and severity of exacerbations in Multiple Sclerosis are unknown.

We utilized a model of Multiple Sclerosis to determine the extent of DeMyelination and ReMyelination in Theiler's Murine EncephaloMyelitis Virus (TMEV)-infected SJL/J mice treated with mouse IFN-/ß for a short (5 weeks) or a long (16 weeks) period.

All mice were chronically infected with TMEV to simulate the clinical situation in Multiple Sclerosis.

Short-term IFN-/ß treatment increased the percent of ReMyelinated Spinal Cord White Matter by threefold when compared with Phosphate-Buffered Saline (PBS) treatment (P < 0.02), but it did not affect the extent of DeMyelination.

In contrast, long-term IFN-/ß treatment increased the extent of DeMyelination by twofold (P < 0.03).

Long-term treatment increased the absolute area of ReMyelination, but the percent ReMyelination as a function of area of DeMyelination was not changed because of increased DeMyelination.

An ImmunoModulatory mechanism may have contributed to the effect of IFN-/ß on White Matter pathology because treated mice had higher anti-TMEV IgGs in Serum and demonstrated decreased numbers of B and T-Lymphocytes infiltrating the Central Nervous System (CNS).

There was no correlation between the level of anti- IFN-/ß AntiBodies and the extent of DeMyelination or ReMyelination.

These results indicate that the length of Type I IFN treatment may have paradoxical effects on DeMyelination and ReMyelination.

Copyright 2000 Wiley-Liss, Inc.

Objective
To determine the prevalence of Depression in Multiple Sclerosis in the community and to assess how the presence of depression affects patients' perception of their disability.

Design & Setting
Consecutive case series. The study was carried out at a regional Multiple Sclerosis (MS) clinic.

Subjects
Eighty-eight patients with MS.

Main Outcome Measures
Patients were asked to complete the following questionnaires: Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI), Rankin Scale of Disability/Handicap (completed by patient and physician to assess relative perceived Disability) and two visual analogue scales (coping ability and perceived service adequacy).

Results
Thirty-nine per cent were case level for Depression using the BDI criteria of Sullivan; 17% were case level for Depression (34% borderline case) and 34% case level for Anxiety on HADS.

Depressed patients using both BDI and HADS criteria were three times more likely than NonDepressed patients to perceive their Disability as being greater than the physicians' perception (p < 0.001).

Conclusion
Depression is common in MS and adversely affects patients' perception of their Disability.

Objective
To develop an international services and needs assessment instrument (SUN) for people with Multiple Sclerosis and their carers and to pilot this in different countries of the European Community.

Design & Setting
Interview study of people with Multiple Sclerosis, their carers and nominated key professionals examining the unmet needs of patients and carers. Belgium, Estonia, Greece, Italy and the United Kingdom.

Main Outcome Measures
Needs assessment questionnaire.

Results
The study comprised 137 people with Multiple Sclerosis, 125 carers and 111 professionals. Patients reported on average 2.9 unmet needs for themselves; their carers and professionals reported on average 2.4.

Needs were categorized into seven broad categories. Due to difficulties experienced by the local researchers in distinguishing between needs and objectives a large proportion of needs had to be assigned to the 'other' category.

Conclusions
The SUN is a valuable and practicable tool for the identification of unmet needs for people with Multiple Sclerosis and their carers.

Formal validation and reliability testing of the different language versions is recommended.

Objective & Design
The aim of the study was to obtain the views and priorities of people with Multiple Sclerosis (MS), to inform the design of a professionally guided self-care programme. A three-round postal Delphi survey was used as a research tool.

Setting
The study was conducted at the Centre for Research in Rehabilitation at Brunel Univin London.

Subjects
The respondent panel consisted of 200 volunteers with MS, of whom 136 responded to the survey (68%). Respondents were recruited through voluntary organizations throughout the UK. The only selection criterion was that the diagnosis of MS was confirmed by the general practitioner.

Main Outcome Measures
The results from each of the three rounds of the Delphi survey were the outcome measures.

Results
One hundred and one people used ten or more self-care strategies (74%). Round 1 data revealed the diversity of practices reported, crossing many domains of life such as daily chores, leisure, relationships and physical and mental health.

The top five priorities identified in rounds 2 and 3 concerned coping strategies, social support, independence in daily living, rest and mobility.

Complete consensus about priorities was not achieved. However, agreement about priorities approached stability across rounds 2 and 3 and a highly significant Kendall's coefficient of concordance indicated there was good agreement within round 3 group rankings (W= 0.46, chi-squared = 499.37, df = 9, p<0.001, N= 122).

Conclusion
Self-care practices were widespread, and those most commonly used could be identified. This survey method allows the views and priorities of this consumer group to be revealed.

The information obtained can be used to develop services, where the professional guides and encourages appropriate self-management based upon the issues that people with MS consider to be most important.

In a recent communication, Goodin [1] analyzes several clinical trials to point out serious flaws in both design and interpretation that may invalidate the conclusions that are drawn.

We agree with Goodin [1] that the design of clinical studies, particularly of a disease as complex as Multiple Sclerosis, is extremely difficult.

Indeed, a perfectly designed and executed clinical study is a goal that is never achieved because of the problems inherent in providing care to patients while attempting to evaluate a therapeutic modality.

Specifically, in the study of Multiple Sclerosis, none of the clinical trials of the use of Interferons could be considered fully satisfactory: blinding is actually impossible because of the symptoms that are experienced by patients when they receive active drug but not when they receive placebo.

It is quite fashionable and not at all difficult to find problems in the conduct of clinical studies; indeed, if all clinical studies with flaws were discarded, there would be no acceptable clinical studies.

Previous surveys in Finland from the 1960s have documented an uneven geographic distribution of Multiple Sclerosis (MS). In the present study, the incidence of MS was studied during 1979-1993 in the Western Vaasa and Seinajoki regions and in Southern Uusimaa.

The overall difference between the Western and Southern regions persisted; 8.7 per 100,000 in the western, and 5.1 per 100,000 in the southern region.

The incidence of 11.6 per 100,000 in Seinajoki was more than twofold greater than the 5.2 per 100,000 incidence found in neighboring Vaasa.

An increasing incidence trend was observed for men in Seinajoki, and a decrease for both sexes in Vaasa, while in Uusimaa the incidence remained stable for both sexes.

The different incidence trends could not be readily explained by differences in case ascertainment but suggest the effect of environmental factors that have modulated the incidence of MS during the 15-year study period.

Copyright 2000 S. Karger AG, Basel

We have examined the Demographics and long-term outcome of 1044 patients with Sporadic and Familial Multiple Sclerosis in a population-based cohort from London, Ontario.

The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke Disability Status Scale (DSS), DSS 6, 8 or 10.

An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected:

1. First degree only
2. First degree plus others
3. Second or Third degree

The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected.

Familial cases closely resembled those remaining Sporadic in both Demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater.

The times to DSS 6, 8 and 10 did not differ significantly when Sporadic, Familial and Familial Subgroups were compared.

These results provide no clinical support for viewing Familial Multiple Sclerosis as distinct from the Sporadic Form. The observed recurrence rate for siblings in a strictly defined Epidemiological sample was 3.5%, much as projected.

These results validate the recurrence risks which have previously been derived from age-corrected data for these First-degree relatives.

Recent pathological studies have re-emphasized that Axonal injury is present in patients with Multiple Sclerosis, the most common DeMyelinating Disease of the CNS in humans.

However, the temporal profile of DeMyelination and Axonal Loss in Multiple Sclerosis patients and their independent contributions to clinical and ElectroPhysiological abnormalities are not completely understood.

In this study, we used the Theiler's Murine EncephaloMyelitis Virus model of Progressive CNS inflammatory DeMyelination to demonstrate that DeMyelination in the Spinal Cord is followed by a loss of medium to large Myelinated fibers.

By measuring Spinal Cord Areas, Motor-Evoked Potentials, and Motor Coordination and Balance, we determined that Axonal Loss following DeMyelination was associated with ElectroPhysiological Abnormalities and correlated strongly with Reduced Motor Coordination and Spinal Cord Atrophy.

These findings demonstrate that Axonal Loss can follow Primary, Immune-mediated DeMyelination in the CNS and that the severity of Axonal Loss correlates almost perfectly with the degree of Spinal Cord Atrophy and Neurological Deficits.

AutoAntigen-specific T-Lymphocytes are present in patients with AutoImmune Disease and in normal subjects. Little is currently known about the temporal variation (dynamics) of the Immune repertoire of these AutoReactive T-Cells.

We analyzed the long-term variation of the Immune repertoire of T-Cells specific for Myelin Basic Protein (MBP) in five untreated patients with Multiple Sclerosis and four normal control subjects over a mean observation period of 6 years.

MBP-specific CD4⁺ T-Cell lines were selected with purified human MBP, and their Epitope specificity was mapped with overlapping synthetic peptides.

Three distinct patterns of repertoire development were observed:
1. Two patients and three control subjects maintained a broad Epitope response with fluctuations over time.
   
   
2. Two patients initially showed a focused response that broadened over the course of 6 years; this finding could be described as IntraMolecular Epitope Spreading.
   
   
3. In one patient and one control subject, a strikingly focused response, which was directed to a cluster of nested Epitopes in the MBP region 83-102, persisted over time.

T-Cell receptor Vbeta sequence analysis allowed us to trace individual Clones of MBP-specific T-Cells for up to 7 years in the Peripheral Circulation in four of the five patients and three of the four controls.

Suggesting that the long-term persistence of MBP-Specific T-Cell Clones is a common feature of the T-Cell repertoire not unique to Multiple Sclerosis.

The persisting MBP-specific T-Cell Clones were not detectable in the blood of one of the patients by Complementarity-Determining Region (CDR)-3 SpectraTyping, indicating that their frequency does not exceed 1 in 5000 T-Cells.

The temporal characteristics of the MBP-specific T-Cell repertoire described here are relevant to therapeutic strategies targeting AutoAntigen-Specific T-Cells in Multiple Sclerosis and other AutoImmune Diseases.

The accumulation of B-Lymphocyte Clones in the CerebroSpinal Fluid (CSF) of patients with Multiple Sclerosis (MS) and patients with other Neurological Disorders was investigated using PCR technologies.

OligoClonal B-Cell accumulations were detected in 10 of 10 MS patients, but only in 3 of 10 of the patients with Other Neurological Disorders.

Analyzes of the Ig V(D)J sequences on the CSF from MS patients disclosed that VH3 and VH4 Genes were extensively mutated compared with germline sequences.

Moreover, a substantial proportion of the molecular Clones analyzed shared the same third CDR of the H chain variable region Gene (HCDR3) and the same VH Genes, albeit with different numbers and locations of point mutations, thus indicating an ongoing process of IntraClonal Diversification.

A larger number of Clonally related VH sequences could be obtained by using a VH3 gene-specific PCR so that Genealogical trees depicting the process of diversification could be drawn.

Analyzes of the Ig V(D)J from the CSF of a patient with Viral Meningitis and OligoClonal B-Cell accumulations revealed that VH3 Genes were extensively mutated. However, no IntraClonal diversification could be observed even using VH3 gene-specific PCR methodologies.

Clone-specific PCR and sequencing was used to detect the V(D)J found in the CSF of one MS patient in the PBL of the same patient.

Only 1/3 of the V(D)J sequences investigated could be demonstrated in the PBL, indicating that the V(D)J Genes utilized by B-Cells in the CSF are much less represented in the PBL.

Collectively, the data suggest that in MS there is a Compartmentalized Clonal Expansion.

Objective
To estimate the prevalence of Multiple Sclerosis in the L'Aquila district, central Italy.

Methods
All available case sources were screened. Definite and probable cases of Multiple Sclerosis, classified according to the Poser Criteria, were considered as prevalent cases.

Results
On the prevalence day, 31 December 1996, 158 patients (105 women and 53 men; ratio 2:1) affected by Definite (n=131) or Probable (n=27) Multiple Sclerosis were alive and resident in the L'Aquila district.

Mean (SD) age was 38.4 (11.9) years (38.9 (11.7) years for women and 38.5 (12.3) years for men, p=0.9).

The overall crude prevalence was 53.0/100 000 (95% confidence interval (95% CI)=45.4-62.0); 68.4/100 000 (95% CI=56.5-82.8) in women, and 36.7/100 000 (95% CI=28.1-48.0) in men.

The prevalence was similar (55.9/100 000) when standardized to the 1996 European population.

Mean (SD) Age At Onset of Multiple Sclerosis was 29.4 (9.6) years and mean (SD) duration of the disease was 9.4 (7.4) years, without any significant difference between sexes.

Mean age at onset was significantly higher in patients with the Primary/Progressive than in those with the Relapsing/Remitting course (p=0.0002, Scheffe's test).