http://128.242.218.10/fs2/wd5748/wd186/speakers.pdf

September 12th-15th, 2001

S-01
SCALE DEVELOPMENT
Hobart JC.
Clinical Lecturer in Neurology, Neurological Outcome Measures Unit, Institute of Neurology, Queen Square, London WC1N 3BG.

Health rating scales are being used increasingly throughout clinical medicine and research. It is essential that these rating scales are high quality measurement instruments as they generate the data on which we base our evaluations of disease impact and treatment effectiveness.

There are many types of rating scales. Multi-item scales are the most widely used. These consist of multiple items whose scores are summed to generate a total score. This total score quantifies (measures) the aspect of health the rating scale is purported to address (e.g. disability, quality of life). Examples of widely used multi-item measures are the 10-item Barthel Index, the 36-item Medical Outcomes Study Short Form 36-item Health Survey (SF-36), and the 3-item MS Functional Composite (MSFC). The development of multi-item scales is not simply a matter of gathering together a bunch of apparently appropriate items (it is no accident that the SF-36 has 36 items!). There are specific techniques for constructing multi-item scales (psychometric methods) that were developed in the social sciences. When these techniques are used high quality measurement is guaranteed.

This talk, which is an overview for clinicians, has three parts. First, I will outline and demonstrate with examples the methods underpinning the development of multi-item measures. Second, I will demonstrate how the process of scale construction develops empirical models of health that can guide evidence-based disease management. Finally, I will discuss and demonstrate how the impact of new psychometric methods is set to revolutionize the way we measure patient-based outcomes.

S-02
QUALITY OF LIFE MEASURES IN MULTIPLE SCLEROSIS
Vickrey BG.
Department of Neurology, University of California, Los Angeles, California, US.

Over the last decade, the medical literature includes reports of at least a dozen different measures of health-related quality of life (HRQOL) administered in samples of people with multiple sclerosis (MS). Reports regarding newly-developed HRQOL measures for MS have appeared as recently as this year. The majority of these measures are disease-targeted rather than generic. Generic measures include the widely-used SF-36, the Nottingham Health Profile, and the General Health Questionnaire. Only one preference-based measure appears to be reported to date; the remainder are health profiles or a battery of separate measures. There are only a few published reports providing comparative data on the properties of several different measures administered to the same sample. Several studies support the concept that for people with MS, disease-targeted measures provide additional information about HRQOL than that provided by generic measures. Except for generic measures like the SF-36, there is a paucity of data on cross-cultural issues in their translation. Application of these measures as outcomes of longitudinal studies such as MS rehabilitation are rare, perhaps in part because of limited data on the responsiveness of ability to detect change of these measures in MS samples. Ideally, future research should focus on comparisons of several measures within a single study, analysis of responsiveness, evaluation of measurement properties in more severely disabled MS samples, evaluation of utility measures (which could be applied in cost-utility studies), and analysis of cross-cultural applications.

S-03
USE OF QUALTY OF LIFE IN MS TRIALS
Riise T, Nortvedt MW.
University of Bergen, Norway

Clinical trials studying treatment that aims at modifying the disease course should include measures of the overall impact of the treatment. Quality of life (QoL) questionnaires represent such measures which in addition include the patients perspective. These should be used not only to “monitor” adverse events but also as general outcome measures. In MS there is a clear lack of good clinical measures of disease development, and this makes the use of QoL data even more important. However, QoL data are complex since they are both multi-dimensional and longitudinal and therefore impose problems when used as primary outcome measures in trials. Some of these problems might in theory be overcome by defining a priori sub-dimensions of particular focus or by using summary scores.

In spite of this well-founded rationale for the use of QoL-data in clinical trials, there is a noticeable lack of published results of the effect on QoL of beta-interferon and other currently used immuno-modulating treatments in MS. The interpretations of the results from a few non-experimental studies are difficult. These treatments are generally well tolerated measured by compliance rates. Nevertheless, there exists data that suggests that the presence of adverse events related to this type of treatment have a markedly negative impact on the patients QoL. The overall effect of this treatment on QoL should be ascertained, although it will probably be difficult today to launch new randomised placebo-controlled trials for this purpose. New types of treatment examined in the future need to be rigorously evaluated for the effect on QoL.

S-04
MEASURING OUTCOMES IN CLINICAL SERVICES
Young CA.
Walton Centre for Neurology & Neurosurgery, Liverpool, UK.

How can we ensure that outcome measurement is practical and rewarding in clinical services? We must assess case mix, resources and interventions to allow interpretation of outcomes. For outcome measurement important choices include type (generic or disease specific), timing and level of measure, largely influenced by the reason for measurement. Outcomes should measure the target domain of a specified intervention; the pitfalls of using satisfaction as a surrogate will be demonstrated.

Data from a multi-disciplinary team will be presented on global measures, such as the Functional Independence Measure (FIM) or MOS 36-item short form health survey (SF-36). In our experience, the use of Goal Attainment Scaling has dual benefits of personalising outcome measurement to individual patients and improving the therapeutic process.

Finally, the use of the schedule for the evaluation of individual quality of life (SEIQoL) to personalise content and values in quality of life measurement will be explored.

S-05
BRAIN REHABILITATION AND BRAIN PLASTICITY
Robertson IH
Dept of Psychology and Institute of Neuroscience, Trinity College Dublin, Ireland

Cognitive neuroscience can make a significant contribution towards the development of a scientific basis for the practice of brain rehabilitation. Though rehabilitation is a vast, world-wide, industry, there is very little scientific basis for the training and therapy that are designed to help damaged brain circuits recover. The systematic application of cognitive neuroscience models to rehabilitation can not only foster better, more theoretically-grounded rehabilitation, but they can themselves be tested and modified by the data generated by rehabilitation-oriented research. Specific examples from stroke and traumatic brain injury are used here to show how non-intuitive but clinically tractable methods can emerge out of systematic application of cognitive neuroscience to the problem of how to foster dynamic change and recovery in the damaged brain. A number of examples are given as to how rehabilitation methods have been developed that are both derived from theoretical models of cognitive function, and that feed back into these models. Examples include dorsal-ventral stream interactions, perceptuo-motor interactions, interhemispheric inhibitory dynamics, and arousal-spatial attention interactions. Similar theory-practice interactions are possible in most domains of cognitive function, and it will be to the mutual benefit of basic cognitive neuroscience and rehabilitation if this type of research is expanded.

Robertson IH, Mattingley JM, Rorden C and Driver J (1998) Phasic alerting of right hemisphere neglect patients overcomes their spatial deficit in visual awareness. Nature 395, 169-172.
Robertson, I. H., & Murre, J. M. J. (1999) Rehabilitation of brain damage: Brain plasticity and principles of guided recovery. Psychological Bulletin 125, 544-575
Robertson IH (2000) Compensations for brain deficits. British Journal of Psychiatry 176, 412-413.

S-06
FUNCTIONAL IMAGING AND BRAIN PLASTICITY
PM Matthews FMRIB, Department of Clinical Neurology University of Oxford

A remarkable feature of the brain is the ability to flexibly adapt to changing internal or external conditions by altering the strength and nature of brain connectivities. This “plasticity” is most evident early in life, but has increasingly been recognised to be part of the repertoire of the adult brain, allowing learning and contributing to recovery from injury. Functional magnetic resonance imaging (fMRI), which allows localisation of regions of brain involved in cognitive processes, has allowed adaptive brain plasticity after injury to be mapped non-invasively and dynamically. Recent studies have emphasised that brain plasticity may contribute to maintaining function with disease progression and to recovery of function after relapses in multiple sclerosis. Our laboratory has focused on studies of the motor system as a paradigm for understanding these processes. We have found, for example, that contributions of ipsilateral motor pathways to motor planning and control increase with subcortical injury from multiple sclerosis. These changes evolve with the extent and nature of the injury. In chronic disease they are directly related to disease burden. They can occur in patients even prior to development of (TMS) symptoms or disability. Recent studies linking transcranial magnetic stimulation (TMS) to fMRI studies has confirmed a functional role for these ipsilateral pathways in motor control, but there are several issues that remain important to explore. First is understanding the extent of such changes and the magnitude of their potential contribution to maintaining normal behaviour or recovery in patients with multiple sclerosis. Second is learning whether these mechanisms of adaptive recovery are themselves impaired with progression of the disease. Finally, it would be important to develop ways of maximising these functional changes.

S-07
DISEASE MODIFYING DRUGS; EVIDENCE FOR A SIGNIFICANT EFFECT ON DISABILITY
Kappos L, Leppert D, Lienert C.
Department of Neurology, University Hospitals, CH-4031 Basel

Several controlled studies covering observation periods of 2-3 years have provided unequivocal evidence that immunomodulating drugs, especially Interferon b, but also Glatiramer acetate and to some extent immunosuppressants decrease disease activity in MS as depicted clinically by the occurrence of relapses and by measures of inflammatory activity in MRI (gadolinium enhancing lesions, T2 abnormalities). Evidence about an impact on the rate of increase in disability is more controversial. The issue is closely related to our understanding of disease pathogenesis with increasing evidence that inflammation and tissue destruction/degeneration may be to some extent dissociated phenomena, both temporally and causally.

In reviewing the evidence from trials in relapsing and in secondary progressive MS the measures and definitions used for the evaluation of disability must be taken into account. What does "sustained change" in the EDSS mean; do other more sensitive measures like the MSFC provide meaningful information about disability progression?

Despite considerable methodological limitations the results from various studies support an effect on disability which may not meet our and the patients' expectations, but all the same can be meaningful to the patients' performance and quality of life.

S-08
WEAKNESSES IN EFFICACY DATA FROM PUBLISHED RANDOMISED CLINICAL TRIALS IN MS
George Ebers
Dept of Clinical Neurology, The Radcliffe Infirmary, Woodstock Rd., Oxford , UK

The evaluation of efficacy has always been difficult in MS. There was a time when problems in evaluation largely related to diagnosis, blinding, and the general inaffectiveness of therapies. Recent years have brought a surge of studies showing statistical benefit for clinical and/or non-clinical markers. Problems with diagnosis have been mitigated only to the level of confidence we have in the homogeneity of the pathogenic processes in MS. Blinding issues are even less easily resolved.

The predominance of type 1 errors in a previous generation has been partly replaced by type Ib errors derived from randomized placebo controlled clinical trials. Unfortunately the duration of this disease is such that there remains a large gap between the demonstration of efficacy and that of effectiveness.

A review of trials published in high profile journals suggests that the track record of randomised clinical trials in MS has been disappointing. Even if published results are accepted as being valid for what they claim to demonstrate, we remain a long way from showing impact of treatment on outcome measures with face validity. Relapse suppression of one third seems to be common to a variety of therapies but it is an impact on long term disability that is sought. Unfortunately no short term marker adequately predicts impact on long term disability including measures of short term disability. Although data suggesting effects have been published, disability measures in completed MS clinical trials cannot be definitely shown to be free of contamination from the effect of relapses.

Observational studies, although often believed to represent an inferior form of evidence, have some advantages over short term trials. The ability to reach endpoints with face validity may counterbalance or even supersede the downside of sacrificing randomisation. This represents an alternative approach which would need to be validated but could be studied in parallel with RCT design.

S-09
Cognitive barriers to rehabilitation in ms
Feinstein A.
Department of Psychiatry, University of Toronto

Detection: An appreciation of a MS patients cognitive status is an important pre-requisite to rehabilitation. Cognitive dysfunction affects 40% of community based MS patients.

Cognitive difficulties may present in a more subtle way that in disorders such as Alzheimer’s disease, given the predominantly sub-cortical white matter pathology of MS. As such, deficits can easily be overlooked. Furthermore, the relative absence of deficits such as aphasia, agnosia and apraxia, tyoical of cortical dementias, means that well known screening procedures for cognitive dysfunction, such as the Mini-Mental State Examination, lack sensitivity. Furthermore, the lack of a close association between cognitive dysfunction and physical disability, disease duration and disease course may mislead the clinician. As such, the first barrier to rehabilitation may be a failure to detect cognitive problems.Deficits: The second barrier will come from the nature and extent of cognitive deficits. Memory: long term memory, verbal and visual, is more affected than short term and involves failure at both the acquisition and retrieval stages. Deficits are more pronounced on recall than recognition tasks. Attention: impaired attention and speed of information processing speed are the hallmarks of cognitive difficulties in MS. Frontal Tasks: difficulties in executive function, particularly generating concepts as opposed to perseverative responses are present. A thorough appreciation of these deficits elicited by neuropsychological testing is required before implementing compensatory or re-medial rehabilitation strategies.

Management: Compensatory strategies reduce demands on memory, planning and organisation thereby bringing structure and stability to a patients environment. Data with respect to remedial strategies are equivocal. The role of disease modifying drugs in this area has yet to be determined.

S-10
BARRIERS TO REHABILITATION: BLADDER AND SEXUAL
Fowler,Clare J.
Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG.

Disorders of bladder and sexual function are common in patients with Multiple Sclerosis (MS) and may cause major troublesome symptoms. Both result from the spinal cord involvement that characterises the disease. Fortunately there is much that can be done, particularly in the early stages, to treat these problems.

Commonly patients with bladder disorders complain of urgency, frequency and urge incontinence. These symptoms reflect underlying detrusor hyperreflexia and often respond well to oral anticholinergic treatment. It is however important to check that there is not also incomplete emptying because anticholinergic treatment may exacerbate impaired bladder emptying and a persistent residual volume then drives hyperreflexic contractions. Intermittent catheterisation either by the patient them self or by a carer is necessary if symptoms are to be over come.

Following the first line treatments there some experimental interventions which may be tried using intravesical vanilloids such as capsaicin or resinifertoxin to “de-afferent the bladder”. Also we are currently examining the effect of sublingual sprays of medicinal cannabis to treat patients with advanced MS and bladder symptoms, with promising initial results. Finally a stage may be reached when the patient needs an indwelling catheter and a supra-pubic is preferable to a long term urethral one. In men erectile dysfunction is common but responds well to treatment with sildenafil citrate. However difficulty with ejaculation may be a persisting problem. Female sexual dysfunction is probably equally common but much less is known about it and there are no known specific effective treatments, although trials of sildenafil in women with MS are currently in progress.

S-11
SOCIAL AND FAMILY BARRIERS TO REHABILITATION
Miller, D.M.
Mellen Center, Cleveland Clinic Foundation

The goal of rehabilitative therapy for persons with MS is arguably to assist an individual to obtain maximal functioning in the face of a progressive disability. It has been noted that “non-medical problems” are related to the person’s environment and are the most complex issues to be addressed in order for him to attain a satisfying life (Cobble and Burks, 1981). This presentation will address the importance of evaluating and including potential “non-medical” barriers in the development of a treatment plan. While it is not possible to anticipate every potential barrier, there are typical ones to consider in the treatment-planning phase. Among the most important of these is the family members’ attitude towards the MS, their expected responsibility for helping carryout the recommended treatment plan therapy and how they compensate for the usual responsibilities of the family member who is receiving therapy.

Some concerns are far beyond the influence of the individual patient or family and often the medical providers. These factors may include the location of care (in-patient, out-patient or home-based), the payment restrictions imposed by insurance companies, job security and return to work incentives for those undergoing therapy as well as assistance transportation to and from therapy. Any of these could, if discounted , could make it difficul for the best treatment plan to be successful, despite the best intentions of therapists and patients. Working with patients and families to identify and accommodate these barriers can become an important component in the treatment plan itself.

S-12
REALISTIC PROSPECTS FOR REMYELINATION AS A TREATMENT FOR MS
Blakemore WF. Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 OES, UK

Although remyelination can occur in MS, areas of chronic demyelination eventually dominate the pathology of this disease. In experimental models it can be shown that chronic demyelination is associated with loss of function, which is restored by remyelination. Thus, achieving remyelination of the non-remyelinating lesions should benefit MS patients. Two strategies are available, enhancing endogenous remyelination and transplantation of myelinogenic cells. Recent advances in the isolation and expansion of neural stem cells could make the latter approach a clinical reality in the near future. Most experiments that show extensive remyelination following transplantation have been undertaken in developing animals or into acute demyelinating lesions, situations where myelination or remyelination is occurring. In MS remyelination has failed, therefore, our ability to predict the potential success of glial cell transplantation is limited. Experimental paradigms will be presented in which endogenous remyelination is inhibited, allowing comparison of the relative remyelinating capacity of endogenous and transplanted oligodendrocyte progenitors (OPCs), as well as the consequences of delayed recruitment of OPCs into areas of demyelination and the effect of astrocytes can be examined. These show that transplanted cells have five times the remyelinating potential of endogenous cells and that delayed entry of OPCs into areas of demyelination, as well as the presence of astrocytes, have an effect on the extent of remyelination. Such studies indicate that glial cell transplantation has the potential to achieve remyelination but the environment of demyelinated lesions may influences its effectiveness.

S-13
MRI AND THE PATHOGENESIS OF MS - THE EARLIEST PHASE
David Miller
Institute of Neurology, London

In using MR techniques to study the early phase of MS and pathogenic mechanisms, a number of issues needed to be considered. These include:

1. The ability of various MR techniques to define pathology.
2. The evolution of macroscope lesions.
3. Detection of abnormalities in the normal appearing CNS tissues.
4. MR findings in the earliest clinical phase of MS, when patients present with isolated monosymptomatic syndromes. MR techniques and pathological specificity.

Standard T2 weighted image contrast has good sensitivity to pathologically verified MS plaques, but has low pathological specificity: T2 hyperintensity indicates an increased water content, as occurs with vasogenic oedema in acute lesions and an expanded extracellular space secondary to demyelination or axonal loss in subacute and chronic lesions. Gadolinium enhancement indicates blood brain barrier leakage and inflammation. USPIO, a new cell specific contrast agent is more specific for macrophage and micro glial activation. T1 hypointensity, magnetisation transfer imaging, diffusion tensor imaging, and T2 magnetisation decay analysis, are all water based imaging methods that provide more specific analysis of structural integrity, but have not been proven wholly specific for either loss of myelin or axons per se. These methods, and calculated T1, are sensitive tools for detecting subtle abnormalities in normal appearing white matter and grey matter but the small percentage changes found are pathologically non specific. Quantitation of NAA in MR spectroscopy is more specific for neuronal dysfunction and loss.

Earliest event in focal MR lesions.

Standard imaging shows that gadolinium enhancement is a consistent feature of new T2 lesions - indeed, weekly studies suggest it occurs in almost all instances. Major structural changes occur in association with and following enhancement, such as development of T1 hypointensity, rapid decrease in MTR and NAA, rapid increase in diffusion (ADC). The appearance of lipid peaks on MR spectroscopy indicates active demyelination. All these changes show partial resolution, though there is usually a permanent residual T2 lesion with reduced NAA and MTR which indicates structural damage with loss of myelin and axons, although the latter may be mild.

Serial studies for periods ranging from weeks to years have suggested the development of subtle changes in MTR or ADC in prelesional normal appearing white matter. This may indicate a primary CNS process preceding frank blood brain barrier breakdown and demyelination, or there could be low grade blood brain barrier leakage and inflammation, below the threshold for visible detection on gadolinium enhanced scans. Quantitative methods indicate that there is more blood brain barrier leakage than is visibly apparent. The dramatic suppression of new lesion formation using antiadhesion molecule (antiVLA4) antibodies suggests that blood brain barrier breakdown is a key step in lesion formation.

Normal appearing brain tissues.

Several methods, such as regions of interest analyses and the use of segmented histograms, have demonstrated unequivocal abnormalities in the normal appearing white matter and grey matter. These appear more prominent in the later progressive stages of MS. An important pathogenic question is how soon do these abnormalities arise? There have been conflicting findings in patients with clinically isolated syndromes, which probably reflect differences in methodology and patient cohorts. Using SPM99 segmentation histrogram analysis, we have recently observed small but significant abnormalities of MTR in CIS normal appearing brain tissues. These were found in those with a high risk for future relapses (T2 lesions present), and those with a low risk (normal T2 scan) suggesting that they are a marker for susceptibility to demyelination but not prognosis. As normal appearing brain tissue abnormalities become more marked with time, it is likely that their pathological basis changes, e.g. early on they may reflect subtle inflammation, later on Wallerian degeneration.

MRI in CIS

Standard MRI provides important prognostic information in CIS. The presence of T2 lesions indicates that future relapse are likely - if the scan is normal, most patients remain asymptomatic. MRI activity in the early years following CIS also appears prognostically important. In a cohort followed for 14 years, EDSS was best correlated with T2 lesion volume at year 5, and change in T2 volume between year 0 and 5 (r = 0.6), whereas correlations with baseline T2 load and T2 loads at later time points were weaker. The weakening correlations between standard lesion imaging and disability over time coincides with increasing evidence of abnormalities in normal appearing brain tissues, and more extensive neurodegeneration as indicated by increasing brain and cord atrophy.

Summary

MR observations indicated a complex and heterogeneous pathological process in MS. In the earliest phase of the disease, the development of focal lesions in association with blood brain barrier breakdown is a prominent event with long-term prognostic implications. The pathological nature and pathogenic significance of the subtle abnormalities found in normal appearing tissues prior to lesion development and in the earliest clinical stages are not yet clarified.

S-14
THE HETEROGENEITY OF MS LESIONS
Lucchinetti CF A , Bruck W B , Lassmann H C
A Department of Neurology, Mayo Clinic, Rochester, MN; B Institute of Neuropathology,Charite,Berlin,Germany; C Brain Research Institute, Vienna, Austria

Our recent studies suggest heterogeneous pathogenic mechanisms of demyelination in MS. Four different patterns were identified:Pattern I:macrophage associated demyelination; Pattern II:antibody-mediated demyelination; Pattern III:distal oligodendrogliopathy (DOD) and Pattern IV: oligodendrocyte degeneration in the PPWM. Our objectives included to extend the original pathological series and to determine whether specific clinical/paraclinical markers exist which correlate with these patterns. To date, 145 MS cases have been classified with the following distribution: 19% Pattern I, 53% Pattern II, 26% Pattern III, and 2% Pattern IV. All patients with Devic’s disease have Ab-mediated tissue damage, whereas all patients with Balo’s type of concentric lesions have a DOD. Pattern IV has only been found in a small subset of patients with PPMS. No specific association between the pattern of demyelination and the course of prototypic MS has been found. Of 10 patients treated with plasmapheresis (PLEX), substantial clinical improvement was observed in 6 pattern II cases, with no improvement in 3 pattern III cases. The response of patients to PLEX may help characterise Ab-mediated demyelination in vivo. MRI may be helpful in differentiating MS lesional patterns. Pattern I/II lesions have extensive remyelination in contrast to pattern III correlates with ring-enhancement on Gd-T1W MRI. Plaques with a more diffuse macrophage infiltration into the PPWM, typical of pattern III, may have a very different radiologic appearance. Future studies need to confirm whether these or other paraclinical markers will allow for the stratification of MS patients based on defined pathogenic mechanisms, and ultimately lead to subtype-specific therapy.

S-15
DOES MS REHABILITATION WORK?
Thompson AJ
Institute of Neurology, London

One of the major advances over the last decade, stimulated in part by the emergence of partially effective drugs, has been the appreciation of the importance of addressing the broader impact of MS on the patient - encouraging self-management through the provision of up-to-date information and setting up comprehensive services which are patient-centred and address the changing needs of MS in a flexible and accessible fashion. These aims are incorporated within the philosophy of rehabilitation and there has been a major drive to improve and develop these services across the entire range from initial diagnosis to respite care. This development must be informed and guided by clear evidence of what works and what does not. Regrettably, the evaluation of an intervention as all-encompassing as rehabilitation in a disease as poorly understood as MS has proven too daunting for most practitioners. However, if it is approached through a basic understanding of the mechanisms underlying disability in MS, and the utilisation of well chosen, scientifically sound outcome measures in carefully designed clinical trials, the results may be more encouraging. This approach to both individual components and the comprehensive package of rehabilitation has, over the last five years, yielded valuable information on which future services may be developed world-wide.

S-16
VIRAL MODELS OF MS: HOW RELEVANT ARE THEY?
Atkins GJ.
Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin 2, Ireland.

Circumstantial evidence indicates that MS could be triggered by a virus infection, although definitive proof of this has never been obtained. Although it has been assumed that a persistent virus infection could be involved in the etiology of MS, one or more transient virus infections is an equally plausible possibility. Several animal viruses have been studied as models of MS.

Those which have been most intensively studied are Theiler’s virus (a picornavirus) infection of mice, and coronavirus infection of mice and rats. Both of these models involve persistent virus infection of the central nervous system (CNS) which is associated with chronic demyelination. An alternative animal model of virus-induced demyelination is Semliki Forest virus (SFV) infection of mice and rats. For most animal strains, acute demyelination occurs following peripheral infection. For SJL mice, however, infection is associated with chronic demyelination in a proportion of infected mice. This is not associated with persistence of the virus genome in the CNS, but is associated with continuous expression of the pro-inflammatory cytokines TNF-a and interferon-g.

A use of neurotropic viruses that is only just beginning to be exploited, and may be more useful in devising treatment strategies for MS than animal models of demyelination, is transient gene therapy of demyelinating disease. Some progress has been made in treating EAE with cytokine-expressing vectors based on naked DNA vaccines, herpesviruses and adenoviruses. SFV has been used to construct a transient RNA expression vector which can be administered intranasally as recombinant suicide particles. Such particles show transient high level expression, do not persist, and cause little damage to the CNS. Since SFV infects humans as well as laboratory animals, vectors based on the SFV replicon have potential as CNS expression vectors for the treatment of MS and other CNS disorders.

S-17
EPITOPE SPREADING IN EAE AND MS
Tuohy VK
Cleveland Clinic Foundation, Cleveland, OH, USA

The autoimmune T cell repertoire in MS and EAE is characterized by CD4+ T cells of the Th1 phenotype (IFN-ã, IL-2) that recognize peptide determinants of CNS myelin proteins in an MHC class II-restricted manner. In both MS and EAE, a broadening of the T cell repertoire occurs with time. This acquired neoautoreactivity is commonly referred to as “epitope spreading” and is due to endo-genous priming to new self-antigens during the CNS inflammation that accompanies disease onset and relapse. We have shown that disease progression in both MS and EAE is accompanied by two concurrent events, viz., 1) the spontaneous regression of the primary established autoreactivity associated with disease onset, and 2) the emergence of the epitope spreading response associated with disease progression. Thus, in both MS and EAE, disease initiation and disease progression are typically associated with distinctly different autoimmune T cell repertoires. These findings indicate that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an "epitope du jour" and "moving target" perspective. However, the importance of epitope spreading in MS may best be understood from EAE experiments showing: 1) IFN-â prevents epitope spreading by inhibiting IL-12; and 2) disease progression is dramatically inhibited when an immune deviated epitope spreading cascade is preemptively created after EAE onset by transfer of Tr1 T cells producing high levels of IL-10 upon recognition of epitope spreading determinants. These data provide a rationale for "cell-based" antigen-specific intervention in MS by showing that preemptive targeting of the epitope spreading cascade with regulatory T cells effectively creates an immune deviated spreading response capable of inhibiting established inflammatory autoreactivity (supported by NIH grants NS37476 and NS36054 and by NMSS grant RG3070).

S-18
BONE MARROW TRANSPLANTATION IN MS: THE RATIONALE FOR THE CANADIAN STUDY
Freedman MS.
University of Ottawa, Ottawa, Ontario Canada

The body of evidence contends that MS is an autoimmune disease, wherein damage to myelin and axons is most likely mediated by the inflammatory immune network led by the T cell. Current immune modulating therapies affect this T cell network and reduce disease by limiting clinical attacks, slowing progression, and reducing MRI lesion loads.

Immunosuppressive therapy interferes with the proliferation of immune cells and is effective at reducing disease activity when immune modulating therapies have failed in patients with more aggressive disease. We postulate that early intervention with high dose immunosuppression offers the best chance to induce a lasting remission of disease.

Repeated unchecked pockets of inflammation probably induce demyelination and lead to irreversible damage of underlying axons. Immune cells gaining entry to the CNS eventually require replenishment from the periphery. Any therapy must therefore affect not only the immune cells in the periphery, but also those generated and maintained locally in the CNS. A regimen that can effectively address both the intra-CNS and peripheral pool of immune cells is postulated to have a better chance of eradicating the disease. Such a regimen can be chosen for immune ablation, but requires the re-establishment of the entire hematopoietic system, accomplished with minimal morbidity and mortality using autologous stem cell transplantation (ASCT). Other groups have tried to treat MS with ASCT, with mixed success. We feel that these studies could be improved by: selecting patients who still have more active inflammation and less irreversible axonal damage; using an immune ablative conditioning regimen that will penetrate the CNS as well as the periphery; and manipulating the graft by further depleting any potentially autoreactive T cells. Furthermore, by performing simultaneous intensive MRI and immunological monitoring, we hope to reveal important new information regarding the initiation of the disease process, should the disease show signs of re-activation.

S-19
EFFICACY OF STEM CELL TRANSPLANTATION IN TREATMENT OF MULTIPLE SCLEROSIS IN EUROPE
Fassas A, on behalf of the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
George Papanicolaou Hospital, Thessaloniki, Greece.

Phase I-II studies of autologous blood or marrow stem cell transplantation (ASCT) have been conducted in Europe, USA, and Asia using high-dose immunosuppressive and myeloablative chemotherapy, or total body irradiation, to treat chronic progressive and active MS. A total of 106 cases have so far been reported to the EBMT registry from 29 centers. This is an analysis of the first 85 patients with a median post-transplant follow-up time of 16 (3-59) months. Median age was 39 (20-58) years and the median interval from diagnosis to transplant was 7 (1-26) years. The median EDSS score was 6.5 (4.5-8.5). One third of the patients had evidence of disease activity in MRI (gad-enhancing or new or enlarging lesions). Transient neurologic complications ascribed to G-CSF given for blood stem cell mobilisation were experienced in 3 patients before transplant. The stem cell transplants were purged ex vivo of lymphocytes in 52 patients. In 66 (78%), antithymocyte globulins were given with the high-dose regimens to deplete lymphocytes in vivo. Seven patients died, 5 due to toxicity and 2 with neurologic deterioration. A degree of neurotoxicity was observed in 22 patients and was transient in most, although it was associated with MS progression in 6 patients. Neurologic improvement by >1 EDSS point, of at least 6 months’ duration, was seen in 18 (21%) patients. Confirmed progression-free survival was 74% at 3 years, being higher in patients with secondary progressive MS (78%). The probability of confirmed disease progression was 20%. Post-transplant MRI scans showed activity at any time in 5/61 (8%) evaluable cases. ASCT seems to yield promising results in stabilising progressive MS. These are, however, associated with a certain mortality risk and need to be validated in randomised comparative studies.

S-20
Catastrophic ms: definition and treatment approaches
Weinshenker BG.
Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

“Catastrophic multiple sclerosis (MS)" has not been well defined, but is used in two settings that may occur separately or together: 1) catastrophic acute attacks, typically leading to severe impairments and/or disabilities over less than one month, which fail to respond or respond poorly to corticosteroid treatment, and 2) recurring, usually multifocal, inflammatory demyelinating lesions, manifest as frequent relapses or continuous rapid progression of disability, which are not prevented by standard immunotherapies. The goals and strategies to treat patients in these two settings differ, though some patients may benefit from both approaches. In the first setting, rapid restoration of function is the primary goal.

Corticosteroid therapy is the treatment of choice. A randomized controlled trial reported in 1999 has shown that plasma exchange leads to rapid improvement in approximately 40% of patients who fail to respond to corticosteroids in patients with a variety of acute, severe inflammatory demyelinating diseases. In the second, rapid and marked suppression of inflammatory disease activity by immunosuppression is the primary goal. Immunosuppression with potent chemotherapies, such as mitoxantrone and cyclophosphamide, are widely considered treatments of choice; experimental use of stem cell transplantation may be an appropriate consideration in this setting.

S-21
NEUROTROPHIN PRODUCTION BY IMMUNE CELLS: IMPLICATIONS FOR IMMUNOTHERAPY
Reinhard Hohlfeld,
Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81366 Munich, Germany

Autoreactive T cells are present in the normal immune system. It has been proposed that some of these autoreactive T cells may have a protective function. Recent studies support this notion by demonstrating that a) myelin-specific T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro. Furthermore, BDNF is expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. Intriguingly, the corresponding receptor TrkB is also expressed, especially in neurons in the immediate vicinity of MS plaques and in reactive astrocytes in lesions, but not in inflammatory cells. This suggests that BDNF and its receptor are involved in immune-mediated neuroprotective interactions in MS, supporting the idea that immune cells produce both damaging and protective factors in MS lesions. The concept of neuroprotective autoimmunity has obvious implications for the therapy of multiple sclerosis and other neuroimmunological diseases.

S-22
THE ROLE OF B CELLS IN MS LESION PATHOGENESIS
Hartung HP and Archelos JJ.
Department of Neurology, Karl Franzens University, Graz, Austria.

A variety of cellular and humoral immunological abnormalities have been observed in multiple sclerosis (MS). In the past few years, several lines of evidence converged to imply an important role of autoreactive antibodies and B cells in the pathogenesis of MS. Recent data suggest that autoantibodies may be harmful in lesion formation but also potentially beneficial in repair. Recent advances in the concepts of generation and nature of pathogenic autoantibodies, their potential modes of action, mechanisms of their long-term persistence, and the role of the inflamed brain tissue as a B-cell- supporting microenvironment in MS will be reviewed. Based on the presence of specific autoantibodies, it seems possible to define distinct MS subgroups in the near future. The therapeutic relevance of these new findings will be discussed.

S-23
THE CONCEPT OF HEALTH RELATED QUALITY OF LIFE
O'Boyle CA.
Department of Psychology, RCSI, Mercer Building, Lr. Mercer St., Dublin 2.

Assessment of patients' quality of life is assuming increasing importance in medicine and healthcare. Before 1970, healthcare researchers were, by and large, content to focus either on major morbidity and mortality or on measures of physiological function or patient functional performance as the primary indicators of health gain. Improvements in cardiac, pulmonary or renal function, metabolic indices or laboratory exercise capacity were used to justify therapeutic interventions. However, the ultimate aims of treating patients are to make them live longer and/or better. During the past twenty or so years there has been an increasing realisation that surrogate indices such as the physiological parameters outlined above, are inadequate when used to determine whether patients' lives are improved by therapy or impaired by disease. In addition to their biological effects, illnesses, diseases and their treatments can have a significant impact on such areas of function as mobility, mood, spirituality, life satisfaction, sexuality, cognition, and ability to fulfil occupational, social and family roles. Health status measurement has evolved to allow insight into patients' experiences in these areas and quality of life has emerged as a broad term to describe this domain of measurement. The quality of life construct may be viewed as a paradigm shift in the measurement of health gain since it shifts the focus of attention from symptoms to functioning and establishes the primacy, or at least the legitimacy, of the patient perspective. This paper will examine definitions of quality of life and critically review some of the current approaches to its measurement. The importance of the individual perspective will be highlighted and the need to develop theories of quality of life that incorporate psychological models of adaptation will be highlighted.

S-24
HEALTH-RELATED QUALITY OF LIFE – CAN WE MEASURE IT?
Vickrey BG.
Department of Neurology, University of California, Los Angeles, California, US.

Health-related quality of life (HRQOL) is generally recognized as a key “patient-oriented” outcome of high relevance, particularly in studies evaluating therapies for chronic diseases. When appropriately applied in such studies, HRQOL measures can inform the impact of a treatment on patients’ perceptions of their physical, mental, and social health. That is, within such studies, HRQOL measures can ideally summarize the impact on a patient’s health of both direct treatment effects (like side effects) and indirect effects resulting from treatment-related reduction in disease symptoms. The methodology for developing psychometrically sound measures of HRQOL has steadily grown over the last decade. Selection of a measure for a particular treatment trial application should be guided by consideration of: (1) whether to use a generic measure, applicable to general populations and across different diseases, or a disease-targeted measure, applicable to a specific condition; (2) the need for a profile measure or for a utility or preference measure (needed to measure cost-effectiveness of a treatment); (3) whether an HRQOL measure incorporated patients’ (or proxies’) perspectives in its development; (4) the extent to which the reliability and validity of the measure have been previously reported in a similar sample and are adequate; (5) the ability of the measure to detect change over time (if being applied in a longitudinal study); and (6) the feasibility of its use, including consideration of length and mode of administration. These concepts will be illustrated with examples from existing measures and studies of neurologic conditions, including multiple sclerosis.

S-25
MR IMAGING OF THE SPINAL CORD
Dr. Frederik Barkhof, Dutch MS-MR Centre

MRI of the spinal cord is rapidly obtaining an important place in the diagnostic work-up of patients suspected of MS. One of the major advantages of spinal over cranial MRI is the absence of silent lesions with ageing or even hypertension. Even in patients with vasculitis, silent cord lesions are very uncommon. By contrast, almost all MS patients display silent cord lesions. Additionally, diffuse cord abnormality can be demonstrated on proton-density weighted MRI , especially in patients with (primary) progressive MS.

Using high-resolution postmortem spinal MRI, even more lesions are found, many beyond the resolution of in vivo MRI. There appears to be an extremely good correlation between abnormalities on T2-weighted images and areas of demyelination. By contrast, the amount of axonal loss occurs largely independent of demyelination, even in normal-appearing cord tissue.

At postmortem, using in situ whole body MRI, diffuse cord abnormalities on sagittal MR images can be resolved into small focal abnormalities on high resolution ex vivo MRI, indicating a quantitative, rather than a qualitative difference with focally abnormal cords on sagittal MR images. Apparently, the spatial resolution of current in vivo MRI techniques is not sufficient. Reference : Lycklama à Nijeholt GJ et al. Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis: a correlative study with conventional MRI, histopathology and clinical phenotype. Brain. 2001 Jan;124(Pt 1):154-66

S-26
NEW ASPECTS OF THE PATHOLOGY OF THE SPINAL CORD
Esiri MM.
University of Oxford Department of Clinical Neurology and Oxford Radcliffe NHS Trust Department of Neuropathology

This presentation will review recent pathological evidence about axonal loss in the spinal cord in multiple sclerosis. Particular questions that will be considered include the following: How much axonal loss occurs in the spinal cord? When, during the evolution of the disease, does axonal loss occur? What is its cause? How much does it contribute to atrophy? Does it contribute to functional disability? If so, at what stage of the disease? Have we any idea how to prevent it or reduce its severity?

S-27
THE PATHOLOGY OF SEVERE MS
Brett. FM,
Royal College of Surgeons in Ireland, Dublin.

Clinically severe MS is a consequence of long standing disease. One approach to understanding the pathogenesisis is to analyse cases presenting acutely. BBB breakdown is regarded to have a pathogenetic role in disease initiation but the alternative is that the initial reaction is parenchymal and breakdown a beneficial consequential effect. The absence of an animal model, and inability to acquire sequential biopsy material in MS, has resulted in experimental analysis of the early changes in MS being derived from contrast enhanced MRI. Thus the following schema has arisen:

1.Endothelial reaction.
2. BBB breakdown.
3. Demyelination.
4.Macrophage accumulation.
5. Gliosis.

However, activated T and B cells, are constantly trafficking through the CNS. On meeting an antigen to which they have been primed, a reaction is initiated, not necessarily inflammatory. Thus a possible alternative schema arises: 1 Parenchymal reaction. 2. Cytokine/chemokyne positive feedback effect on the endothelium. 3. BBB breakdown. 4. Defensive inflammatory response. What happens at the endothelium in schema 1, or what antigen is present in the brain in scheme 2, remains unanswered. Gadolinium enhanced MRIs are thought to reflect the initial changes in human demyelination. Gadolinium is a relatively crude measure of leakage from endothelial junctions so it is not unreasonable to assume that much pathological change has occurred before enhancement becomes evident. If contrast uptake occurs later in the disease (as suggested by water diffusion imaging and magnetization transfer imaging), much of the previous hypotheses based on MRI findings must be reviewed. Thus, subtle pathological changes may exist. The alternative is that there has truly been a breakdown of the BBB, but not of sufficient degree to allow passage of gadolinium. To date there are no pathological data available to clarify this question. In the light of the foregoing, we selected from our human pathological material on acute demyelination, those cases who had florid clinical disease and no uptake of contrast on MRI.

S-28
THE EUROPEAN MATRIX OF MULTIPLE SCLEROSIS
McDonald, I
Royal College of Physicians,11 St Andrews Place, London, NW1 4LE. UK.

Multiple Sclerosis originated in Europe where its ravages have been recorded at every level of society. It occurs with relatively high frequency in populations originating from Europe, though there are exceptions which may provide a clue to the factors determining susceptibility. Progress towards understanding the cause of multiple sclerosis and its pathogenesis, and towards developing effective treatments for it, is real, but major questions remain about most facets of the disease. International collaboration will be important in answering them expeditiously.