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Background: There is a growing number of cohorts and registries collecting phenotypic and genotypic data from groups of multiple sclerosis patients. Improved awareness and better coordination of these efforts is needed. Objective: The purpose of this report is to provide a global landscape of the major longitudinal MS patient data collection efforts and share recommendations for increasing their impact. Methods: A workshop that included over 50 MS research and clinical experts from both academia and industry was convened to evaluate how current and future MS cohorts could be better used to provide answers to urgent questions about progressive MS. Results: The landscape analysis revealed a significant number of largely uncoordinated parallel studies. Strategic oversight and direction is needed to streamline and leverage existing and future efforts. A number of recommendations for enhancing these efforts were developed. Conclusions: Better coordination, increased leverage of evolving technology, cohort designs that focus on the most important unanswered questions, improved access, and more sustained funding will be needed to close the gaps in our understanding of progressive MS and accelerate the development of effective therapies.

Background: White matter (WM) and grey matter (GM) brain damage in multiple sclerosis (MS) is widespread, but the extent of cerebellar involvement and impact on disability needs to be clarified. Objective: This study aimed to assess cerebellar WM and GM atrophy and the degree of fibre coherence in the main cerebellar connections, and their contribution to disability in relapsing–remitting MS (RRMS) and primary progressive MS (PPMS). Methods: Fourteen patients with RRMS, 12 patients with PPMS and 16 healthy controls were recruited. Cerebellar WM and GM volumes and tractography-derived measures from the middle and superior cerebellar peduncles, including fractional anisotropy (FA), mean diffusivity (MD), and directional diffusivities, were quantified from magnetic resonance imaging (MRI). Patients were assessed on clinical scores, including the MS Functional Composite score subtests. Linear regression models were used to compare imaging measures between 12 RRMS, 11 PPMS and 16 controls, and investigate their association with clinical scores. Results: Patients with PPMS showed reduced FA and increased radial diffusivity in the middle cerebellar peduncle compared with controls and patients with RRMS. In PPMS, lower cerebellar WM volume was associated with worse performance on the upper limb test. In the same patient group, we found significant relationships between superior cerebellar peduncle FA and upper limb function, and between superior cerebellar peduncle FA, MD and radial diffusivity and speed of walking. Conclusion: These findings indicate reduced fibre coherence in the main cerebellar connections, and link damage in the whole cerebellar WM, and, in particular, in the superior cerebellar peduncle, to motor deficit in PPMS.

Background:The increasing influence of patient-reported outcome (PRO) measurement instruments indicates their scrutiny has never been more crucial. Above all, PRO instruments should be valid: shown to assess what they purport to assess.Objectives:To evaluate a widely used fatigue PRO instrument, highlight key issues in understanding PRO instrument validity, demonstrate limitations of those approaches and justify notable changes in the validation process.Methods:A two-phase evaluation of the 40-item Fatigue Impact scale (FIS): a qualitative evaluation of content and face validity using expert opinion ( n=30) and a modified Delphi technique; a quantitative psychometric evaluation of internal and external construct validity of data from 333 people with multiple sclerosis using traditional and modern methods.Results:Qualitative evaluation did not support content or face validity of the FIS. Expert opinion agreed with the subscale placement of 23 items (58%), and classified all 40 items as being non-specific to fatigue impact. Nevertheless, standard quantitative psychometric evaluations implied, largely, FIS subscales were reliable and valid.Conclusions:Standard quantitative ‘psychometric’ evaluations of PRO instrument validity can be misleading. Evaluation of existing PRO instruments requires both qualitative and statistical methods. Development of new PRO instruments requires stronger conceptual underpinning, clearer definitions of the substantive variables for measurement and hypothesis-testing experimental designs.

Background/Objectives: The objective of this study was to investigate associations between the spatial distribution of brain lesions and clinical outcomes in a cohort of people followed up 20 years after presentation with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). Methods: Brain lesion probability maps (LPMs) of T1 and T2 lesions were generated from 74 people who underwent magnetic resonance imaging (MRI) and clinical assessment a mean of 19.9 years following a CIS. One-tailed t-test statistics were used to compare LPMs between the following groups: clinically definite (CD) MS and those who remained with CIS, with an abnormal MRI; people with MS and an Expanded Disability Status Scale (EDSS) ≤3 and >3; people with relapsing–remitting (RR) and secondary progressive (SP) MS. The probability of each voxel being lesional was analysed adjusting for age and gender using a multiple linear regression model. Results: People with CDMS were significantly more likely than those with CIS and abnormal scan 20 years after onset to have T1 and T2 lesions in the corona radiata, optic radiation, and splenium of the corpus callosum (periventricularly) and T2 lesions in the right fronto-occipital fasciculus. People with MS EDSS >3, compared with those with EDSS ≤3, were more likely to have optic radiation and left internal capsule T2 lesions. No significant difference in lesion distribution was noted between RRMS and SPMS. Conclusion: This work demonstrates that lesion location characteristics are associated with CDMS and disability after long-term follow-up following a CIS. The lack of lesion spatial distribution differences between RRMS and SPMS suggests focal pathology affects similar regions in both subgroups.

Background: In multiple sclerosis (MS), demyelination and neuroaxonal damage are seen in the hippocampus, and MRI has revealed hippocampal atrophy. Objectives: To investigate and compare hippocampal volume loss in patients with relapsing—remitting MS (RRMS) and primary progressive MS (PPMS) using manual volumetry, and explore its association with memory dysfunction. Methods: Hippocampi were manually delineated on volumetric MRI of 34 patients with RRMS, 23 patients with PPMS and 18 controls. Patients underwent neuropsychological tests of verbal and visuospatial recall memory. Linear regression was used to compare hippocampal volumes between subject groups, and to assess the association with memory function. Results: Hippocampal volumes were smaller in MS patients compared with controls, and were similar in patients with RRMS and PPMS. The mean decrease in hippocampal volume in MS patients was 317 mm3 (9.4%; 95% CI 86 to 549; p = 0.008) on the right and 284 mm3 (8.9%; 95% CI 61 to 508; p = 0.013) on the left. A borderline association of hippocampal volume with memory performance was observed only in patients with PPMS. Conclusion: Hippocampal atrophy occurs in patients with RRMS and PPMS. Factors additional to hippocampal atrophy may impact on memory performance.

Fewer gadolinium-enhancing lesions are seen in established primary progressive multiple sclerosis (PPMS) compared with other subtypes. Previously, we found unexpectedly high enhancement levels in early PPMS (42%), suggesting an early inflammatory phase. The objective of this study was to investigate whether this level of enhancement was maintained, and whether it influenced clinical progression, over 5 years. Forty-five patients with PPMS, within 5 years of onset, were scored on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) and its subtests (including the timed walk test [TWT]) 6-monthly for 3 years, and at 5 years. T1-weighted brain and spinal cord images after triple dose gadolinium—DTPA, and T2-weighted brain sequences were also acquired. A mixed effect logistic model evaluated change in the percentage of patients with enhancing lesions. Ordinal logistic and multiple linear regression models identified predictors of progression, adjusted for T2 lesion load. The percentage of patients with enhancing lesions in the brain and spinal cord declined over 5 years ( p = 0.03). Among patients with enhancement, more enhancing lesions at baseline predicted greater decline in mobility on the TWT over 5 years ( p = 0.02). In conclusion, a proportion of patients with PPMS may undergo an early inflammatory phase, which has some impact on subsequent mobility.

The pathological effects of multiple sclerosis are not confined to lesions; tissues that appear normal on conventional magnetic resonance imaging scans are also affected, albeit subtly. One imaging technique that has proven sensitive to such effects is T1-relaxation time measurement, with previous work demonstrating abnormalities in normal-appearing white matter and grey matter. In this work we investigated the evolution of T1-relaxation time changes in normal-appearing white matter and grey matter in relapsing—remitting multiple sclerosis. Three- and five-year follow-up data from 35 people with clinically early (a mean of 1.6 years from first clinical event) relapsing—remitting multiple sclerosis and 15 healthy controls were analysed. T1-relaxation time histograms were extracted from normal-appearing white matter and grey matter, and mean, peak height and peak location values were estimated. T1-relaxation time peak height declined in the multiple sclerosis normal-appearing white matter and grey matter, but not the control group (rate difference p = 0.024 in normal-appearing white matter, in normal-appearing grey matter p = 0.038); other T1-relaxation time changes were not significantly different between groups. Changes in T1-relaxation time measures did not correlate with increases in brain T2-weighted lesion loads or Expanded Disability Status Scale scores. These results suggest that the processes underlying changes in normal-appearing white matter and grey matter T1-relaxation times are not immediately linked to white matter lesion formation, and may represent more diffuse but progressive sub-clinical pathology in relapsing—remitting multiple sclerosis.

Background Regional atrophy measures may offer useful information about the causes of specific clinical deficits in multiple sclerosis (MS). Objective To determine the magnitude of cerebellar gray and white matter (GM and WM) atrophy in patients with clinically isolated syndromes (CIS) and MS, and their role in clinical manifestations of cerebellar damage. Methods T1-weighted volumetric magnetic resonance imaging (MRI) of 73 patients [29 CIS, 33 relapsing–remitting MS (RRMS), 11 secondary progressive MS (SPMS)] was compared with 25 controls. GM and WM regions were generated using SPM5 and cerebellar regions delineated. Linear regression was used to investigate differences in tissue-specific cerebellar volumes between groups and the association with clinical measures. Results Mean cerebellar GM volume (CGMV) was 100.1 cm3 in controls, 96.4 cm3 in CIS patients, 91.8 cm3 in RRMS patients, and 88.8 cm3 in SPMS patients. Mean cerebellar WM volumes (CWMV) were 21.3 cm3, 20.4 cm3, 19.9 cm3, and 18.8 cm3, respectively. CGMV was reduced by 4.8 cm3 ( P = 0.054) in RRMS patients, and 8.5 cm3 ( P = 0.012) in SPMS patients, relative to controls. Only patients with SPMS showed a borderline significant reduction in CWMV compared with controls (mean 2.1 cm3, P = 0.053). CGMV was significantly smaller in patients assessed as having cerebellar dysfunction compared with patients who had normal cerebellar function. Significant associations of CGMV and CWMV with performance on the nine-hole peg test were also observed. Conclusion Clinically relevant GM atrophy occurs in the cerebellum of MS patients and is more prominent than WM atrophy. As such, it may provide complementary data to other regional atrophy and intrinsic tissue measures.

Gadolinium (Gd) enhancement of lesions indicates inflammatory lesion activity in multiple sclerosis (MS). The question arises whether early inflammatory lesion activity – measured sensitively using triple dose Gd – is related to the future clinical course, or to the development of brain atrophy that is thought to reflect the underlying pathological progression of the disease. In this study, 26 patients with early relapsing-remitting (RR) MS (median disease duration: 1.7 years) were followed up over two years. Associations were explored between their levels of Gd-lesion enhancement in the first six months and later clinical (Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC)) and magnetic resonance imaging (MRI) (brain volume, T2 and T1 lesion volumes) measures. The extent of Gd-enhancement in the first six months correlated weakly with concurrent relapses (P = 0.041), but there was no consistent correlation with clinical and MRI outcomes at two years. More prolonged follow-up is warranted to clarify the relationship between early inflammatory lesions and long-term clinical course. Multiple Sclerosis 2007; 13: 178–185. http://msj.sagepub.com

This study evaluates the effects of dynamic foot orthoses (DFO) on walking and balance performance in people with multiple sclerosis (MS). Sixteen ambulant subjects with MS and ten age-matched healthy control subjects were studied on initial receipt of foot orthoses and after four weeks of daily wear. Walking speed, MS Walking Scale-12 (MSWS-12) and standing balance were assessed with and without orthoses at both these times. During standing, stance width and vision were varied, and performance was quantified using the velocity of the centre of pressure (COP), body sway velocity and the mean COP position relative to the shoe. People with MS walked slower (p Dynamic foot orthoses may increase sway and change COP position by altering foot alignment and/or plantar afferent stimulation. Improvement in body sway over time may be an overall training effect of the DFOs, as MS subjects adapt to the initial de-stabilization.

While there is now evidence for thalamic abnormality in established secondary progressive and relapsing—remitting multiple sclerosis (MS), it remains unclear when such abnormality begins. This study investigated the emergence of thalamic abnormality in relapsing—remitting MS by assessing the thalamic magnetization transfer ratio (MTR) in a cohort with clinically early disease. Twenty-three patients with early relapsing—remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0-3) and 19 healthy controls (mean age 34) were imaged yearly with a magnetization transfer imaging sequence. Twenty-two MS patients and 14 controls completed two-year follow-up. Regions of interest were placed in both thalami and mean thalamic MTR calculated. At baseline, significant differences between patient and control thalamic MTR were not observed. However, at years one and two, the thalamic MTR in patients was significantly lower than control MTR. Although baseline lesion volume did not correlate with baseline thalamic MTR, at year one, an association between baseline lesion volume and year one thalamic MTR emerged. There was also a significant inverse correlation between EDSS and thalamic MTR (r= −0.47, P=0.02). The study suggests that thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled.

This study used a model for magnetization transfer (MT) to estimate two underlying parameters: the macromolecular proton fraction (f) and the bound pool T2 (T2b) in patients with multiple sclerosis (MS). Sixty patients with clinically definite MS and 27 healthy controls were imaged using: (1) a dual echo fast spin echo sequence, (2) a MT sequence (with ten MT power and offset frequency combinations) and (3) proton density and T1 weighted sequences (for T1 relaxation time estimation). Fourteen normal-appearing white matter (NAWM) regions of interest (ROI) and six normal-appearing gray matter (NAGM) ROIs were outlined in all subjects. Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f. Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in secondary progressive MS. NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed. Multiple Sclerosis (2004) 10, 607/613

This short monograph describes the rationale, design and outcome of a pilot study of beta interferon in patients with primary progressive MS. A total of 50 patients were studied for 2 years using a randomized, double-blinded, placebo-controlled design. There was an emphasis on using MRI measures to evaluate outcome. The study showed that with the numbers studied, useful data could be obtained on safety and on efficacy on certain MRI measures. A larger study would be required to evaluate treatment on disability in this patient cohort and further work is needed to elucidate the relationship between quantitative MR and clinical measures over the longer term.

Patients with the primary progressive form of multiple sclerosis (PPMS) have a unique clinical course and demonstrate additional demographic and imaging features, which separate them from the relapsing/remitting form of the condition. Whether these features indicate a fundamental difference in the underlying patho genesis of the condition or simply reflect opposite ends of a clinical spectrum is unclear. What is clear, however, is that this form of MS provides a valuable model of progression, which has the potential to explain this most disabling component of the disease process. The lack of the hallmark relapses and remissions in PPMS poses diagnostic difficulties, some of which have been addressed by recently published diagnostic criteria. Following diagnosis, the need for information, specific to this form of MS, must be recognized and addressed.

Self-efficacy is a belief that one can competently cope with a challenging situation. If self-efficacy is a strong predicto r of health status in multiple sclerosis (MS), it may be an important area to target in clinical practice, as such beliefs may be modifiable. The aim of this study was to examine the predictive value of self-efficacy on self-reported health status in MS. Eighty-nine people with MS completed the Multiple Sclerosis Self-efficacy Scale (MSSE function and control scales), the Multiple Sclerosis Impact Scale (MSIS-29), and the Multiple Sclerosis Walking Scale (MSWS-12) at two time points: 1) admission to an inpatient rehabilitation unit (n=43) or for steroid treatment for relapses (n=46); and 2) discharge (rehabilitation group) or six weeks later (steroid group). Multiple regression analyses examined whether baseline and changes in self-efficacy predict changes in self-reported health status. Both baseline and changes in self-efficacy were strong and independent predictors of changes in health status (P-values ranged from 0.025 to B-0.001). That is, pretreatment self-efficacy scores and increases in self-efficacy scores from baseline to follow-up (improvement), were significantly associated with decreases (improvement) in perceived walking ability and physical and psychological impact of MS. The findings suggest that self-efficacy predicts improvement in health status and that self-efficacy would be an important domain to measure and manage actively in education and rehabilitation programs.

We compared the relative measurement precision (RMP) of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functio nal C omposite (MSFC) for discriminating between groups of patients known to differ in their extent of multiple sclerosis (MS). A total of 133 patients were rated with the EDSS and MSFC and had magnetic resonance imaging (MRI) scans. Patients were grouped on the basis of MRI appearances (T1- and T2-weighted lesion loads, parenchymal and ventricular fractions - T1LL, T2LL, PF, VF, respectively) and RMP was determined using the method of group differences. For each MRI parameter, the total sample was arranged in ascending order of magnitude and divided into two, three, four and five similar sized groups. For each division (two, three, four or five groups), EDSS and MSFC scores for the groups were compared using parametric (paired samples t-tests, one-way A NOVA) and nonparametric (Wilcoxon’s rank-sum test, Kruskal -Wallis analysis of variance) statistical methods and RMP was estimated. The EDSS and MSFC were correlated substantially (r = -0.64). Relative to the MSFC, the EDSS had inferior measurement precision regardless of the number of groups into which the total sample was divided, or the statistical method. However, the RMP of the EDSS compared with the MSFC varied from 2% to 86%. Results suggest the MSC F is better than the EDSS for detecting differences between groups of patients, defined by these MRI markers of MS. However, the finding that both scales correlated weakly with MRI markers, indicated that they are limited as predicto rs of MS patho logy as defined by MRI. A n explanatio n for this well-established clinical -MRI paradox is that rating scales and MRI measure fundamentally different manifestations of MS.

In order to compare a newly established diagnostic clinic with two existing clinical settings in the management of the diagnostic phase of multiple sclerosis (MS), a retrospective audit was performed over a 12-month period comparing the length of time, adherence to recently published standards and price charged in diagnosing MS in three different clinical diagnostic settings operating within the same hospital: a specifically designed demyelinating disease diagnostic clinic (DDC), a general neurology clinic (GNC) and an inpatient investigation unit (IIU). An audit tool was created to measure the standards advocated by the UK MS Society on management of the diagnostic phase of MS. The costing tool was the price charged to health authorities. A randomized retrospective case note and referral letter review method was used. The entry criterion was a confirmed diagnosis of MS documented in the medical notes following investigation during the period April 1999-April 2001. The time between referral and first appointment favoured the DDC with a mean time of 5.9 weeks, compared to 7.7 weeks for the GNC and 10.0 weeks for the IIU. The mean times between the first appointment and receipt of results were 4.7 weeks (DDC), 18.8 weeks (GNC) and 21.2 weeks (IIU). Prices ranged from pounds sterling 395-pounds sterling 790 (DDC), pounds sterling 95-pounds sterling 380 (GNC) and pounds sterling 1940-pounds sterling 2700 (IIU). This study suggests that the UK MS Society standards are achievable in most areas without excessive additional costs and provides evidence that the DDC offers a better service than other existing models.

We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearman’s rank correlation coefficient (rs) =-0.97, P s =0.80, P

B ackground and aim: C onversion to multiple sclerosis (MS) after optic neuritis and myelitis has been thoroughly studied; however, limited data are available regarding conversion to MS after a clinically isolated syndrome of the brainstem (CISB). The aim of this study was to investigate conversion to MS in patients with C ISB. Methods: Fifty-one patients with C ISB were prospectively studied. C ranial magnetic resonance imaging (MRI), determination of oligoclonal bands (OBs) in the cerebrospinal fluid (C SF) and evoked potentials (EPs) were performed. Based on conversion to MS at follow-up, the sensitivity, specificity, accuracy and positive and negative predictive values of these tests were calculated. Results: C linically definite MS developed in 18 (35%) patients after a mean follow-up of 37 months. Paty’s MRI criteria showed a sensitivity of 89%, a specificity of 52% and an accuracy of 65%; Fazekas’ criteria showed a sensitivity of 89%, a specificity of 48% and an accuracy of 63%; Barkhof’s criteria showed a sensitivity of 78%, a specificity of 61% and an accuracy of 67%. The presence of O Bs in the C SF showed a sensitivity of 100%, a specificity of 42% and an accuracy of 63%. No differences for neurophysiological parameters were found between patients who did and those who did not convert to MS. C onclusion: Fulfilling Paty’s, Fazekas’ or Barkhof’s MRI criteria and the presence of O Bs in the C SF are associated with a higher risk of conversion to MS in patients with C ISB. Determinatio n of O Bs in the C SF has the greatest sensitivity of all tests. Barkhof’s MRI criteria have greater specificity (although less than previously published for mixed cohorts of clinically isolated syndromes) in predicting conversion to MS for C ISB than either Paty’s or Fazekas’ criteria.

This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.

Diffusion tensor magnetic resonance imaging (DTI) indices are abnormal in patients with established multiple sclerosis (MS). The objective of this study was to examine the diffusion characteristics of MS lesions, normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in MS patients with early relapsing-remitting disease. A further objective was to investigate the relationship between three DTI parameters (fractional anisotropy (FA), mean diffusivity (MD) and volume ratio (VR)) and clinical outcome measures (Kurtzke expanded disability status scale (EDSS) and MS Functional Composite Measure) in early disease. DTI was performed in 28 patients and 27 controls. Analysis was carried out using a region of interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions. Significant differences were found in FA, MD and VR between lesions and NAWM (P

MTR and T1 relaxation times are abnormal in MS lesions and NAWM, and may reflect tissue damage such as demyelination and axonal loss. Their relationship and potential to provide complementary information in tissue characterisation is explored. The aim of this study was to document the relationship between magnetisation transfer ratio (MTR) and T1 relaxation time in Multiple Sclerosis (MS) lesions and normal appearing white matter (NAWM) in order to determine whether the combination provides a more comprehensive tissue characterisation than either parameter in isolation. Ten patients with relapsing remitting MS and 10 age matched healthy controls underwent imaging using a protocol which included the measurement of both MTR and T1 relaxation times. The MTR and T1 values were compared statistically using a commonly adopted correlation approach and a mixed-model regression approach. There was a strong correlation between MTR and T1 in MS lesions (r=0.74). The correlation was seen equally in T1 hypointense and isointense lesions. The relationship was much weaker in MS NAWM (r=0.24) and no correlation was found in control white matter (r=0.06). Mixed-model regression analysis confirmed that the relationship between T1 and MTR is strongly dependent upon tissue type (MS lesion, MS NAWM, or control white matter). The relationship between MTR and T1 relaxation time measurements varies markedly between pathological and normal tissue types. In MS, the complementary information obtained from MTR and T1 is most apparent in NAWM. The results emphasise the potential for combinations of MR parameters to improve tissue characterisation, which in turn should improve understanding of disease pathology and treatment monitoring. Multiple Sclerosis (2000) 6 327 - 331

Patients with primary progressive multiple sclerosis may develop severe disability despite a paucity of lesions on conventional magnetic resonance imaging, raising the possibility that intrinsic changes in normal appearing white matter (NAWM) contribute to disability. This study has measured magnetisation transfer ratio (MTR), an index of tissue damage, of NAWM in 52 patients with primary progressive multiple sclerosis and 26 healthy controls. Absolute values of MTR were obtained from the genu of the corpus callosum and pons, and mean values were calculated from bilateral regions in the centrum semiovale, frontal white matter, parieto-occipital white matter and posterior limb of the internal capsule. The median MTR was lower in all regions in patients compared to controls. Median values (per cent units) were significantly lower in corpus callosum (39.73 vs 40.63; P=0.01), frontal white matter (39.11 vs 39.59; P=0.01) and centrum semiovale (37.21 vs 37.82; P50.05). This study has demonstrated small but widespread decreases in MTR in NAWM in primary progressive multiple sclerosis supporting the hypothesis that there are intrinsic changes in NAWM which may contribute to disability in this patient group.

Handicap, shortly to be renamed participation, is a well defined though somewhat neglected entity which addresses an important aspect of the impact disease has on the individual. It is particularly relevant in Multiple Sclerosis (MS) which has such a major impact on issues such as employment, relationships, transport and social integration. Few validated measuring tools exist, and the generic London Handicap Scale is probably the best currently available but is only appropriate for group comparison. Handicap should be monitored in MS and is particularly appropriate in the evaluation of rehabilitation strategies.