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[FIGURE 1 OMITTED] How should MS be diagnosed? What investigations should be carried out? What are the evidence-based treatment options? MULTIPLE SCLEROSIS (MS) IS AN INFLAMMATORY AND DEGENERATIVE DISEASE OF [...]

ObjectiveTo evaluate whether structural brain network metrics correlate better with clinical impairment and information processing speed in multiple sclerosis (MS) beyond atrophy measures and white matter lesions.MethodsThis cross-sectional study included 51 healthy controls and 122 patients comprising 58 relapsing–remitting, 28 primary progressive and 36 secondary progressive. Structural brain networks were reconstructed from diffusion-weighted MRIs and standard metrics reflecting network density, efficiency and clustering coefficient were derived and compared between subjects’ groups. Stepwise linear regression analyses were used to investigate the contribution of network measures that explain clinical disability (Expanded Disability Status Scale (EDSS)) and information processing speed (Symbol Digit Modalities Test (SDMT)) compared with conventional MRI metrics alone and to determine the best statistical model that explains better EDSS and SDMT.ResultsCompared with controls, network efficiency and clustering coefficient were reduced in MS while these measures were also reduced in secondary progressive relative to relapsing–remitting patients. Structural network metrics increase the variance explained by the statistical models for clinical and information processing dysfunction. The best model for EDSS showed that reduced network density and global efficiency and increased age were associated with increased clinical disability. The best model for SDMT showed that lower deep grey matter volume, reduced efficiency and male gender were associated with worse information processing speed.ConclusionsStructural topological changes exist between subjects’ groups. Network density and global efficiency explained disability above non-network measures, highlighting that network metrics can provide clinically relevant information about MS pathology.

Multiple sclerosis continues to be a challenging and disabling condition but there is now greater understanding of the underlying genetic and environmental factors that drive the condition, including low vitamin D levels, cigarette smoking, and obesity. Early and accurate diagnosis is crucial and is supported by diagnostic criteria, incorporating imaging and spinal fluid abnormalities for those presenting with a clinically isolated syndrome. Importantly, there is an extensive therapeutic armamentarium, both oral and by infusion, for those with the relapsing remitting form of the disease. Careful consideration is required when choosing the correct treatment, balancing the side-effect profile with efficacy and escalating as clinically appropriate. This move towards more personalised medicine is supported by a clinical guideline published in 2018. Finally, a comprehensive management programme is strongly recommended for all patients with multiple sclerosis, enhancing health-related quality of life through advocating wellness, addressing aggravating factors, and managing comorbidities. The greatest remaining challenge for multiple sclerosis is the development of treatments incorporating neuroprotection and remyelination to treat and ultimately prevent the disabling, progressive forms of the condition.

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.

To investigate whether (1) there were differences between HLA-DRB115-positive and -negative patients at baseline, and (2) HLA-DRB115-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow-up, compared with HLA-DRB115-negative patients.

To apply a novel postprocessing voxel-based analysis for diffusion tensor imaging of the cervical spinal cord in multiple sclerosis (MS) in a prospective cross-sectional study.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions.

Asymmetric cortical representation of cardiac function is a matter of debate and large inter‐individual variability of cortical autonomic networks and different study designs may contribute to this controversy. Lateralised seizure activity in individual patients may provide valuable insights into cortical regulation of cardiac function. We report two patients with focal epilepsy who had seizures arising from both hemispheres. In Patient 1, heart rate increased over two‐fold with seizures arising from the right hemisphere, whereas heart rate increased invariably less with seizures arising from the left hemisphere. In Patient 2, heart rate increased 1.3 fold or less with seizures arising from the left hemisphere, whereas a seizure with right‐sided onset was followed by bradycardia and asystole. Our findings support the notion that effects on autonomic function are lateralised, although lateralisation varies from patient to patient. This may partially explain the difficulty in determining cortical representation of cardiac autonomic function.

Several studies with optical coherence tomography (OCT) have demonstrated thinning of the retinal nerve fiber layer (RNFL) in patients with optic neuritis and multiple sclerosis. Similar studies have not been performed with scanning laser polarimetry (SLP), which relies on different physical phenomena. This study was designed to use SLP to measure axonal loss following a single episode of optic neuritis and to determine if there is a relationship between the degree of axonal loss and the degree of residual visual dysfunction.

BACKGROUND Magnetization transfer imaging has the potential to provide a surrogate marker for progression in primary progressive multiple sclerosis (PPMS). OBJECTIVES To investigate whether brain magnetization transfer imaging, T2 lesion load, and atrophy changes over 3 years reflect concurrent clinical changes, and which baseline imaging measure best predicts progression over 3 years in early PPMS. DESIGN Prospective study. SETTING National Hospital for Neurology and Neurosurgery and the Institute of Neurology, London, England. PATIENTS Forty-seven patients with PPMS (of whom 43 completed the study) and 18 control subjects. INTERVENTIONS Brain magnetization transfer imaging (including T2-weighted images) and volume sequences every 6 months for 3 years. MAIN OUTCOME MEASURES Changes in Expanded Disability Status Scale (EDSS) score and associations with rate of change in imaging variables. RESULTS More rapid decline in gray matter mean and peak location magnetization transfer ratio and T2 lesion load increase were associated with greater rates of progression on the EDSS. Baseline gray matter peak height magnetization transfer ratio best predicted progression over 3 years. CONCLUSION Gray matter magnetization transfer ratio meets many of the criteria for a surrogate marker of progression in early PPMS.Arch Neurol. 2008;65(11):1454-1459--

OBJECTIVE To investigate whether patients with early primary progressive multiple sclerosis show changes in T1 relaxation time (T1-RT) in normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM) during 2 years and whether T1-RT at baseline predicts disability. METHODS Twenty-one patients and 12 control subjects were studied at baseline and after 2 years. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were assessed. T1 relaxation time histograms of NAWM and NAGM were obtained in all subjects, and mean, peak height, and peak location of the histograms were measured. Paired t tests were used to compare baseline and 2-year histogram values in patients and control subjects. To investigate whether T1-RT predicted clinical changes, multiple linear regression analysis was used. RESULTS Patients showed increases in NAWM and NAGM T1-RT mean and peak location during follow-up, and significant decreases in NAWM and NAGM peak height. Baseline NAWM T1-RT mean values and peak height predicted disability at 2 years, as measured with the Multiple Sclerosis Functional Composite score. CONCLUSION T1 relaxometry is a good marker of disease progression and has prognostic potential in primary progressive multiple sclerosis.Arch Neurol. 2007;64:411-415 --

Objective.Functional magnetic resonance imaging (fMRI) provides an opportunity to study the relationship between cerebral reorganization and functional recovery after stroke. The authors set out to demonstrate the feasibility of using fMRI to investigate mechanisms of recovery in individual patients presenting with severe motor impairment. Methods. fMRI was performed during passive movement at both affected and unaffected wrists separately in 2 patients with pure motor stroke. Six scanning sessions were performed in each patient over the first 4 months after stroke. Seven control subjects were also studied, 1 of them over 6 sessions. The authors examined for longitudinal changes in cerebral responses to proprioceptive afferent input that correlated with motor recovery. Results.In control subjects, passive movement of either wrist led to relative increases in brain activation in the contralateral sensorimotor cortex and supplementary motor area, the bilateral inferior parietal cortex and secondary somatosensory areas, and the ipsilateral cerebellum. Increases in brain activation correlating with motor recovery were observed in both the ipsilesional primary sensory and primary motor cortex in 1 patient with good motor recovery but not in another patient with poor recovery. No longitudinal changes were seen in the control subject. Conclusions.These 2 case reports demonstrate that functionally relevant changes in cerebral organization can be identified in individual patients.

BACKGROUND Gray matter (GM) atrophy has been reported in multiple sclerosis (MS). However, little is known about its regional distribution. OBJECTIVE To investigate the regional distribution of GM atrophy in clinically early primary progressive MS (PPMS). DESIGN AND PATIENTS Thirty-one patients with PPMS within 5 years of symptom onset (mean age, 43.2 years; median Expanded Disability Status Scale score, 4.5) and 15 healthy control subjects (mean age, 43.7 years) were studied. All subjects underwent a 3-dimensional inversion-recovery fast spoiled gradient-recalled echo sequence that was repeated after 1 year in patients only. Magnetic resonance images underwent an optimized voxel-based morphometric analysis that segments magnetic resonance data volumes in a normalized space and quantifies tissue atrophy on a voxel-by-voxel basis. A lesion mask was created for each patient and used in normalization and segmentation steps to minimize bias from lesions. A multisubject design was used in the cross-sectional study to compare patients with PPMS and controls. A 1-way analysis of variance (within-subjects) design was used in the longitudinal study. RESULTS At baseline, patients with PPMS displayed bilateral thalamic atrophy compared with controls. In addition, a significant association between lesion load and decreased GM volume was found for the thalami. Loss of GM in the putamen, caudate, thalami, and cortical and infratentorial areas was observed in patients after 1 year of follow-up. CONCLUSIONS Atrophy is most obvious in deep GM in clinically early PPMS. This may reflect increased sensitivity of these regions to neurodegeneration. Cortical and infratentorial atrophy developed as the disease evolved.Arch Neurol. 2006;63:1175-1180 --

Patients with clinically isolated syndromes suggestive of multiple sclerosis have evidence for abnormality in normal appearing grey matter detected using the magnetization transfer ratio (MTR), a quantitative MRI measure. One potential mechanism for the decreased grey matter MTR (GM MTR) observed is trans-synaptic morphological abnormality secondary to demyelinating lesions that are in an anatomically linked pathway but remote location. We investigated this potential association by studying the location of abnormalities using voxel-based analysis of GM MTR maps in a group of 80 patients studied within 6 months of presenting with isolated optic neuritis and compared the findings with those seen in 50 age- and sex-matched healthy controls. Occipital cortex and whole brain analysis comparing all optic neuritis patients and controls revealed a selective decrease of MTR bilaterally in the visual cortex in patients [Brodmann area (BA) 17]. Whole brain analysis of patients fulfilling the McDonald criteria for multiple sclerosis (n = 20) showed a lower MTR compared to controls bilaterally in the visual cortex (BA 17/18), left hippocampus, bilateral superior temporal gyrus, bilateral lenticular nuclei and the right cerebellum. There was no significant difference in the percentage of grey matter between patients and controls in the regions of abnormal MTR detected in the visual cortex. The intrinsic MTR decrease seen in patients suggests that there are structural changes in the visual cortex following an attack of optic neuritis. Potential mechanisms for this include trans-synaptic neuronal degeneration and cortical synaptic morphological changes; such abnormalities may also contribute to MTR abnormalities observed in the normal appearing grey matter in multiple sclerosis.

Movement-related brain activation patterns after subcortical stroke are characterized by relative overactivations in cortical motor areas compared with controls. In patients able to perform a motor task, overactivations are greater in those with more motor impairment. We hypothesized that recruitment of motor regions would shift from primary to secondary motor networks in response to impaired functional integrity of the corticospinal system (CSS). We measured the magnitude of brain activation using functional MRI during a motor task in eight chronic subcortical stroke patients. CSS functional integrity was assessed using transcranial magnetic stimulation to obtain stimulus/response curves for the affected first dorsal interosseus muscle, with a shallower gradient representing increasing disruption of CSS functional integrity. A negative correlation between the gradient of stimulus/response curve and magnitude of task-related brain activation was found in several motor-related regions, including ipsilesional posterior primary motor cortex [Brodmann area (BA) 4p], contralesional anterior primary motor cortex (BA 4a), bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral prefrontal cortex and contralesional superior cingulate sulcus. There were no significant positive correlations in any brain region. These results suggest that impaired functional integrity of the CSS is associated with recruitment of secondary motor networks in both hemispheres in an attempt to generate motor output to spinal cord motoneurons. Secondary motor regions are less efficient at generating motor output so this reorganization can only be considered partially successful in reducing motor impairment after stroke.

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The “McDonald Criteria” have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity. Ann Neurol 2005

Axonal loss is thought to be a likely cause of persistent disability after a multiple sclerosis relapse; therefore, noninvasive in vivo markers specific for axonal loss are needed. We used optic neuritis as a model of multiple sclerosis relapse to quantify axonal loss of the retinal nerve fiber layer (RNFL) and secondary retinal ganglion cell loss in the macula with optical coherence tomography. We studied 25 patients who had a previous single episode of optic neuritis with a recruitment bias to those with incomplete recovery and 15 control subjects. Optical coherence tomography measurement of RNFL thickness and macular volume, quantitative visual testing, and electrophysiological examination were performed. There were highly significant reductions (p< 0.001) of RNFL thickness and macular volume in affected patient eyes compared with control eyes and clinically unaffected fellow eyes. There were significant relationships among RNFL thickness and visual acuity, visual field, color vision, and visual‐evoked potential amplitude. This study has demonstrated functionally relevant changes indicative of axonal loss and retinal ganglion cell loss in the RNFL and macula, respectively, after optic neuritis. This noninvasive RNFL imaging technique could be used in trials of experimental treatments that aim to protect optic nerves from axonal loss. Ann Neurol 2005

This review of recent work in the area of neurorehabilitation of multiple sclerosis patients surveys progress and underscores the need for further work to evaluate the effectiveness of treatments.

We have recently reported brain atrophy in the early stages of primary progressive multiple sclerosis (PPMS), affecting both grey and white matter (GM and WM). However, to date no clinical or radiological predictors of GM and WM atrophy have been identified. The aim was to investigate short-term changes in GM and WM volumes and to assess the predictive value of demographic, clinical and radiological variables in order to gain a better understanding of the pathological substrate underlying these changes. Thirty-one subjects with PPMS within 5 years of symptom onset were studied at baseline and after 1 year. At baseline, patients underwent neurological examination and were scored on the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite. They had 3D inversion-prepared fast spoiled gradient recalled (FSPGR), dual-echo and triple-dose post-contrast T1-weighted spin echo MRI scans. Proton density and enhancing lesion loads were determined. The 3DFSPGR sequence was repeated after 1 year and brain volume changes were calculated using two techniques, SPM99 (statistical parametric mapping) and SIENA (structural image evaluation, using normalization, of atrophy). Stepwise linear regression models were applied to baseline variables to identify independent predictors of atrophy development. Using SPM99, a decrease in brain parenchymal fraction (−1.03%; P < 0.001) and GM fraction (−1.49%; P < 0.001) was observed. The number of enhancing lesions independently predicted decrease in brain parenchymal fraction (P = 0.019) and decrease in WM fraction (P = 0.002). No independent predictors of GM fraction decrease were found. A mean brain volume change of −0.63% (range −4.27% to +1.18%; P = 0.002) was observed using SIENA, which was independently predicted by EDSS (P = 0.004). Global and GM atrophy can be detected over a 1-year period in early PPMS. The former may be predicted by the degree of inflammation, while the latter seems to be independent of it. SIENA and SPM-based methods appear to provide complementary information.

The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at baseline, 1, 3, 6, and 12 months. We performed three types of correlation analyses to investigate the relationships between fMRI activity, clinical function, and optic nerve structure. The first analysis directly correlated the fMRI response to clinical function or optic nerve structure and found dynamic relations especially within the first 3 months. The second analysis used a novel technique that modeled the fMRI response and optic nerve structure together with clinical function, to determine the contribution fMRI made to clinical function after accounting for structural factors. Significant effects were found at baseline only, within the right peristriate cortex, and bilaterally in the lateral occipital complexes, which are normally involved in higher order visual processing. The third analysis investigated the relation between the modeled visual recovery rate and fMRI response but found no significant effects. The key findings of this study are from the second analysis and suggest a genuine adaptive role for cortical reorganization within extrastriate visual areas early after optic neuritis. Ann Neurol 2005;57:622–633

This study assessed optic nerve mean area on serial MRI in a cohort of patients with a first episode of acute unilateral optic neuritis to assess the effects of a single acute inflammatory demyelinating lesion. Twenty-nine patients with a median delay from onset of visual symptoms of 13 days (range 7–24 days) were recruited. After a clinical examination and visual evoked potential (VEP) measurement, each patient had their optic nerves imaged with a coronal fat-saturated short echo fast fluid-attenuated inversion recovery sequence. Twenty-one patients had serial examinations after 2, 4, 8, 12, 26 and 52 weeks. In addition, 32 control subjects had their optic nerves imaged up to three times. The mean cross-sectional area of the intra-orbital portion of each optic nerve was calculated by a blinded observer using a computer-assisted contouring technique. At baseline, the mean area of diseased optic nerves was 16.1 mm2 compared with 13.4 mm2 for healthy contralateral optic nerves (20.1% higher, P < 0.0001) and 13.6 mm2 for controls (18.4% higher, P = 0.0003). The diseased optic nerve mean area declined over time, from initial swelling to later atrophy. The mean decline at 52 weeks was −0.0018 mm2/day (95% confidence interval −0.0038 to −0.00051). At 52 weeks, the mean area of diseased optic nerves was 11.3 mm2 compared with 12.8 mm2 for healthy contralateral optic nerves (11.7% lower, P = 0.032) and 13.1 mm2 for controls (13.7% lower, P = 0.008). The 52 week diseased optic nerve mean area was not significantly affected by the baseline mean area. There was an association between baseline optic nerve mean area and logMAR visual acuity (rS = 0.46, P = 0.012) and visual field mean deviation (rS = −0.55, P = 0.002), but there was no evidence of an association between 1 year mean area and visual outcome. There was no evidence of association between baseline, rates of decline or 1 year diseased optic nerve mean areas and any of the baseline, 1 year or time-averaged VEP variables. The present study shows a consistent pattern of changes associated with individual inflammatory demyelinating lesions in the optic nerve. Acutely, there was swelling, consistent with the presence of acute inflammation, which was related to visual impairment. Over the longer term, there was loss of tissue. The lack of association between 1 year optic nerve mean area and visual outcome may reflect a mild loss of tissue, redundancy or remodelling of function.

After stroke, the pattern of brain activation during performance of a motor task is related to outcome. Here, we compare this relationship in the early (10–14 days) and late (at least 3 months) phases after first‐ever stroke. A negative linear relationship between task‐related brain activation, as measured by functional magnetic resonance imaging, and outcome is seen in several identical primary and nonprimary motor regions that is independent of time after stroke. In other words, patients with poorer outcome scores recruit more widely within motor‐related regions in both the early or late poststroke phase. However, in contralesional middle intraparietal sulcus, contralesional cerebellum, and ipsilesional rostral premotor cortex, this relationship is seen only in the early poststroke phase. Thus, patients with poorer outcome scores recruit these areas in only the early and not the late poststroke phase. These results suggest that there are differences in the cerebral implementation of action in patients with poor outcome that are dependent on the time since stroke. Thus, in those patients with the most to gain from rehabilitation, different therapeutic approaches may be required at different stages after stroke.

We performed a retrospective review of all patients admitted to a neurological rehabilitation unit over a 5-year period to identify the benefits and problems associated with inpatient rehabilitation of patients with a life-limiting illness. Twenty-one patients (14 men; mean age 54 years) with primary or nonprimary neurological malignancy resulting in disability were studied. For each patient the following data was extracted: gender, age, diagnosis, source of referral, mechanism of disability, prognosis at time of referral, length of inpatient stay, disability on admission and discharge, and the place of discharge. All patients made functional gains, and all but 2 were discharged home. One patient died and 4 required readmission to an acute unit because of worsening discomfort or debility within a month of discharge. Patients with life-limiting illness resulting in neurological disability can benefit from inpatient rehabilitation. Optimal management of such patients demands careful liaison with palliative care teams.

While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed‐up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI‐visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was –0.017 (–3.3%) and was significantly larger than in the combined lesion‐positive and lesion‐negative CIS subjects [–0.005 (–1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = –0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer‐term follow‐up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.

Background/Aim: conventional teaching on integrated care pathways (ICP) suggests that they have to be specific both to a particular setting and to a specific diagnosis. We wished to explore the potential for a generic process-based care pathway. Study design: we evaluated three different, disease-specific ICPs in use on a neurological rehabilitation unit to identify prompts common to and differing between them. Variance types and goal outcomes in all three diagnostic groups were compared. Results: 93% of prompts on the care pathway were common to all three diagnostic groups. The prompts that differed were unique to each diagnostic group and provided important guidelines about management. Conclusion: in neurorehabilitation, where the process of multidisciplinary care is well defined, it is possible to develop a process-based ICP. Process-based ICPs may not be unique to rehabilitation but may also be relevant to other settings in which patients with differing diagnoses share similar needs.

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium‐enhancing lesions for dissemination in time at a 3‐month follow‐up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients. Ann Neurol 2003;53:673–676

MRI methods are widely used to follow the pathological evolution of multiple sclerosis in life and its modification by treatment. To date, measures of the number and volume of macroscopically visible lesions have been studied most often. These MRI outcomes have demonstrated clear treatment effects but without a commensurate clinical benefit, suggesting that there are other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis pathology, whether it arises in macroscopic lesions or in the normal appearing tissues. An International Workshop recently considered the measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss of these structures, especially axons, although variable effects on tissue volumes may also arise from glial cell proliferation or loss, gliosis, inflammation and oedema. Significant correlations found between brain volume and other putative MR neuronal markers also indicate that atrophy reflects axonal loss. Numerous methods are available for the measurement of global and regional brain volumes and upper cervical cord cross‐sectional area that are highly reproducible and sensitive to changes within 6–12 months. In general, 3D‐T1‐weighted acquisitions and largely automated segmentation approaches are optimal. Whereas normalized volumes are desirable for cross‐sectional studies, absolute volume measures are adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis, developing gradually following the appearance of inflammatory lesions. This probably reflects both inflammation‐induced axonal loss followed by Wallerian degeneration and post‐inflammatory neurodegeneration that may be partly due to failure of remyelination. One component of atrophy appears to be independent of focal lesions. Existing immunomodulatory therapies have had limited effects on progressive atrophy, concordant with their modest effects on progressive disability. Atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti‐inflammatory, remyelinating or neuroprotective therapies.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow‐up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

Despite being acknowledged as an important component in the overall management of multiple sclerosis, the relatively few evaluative studies in symptomatic treatment and rehabilitation have meant that the evidence base is still poor. The encouraging work on health outcome measures, together with an improved understanding of the mechanisms underlying disability, provide a useful base for improving the lot of patients with multiple sclerosis. These advances need to be associated with improved models of care which provide comprehensive and accessible services throughout the course of the disease.

The pathogenesis of fatigue in patients with MS is poorly understood.

Recently, the clinical efficacy of interferon β-1b (IFNβ-1b) was demonstrated for secondary progressive (SP) multiple sclerosis in a European multicentre study. We evaluated the effect of IFNβ-1b treatment on the rate of development of hypointense T1 MRI lesions, a putative marker of axonal damage. Unenhanced T1-weighted images were obtained in a subgroup of 95 multiple sclerosis patients from five centres at 6-month intervals; this subgroup was similar to the total study population for all demographic, clinical and MRI parameters. An experienced observer blinded to the clinical data and treatment allocation measured volumes. The median baseline lesion load for hypointense T1 lesions was 5.1 cm3 for placebo-treated and 4.9 cm3 for IFNβ-1b-treated patients (P = 0.56). Placebo-treated patients showed an increase in T1 lesion load by a median of 14% per year (P = 0.0002 compared with baseline); this was reduced to 7.7% per year in the IFNβ-1b-treated patients (P = 0.003 versus placebo). In the IFNβ-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T1 lesion load by month 36 (r = 0.38, P = 0.0015). In patients with SP multiple sclerosis, IFNβ-1b treatment reduces the development of hypointense T1 lesions, suggesting that reduced axonal damage in lesions may play a part in the beneficial effect that is observed clinically.

1H magnetic resonance spectroscopy (MRS) provides a unique tool to detect and quantify brain metabolites. In multiple sclerosis it can be used to investigate axonal loss or dysfunction through measurement of N-acetyl aspartate (NAA), a neuronal marker. Previous studies in adults have reported variable effects of aging on metabolite concentrations but have predominantly focused on changes in the elderly. This study has examined a younger adult age group to provide a reference database more applicable to the multiple sclerosis population. Single voxel 1H MRS was carried out in 44 subjects between 22 and 62 years of age. Sixteen subjects underwent repeat examination after one year. Absolute concentrations of NA (the sum of NAA and N-acetyl aspartate glutamate), NAA, creatine/phosphocreatine (Cr), choline containing compounds (Cho) and myo-inositol (mI) were measured. NA, NAA and mI concentrations did not correlate with age but there were significant correlations between age and Cr (r= 0.43, p= 0.004) and Cho (r= 0.38, p= 0.011) concentrations. No significant differences in metabolite concentrations were seen over one year. This study provides evidence that age-related changes of metabolite concentrations occur even in a young to middle aged adult population. This emphasizes the need to perform absolute quantification of metabolite concentrations rather than ratios and the importance of age-matching in 1H MRS studies of multiple sclerosis.

Magnetic resonance (MR) techniques provide an objective, sensitive and quantitative assessment of the evolving pathology in multiple sclerosis. There is an increasing definition of the pathological specificity of newer techniques, and more robust correlations with clinical evolution are emerging. As the pathophysiological basis of in vivonuclear MR signal abnormalities is further elucidated, it is likely that the importance of MR as a tool to monitor new therapies will increase.

In the light of current NHS strategy, assessment of needs, particularly among those with significant disability, has become highly topical. This article outlines the complexity and skill required for assessing and managing neurologically-related disability. The multifaceted nature of assessment in rehabilitation is indicated, along with an example of such an assessment service developed in practice. The benefits of an assessment strategy in neurorehabilitation is emphasized in terms of resources, patient outcomes and staff development.

Integrated care pathways (ICPs) map the predicted course of an episode of patient care. This paper describes an ICP combined with outcome measurement to audit the goal-oriented neurorehabilitation of patients with stroke. Reasons for departure from the pathway and failure to achieve goals are evaluated. Analysis of this variance and its causes allows the development of more efficient and effective patient care.

Serial magnetic resonance imaging (MRI) detects substantial subclinical disease activity in multiple sclerosis (MS) and is presently included in most treatment trials as an objective outcome measure. Our current knowledge of the role of MRI in MS treatment trials is derived from very limited patient studies, and the aim of this paper is to identify strategies to optimize the use of MRI in monitoring disease activity in treatment trials. The number of active lesions revealed by MRI can be used as the primary outcome measure in exploratory treatment trials. With monthly scanning, the majority of active lesions will be seen by virtue of a limited number of new areas of gadolinium enhancement. The contrast between enhancing lesions and background could be increased by: (1) using higher doses of gadolinium, (2) suppressing the background signal with magnetization transfer, (3) delayed scanning, or (4) a combination of these. Following a systematic comparison of those approaches, the effect on the sensitivity in detecting active lesions should be analysed with reference to the power of treatment trials. We present preliminary results showing marked agreement between observers in reporting enhancing lesions; however, with new acquisition strategies, the observer variation should be re-established in a multicentre fashion. In definitive trials, the increase in total lesion load serves as a secondary outcome measure. Since the majority of lesions making up the total lesion load are inactive during the study, spatial resolution should be maximized in order to preclude any artificial changes in lesion load to be superimposed (noise) upon the relatively small actual change (information). Reduction in measurement error can be attempted by improved acquisition techniques with increased lesion to background contrast. More importantly, improvement in quantitation techniques is warranted. With a 6% coefficient of variation in measuring a baseline lesion load, we calculate the standard error of the mean yearly increase in T2 lesion load (typically 10% in untreated patients) in a treatment arm of 124 patients to be 7.5%. A comparison of several quantitation techniques should be performed in a multicentre longitudinal fashion in order to include variation caused by both scanner and segmentation technique, in addition to biological activity.

Recent reports have suggested that fluid attenuated inversion recovery (FLAIR) is a technique superior to conventional (CSE) or fast spin echo (FSE) T2-weighted sequences in detecting intrinsic lesions both in the brain and spinal cord. We report our experience of an inversion recovery prepared FSE, which we refer to as fast FLAIR, in a comparative study of ten patients with clinically definite multiple sclerosis (MS) who underwent cervical cord and brain imaging with both FSE and fast FLAIR. The results showed that in the cerebral hemispheres fast FLAIR detected more lesions than FSE (P< 0.001). However, FSE detected more lesions than fast FLAIR in the posterior fossa (P= 0.02) and in the cord fast FLAIR was much inferior detecting only 2 of 33 lesions seen on FSE. Estimating the T2 relaxation times of lesions in each of three areas (periventricular, posterior fossa, cervical cord) showed that the T2 value of posterior fossa and cervical cord lesions was significantly lower than that of periventricular lesions, suggesting that the lesion composition is different and consequently their imaging appearances are different. In conclusion, although fast FLAIR improves the detection of MS lesions in the cerebral hemispheres, its substantially lower sensitivity in the posterior fossa and spinal cord is a potentially important limitation to its use as a tool for the diagnosis of MS and for monitoring therapies. Further studies are needed to elucidate the mechanisms underlying the loss of sensitivity.

In patients with primary and secondary progressive multiple sclerosis (MS), major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid–enhanced MRI over a 6‐month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (18.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6‐month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials.

The steady flow of potential new treatments for multiple sclerosis continues with data resulting from studies ranging in complexity from early pilot trials to phase three studies. While this is in itself encouraging, interpretation of the data presented, and in particular evaluation of the potential clinical usefulness of an agent, is often less than straightforward. Improved understanding of the immunopathogenesis of multiple sclerosis and better trial design incorporating more appropriate and responsive outcome measures should be grounds for continuing therapeutic optimism.