Not all stroke patients are admitted to hospital. The literature indicates that between 22% and 60% of stroke patients remain in the community, often with little or no rehabilitation. Occupational therapy is commonly used in the treatment of stroke patients and aims to promote recovery through purposeful activity. Several small trials have suggested that this approach may be effective in reducing disability but none has examined the effect of occupational therapy on stroke patients not admitted to hospital. Therefore the aim of this study was to evaluate the effect of occupational therapy on the disability and handicap experienced by stroke patients who remain in the community. Patients were recruited to the study from a community stroke register. This register covered a geographical area of Nottingham and Southern Derbyshire, incorporating 73 general practitioner practices, covering 494,000 patients. Patients were included in the study if they fulfilled the WHO definition of stroke and had not been admitted to hospital. Patients were excluded if they lived in a nursing or residential home, could not speak or understand English prior to their stroke or had a previous history of dementia. At one month after stroke patients were assessed on a series of physical and cognitive assessments. Patients were then randomly allocated to a treatment group or a control group. Patients allocated to the treatment group received visits from a research occupational therapist for up to five months. The main aim of treatment was independence in personal and extended activities of daily living. Patients were also encouraged to participate in leisure activities. Two hundred and forty patients were notified to the study and of these, 55 patients were excluded. Of the remaining 185 patients, 94 were randomly allocated to the treatment group and 91 to the control group. All baseline assessments and demographic data were well matched between the groups. Twenty-two patients could not be assessed at six months; 13 patients had died during follow up and nine withdrew from the study. Significant differences were found between the groups at six months after stroke on the Barthel Index (p=0.002, 95% CI 0 to 1), Nottingham Extended Activities of Daily Living (p=0.009, 95% CI 1 to 4), Rivermead Gross Function (p=0.004, 95% CI 0 to 2), Caregiver Strain Index (p= 0.02, 95% CI 0 to 2) and the London Handicap Scale (p=0.03, 95% CI 0.3 to 13.5). There were no significant differences between the groups on the Hospital Anxiety and Depression scale. General Health Questionnaire 28 for either the patient or the carer or on the Nottingham Leisure Questionnaire. This study demonstrated that occupational therapy significantly reduced the level of disability and handicap experienced by stroke patients who remained in the community and also significantly reduced the strain of the carer. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.

Until recently, meta-analyses have usually been performed based on summary data methods. Individual patient data methods are becoming more popular, but the advantages of using these methods have not been fully investigated with regards to assessing and exploring heterogeneity. This thesis has assessed whether there are any clinically important differences in the results from analysing data from three meta-analyses of randomised controlled trials in the area of stroke medicine, using summary and individual patient data methodologies. Blood pressure ill Acute Stroke Collaboration (BASC) The management of blood pressure during the acute phase of stroke remains an enigma, therefore a systematic review and meta-analysis of existing randomised controlled trials was conducted to assess the effects of vasoactive drugs on outcome. Trends towards an increase in the risk of death, and death or dependency at the end of trial were found in patients randomised to a vasoactive drug as compared to those randomised to control. When baseline systolic blood pressure was taken into account in the analyses, patients randomised to a vasoactive drug had a significantly higher risk of death at the end of trial. Analyses also indicated that patients recruited early and within 48 hours has significant increases in the risk of death at the end of trial. However, no significant effects were seen for early change in systolic blood pressure. Community occupational therapy in stroke patients An evaluation of the efficacy of occupational therapy given in the community to stroke patients was performed using a systematic review and meta-analysis of randomised controlled trials. At the end of intervention, patient randomised to occupational therapy had significantly higher scores for extended and personal activities of daily living, and non-significantly higher scores for leisure participation. These effects appeared to be maintained over time. No effects were seen between the groups for death or minor psychiatric disorders as measured in patients or their carers. Subgroup analyses revealed that the benefits of occupational therapy were greatest when targeted interventions were used. Also, being male or independent at baseline was found to be important predictor of extended activities of daily living scores. Dipyridamole in Stroke Collaboration (DISC) Results from randomised controlled trials of dipyridamole, given with and without aspirin, for secondary prevention after stroke or transient ischaemic attack have given conflicting results; therefore, we performed a systematic review and meta-analysis. The risk of subsequent fatal or non-fatal stroke was reduced using the dual treatment of aspirin and dipyridamole as compared to either aspirin alone, dipyridamole alone, or control. Additionally, the dual treatment lowered the risk of non-fatal stroke, and subsequent vascular events defined by a composite outcome (non-fatal stroke, non fatal myocardial infarction, or vascular death). Analyses indicated that these results were independent of method of formulation of dipyridamole, dose of aspirin, type of qualifying event, and gender of the patients. However, increasing age was found to be an important predictor of subsequent stroke. These systematic reviews demonstrate that collaborations within the area of stroke medicine can be successful and much data can be shared. The findings from meta-analyses can be informative about the effectiveness of particular treatment and about which patients should be targeted for treatment; and may help steer the direction of future trials. Although summary data meta-analyses are practically easier to perform, it is important that assessments and explorations of heterogeneity should always be performed. Meta-analyses based on individual patient data may be needed to allow for more in depth investigations of heterogeneity, especially of patient characteristics. However, they themselves are not the panacea to all difficulties since they are subject to particular problems, mainly related to obtaining individual patient data to enable these in depth analyses to be performed.

People who have suffered a stroke can become housebound and miserable because they cannot access suitable transport. They can have difficulty getting to the shops, doctors and hospital and this can have an effect on their quality of life. Occupational therapists routinely aim to help these people overcome their outdoor mobility problems by providing information and verbal instructions but these interventions do not appear to be effective. The aim of this research was to design and evaluate a new occupational therapy outdoor mobility intervention. The intervention was modeled on travel training that is provided for other conditions and the outdoor mobility experiences and needs of people with stroke. Qualitative semi structured interviews were used to investigate 24 peoples experiences of both using transport and their outdoor mobility after they had suffered a stroke. It was found that people wanted to travel for a variety of reasons; shopping, work, getting to the doctors, social reasons, meeting friends, visiting family and just for the sake of traveling. People were prevented from traveling because of physical difficulties such as stepping onto the bus, psychological problems such as confidence and environmental barriers such as the weather or lack of information. The results were used to define the main components of an Occupational Therapy Outdoor Mobility Intervention. A randomised controlled trial was used to evaluate the effects of this Occupational Therapy Outdoor Mobility Intervention (OTOMI) by comparing it to the routine occupational therapy intervention. Participants with stroke in the last 36 months were recruited from primary care services and randomly allocated to receive either the OTOMI or the routine occupational therapy. Participants in the OTOMI received up to seven individualised occupational therapy sessions. The sessions aimed to increase confidence, encourage use of different types of transport and provided tailor-made information. Outcomes were measured by postal assessment 4 and 10 months after recruitment. The primary outcome measure was a yes/ no question, Do you get out of the house as much as you would like? Secondary outcomes included the number of journeys, mood, performance of activities of daily living and leisure. 168 participants who had had a stroke in the last 36 months were recruited into the study over eighteen months, 82 in the control group and 86 to the OTOMI group. 10 people were unable to provide follow-up information at the four month assessment and 21 people at the ten month assessment. Intention-to-treat analyses were undertaken. For the principal outcome measure, participants who were dead at the point of assessment were allocated the worst outcome, and for others lost to follow up their baseline or last recorded responses were used. For the other analyses all missing values were imputed using baseline values. Participants in the treatment group were more likely to get out of their house as often as they wanted at 4 months (RR 1.72,95% CI 1.25 to 2.37) and at 10 months (RR 1.74,95 Cl 1.24 to 2.44). The treatment group recorded more journeys outdoors in the month prior to assessment at 4 months (intervention group median 37, control group median 14, Mann-Whitney p<0.01) and at 10 months (intervention group median 42, control group median 14, Mann-Whitney: p<0.01). At 4 months the NEADL mobility scores were significantly higher in the intervention group, but there were no significant differences in the other secondary outcomes. There were no significant differences in these measures at 10 months. The interview study demonstrated that participating in outdoor mobility is a major problem for people who have had a stroke. The randomised controlled trial demonstrated that a relatively simple and feasible, individualized, properly organised, focused and adequately resourced occupational therapy outdoor mobility intervention can increase participation in outdoor mobility activities, allowing people to get out of the house as much as they wish.

The aims of this study were to investigate (i) the levels of catecholamines, indoleamines, substance P and thyrotrophin-releasing hormone (TRH) in the post-mortem spinal cord of subjects who had died with Parkinson's disease and to compare them with those of control subjects (ii) adrenergic and serotonergic receptors in the post-mortem Parkinsonian and control spinal cord and (iii) the effects of subject age and sex and the interval between death and post-mortem (PMI) on the levels of neurotransmitters and neuropeptides and on receptor binding in post-mortem tissue. To perform these investigations (i) a sensitive radioimmunoassay which is specific for substance P and has low cross-reactivity with other similar peptides and (ii) a common extraction medium for the concomitant extraction of catecholamines, indoleamines, substance P and TRH from CNS tissue were developed. The main findings were: There were significant correlations between the levels of 5HT, TRH and α2-adrenoceptor binding and both subject age and the PMI. In Parkinson's disease compared with control subjects: (i) the levels of noradrenaline were significantly reduced in the thoracic ventral region of the spinal cord,(ii) dopamine levels were higher in the thoracic ventral and dorsal spinal cord,(iii) in the lumbar spinal cord 5HT levels were significantly reduced in the dorsal horn with an increase in the ratio of 5HIAA/5HT, (iv) noradrenaline levels were reduced in both dorsal and ventral horns of the lumbar spinal cord and (v) there were no differences between the levels of substance P and TRH in any spinal cord region. There were no measurable 5HT1A or 5HT2 binding sites in the human spinal cord under the conditions used. However, specific α2-adrenoceptor binding was defined in terms of binding affinity and number of receptors in the spinal cord.

Background: Stroke is among the most common causes of disability and stroke survivors may experience cognitive impairment, low mood and fatigue. These three are often associated, as mood and fatigue share some common symptoms and fatigue can also be expressed in a cognitive manner. Fatigue is multifaceted and cannot be easily defined which complicates its measurement. There is a lack of understanding regarding the relationship between fatigue and cognition after stroke and the studies suffer methodological limitations. Objective: This project examined the above concepts and the relationship between fatigue and cognition, more specifically, speed of information processing, sustained and selective attention. Methods: The relationship was examined by: i) systematically reviewing current evidence on this relationship and ii) by conducting three studies that investigated the relationship between fatigue, mood and cognitive impairment in first stroke survivors in the acute phase without depression, in first stroke survivors in the acute phase with depression and in chronic stroke survivors measuring cognitive aspects of fatigue (Fatigue Scale for Motor and Cognitive Functions) as well. We also iii) explored the reliability of and the components assessed by the Fatigue Severity Scale. Results: The systematic review identified 11 studies that examined the relationship. Results were inconclusive as some studies confirmed a significant relationship while others did not. Overall, the findings suggested that memory, attention and speed of information processing are associated with fatigue after stroke, with coefficients ranging from r= .36 to .46. Levels of fatigue and cognitive impairment were reported as moderate. Our three studies did not reveal any statistically significant association between fatigue (general, cognitive or motor) and cognitive performance (either selective and sustained attention or speed of information processing). We also confirmed the uni-dimensionality of the Fatigue Severity Scale in our sample with the use of component analysis; the scale also revealed nearly excellent internal consistency (α=0.95). Conclusion: The Fatigue Severity Scale is a reliable fatigue scale that is commonly used in stroke research. The Fatigue Scale for Motor and Cognitive Functions is a relatively new fatigue scale with high psychometric properties. The lack of significant relationship between fatigue and cognitive impairment may be attributed to the choice of cognitive components that were examined in this study. Implication of Project/Findings: Cognitive impairment after stroke is very common and so is fatigue. If these two are associated in any way, it will be beneficial to explore such a relationship, or even the lack of it, in order to better understand cognitive mechanisms of fatigue and to potentially incorporate them in future psychological interventions. Further Suggestions: Future studies may benefit from incorporating general and cognitive fatigue scales as well as including domain specific and general cognitive test. The findings of this study highlight the complexity of fatigue and speed of information processing as phenomena. Despite not revealing any significant relationship between certain cognitive aspects and fatigue, it may be worth examining the relationship between fatigue and memory components which are less commonly included in similar studies. Funding: This project was funded by the University of Nottingham (Vice Chancellor’s Scholarship for Research Excellence-European Union; Scholarship Reference Number: RFDX42DB2). No financial or other conflict is declared.

Psychogenic non-epileptic seizures (PNES) are a relatively common condition, however, seizures can be debilitating for patients and are associated with high levels of psychological distress, reduced quality of life and reduced functionality. Despite the debilitating effects of the condition, there is thus far no recommended treatment. Although psychological therapy is often sought following the diagnosis of PNES, there remains relatively little research in the area comparing treatment efficacy. Nevertheless, many treatment efficacy studies focus on the application of cognitive behavioural therapy to PNES and the results produced so far appear promising, however, the psychotherapeutic mechanisms of change for such therapies are less clear. Acceptance and Commitment Therapy (ACT) is a third-wave behavioural approach based on theoretical mechanisms of change. ACT may have benefits over other traditional therapies, as its contextual approach may be more acceptable to individuals with PNES, especially if they have had difficulty in adjusting to the concept that their seizures are caused by psychological, rather than physical processes. A single case experimental design was carried out to assess the efficacy of an ACT guided self-help intervention on psychological flexibility, psychological distress, quality of life and seizure frequency. Participants also completed a qualitative change interview at one-month follow up. The intervention was replicated six times. All participants demonstrated an increase in psychological flexibility following the ACT self-help intervention. Four of the six participants demonstrated reliable improvements in quality of life and psychological distress. The same four participants also reported a significant decrease in seizure frequency following the intervention, with three participants reporting that they were seizure free at one-month follow-up. Triangulation of the quantitative time-series data and qualitative change interviews indicated that openness to awareness processes (acceptance and cognitive defusion) were key mechanisms of change for individuals with PNES. The study demonstrated the utility of an ACT treatment approach delivered in a self-help format for individuals with PNES. The implications of the study findings for future research and clinical practice are discussed.

Cognitive impairment and fatigue are prevalent and impactful symptoms of multiple sclerosis (MS). Effective markers are required by clinical studies to accurately test the efficacy of treatments for these symptoms. Graph analysis of brain networks based on magnetic resonance imaging (MRI) data can feasibly provide useful candidate markers of cognitive impairment and fatigability in MS which may be more objective, reliable and specific than existing markers. My original contribution to knowledge is therefore an exposition of the following hypothesis: “summary graph-theoretic descriptors of brain network organisation are good candidate markers of cognition or fatigue in MS”. To achieve this, network metrics were assessed based on three main criteria: reliability (“are the measurements the same across time and settings?”), validity (“do they measure what they are supposed to measure?”) and responsiveness (“are they altered when a change in cognitive state is induced?”). The applicability of the graph-theoretic approach was first established with a spatial meta-analysis of tract integrity and its relevance to cognition and disability. Reliability over time in healthy subjects was assessed by systematic review and reliability between different scanners and between MS and control groups was assessed in two longitudinal datasets by measuring intra-class correlation (ICC) of graph metrics. The validity criterion was assessed in an analysis of covariance and linear regression of cognitive and fatigue measures with brain network metrics in people with MS. Finally, an exploration of network dynamics during a sustained attention task with a sliding-window approach was performed to test the immediate responsiveness of the measures to alterations in cognitive state. Spatial meta-analysis of white matter tract degradation was performed using the Signed Differential Mapping method. Statistical maps were gathered from the original authors of studies which performed voxelwise correlations between fractional anisotropy (a measure of white matter integrity based on diffusion tensor imaging data) and measures of either cognitive impairment or physical disability. The combined sample included 495 people with MS and 253 controls from 12 studies. MS diagnosis was significantly associated with widespread lower tract fractional anisotropy. Distributions of voxels with significantly lower fractional anisotropy in relation to cognition and physical disability were only minimally overlapping. The number of and effect sizes for significant clusters in the cognition comparison were greater than those for the physical disability comparison, suggesting a greater relevance of cerebral white matter damage to cognition. The main results remained significant when using a stringent p-value threshold of 0.00001 to control for false positives. The next analysis was a systematic review of the reproducibility of graph metrics over time in healthy people. Online databases were searched for articles reporting ICCs for graph metrics based on imaging data and information was recorded on the sample size, acquisition method, inter-scan interval and reported ICCs. Twenty-six articles were included, with a combined sample size of 676. Overall, reproducibility over time was rated as “good”, but heterogeneity of methods precluded in-depth quantitative analysis. A qualitative synthesis of results highlighted the main methodologic factors affecting reproducibility, which included: ICC type, retest interval, fibre tracking algorithm, graph metric type, image processing strategy, region of interest size, graph threshold and acquisition method. Reliability of brain network metrics between scanners was tested using a travelling-subjects dataset in which 5 subjects each underwent a resting-state functional MRI scan at 10 sites. Graph metrics were calculated for each scan and then tested for ICC across sites. Reproducibility was “poor” for most metrics (characteristic path length ICC=0.23, global efficiency ICC=0.18, modularity ICC=0.24) and “fair” for two (clustering coefficient ICC=0.43, small-worldness ICC=0.42). There was limited evidence that some subjects tended to produce less reliable results and that magnets with higher field strengths did not produce more reliable results. The main implication is that multi-site studies using graph analysis of brain MRI data should investigate inter-site reproducibility beforehand. To investigate the validity of graph metrics as markers of cognitive impairment and fatigue, MRI and neurocognitive data were first gathered from 37 people with MS and 23 matched controls. The sample was characterised in detail and comprised a range of cognitive abilities. Data quality was investigated and the small-world structure of the data was confirmed by comparison to random and lattice graphs. Analysis of covariance controlling for age, sex and education showed significant group differences for all but one graph metric. Linear regression models predicted the main measures of cognitive impairment in the MS group, but not in the control group. Measures of fatigue were not well-explained by graph metrics. The direction of the relationships indicated that greater levels of cognitive impairment were related to increased network clustering and modularity, longer average path lengths, lower small-worldness, lower levels of education, old age and sleep disturbance. Finally, responsiveness of graph metrics was investigated in an analysis of functional network dynamics during performance of a sustained attention task. A “sliding-window” approach was taken, in which network metrics were calculated for 84 100-second windows at increments along the fMRI timeseries. Reaction times in the task showed a learning effect for both groups, but were consistently slower for the MS group. Plots of graph metrics over time showed differing responses to the task and to the transition between task and rest periods between groups. The small-worldness and clustering coefficient metrics were correlated with reaction times for both MS (small-worldness: r=0.623, < 0.001; clustering coefficient: r=0.554, p= < 0.001) and control (small-worldness: r=0.586, < 0.001; clustering coefficient: r=0.627, p= < 0.001) groups, but the characteristic path length metric was not (MS: r=-0.154, p=0.313; control: r=0.343, p=0.021). Disconnection of cortical areas by degradation of white matter is a viable explanation for cognitive symptoms in MS. There is some evidence that increased network segregation and decreased network integration may explain cognitive symptomatology. Graph theoretic summary brain network metrics do have potential for use as complimentary information to existing markers of cognitive impairment in clinical studies.

Background: Approximately 152,000 people have a stroke in the UK every year, a quarter are working age and only 40% return to work. Vocational rehabilitation (VR) provision is patchy in the UK and has not been evaluated for the stroke population. Aim: This study aimed to develop, deliver and evaluate stroke specific VR in a feasibility randomised controlled trial (RCT) in one English county. Method: A qualitative interview study with key stakeholders sought to explore barriers to and unmet needs for support for stroke survivors intending to return to work. The findings, two case studies and an expert panel informed the development of a stroke specific VR intervention. Its potential effectiveness in influencing occupational status at 12 months post baseline was measured in a feasibility RCT. Intervention content was analysed and the stroke survivors and employers who received it were interviewed about its usefulness and acceptability. Results: 18 key stakeholders identified barriers to VR in existing service design and delivery. Stakeholders identified the need for individualised, responsive, timely and flexible intervention including support for family members and employers. 46 people, with mainly minor and moderate strokes, were recruited to the feasibility trial and 23 randomised to stroke specific VR. Delivery and compliance with intervention was feasible. Only one participant withdrew. Follow-up was feasible at three, six and 12 months post baseline as indicated by an overall response rate of 73.9%. Twice as many participants returned to work in the intervention group. Data collection on income and benefit status was problematic due to missing data. Secondary measures included quality of life, function, mood and participation. A proforma was successfully used to record and measure intervention content, which showed that stroke specific VR is an individually tailored complex intervention involving cross sector working. 12 stroke survivors and six employers interviewed following the trial, valued this flexible, individualised intervention which positively influenced return to work experiences and outcomes. Discussion: Stroke severity influenced participation and a different model may be needed for those with severe stroke and those unable to return to an existing job. Employer contact was not always possible or desired by the stroke survivor. Funding, targeting and implementing this type of intervention requires further consideration. Conclusion: Early intervention can potentially influence job retention rates in people with mild and moderate stroke but a larger trial is needed to demonstrate effect.

Convulsive status epilepticus (CSE) is an emergency condition associated with mortality and morbidity. It is commonly treated with antiepileptic drugs (AEDs), but these may cause serious adverse events and even death in children. Research on their effectiveness for CSE, and related adverse events in children remains limited. The primary aim of this research was thus to evaluate the effectiveness and safety of AEDs in treating acute tonic-clonic seizure including convulsive status epilepticus (CSE). Two systematic reviews and meta-analyses were conducted to address these aims. The first evaluated the effectiveness of AEDs in children with acute tonic-clonic seizures including (CSE). The second evaluated the safety of AEDs in this population. The systematic review of AED effectiveness identified 20 studies published between 1946 and April 2015. It showed that buccal midazolam was more effective than rectal diazepam for treating acute tonic-clonic seizures including CSE in children, and was associated with a lower recurrence rate. Lorazepam and diazepam were equally effective in terminating seizures, but for lorazepam, intravenous administration was more effective than the buccal, sublingual or intranasal routes. Intravenous valproate appeared to be more effective than intravenous phenytoin and phenobarbital; however, the difference was not significant. The systematic review of AED safety for children with acute tonic-clonic seizures identified 25 studies, published between 1946 and April 2015. These studies were predominantly randomised controlled trials and of these 19 studies reported more than one adverse event, while 6 reported none. A total of 203 adverse events were documented, most commonly respiratory depression (101 children), mainly after treatment with diazepam (46 children). The rates of respiratory depression with buccal midazolam and rectal diazepam were similar (3.0% and 3.3%, respectively). Compared to intravenous diazepam, intravenous lorazepam was associated with less respiratory depression. No child suffered respiratory depression associated with intravenous valproate treatment, compared to one child with intravenous phenobarbital. When looking at all adverse events, intravenous valproate was significantly safer than intravenous phenobarbital. Respiratory depression was not noted in children who received intravenous levetiracetam; however, all levetiracetam studies identified in this review were cohort and non-comparative. In conclusion, in the treatment of acute tonic-clonic seizures (including CSE), buccal was the best administration route for children admitted to the emergency department. Intravenous lorazepam treatment was associated with less respiratory depression than intravenous diazepam. Where IV access was practicable, intravenous lorazepam was the drug of choice. More randomised control trials are needed to evaluate the effectiveness and safety of AEDs as a second-line treatment.

Multiple Sclerosis (MS) has long been considered as White matter (WM) disease. The last decade, the significance of cortical lesions (CL) and their contribution to MS pathology has been intensely investigated. They have been shown to play a major role in physical and cognitive impairment in MS patients. CL detection has proven to be challenging, mainly due to poor contrast between cortical lesion and surrounding normal grey matter (GM) tissue. Various magnetic resonance imaging (MRI) sequences have been used to improve cortical lesion detection in MS patients. In recent years, Double inversion recovery (DIR), Phase sensitive inversion recovery (PSIR) and 7 Tesla T2* have been found to improve CL detection. Magnetization Transfer Imaging (MTI) has the advantage over conventional imaging as it reflects tissue myelin content. In this thesis, I present our studies using MTI at 7 Tesla to study cortical pathology in MS. 1) For a pilot study aiming to validate the use of magnetization transfer ratio (MTR) to detect cortical lesions, We examined the sensitivity of MTR to detect cortical lesions in comparison with 3 T DIR, 7 T PSIR, and 7 T T2* in 18 MS patients and 9 healthy controls. 2) A further 42 patients (11 clinically isolated syndrome (CIS), 11 relapsing remitting MS (RRMS), 10 primary progressive MS (PPMS), and 10 secondary progressive MS (SPMS)) and 8 healthy controls were scanned at baseline, 23 of these patients had a follow up scan at 12 months. MTR at 7 Tesla has increased sensitivity to detect cortical lesions compared to 3T DIR, 7T PSIR and 7T T2*. CL myelin content as measured by the mean MTR lesional values were the lowest in SPMS patients in comparison with the rest of MS phenotypes. CL mean MTR values, more than volume was associated with the degree of physical and cognitive disability in MS patients. When MTR was studied in a longitudinal study, we have seen more changes in average MTR of cortical lesions in SPMS and CIS patients compared to RRMS and PPMS patients.