Hypertonia is seen in 85% of people with Multiple Sclerosis (pwMS) resulting in disability and functional restrictions. Hypertonia can be caused by increases in passive stiffness and enhanced stretch reflexes (spasticity) and is frequently managed clinically using passive stretches. However, the optimal parameters of stretching such as the applied torque and stretch duration remain unclear. During commonly prescribed ankle plantarflexor stretches pwMS produced higher torques when standing in a weight bearing position compared to stretches applied using the upper limbs. Stretches could be held for 120 seconds on average and stretch duration was mainly limited by fatigue. People with higher disability tended to favour more supported stretching positions. The effects of stretching for either 30 or 10 minutes using a customised motor at three torque levels covering the range that MS participants could produce was investigated. Compared to the 10 minute stretch, greater reductions in passive stiffness and greater increases in range of movement (ROM) were seen immediately following the 30 minute stretch with the effects being sustained for the 30 minute post stretch period. Higher levels of applied torque resulted in a greater change in ROM however; there was no effect of applied torque on passive stiffness. Stretch reflex mediated stiffness was unaffected by the stretching intervention and showed transient post stretch increases. Ultrasonography was used to investigate changes in muscle–tendon length and strain in pwMS and controls and following stretching. PwMS showed evidence of stiffer muscles and increased tendon length at baseline compared to controls. Following a 10 minute stretch overall muscle length did not increase in pwMS, although increases in strain in the musculotendinous junction region were observed suggesting that more proximal regions of the muscle was likely to have contributed significantly to overall stiffness. This work highlights that stretch duration and levels of applied torque are critical factors in determining the effectiveness of stretches. The pathological mechanisms underlying hypertonia at a molecular and structural level and the effects of stretching on components of the musculo-tendinous structure and on functional ability should be ascertained.

This PhD thesis examines the relationship between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). ALS is a rapidly progressive neurodegenerative movement disorder characterized by muscle weakness, spasticity and abnormal reflexes. In a very small subset of patients (5-15%), ALS is associated with FTD. Furthermore, a larger subset of patients who do not suffer from overt dementia, develop subtle deficits in cognition and behaviour (up to 50%). The changes have mostly been observed in the domains of executive functions, language and behavioural functioning. These observations have led some researchers to propose a continuum of dysfunction between ALS and FTD, ranging from an absence of neuropsychological abnormalities to mild, subclinical changes to a profile consistent with a full-blown FTD-syndrome in ALS. FTD consists of three subsyndromes; the first ‘executive-behavioural’ type, frontal variant FTD (fvFTD), is predominantly characterized by behaviour abnormalities, difficulties with using strategies and social judgement. In contrast, the other two types mainly involve problems with ‘language’, including a central degradation of knowledge for words, objects, people (semantic dementia; SD) as well as complications with speaking, spelling and the sounds of language (progressive non-fluent aphasia; PNFA). The current study aims to explore whether the cognitive-behavioural deficits found in nondemented ALS-patients can be classified as subclinical forms of the first two FTDsyndromes, i.e. fvFTD and SD. In addition, the study further examined whether executive and language impairments co-exist or rather occur independently. To answer the research questions, a battery of neuropsychological tests was employed, adapted to patients’ speech and motor disabilities, as well as behavioural questionnaires. The data revealed there was evidence of both executive and language involvement characteristic of FTD, albeit to a subtle extent. ALS-patients showed deficits on a test of Theory of Mind (ToM). On this test, participants were asked to judge the thoughts and feelings of another, using the direction of eye gaze, a cue considered to be important for social interaction. Results indicated that ALS patients had difficulties with affective ToM, i.e. recognizing feelings of others, and this effect was not driven by perceptual or attentional difficulties. In addition, patients exhibited a subtle deficit with empathy as well as a range of behavioural abnormalities. Furthermore, ALS-patients showed abnormal performance on a complex multi-modal semantic association task which involved assigning the correct picture iii to the sound of an object. This central deficit emerged in the presence of normal audio-visual information processing and episodic memory functions. Moreover, a category-specific deficit for man-made objects was detected in patients. Individual case-analyses showed that various subsets of patients were impaired on the language and executive tasks. These analyses also showed that executive and language problems can occur independently as well as simultaneously in patients with ALS. In addition, analysis of individual cases revealed that some patients’ performance on the decision making tasks was similar to that found in patients with either orbitofrontal or dorsolateral dysfunction, while there was little if any evidence of a pattern of impairment similar to that seen with anterior cingulate dysfunction. The observed difficulties with social cognition and semantic processing indicate that executive and language problems, characteristic of the two FTD syndromes, can be detected in patients with classical ALS.

No description available.

♠ Abstract ♠ Title Interdisciplinary rehabilitation, with its focus on physiotherapeutic and alternative techniques, as symptomatic therapy, and its effect on quality of life of multiple sclerosis patients: a literature review Background Multiple sclerosis (MS) is an autoimmune anti-inflammatory demyelinating disease that gives rise to multiple symptoms, which affect the patient's quality of life (QoL). Up to date, a cure does not exist, yet recent research with the use of mesenchymal and haematopoetic stem cells is promising. The first line of treatment is pharmacological management of the auto-immune response, followed by the management of the symptoms. That is why a comprehensive inter-disciplinary management is required with different interventions and techniques to provide more personalised care. Moreover, due to the unpredictable and progressive nature of the disease, the prevalence of MS patients seeking complementary and alternative therapies (CAM) has increased, specifically in the form of acupuncture and Qigong. Aim The purpose of this thesis is to outline and integrate the different methods and techniques that could be used within a comprehensive team, with the integration of acupuncture and Qigong towards the management of MS. With the main goal of achieving the most realistic and achievable QoL...

Cyclophosphamid (Endoxan) ist ein zytostatisches Medikament, welches wegen seiner immunsuppressiven Wirkung eine breite Anwendung in der Therapie systemischer Autoimmunerkrankungen findet. Es wird als Medikation bei schwerer chronisch-progressiver Multipler Sklerose empfohlen, um die weitere Progredienz einzuschränken oder zu verhindern. Bisherige klinische Studien über den Wert dieses therapeutischen Einsatzes liefern aber kontroverse Ergebnisse. Aus diesem Grund erschien es sinnvoll, die über einen längeren Zeitraum an der Neurologischen Universitätsklinik Würzburg mit der Cyclophosphamid-Therapie bei MS-Patienten gesammelten Erfahrungen in einer retrospektiven Analyse darzustellen. Patienten und Methoden: Zwischen 1983 und 2000 wurden 118 MS Patienten (75 Frauen, 43 Männer, durchschnittliches Alter zu Beginn der Therapie 46,6 ± 8,5 Jahre, durchschnittliche Krankheitsdauer zu Beginn der Therapie 9,7 ± 5,1 Jahre) mit Cyclophosphamid behandelt. 103 Patienten (87%) litten an chronisch progressiver MS (69 SPMS, 25 PPMS, 5 CP, 4 CP mit RR) und 2 an einem schubförmigen Verlauf. Bei den meisten Patienten war eine rapide Verschlechterung (Mittlerer EDSS-Wert 6,5), mit Gefahr des Gehverlustes, Grund für den Therapiebeginn. Die Induktionstherapie wurde mit 350 mg/m2 Körperoberfläche Cyclophosphamid, zumeist in Kombination mit 1000mg Methylprednisolon, über 3 - 5 Tage eingeleitet und mit 600 - 1000 mg/m2 in 4 - 12-wöchigen Abständen beibehalten. Die EDSS-Werte wurden zu Beginn, jährlich und nach Beendigung der Therapie erfasst. Der Progressions-Index wurde als Quotient aus EDSS-Wert und Krankheitsdauer definiert. Ergebnisse: 63 Patienten erhielten Cyclophosphamid länger als ein Jahr und wurden eingehender untersucht. Die vorherrschenden Gründe für einen vorzeitigen Therapieabbruch waren weitere Progression (n=18) oder nicht tolerable Nebenwirkungen (n=9). Zwei Patienten nahmen die Therapie nach einer Pause wieder auf. Die länger als ein Jahr behandelten Patienten vertrugen die Therapie gut. Nebenwirkungen wurden von 82 % berichtet, wobei die meisten als mild bezeichnet wurden (WHO Grad 1). Bei 9 % waren sie schwerwiegend (WHO Grad 2), bei weiteren 10 % führten sie zum Therapieabbruch (WHO Grad 3). Die durchschnittliche Behandlungsdauer betrug 28,8 +/- 12,3 Monate, mit einer durchschnittlichen kumulativen Dosis von 12,3 ± 7,4 g. Der durchschnittliche Nachbeobachtungszeitraum betrug 39,3 ± 28,7 Monate. Der mittlere EDSS-Wert stieg signifikant von 5,0 auf 6,25 in den zwei Jahren vor Therapiebeginn, blieb stabil während der Behandlung und stieg nach Beendigung der Therapie weiter auf 7,0. Parallel dazu war der Progressions-Index am höchsten bei Therapiebeginn mit 0,64, fiel zum Ende der Therapie auf 0,50 und sank weiter auf 0,44 während des Follow-Ups. 71% blieben stabil während der Behandlung, 13% verbesserten sich, und 16% verschlechterten sich. Schlussfolgerung: Die Daten dieser retrospektiven Analyse zeigen, dass bei Versagen der Standardtherapie einer schweren chronisch-progredienten Multiplen Sklerose Cyclophosphamid in Form einer Induktionstherapie mit Auffrischzyklen alle 4-12 Wochen im Rahmen einer Eskalationstherapie effektiv und vertretbaren NW eingesetzt werden kann. / Cyclophosphamide is a cytostatic medication is widely appied due to its immuno-suppressive potential in the thapy of auto-immun diseases. It is recommended in the treatment of multiple sclerosis in order to prevent further disease progression although clinical evidence is limited. This retrospective study evaluates clinical data of the University Hospital of Neurology, Wuerzburg. Results: Cyclophosphamid is effective and safe in therapy-refractory Multiple sclerosis.

Background: Multiple sclerosis (MS) is a neurological disorder and the most frequent neurological cause of disability in young adults. 40-65% of MS patients experience cognitive difficulties (Bennedict et al., 2012), with problems in memory, attention and information processing speed being most frequently reported. However, visuoperceptual and language functions are much less studied in MS, but the few studies that looked into them (Vleugels, 2001; Grossman, 1995) have found prevalence of significant posterior deficits in MS. Up to today no study has investigated the domain-specificity of cognitive dysfunction in MS and its longitudinal progression. Aims: The primary aim of this project was to investigate the dimensionality of MS-related cognitive impairment longitudinally. The second aim was to determine the predictors of the observed longitudinal changes. The third aim was to investigate whether the participants themselves were aware of their cognitive changes, and what predicted the self-perception of change. Methods: To address these aims I followed a sample of MS patients and compared their performance on cognitive tests measuring five cognitive domains (verbal memory, visuospatial memory, processing speed, visuoperceptual and language) at baseline and at follow-up three years apart. Then I’ve composed separate models to explain the predictors first of the actual changes, and then of the perceived changes in performance. Moreover, as part of this project I have analysed pre-existing data to evaluate the instruments and optimized the baseline test battery for use in performing the followup assessments. Findings: I have managed to collect follow-up data on 82 MS patients and 23 matching healthy controls, acquiring high (76% and 79% respectively) recruitment rates. My MS sample (24% PPMS, 34% SPMS and 46% RRMS) was representable of the overall MS population. I found that deficits were seen in all cognitive domains (none were spared) and that new deficits were picked up sporadically, although with higher predisposition towards the information processing speed, visuoperceptual and memory domains. The new deficits showed the tendency to slowly accumulate, leading to development of major problems with longer disease duration. Interestingly it was found that even though the factors that influenced cognitive decline were specific for each of the cognitive domains, however, neurological disability, MS type and levels of depression were the most common predictors of change in cognitive functioning. I found that in general MS patients perceived longitudinal changes on the BRBN battery more accurately than on visuoperceptual and language tests, and the factors that played a role in the self-perception of change were executive dysfunction, neurological disability and MS impact. Implications: The results of this study add significant contribution to the field of longitudinal change in cognition in MS. Not only I explored the dimensionality of MS-related cognitive deficits, but also examined the factors that led to poorer performance, and the patients’ own perspective of their cognitive change. Moreover, with this project I have addressed common problems in the field of longitudinal research in MS – definition of normal variation in performance; the sensitivity of cognitive tests to pick up MS-related deficits; and heterogeneity of cognitive impairments in MS; - and I have used the performance of my own controls in attempts to account for all of that. I believe that this study will be of interest not only to those who specialize in cognitive functioning in MS, but also to those who question the methods employed in clinical research to define impairments and to account for individual differences.

No description available.

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system and is considered to be a T-cell mediated autoimmune disease. The “ideal” method in treating MS would be an antigen-specific therapy that does not require generalized immunosuppression. To date there are no definitive treatments for MS but there are several licensed therapies such as -interferon. Unfortunately the effect of interferon (IFN) is reduced by the development of neutralizing antibodies (NAbs) in up to 35% of MS patients within two years of starting treatment. An immunization schedule was developed in the BALB/c mice by subcutaneous administration of recombinant human IFN, and this resulted in development of high incidence of NAbs to the protein in the BALB/c model termed “NAbs model”. The mechanism of NAbs formation in this model is believed to be similar to that observed in IFN-treated MS patients with NAbs, which is as a result of an immune response to the protein. We elected to study NAbs in the context of IFN rather than MS directly to investigate the effects of antigen-specific tolerization strategies on the outcome of NAbs and indirectly on the outcome of IFN treatment in MS disease. The depletion of the immune cells triggers a reconstitution program that leads to renewal of the immune cell repertoire. Tolerance can be induced by intravenous administration of a protein. Within this window of reconstitution following depletion, it is hoped that the immune system can be manipulated to tolerate an otherwise foreign protein (human recombinant IFN). The tolerance strategy employed in this project was immune cell depletion using antibodies and mitoxantrone, followed by intravenous re-introduction of rhIFN. Tolerance was successfully induced in the NAbs model by intravenous administration of rhIFN, and further enhanced by immune cell depletion prior to intravenous administration of rhIFN. The BALB/c “NAbs model” offers a suitable model for use in investigating induction of tolerance to rhIFN following the formation of NAbs to the protein. The antigen of interest is known and the time to NAbs formation is also known. Tolerance induction can be monitored and investigated in this model.

Background: Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune inflammatory disorder of the central nervous system, with significant morbidity and mortality. The lymphocyte depleting, anti-CD52 monoclonal antibody alemtuzumab is a highly effective treatment option in RRMS, though associated with high rates of secondary autoimmune disorders. As alemtuzumab is now in routine clinical use, following licensing in Europe and the US, understanding the effects of repeated treatment cycles and reducing the risk of secondary autoimmunity is timely and essential. In this thesis, I explore how repeated treatment impacts the extent of lymphodepletion. I also study the role of soluble CD52, recently described as suppressive via interaction with Siglec-10, in the mechanism of secondary autoimmunity, and determine the biomarker potential of pre-treatment cytokine levels. Findings: CD4 and CD8 lymphocytes are less effectively depleted with repeated treatment cycles. Lymphocyte surface CD52 density was found by flow cytometry to be significantly lower after alemtuzumab treatment, although CD52-negative clones are not seen. In a cytolysis assay, reduced CD52 density was shown to correlate with reduced susceptibility to alemtuzumab. In addition, activated proliferating T lymphocytes, as observed after treatment, downregulated CD52 expression in a gene expression assay and shed the antigen from cell surface as demonstrated by ELISA and flow cytometry. The development of immunoassays to detect and quantify anti-idiotype antibodies to alemtuzumab is presented. The occurrence of antibodies at retreatment did not reduce lymphocyte depletion. A regulatory role for soluble CD52 was not found in suppression assays, and the proportion of antigen-activated CD52hi T cells did not vary between healthy controls and RRMS individuals. Siglec-10 was not seen on cell surface of activated T cells by flow cytometry and gene expression; thus concluding that soluble CD52 does not play a role in post-alemtuzumab induced autoimmunity. Prior to treatment, the only serum cytokine found to distinguish individuals who develop autoimmunity from those who do not was IL-21 (higher in the autoimmune cohort), however currently commercially available IL-21 immunoassays have no utility as predictive biomarker tests.

The subject of this thesis is the use of Magnetic Resonance (MR) Imaging to quantify biometric MR indices in the Multiple Sclerosis (MS) fixed post-mortem central nervous system (CNS) tissue. Evaluating these indices in fixed tissue allows for the use of histology to verify the findings of MRI. However, it must first be discovered if the indices can be evaluated in fixed post-mortem spinal cord tissue. There is very little literature in this specific area, though some in the fixed brain, the results of which have been assumed to be equivalent in the spinal cord without proof. Therefore, the methodology must first be verified before the consideration of any index as useful and translatable to in-vivo spinal cord. This thesis concentrates on the evaluation of MR relaxometry methods using the indices T1 and T2 by themselves and to evaluate the myelin content of fixed post-mortem CNS tissue. The Carr-Purcell-Meiboom-Gill (CPMG) and Multicomponent Driven Equilibrium Single Pulse Observation of T1 & T2 (mcDESPOT) sequences are used to calculate T1, T2 and the Myelin Water Fraction (MWF) which is believed to be proportional to myelin content in the CNS. This is performed at 3T in a clinical scanner and at 7T in a small animal and wholebody scanner. The methods are first evaluated for use in fixed post-mortem CNS tissue. The two myelin measurement methods are then compared to histological staining if appropriate and where available to verify that the results obtained are proportional to myelin content. The T1 and T2 values in fixed tissue were found to be shortened in fixed tissue, T2 values were so short as to be at the limits of measurement by a clinical scanner, and values converged in white and grey matter, and therefore contrast was found to be limited between these tissues. Proton density images provided the most contrast between tissues. However, even with shortened T2 values, the CPMG sequence was able to identify the myelin water component in fixed tissue. The mcDESPOT algorithm struggled to separate the myelin water component due to clinical scanner limitations and the shortened, converging T1 and T2 values. However, the mcDESPOT algorithm was successful in discerning the myelin water component in the high signal situation of a small bore 7T peclinical scanner. An evaluation was then made of the usefulness of these indices for translation into clinical imaging. The CPMG sequence was found to be proportional to myelin content under all conditions, and therefore useful for disease monitoring in demyelinating diseases. The mcDESPOT sequence, was found to be proportional to myelin in some conditions, and is likely to be useful for monitoring myelination, though the sequence could not be fully validated in this thesis.