Anatomy and Neuroscience - Theses
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ItemNormal appearing brain tissue changes in optic neuritis patients at risk of MS( 2013)Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which affects white matter (WM), grey matter (GM) and normal appearing brain tissue (NABT). In 85-90% of MS patients, the first manifestation of the disease is an acute, remitting clinically isolated syndrome (CIS). One of the most frequent symptoms of CIS is optic neuritis (ON). The risk of conversion to MS in isolated optic neuritis (ION) patients with abnormal baseline magnetic resonance imaging (MRI) is about 40% one year post onset. The chance of conversion to MS significantly increases based on the number of lesions on baseline MRI. Therefore, ION patients at risk of MS provide an excellent opportunity to study the events occurring at the early stages of the disease. Pathological studies and MRI provide good diagnostic and prognostic information about MS. MRI techniques as in-vivo non-invasive tools have helped to better understand the substrate, pathophysiology and mechanisms underlying the development and evolution of focal lesions and diffuse damage in MS. There is a strong correlation between pathological changes in GM and NABT and future clinical disability of MS patients. Therefore, advanced MRI techniques such as diffusion tensor imaging (DTI) have been widely applied to discover injuries in both GM and NABT with more specificity and sensitivity. Early diagnosis of MS is essential for initiation of early treatment leading to better prognosis and fewer disabilities in future. In this thesis, the main aim was to investigate longitudinal microstructural changes in NABT in the visual pathways and beyond in ON patients at risk of MS using different modalities of MRI including volumetric and diffusion imaging techniques. Twenty three patients (17f/6m; mean ± SD age = 34.6 ± 8.6 yrs) and eleven healthy age matched controls (8f/3m; mean ± SD age = 36.4 ± 4.9 yrs) were recruited for the studies of this thesis. Patients were scanned around two weeks after their first presentation of ON and then at 1, 3, 6 and 12 months, and controls were scanned with one month separation. Following each scan session; multifocal visual evoked potentials (mfVEP) and optical coherence tomography (OCT) were acquired by a neuro-ophthalmologist. After completing the MRI safety questionnaire, all participants were scanned at the Royal Children’s MRI Centre, Melbourne, Australia on a 3T Siemens MRI scanner with a 12 channel receiver head coil. Each MR session consisted of whole brain and optic nerve T1-weighted images, whole brain and optic nerve T2 fluid-attenuated inversion recovery (FLAIR) images, and one DTI study. The baseline MR session also included gadolinium enhanced MRI. For the purpose of this thesis, whole brain T1-weighted, T2-FLAIR, and DTI images were used. In the first study, in order to investigate longitudinal microstructural changes in NABT in the visual pathway following ON, we chose the body of optic radiations (BORs) as the regions of interest (ROIs). BORs are highly indicative of tightly packed and collinear axon bundles, and diffusion findings in these regions in comparison to the other areas of the optic radiations are more reliable. More than half of the participants (52.2%) converted to MS after 12 months which made our participants an ideal sample of patients in the very early stages of MS. By using DTI, we demonstrated longitudinal microstructural changes in NABORs in ION patients during one year follow up. Most of the longitudinal diffusion parameter alterations were observed in the right NABOR. Microstructural changes were found to commence at a very early stage of MS, nearly one month following ON. We also showed that in ION patients there was a progressive longitudinal decrease in retinal nerve fiber layer (RNFL) thickness, and that earlier axonal loss in the optic nerve correlated with later diffusion changes in NABORs. Furthermore, there was a correlation between left visual hemifield amplitude asymmetry and FA value in the right NABOR a year following ON. The results of this study confirmed previous imaging findings that DTI technique allows to explore subtle WM degeneration and to investigate integrity of neuronal bundles in the brain. Furthermore, our results provided evidence that the involvement of NABORs following ON can be the result of the trans-synaptic damages following ON. In the second study, we chose visual cortices (VCs) as the ROIs to investigate atrophy in normal appearing grey matter (NAGM) in the visual pathway following ON during one year in ION patients at risk of MS. Furthermore, to investigate microstructural changes in beyond the secondary order neurons in the visual pathways, we focused on the connection between primary visual cortices (V1s) and the splenium of the corpus callosum (CC), called cortico-splenial (CS) tracts. CS tracts were defined using probabilistic tractography. By using volumetric assessment, we demonstrated longitudinal decrease in the volume of the right normal appearing primary visual cortex (NAV1). Atrophy in the right NAV1 was observed to commence at the very early stage, nearly one month following ON. We also revealed a correlation between volume of the right NAV1 and left visual hemifield amplitude in the affected eye at 12 months. By using DTI, we showed that there is a progressive microstructural change in bilateral CS tracts. The commencement of the microstructural changes in the CS tracts was observed to be at the very early stage of MS. We also found a correlation between early axonal loss in the optic nerve and later microstructural changes in the CS tracts. The results of this study supported the potential role of MRI as a biomarker in early diagnosis of the disease. Moreover, this study provided further evidence of the involvement of NABT in the visual pathway and beyond following ON due to trans-synaptic damage. In our first two studies we provided evidence supporting the role of trans-synaptic damage in microstructural changes and atrophy in NABT in the visual pathway and beyond following ON. It would therefore be interesting to investigate whether only areas related to the visual pathways are affected in patients with ON, or are there other areas in the brain show microstructural damages? Early recognition of the involvement of the WM or GM and the possible mechanisms of the involvement in ION patients at risk of MS is very important because early diagnosis helps with decisions regarding appropriate treatments and options. Furthermore, early treatment can lead to better prognosis and fewer disabilities. In order to address these questions, we undertook an exploratory study to investigate other WM or GM regions of the brain which have microstructural changes or atrophy following ON. We used tract-based spatial statistics (TBSS) method to investigate areas of the whole brain WM with significant longitudinal diffusion changes during one year follow up in ION patients at risk of MS. The voxel-based morphometry (VBM) was used to investigate longitudinal decrease in the volume of GM areas in whole brain. We found progressive microstructural changes during one year in different WM areas of the brain in ION patients. The regions include ORs (mainly right), all parts of the CC; splenium, body and genu, as well as the left and right thalamus. Moreover, we demonstrated progressive atrophy in the GM areas of the brain including VCs, frontal lobe, and primary motor and somatosensory cortex during one year follow up in ION patients. The results of this study provided evidence for diffuse whole brain longitudinal WM microstructural changes and brain atrophy in ION patients at risk of MS during one year follow up. Pathophysiology underlying the diffuse involvement of the brain WM and GM in ION patients at risk of MS is still unclear. In summary, the results of our studies support DTI as a suitable technique for exploring subtle WM degeneration. Moreover, the findings provide evidence of trans–synaptic neuronal damage as the mechanism involved in the early progressive changes of the NABT in the visual pathways and beyond following ON at the early stage of MS even before the definite diagnosis of MS. Therefore, the results support the potential role of multi-modal MRI as a biomarker in the evaluation of disease evolution and progression, as well as response to treatment. The third study provided evidence for whole brain diffuse longitudinal WM microstructural changes and brain atrophy in ION patients at risk of MS during one year follow up. However, pathophysiology and mechanisms underlying the diffuse involvement of the brain WM and GM in ION patients at risk of MS require further investigations. Our findings suggest that ION patients with abnormal baseline MRI should be considered as an important group of patients with higher risk of conversion to MS and not just treated as patients with simple inflammatory disease. It has been shown that early treatment leads to less disability in future. Therefore, ION patients with abnormal MRI need to be closely monitored for early commencement of MS treatment. We hope that the findings of this thesis will lead to the identification of new outcome measures to monitor the evolution of MS and treatment response and, ultimately to improving disease management in individual patients.
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ItemTesting paraclinical outcome markers in optic neuritis and a study of the phenomenology and treatment of tremor in multiple sclerosis( 2012)Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterised by multi-focal inflammatory demyelinating plaques and significant neuroaxonal degeneration. The clinical presentation and disease course of MS is heterogeneous and ranges from clinically isolated syndromes such as optic neuritis (ON), to disabling progressive disease at which stage tremor can be a feature. This heterogeneity reflects the multi-focal nature of the CNS injuries and suggests that the relationships between neuronal injury and clinical presentations are complex. Focused clinical and paraclinical assessments of defined neural pathways associated with discrete clinical presentations can help improve our understanding of complex clinico-pathological relationships. This thesis examined clinical manifestations and outcomes in two models at the opposite ends of the MS clinical spectrum namely acute isolated ON and MS-related tremor. The aims of section one was to comprehensively study changes in clinical and paraclinical markers after ON and more specifically to evaluate the ability of these markers to serve as predictive biomarkers of clinical and axonal outcomes after ON. The second part of this thesis aimed to perform a detailed clinical phenomenology study in MS tremor patients to help define possible underlying neuroanatomical networks and broaden understanding of injury in secondary progressive MS in general. In addition, the efficacy and safety of onabotulinumtoxin-a in the treatment of MS tremor was evaluated. In Section one, forty patients with acute, idiopathic, unilateral optic neuritis with early MS or at high risk of MS were recruited. Patients were studied prospectively over 12 months at multiple time-points. Ten healthy age and sex-matched controls were tested twice to inspect inter-scan and inter-subject variability. All participants had a detailed neurological assessment, visual acuity testing (high and low-contrast and colour vision), optic nerve diffusion tensor imaging (DTI), multi-focal visual evoked potential (mfVEP), and optical coherence tomography (OCT). The main outcome measures were 2.5% low contrast visual acuity, mfVEP amplitude and retinal nerve fibre layer thickness (RNFL) at 12 months after ON. Significant changes in clinical and paraclinical measures after ON, particularly in the first 3 months were demonstrated. Despite some initial recovery, persistent visual, functional and neuroaxonal deficits persisted at 12 months. Multivariate models identified decreased high contrast visual acuity (logMAR notation) at 1 month after ON to be the earliest predictor of persistent visual loss at 12 months. Decreased 3-month colour vision and RNFL thickness also both significantly predicted poor visual recovery. The earliest predictors of axonal outcomes at 12 months after ON were decreased 1-month mfVEP amplitude, low contrast acuity and optic nerve axial diffusivity. Decreased optic nerve axial diffusivity was the best predictor of severe combined (persistent mfVEP amplitude loss and/or RNFL thinning of greater than 30%) axonal loss. Both mfVEP amplitude and clinical assessments are limited in the hyper- acute setting due to inflammatory oedema, conduction block and variable patient performance. Therefore, the finding of an early structural marker, optic nerve axial diffusivity, that is able to predict axonal outcome after ON is important as this measure could serve as a biomarker in future studies of putative neuroprotective therapies by identifying those patients at most risk of permanent axonal loss. In Section 2 of the thesis, a cross-sectional study of 54 MS patients with and without tremor was undertaken. Of the 27 tremor cases, 25 were included in a double-blind randomized placebo-controlled crossover trial (RCT) to evaluate the efficacy of onabotulinumtoxin-a. A detailed comparison between MS patients with and without tremor was completed. Patients underwent a detailed history and neurological assessment that included the Expanded Disability Severity Scale (EDSS) as well assessments of cerebellar ataxia, dystonia and tremor-related quality of life. All patients were assessed for the presence of tremor and tremor severity was rated using the Bain score, a validated MS tremor severity score to rate tremor severity, writing and drawing an Archimedes spiral. Functional tasks such as writing, drawing, drinking from a cup and pouring water from one cup to another were completed. A blinded, independent observer, rated standardized video assessments. In the RCT, patients were assessed 6 weekly for 6 months with baseline and 3 months injections of either onabotulinumtoxin- a or placebo. MS tremor was found to be predominantly an action tremor of the upper limb with prominent cerebellar and dystonic features. Dystonic features (including geste antagonistes, mirror movements, dystonic posturing and writer’s cramp) were more prominent and more severe in patients with tremor than those without. A further novel finding was the impact of dystonia severity in the affected limb on tremor severity. This result highlights the complexity of MS tremor as a movement disorder with injury that is not localized to the cerebellum alone, but rather to the wider cerebello-thalamo-cortical, pallido-thalamic as well as cortico-cerebellar network. In a RCT of the efficacy of onabotulinumtoxin-a in MS tremor, the drug was found to reduce MS tremor severity by an average of 40%, with writing and drawing severity improving by an average of 30%. Injections were well tolerated with transient focal weakness being the predominant side effect. The efficacy of onabotulinumtoxin-a likely reflects modulation of the central tremor-generating networks by modification of peripheral stretch reflexes and muscle- spindle excitability. In addition, the efficacy of a drug used predominantly for focal dystonia underscores the importance of recognizing dystonia as a feature of MS tremor.