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ItemTesting paraclinical outcome markers in optic neuritis and a study of the phenomenology and treatment of tremor in multiple sclerosisVAN DER WALT, ANNEKE ( 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.