Vascular Investigation and Management of Ischaemic Stroke

A variety of aetiological factors serve as targets for both treatment and prevention in ischaemic stroke. Research has shifted towards acute therapy and improving the risk / benefit ratio in secondary prevention. Current evidence based practice in ischaemic stroke is discussed in chapter one, and the background to subsequent chapters is introduced. The thesis is then divided into two broad areas that examine mechanisms by which vascular disease may cause ischaemic stroke, and the manner in which vascular risk may be modulated. Chapters two to four highlight controversies in investigation and management. Chapter two addresses a clinical dilemma - essentially whether a carotid lesion ipsilateral to a lacunar stroke should be considered symptomatic. Observational data comparing incidence of lacunar disease contralateral (group 1) or ipsilateral (group 2) to carotid artery disease, and stroke recurrence in patients in whom co-existent lacunar and carotid disease had been identified, were analysed. 32 patients had carotid disease contralateral to their lacunar stroke, compared to 61 patients with ipsilateral lacunar disease. Chi-squared testing indicated a positive association between unilateral lacunar stroke and ipsilateral carotid disease (p=0.003), and a just significant trend towards more severe carotid disease in group 2 (p=0.049). Recurrent ischaemic stroke occurred more commonly in group 2 than group 1, although this difference just failed to reach statistical significance (p=0.059). A positive association therefore exists between lacunar stroke and ipsilateral carotid disease that confers a poor prognosis. Cryptogenic stroke accounts for approximately 30% of ischaemic stroke. Inter-atrial septal abnormalities (patent foramen ovale (PFO) and atrial septal aneurysm) have been proposed as a cause of stroke. Chapter three details a meta-analysis of data examining the relationship between inter-atrial septal abnormalities and stroke. Comparing ischaemic stroke to controls, the odds ratio (OR) associated with PFO for all ages was 1.83 (95% C.I.=1.25-2.66). For atrial septal aneurysm it was 2.35 (1.46-3.77), and for both lesions in conjunction it was 4.96 (2.37-10.39). Homogeneous results were found within the group 55 years (1.27 (0.80-2.01), 3.43 (1.89-6.22) and 5.09 (1.25-20.74) respectively). Comparing cryptogenic stroke patients to patients with known stroke cause, heterogeneous results derived from total group examination (PFO 3.16 (2.30-4.35), atrial septal aneurysm 3.65 (1.34- 9.97), PFO and atrial septal aneurysm 23.26 (5.24-103.20)). In those 55, 3 studies produced heterogeneous results for PFO (2.26 (0.96-5.31)), while no data were available on atrial septal aneurysm prevalence. Meta-analysis therefore demonstrates significant association between both PFO and atrial septal aneurysm and ischaemic stroke in patients 55 years. The climate of uncertainty that surrounds the subject of 'PFO-associated stroke' has led to a wide spectrum of practice amongst specialists, which is examined in chapter four, using a questionnaire. 17% of respondents would investigate for PFO in all cryptogenic stroke patients, while 60% investigate only in those 55 years, and by 33% of respondents for those <55 years (p<0.01 for comparison of proportions). In a patient of any age with recurrent events, less than 5% of respondents would continue to use antiplatelet therapy alone. 45% would use warfarin, and 42% would refer the patient for a corrective procedure. For a patient with a large PFO, 57% (55 years) would refer (p=0.01), and for a patient with concomitant atrial septal aneurysm, 62% (55 years) would refer (p<0.01). A large PFO was felt to be the most important factor in decisions regarding lesion correction. Investigation practice varied considerably amongst specialists. Randomised trial design should reflect management practice in this area. The second part of the thesis reports clinical trials designed to examine the manner in which agents aimed at the modification of vascular risk may act in the acute and subacute phase of ischaemic stroke. The cholesterol- independent effects of statins may explain their efficacy in patients at high vascular risk. (Abstract shortened by ProQuest.)

Factors influencing multiple sclerosis disease-modifying treatment prescribing decisions in the United Kingdom: A qualitative interview study

Background The proportion of people with relapsing-remitting multiple sclerosis prescribed disease modifying treatments (DMTs) in the United Kingdom (UK) is considered low compared with other countries. There are differences in DMT prescription rates between UK nations (England, Wales, Scotland, Northern Ireland). Despite this, there has been little research into decision-making processes and prescribing practices. Objective To investigate views and experiences of neurologists prescribing DMTs and MS specialist nurses to identify factors influencing prescribing. Methods Semi-structured interviews with 18 consultant neurologists and 16 specialist nurses from diverse settings across the four UK nations. Data were analysed using thematic framework analysis. Results Prescribing practices are influenced by organisational prescribing “cultures”, informal “benchmarking” within peer networks, and prior experience with different DMTs. Health professionals differ in their perceptions of benefits and risks of DMTs and personal “thresholds” for discerning relapses and determining eligibility for DMTs. Prescribers in England felt most constrained by guidelines. Conclusion To achieve equity in access to DMTs for people with MS eligible for treatment, there is a need for public discussion acknowledging differences in health professionals’ interpretations of “relapses” and guidelines and perceptions of DMTs, variation in organisational prescribing “cultures”, and whether the prevailing culture sufficiently meets patients’ needs

Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO)

Background: Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE. Objectives: CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design: CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints: The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion: The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p &amp;lt; 0.001). Lesion volume (Spearman’s rho rs= 0.38, p &amp;lt; 0.001) and g-ratio (rs= 0.24 p &amp;lt; 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p &amp;lt; 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation

Stardust melodies: an exhibition of sheet music from the Rare Books Collection 22 June - 5 September 2011

The exhibition was held in the Rare Books Exhibition space, Sir Louis Matheson Library, Monash University from 22 June - 5 September 2011 Opening address given by Dr. Joel Crotty, Senior Lecturer, School of Music, Monash University. Before recordings and radio conveyed the latest popular tunes, sheet music was the means of mass marketing the latest musical vogues and hits: Charles K. Harris's 1892 song, After the Ball, reportedly sold 5 million copies. Sheet music, and illustrated sheet music in particular, preserves an evocative record of our musical, cultural and social past. It is also a repository of personal memories, especially – in the words of the song, "Stardust" – 'the memory of love's refrain'

Cookbooks: the Sandy Michell collection: an exhibition of material from the Monash University Rare Books Collection 22 March - 31 Mat 2011

The exhibition was held in the Rare Books Exhibition space, Sir Louis Matheson Library, Monash University from 22 March - 31 May 2011 Opening address given by Rita Erlich, former editor, The Age Good Food Guide. This exhibition celebrates the gift of valuable seventeenth to nineteenth century French and English cookbooks made by Alexandra (Sandy) Michell, beginning in 1988. The collection has been further developed and expanded to include a fine collection of early Australian cookbooks, and a selection of twentieth century material

20th century poetry: Britain and America: an exhibition from the Rare Books Collection 14 June - 27 September 2013

The exhibition was held in the Rare Books Exhibition space, Sir Louis Matheson Library, Monash University from 14 June - 27 September 2013. Opening address given by Dr. John Hawke, Lecturer, School of English, Communications and Performance Studies. This Rare Books Collection exhibition features T.S. Eliot, the Beat poets, Sylvia Plath and Ted Hughes, among others