Papers by Richard Macdonell
Journal of Clinical Neuroscience, 2014
Modified-release 4-aminopyridine (fampridine) is licensed in Australia for the symptomatic treatm... more Modified-release 4-aminopyridine (fampridine) is licensed in Australia for the symptomatic treatment of walking disability in patients with multiple sclerosis (MS). Its potential for use in other neurological domains, its mode of action, and the reasons for widely variable responses in treated patients remain unknown. This study aims to test the following hypotheses: (1) modified-release fampridine is associated with improvements in upper limb impairment in patients with multiple sclerosis, and (2) objective electrophysiological measures differ between patients on and off treatment, and can potentially be used to differentiate clinical responders and non-responders. We conducted two substudies. Substudy 1 is a randomised, double-blind, placebo-controlled trial in patients with MS and upper limb impairment. Clinical and electrophysiological measurements are made at baseline, conclusion and on three occasions while participants are taking fampridine-modified release or placebo. Substu...
Cancer Treatment and Research Communications
Journal of Clinical Neuroscience, Nov 1, 2014
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2014
In this third and final part of our review of multiple sclerosis (MS) treatment we look at the pr... more In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse...
Patients with the 'aggressive' form of MS accrue disability at an accelerated rate, typic... more Patients with the 'aggressive' form of MS accrue disability at an accelerated rate, typically reaching EDSS >= 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive MS, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive MS is essential to optimise treatment in this MS subtype. We evaluated whether patients who will develop severe MS can be identified based on early clinical markers, and to replicate this analysis in an independent cohort. Patient data were obtained from MSBase. Inclusion criteria were (a) first recorded disability score (EDSS) within 12 months of symptom onset, (b) at least 2 recorded EDSS scores, and (c) at least 10 years of observation time. Patients were classified as having 'aggressive MS' if they: (a) reached EDSS >= 6 within 10 years of symptom onset, (b) EDSS >=6 was confirmed and...
Brain, 2020
In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whi... more In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represente...
Brain, 2020
In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whi... more In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represente...
Supplemental material, sj-docx-5-anp-10.1177_00048674211043788 for Characterising DSCATT: A case ... more Supplemental material, sj-docx-5-anp-10.1177_00048674211043788 for Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks by Jesse Schnall, Georgina Oliver, Sabine Braat, Richard Macdonell, Katherine B Gibney and Richard A Kanaan in Australian & New Zealand Journal of Psychiatry
Supplemental material, sj-xlsx-1-anp-10.1177_00048674211043788 for Characterising DSCATT: A case ... more Supplemental material, sj-xlsx-1-anp-10.1177_00048674211043788 for Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks by Jesse Schnall, Georgina Oliver, Sabine Braat, Richard Macdonell, Katherine B Gibney and Richard A Kanaan in Australian & New Zealand Journal of Psychiatry
Supplemental material, sj-docx-1-tan-10.1177_1756286421998915 for High rates of JCV seroconversio... more Supplemental material, sj-docx-1-tan-10.1177_1756286421998915 for High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients by Christopher M. Dwyer, Vilija G. Jokubaitis, Jim Stankovich, Josephine Baker, Jodi Haartsen, Helmut Butzkueven, Adriana Cartwright, Neil Shuey, Yara Dadalti Fragoso, Louise Rath, Olga Skibina, Kylie Fryer, Ernest Butler, Jennifer Coleman, Jennifer MacIntrye, Richard Macdonell and Anneke van der Walt in Therapeutic Advances in Neurological Disorders
Developmental Medicine & Child Neurology, 2010
Epileptic disorders: international epilepsy journal with videotape
The epilepsies have been regarded as clinically distinct from the paroxysmal movement disorders. ... more The epilepsies have been regarded as clinically distinct from the paroxysmal movement disorders. Recently, a variety of ion channel defects have been identified as the biological basis of certain familial epilepsies and paroxysmal movement disorders. We studied two families with the co-occurrence of epilepsy, movement disorders and migraine. Information was obtained on 147 individuals in the two families. In family WF, there was a co-occurrence of epilepsy (benign infantile convulsions, idiopathic generalized epilepsy), episodic ataxia (with cerebellar atrophy and without myokymia) and common migraine. In family CL, epilepsy (febrile seizures, febrile seizures plus), kinesigenic paroxysmal dyskinesia and migraine (including hemiplegic migraine) were observed in various combinations over 3 generations. The observations in these two families, together with review of the literature, suggest that the co-occurrence of epilepsy (particularly benign infantile convulsions), paroxysmal movement disorders and migraine is not due to chance. Thus, these distinct clinical phenomena could have a shared biological basis and ion channel defects are an attractive possibility.
Stroke, 2012
Background and Purpose— Smoking may exacerbate the risk of death or further vascular events in th... more Background and Purpose— Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited. Methods— 1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke). Results— Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06–1.60; P =0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (...
International Journal of Stroke, 2008
Background Specific information about the nature of recurrent events that occur after each subtyp... more Background Specific information about the nature of recurrent events that occur after each subtype of index stroke may be useful for refining preventive therapies. We aimed to determine whether stroke recurrence rates, the pattern of subtype recurrence, and prescription of secondary prevention agents differed according to initial stroke subtype. Methods Multiple overlapping sources were used to recruit all first-ever stroke patients from a geographically defined region of Melbourne, Australia over a 3-year period from 1996 to 1999. Potential stroke recurrences (fatal and nonfatal) occurring within 2 years of the initial event were identified following patient interview and follow up of death records. Subjects were classified into the different Oxfordshire groups and the type of first-ever stroke was compared with recurrent stroke events. Results One thousand, three hundred and sixteen first-ever strokes were registered during the 3-year period (mean age 74·4 years). A total of 103 f...
Cerebrovascular Diseases, 2009
Handicap is rarely comprehensively examined after stroke. We examined handicap among 5-year strok... more Handicap is rarely comprehensively examined after stroke. We examined handicap among 5-year stroke survivors from an 'ideal' stroke incidence study. Survivors were assessed with the London Handicap Scale [LHS, score range: 0 (greatest handicap) to 100 (least handicap)]. Multivariable regression was used to examine demographic, risk and stroke-related factors associated with handicap. 351 of 441 (80%) survivors were assessed. Those assessed were more often Australian born than those not assessed (p < 0.05). The mean LHS score was 73 (SD = 21). The greatest handicap was present for physical independence and occupation/leisure items. Handicap was associated with older age, manual occupations, smoking, initial stroke severity, recurrent stroke and mood disorders. Reducing recurrent stroke, through better risk factor management, is likely to reduce handicap. The association between handicap and mood disorders, which are potentially modifiable, warrants further investigation.
Cerebral Cortex, 2008
A missense mutation of the g2 subunit of the g-aminobutyric acid A (GABA A) receptor has been lin... more A missense mutation of the g2 subunit of the g-aminobutyric acid A (GABA A) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABA A receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 6 15 years) and 24 controls (11 males, mean age: 38 6 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 6 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net shortinterval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
Neurology, 2010
Objectives: Women may have poorer outcomes after stroke than men because of differences in their ... more Objectives: Women may have poorer outcomes after stroke than men because of differences in their acute management. We examined sex differences in presentation, severity, in-hospital treatment, and early mortality in a cohort of first-ever-in-a-lifetime stroke patients. Methods: Data were collected from May 1, 1996, to April 30, 1999, in the North East Melbourne Stroke Incidence Study. Stroke symptoms, prestroke medical history, in-hospital investigations, admission and discharge medications, initial stroke severity, and 28-day mortality were recorded. Multivariable regression was used to estimate sex differences in treatment, investigations, and 28-day mortality. Results: A total of 1,316 patients were included. Women were older (mean age 76 Ϯ 0.6 vs 72 Ϯ 0.6, p Ͻ 0.01), had more severe strokes (median NIH Stroke Scale score 6 vs 5, p Ͻ 0.01), and more likely to experience loss of consciousness (31% vs 23%, p ϭ 0.003) and incontinence (22% vs 11%, p ϭ 0.01) than men. Women were less often on lipid-lowering therapy on admission. Echocardiography and carotid investigations were less frequently performed in women due to greater age and stroke severity. Women had greater 28-day mortality (32% vs 21%, p Ͻ 0.001) and stroke severity (44% vs 36%, p ϭ 0.01) than men, but adjustment for age, comorbidities, and stroke severity (for mortality only) completely attenuated these associations. Conclusion: Sex differences seen in this study were mostly explained by women's older age, greater comorbidity, and stroke severity. The reasons for differences according to age may need further examination. Neurology ® 2010;74:975-981 GLOSSARY AF ϭ atrial fibrillation; CI ϭ confidence interval; CVD ϭ cardiovascular disease; DM ϭ diabetes mellitus; MI ϭ myocardial infarction; NEMESIS ϭ North East Melbourne Stroke Incidence Study; NIHSS ϭ NIH Stroke Scale; OCSP ϭ Oxfordshire Community Stroke Project; PR ϭ prevalence ratio; PVD ϭ peripheral vascular disease. Women who have a stroke have poorer quality of life and greater dependency than men. 1-3 One explanation is that the clinical presentation may differ between the sexes, leading to differences in diagnosis and treatment. Data on this issue are conflicting, with some authors reporting sex differences in presenting signs and symptoms, 2,4,5 while others have not. 6-8 Whether stroke severity differs for women and men is inconclusive. While some authors report that women have more severe strokes, 9,10 this is not universal. 5,6,11 Differences in the acute management of stroke may also contribute to poorer outcomes for women. Investigators from the Canadian Stroke Register reported no sex differences in stroke unit admission, thrombolysis, or antithrombotic therapy at discharge after adjustment for age, prestroke dependency, comorbidity, and stroke severity. 5 In contrast, others have shown sex
Therapeutic Advances in Neurological Disorders, 2021
Aims: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversio... more Aims: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. Background: Natalizumab is highly effective for the treatment of relapsing–remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. Methods: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. Results: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initiall...
Multiple Sclerosis Journal
Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched ... more Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). Results: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95...
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Papers by Richard Macdonell