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Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND. [ABSTRACT FROM AUTHOR]

Introduction: Children with congenital hemiplegia often present with limitations in using their impaired upper limb which impacts on independence in activities of daily living, societal participation and quality of life. Traditional therapy has adopted a bimanual training approach (BIM) and more recently, modified constraint induced movement therapy (mCIMT) has emerged as a promising unimanual approach. Evidence of enhanced neuroplasticity following mCIMT suggests that the sequential application of mCIMT followed by bimanual training may optimise outcomes (Hybrid CIMT). It remains unclear whether more intensely delivered group based interventions (hCIMT) are superior to distributed models of individualised therapy. This study aims to determine the optimal density of upper limb training for children with congenital hemiplegia. Methods and analyses: A total of 50 children (25 in each group) with congenital hemiplegia will be recruited to participate in this randomized comparison trial. Children will be matched in pairs at baseline and randomly allocated to receive an intensive block group hybrid model of combined mCIMT followed by intensive bimanual training delivered in a day camp model (COMBiT; total dose 45 hours direct, 10 hours of indirect therapy), or a distributed model of standard occupational therapy and physiotherapy care (SC) over 12 weeks (total 45 hours direct and indirect therapy). Outcomes will be assessed at 13 weeks after commencement, and retention of effects tested at 26 weeks. The primary outcomes will be bimanual coordination and unimanual upper-limb capacity. Secondary outcomes will be participation and quality of life. Advanced brain imaging will assess neurovascular changes in response to treatment. Analysis will follow standard principles for RCTs, using two-group comparisons on all participants on an intentionto- treat basis. Comparisons will be between treatment groups using generalized linear models. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication. [ABSTRACT FROM AUTHOR]

Background: Congenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia. Methods/Design: A matched pairs randomised comparison design will be used with children matched by age, gender, side of hemiplegia and level of upper limb function. Based on power calculations a sample size of 52 children (26 matched pairs) will be recruited. Children will be randomised within pairs to receive either CIMT or BIM training. Both interventions will use an intensive activity based day camp model, with groups receiving the same dosage of intervention delivered in the same environment (total 60 hours over 10 days). A novel circus theme will be used to enhance motivation. Groups will be compared at baseline, then at 3, 26 and 52 weeks following intervention. Severity of congenital hemiplegia will be classified according to brain structure (MRI and white matter fibre tracking), cortical excitability using Transcranial Magnetic Stimulation (TMS), functional use of the hand in everyday tasks (Manual Ability Classification System) and Gross Motor Function Classification System (GMFCS). Outcomes will address neurovascular changes (functional MRI, functional connectivity), and brain (re) organisation (TMS), body structure and function (range of motion, spasticity, strength and sensation), activity limitations (upper limb unimanual capacity and bimanual motor coordination), participation restrictions (in home, school and recreation), environmental (barriers and facilitators to participation) and quality of life. Discussion: This paper outlines the theoretical basis, study hypotheses and outcome measures for a matched pairs randomised trial comparing CIMT and BIM training to improve outcomes across the ICF. [ABSTRACT FROM AUTHOR]

Background: Handicap is rarely comprehensively examined after stroke. We examined handicap among 5-year stroke survivors from an ‘ideal’ stroke incidence study. Methods: 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. Results: 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. Conclusion: 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. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: In the 2-year CARE-MS trials (trial registration: NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/magnetic resonance imaging outcomes vs subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). Efficacy in alemtuzumab-treated patients was maintained through year 9 in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). Objectives: To evaluate the status of disability over 9 years in pooled CARE-MS patients who had either 6-month confirmed disability improvement (CDI) or 6-month confirmed disability worsening (CDW) by years 2 or 9. Methods: Alemtuzumab-treated CARE-MS patients with baseline Expanded Disability Status Scale (EDSS) score ≥2 were stratified into 3 subgroups: with CDI, with CDW, or with stable disability. CDI and CDW were defined as ≥1-point decrease and increase, respectively, in EDSS score from core study baseline confirmed over 6 months. Improved and stable EDSS scores each year were defined as ≥1-point decrease and ≤0.5-point change in either direction, respectively, from core study baseline in available patients. Results: 511/811 (63%) alemtuzumab-treated patients had baseline EDSS score ≥2. Of these, 222 (43%) patients had 365 unique CDI events and 172 (34%) patients had 217 CDW events at any time during the 9-year study; 31 (6%) had both CDI and CDW. Few patients (n = 12) had a CDW event after CDI. Of patients with CDI at any time over 9 years, mean EDSS score change was --0.58 at year 9 vs core study baseline, and 51% had lower EDSS scores at year 9. Similar EDSS outcomes were observed at year 9 in the subset of patients who achieved CDI within the first 2 years of the study. However, patients with CDW any time over 9 years had worsened disability at year 9, with a +1.71 mean change in EDSS score from core study baseline; patients with CDW in the first 2 years of the study had a +2.27 EDSS score change by year 9. EDSS scores remained stable at 9 years (mean change, --0.10) in the 148 (29%) patients who had neither CDI nor CDW. Compared with previous years, no new safety signals were identified in year 9 in CARE-MS extension study patients. Conclusions: Achievement of CDI at any point in the CARE-MS studies was associated with improved disability at year 9 vs baseline. However, those with CDW had increased disability over 9 years regardless of when worsening occurred. These findings suggest that both CDI and CDW are meaningful end points for predicting long-term disability outcomes in patients with RRMS. [ABSTRACT FROM AUTHOR]

Background: Although a number of acute stroke interventions are of proven efficacy, there is uncertainty about their community benefits. We aimed to assess this within a defined population. Methods: Eligibility for tissue plasminogen activator (tPA), aspirin, stroke unit management and neuroprotection were assessed among incident stroke cases within the community-based North East Melbourne Stroke Incidence Study. Results: Among 306,631 people, there were 645 incident strokes managed in hospital. When eligible patients were extrapolated to the Australian population, for every 1,000 cases, 46 (95% CI 17–69) could have been saved from death or dependency with stroke unit management, 6 (95% CI 1–11) by using aspirin, 11 (95% CI 5–17) or 10 (95% CI 3–16) by using tPA at 3 and 6 h, respectively. Conclusions: Although tPA is the most potent intervention, management in stroke units has the greatest population benefit and should be a priority. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The past 10 years have brought a wide variety of therapeutic options to Australian patients with relapsing-remitting multiple sclerosis (RRMS). In a complex treatment landscape for an unpredictable disease, it is important to understand how patients view the various factors that contribute to making an informed therapeutic choice. Objectives: Identify the factor rated by patients with RRMS (PwRRMS) as having the most influence on treatment choice. Methods: This noninterventional, exploratory study prospectively enrolled 78 patients assigned to 1 of 3 groups: 1) initial treatment (n = 25), 2) switching to alternate treatment (n = 27), and 3) stable on treatment (n = 26). Baseline demographic and MS data were collected. Participants completed the survey where they rated factors from most to least important: drug safety, efficacy, ease of use, mode of administration, mechanism of action, concern about disability, requirement for follow-up safety monitoring, balance of risk/benefit, and value of discussion with MS nurse and neurologist. Results: The factors ranked first by most participants in influencing treatment choice were (in order): 1) concern about disability (31/78 participants), 2) perception of efficacy (16/78), and 3) perception of safety (11/78). This ranking order was consistent across all groups. 97% of participants were satisfied with the process around choosing treatment, and 92% reported they felt extremely comfortable with their treatment decision. Conclusions: Our data indicates that concern about disability is the largest driving factor for PwRRMS choosing between treatments regardless of whether they are starting for the first time, planning a switch in therapy, or are currently stable on an MS medication. [ABSTRACT FROM AUTHOR]

Background: In CARE-MS I and II (trial registration: NCT00530348, NCT00548405), alemtuzumab treatment (12 mg/day; baseline: 5 days; 12 months later: 3 days) improved clinical and magnetic resonance imaging (MRI) outcomes vs subcutaneous interferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis (MS). In 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]), patients could receive additional alemtuzumab (12 mg/day; 3 days; ≥12 months apart). Objectives: Evaluate yearly efficacy and safety of alemtuzumab in pooled CARE-MS patients who did or did not receive additional alemtuzumab through year 9. Methods: Pooled CARE-MS patients were stratified by the total number of courses received (exactly 2 courses, exactly 3 courses, ≥4 courses). Inclusion criteria: additional alemtuzumab (ie, courses 3 or 4) received by month 97 to allow ≥12 months of follow-up; no other disease-modifying therapy through year 9. Data were censored at course 5 (if received) in the ≥4 courses group. Outcomes data were rebaselined after the last alemtuzumab course. Results: 742/811 (91%) alemtuzumab-treated patients entered the extension and could receive additional courses; courses 3 and 4 were given most frequently in years 3 (19%) and 4 (6%), respectively. Of 742 extension patients, 359 (48%), 148 (20%), and 121 (16%) were included in the 2-, 3-, and ≥4-courses groups, with 303, 76, and 15 remaining on study in year 4 after last course, respectively. Over 4 years after last course, annualized relapse rate was 0.07, 0.08, and 0.23 in the 2-, 3-, and ≥4-courses groups, respectively, and change in mean Expanded Disability Status Scale score at year 4 vs after last course was -0.06, +0.08, and +0.56, respectively. Over 4 years, 83%, 85%, and 94% were free of 6-month confirmed disability worsening, and 23%, 11%, and 15% had 6-month confirmed disability improvement in the 2-, 3-, and ≥4-courses groups, respectively. In year 4, 78%, 73%, and 69% were free of MRI disease activity. Serious adverse events were generally similar between cohorts during years 1-3 after last treatment (5.1%-11.4% per year), but low patient numbers in the ≥4-courses group confounded analysis of serious adverse events in year 4 after last course. Conclusions: Efficacy of additional alemtuzumab was maintained over 4 years after last course in CARE-MS patients, although the ≥4-courses group had higher disease activity and disability, as expected. Alemtuzumab safety was generally consistent between groups, except for the ≥4-courses cohort in year 4 after last course wherein interpretation was limited by low numbers of available patients. [ABSTRACT FROM AUTHOR]