Objective: We sought to define the significance of brachial amyotrophic diplegia (flail arm syndrome [FA]) and the pseudopolyneuritic variant (flail leg syndrome [FL]) of amyotrophic lateral sclerosis (ALS; motor neuron disease). Methods:We analyzed survival in clinic cohorts in London, UK (1,188 cases), and Melbourne, Australia (432 cases). Survival from disease onset was analyzed using the Kaplan-Meier method and Cox proportional hazards model. Results:In the London cohort, the FA syndrome represented 11% and the FL syndrome 6% of the sample. Median survival was 35 months for limb onset and 27 months for bulbar onset ALS, whereas this was 61 months for FA syndrome (p Ͻ 0.001) and 69 months for FL syndrome (p Ͻ 0.001). Five-year survival in this cohort was 8.8% for bulbar onset, 20% for limb onset, 52% for FA syndrome, and 64% for FL syndrome. The ratio of men to women was 4:1 in the FA group compared to 2:1 in other limb onset cases. Excluding lower motor neuron FA and FL cases, progressive muscular atrophy comprised 4% of the sample and had a prognosis similar to typical limb onset ALS. In the Melbourne cohort, median survival for limb onset ALS was 31 months, bulbar onset 27 months, FA syndrome 66 months (p Ͻ 0.001), and FL syndrome 71 months (p ϭ 0.001). Amyotrophic lateral sclerosis (ALS) comprises several clinical phenotypes united by a common cellular and molecular pathology. Conclusions:1 The three main clinical categories defined by Aran, Charcot, Duchenne, and others in the 19th century and which were subsequently shown to have both diagnostic and prognostic significance were progressive bulbar palsy (bulbar onset ALS), classic limb onset (Charcot) ALS, and a lower motor neuron form termed progressive muscular atrophy (PMA).2-5 Prognostic factors in these forms of ALS have been delineated through clinic and population-based studies. 6,7 Bulbar onset tends to have a worse prognosis than limb onset, and both forms have a worse prognosis than PMA.2,4-7 However, these three phenotypic categories do not fully capture the spectrum of clinical heterogeneity in ALS. This heterogeneity may contribute to diagnostic error and delay, and with the advent of large-scale whole genome studies that have the potential to identify genetic variants influencing both risk and phenotype,

Neurodegeneration and dementia pose a major public health challenge worldwide owing to their devastating impact on quality of life and the tremendous burden they place on health-care systems 1,2 . The number of adults with a diagnosis of neurodegenerative disease across the globe is set to increase dramatically in the coming decades -the ageing population harbours a potential epidemic of functional disability, pain and loss of independence 3-5 . Among the neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) is the most rapidly fatal 6 -the typical time from symptom onset to death is 2-3 years 7,8 .Research in the past 25 years has improved our understanding of the pathophysiology of ALS, but the translation of this knowledge into effective treatments has been disappointing -even today, most patients with ALS do not have the opportunity to participate in clinical trials 9 . Previously unrecognized bottlenecks in the translational process have been revealed, including a lack of large-scale research infrastructure and of the coordination necessary to initiate trials. In addition, inherent disease characteristics, such as disease heterogeneity, make a one-size-fits-all solution unworkable and long durations of clinical trials are necessary

Between 1991 and 2011, 1198 patients diagnosed with ALS/MND were registered. 929 patients (77.5%) fulfilled the selection criteria and their data were analysed. Median tracheostomy free survival from symptom onset was 28 months in NIV-treated patients compared to 15 months in untreated (Univariate Cox regression HR=0.61 (0.51 to 0.73), p<0.001). The positive survival effect of NIV persisted when the model was adjusted for age, gender, riluzole and percutaneous endoscopic gastrostomy use (HR=0.72 (0.60 to 0.88, p=0.001). In contrast with the only randomised controlled trial, NIV statistically significantly increased survival by 19 months in those with ALS-bulbar onset (Univariate HR=0.50 (0.36 to 0.70), multivariate HR=0.59 (0.41 to 0.83)). These data confirm that NIV improves survival in MND/ALS. The overall magnitude of benefit is 13 months and was largest in those with ALS-bulbar disease. Future research should explore the optimal timing of NIV initiation within phenotypes in order to optimise respiratory function, quality of life and survival.

The murine and human ALS data suggest that the p75 neurotrophin receptor may play a death-signalling role in the pathogenesis of motor neuron degeneration. The precise mechanism by which this receptor drives the apoptotic process, both in murine SOD1-G93A motor neuron degeneration and in human amyotrophic lateral sclerosis, remains to be determined.

While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.

The fourth in a series of articles about the practical aspects of telehealth, this paper provides advice and information for specialists to communicate effectively with patients during a telehealth video consultation.

From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations.

ObjectiveTo establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts.MethodsWe generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population.ResultsWe identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r2 = 0.99, Japan r2 = 0.99, South Korea r2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8–5.5) in Japanese, 5.4 (95% CI, 5.2–5.7) in Australian, and 4.4 (95% CI, 4.2–4.8) in South Korean patients.ConclusionsThe linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.