Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.

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.

Practical aspects of telehealth: establishing telehealth in an institution.

The fifth in a series of papers on practical aspects of telehealth, this paper discusses telehealth models that can facilitate the provision of specialist services to rural and remote patients closer to home. Some of the barriers to successful implementation of these models relates to workforce, funding and infrastructure at rural sites, as well as the traditional mindset of healthcare professionals. Therefore, the rural sector needs to be adequately resourced for telehealth models to be substantive and successful. This paper describes the development of a large teleoncology network over a vast geographical area in North Queensland. Adequate resourcing for the rural sites and undertaking quality improvement activities has continually enhanced the model over a 5- to 6-year period. The benefits of this model of care are twofold: (i) patients received their care closer to home and (ii) the workforce, service capabilities and infrastructure for the hospital in Mt Isa (a rural town 900 km away from its tertiary centre) has improved.

Practical aspects of telehealth: doctor-patient relationship and communication.

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.

Practical aspects of telehealth: set-up and preparation for video consultations.

The third in a series of articles about the practical aspects of telehealth, this paper gives guidance on suitable setup for video consultations, including layout of rooms, managing sound and image quality, scheduling, testing and best practice in telehealth videoconferencing.

Practical aspects of telehealth: financial considerations.

The second in a series of articles about the practical aspects of telehealth, this paper includes information and a case history on the cost-benefits for patients and practitioners using telehealth. The case history demonstrates that telehealth can save travel time for patients, carers and specialists, and can reduce out-of-pocket expenses. The practical aspects of telehealth article series considers the contextual, clinical, technical and ethical components of online video consultations.

Practical aspects of telehealth: are my patients suited to telehealth?

The first in a series of articles that demonstrate the practical aspects of telehealth, this paper provides three case studies that examine the suitability of telehealth for patients living in rural and remote areas who require ongoing specialist care.

Natural history and clinical features of the flail arm and flail leg ALS variants.

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 < 0.001) and 69 months for FL syndrome (p < 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 < 0.001), and FL syndrome 71 months (p = 0.001). CONCLUSIONS: The flail arm (FA) and flail leg (FL) syndromes had significantly better survival than typical amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy cases that were not classified as FA or FL. Our findings underline the clinical and prognostic importance of the FA and FL variants of ALS.

Sporadic encephalitis lethargica.

Three women (aged 21-36 years) developed acute illnesses that were similar to epidemic encephalitis lethargica. Each presented with a neuropsychiatric disturbance that was succeeded by pyrexia, a fluctuating conscious state and involuntary movements including oculogyria. Cerebrospinal fluid examination showed a predominantly lymphocytic pleocytosis (64-120x10(6) cells/L) and oligoclonal bands were detected in two cases. Two patients died, while the third made a gradual recovery. Post-mortem examination in the two fatal cases showed changes of lymphocytic meningitis and focal diencephalic lymphocytic infiltration, although these changes were mild relative to the effects of the clinical illness. The diagnosis of sporadic encephalitis lethargica relies on identifying shared clinical features with the past epidemic disease plus circumstantial evidence of immunological activity from laboratory investigations and some tests of exclusion of other disorders.

A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis.

INTRODUCTION: The p75 neurotrophin receptor has been recognized as a death-signalling molecule under certain circumstances. Its role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS) was analysed in SOD1-G93A transgenic mice and in spinal cords from human amyotrophic lateral sclerosis. METHOD: The precise loss of motor neurons in SOD1-G93A transgenic mice from birth to adulthood was established using the unbiased fractionator/optical dissector neuronal counting technique. RESULTS: This study showed an early trend in the loss of lumbar motor neurons in SOD1-G93A mice, beginning at birth and progressing to a massive 80% reduction by 4 months of age, when the disease is severe. This study also found that the p75 neurotrophin receptor was expressed in lumbar motor neurons in symptomatic SOD1-G93A mice and in motor neurons in the cervical spinal cords of patients with ALS. CONCLUSIONS: 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.

Lineage specification of neuronal precursors in the mouse spinal cord.

We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and > 83% expressed the motor neuron markers choline acetyltransferase, peripherin, calcitonin gene-related peptide, and L-14. By comparison, < 10% of the neurons arising on monolayers of other neural cell lines or 3T3 fibroblasts had motor neuron characteristics. Cells derived from dorsal, intermediate, and ventral regions of the spinal cord all behaved similarly and gave rise to motor neuron-like cells when plated onto Ast-1. By using cells that expressed the lacZ reporter gene, it was shown that > 93% of cells present on the Ast-1 monolayers were motor neuron-like. Time-lapse analysis revealed that the precursors on the Ast-1 monolayers gave rise to neurons either directly or following a single cell division. Together, these results indicate that precursors in the murine spinal cord can be induced to differentiate into the motor neuron phenotype by factors produced by Ast-1 cells, suggesting that a similar factor(s) produced by cells akin to Ast-1 may regulate motor neuron differentiation in vivo.

Regulation of neural precursor differentiation in the embryonic and adult forebrain.

1. Precursors form the neuroepithelium of the developing cortex and also from the adult sub-ventricular zone, can be cloned in vitro after stimulation with fibroblast growth factor (FGF)-2 and have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyteprecursor line, Ast-1, or FGF-1. 2. Neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol-lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the PCL gamma pathway. 3. The sequential expression of FGF-2 and FGF-1 within the developing forebrain neuroepithelium fits with the different functions the two FGF play in precursor regulation. 4. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan (HSPG) expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2; however, the differentiation into GFAP positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor beta receptor.

Factors regulating the differentiation of neural precursors in the forebrain.

Precursors from the neuroepithelium of the developing cortex and the adult subventricular zone can be cloned in vitro after stimulation with fibroblast growth factor 2 (FGF-2), and they have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyte precursor line, Ast-1, or FGF-1. We have shown that neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the phospholipase C gamma pathway. The sequential expression of FGF-2, followed by FGF within the developing forebrain neuroepithelium, fits with the different functions that the two FGFs play in precursor regulation. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2F however, the differentiation into glial fibrillary acidic protein-positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor-beta receptor.

Regulation of the early development of the nervous system by growth factors.

Development of the nervous system, although patterned by intrinsic genetic expression, appears to be dependent on growth factors for many of the differentiation steps that generate the wide variety of neurons and glia found in the both the central and peripheral nervous system. By using in vitro assays, including clonal analysis, the precise function of the various growth factors and the differentiation potential of the various neural populations has begun to be described. This review discusses some of the recent findings and examines how neuronal differentiation may result from the interaction of several growth factors.

The differentiation and survival of murine neurons in vitro is promoted by soluble factors produced by an astrocytic cell line.

The influence of accessory cells on the generation of neurons and neuronal survival has been studied in vitro using an immortalised, cloned cell line, Ast-1, which has many of the functional and phenotypic characteristics of cells of the astrocytic lineage. It was found that monolayers of Ast-1 cells were equivalent to monolayers of primary astrocytes in their ability to promote the generation of neurofilament positive neurons from neuroepithelial cells obtained from embryonic day 10 (E10) mice; and both were superior to NIH 3T3 cells. Ast-1 cell monolayers were also found to provide a suitable substrate for the prolonged survival (at least 3 days in vitro) of neurofilament positive neurons obtained from E17 mice, whereas neurons plated onto NIH 3T3 cells were all dead after 2 days. Medium conditioned by Ast-1 cells displayed similar biological activities to that of the monolayers: it increased the number of neurons generated from the E10 neuroepithelial cells, whether they were plated directly onto glass coverslips or onto monolayers of NIH 3T3 cells; and it increased the survival of E17 neurons plated directly onto glass coverslips. In addition, the Ast-1 conditioned medium was shown to promote the survival of the neuroepithelial cells. These results confirm that one of the mechanisms by which astrocytes or their precursors may regulate neuronal development is by secreting soluble growth factors, as has been previously documented in the case of fibroblast growth factor (FGF) (Hatten et al., 1988; Drago et al., 1991a). However, it appears in this system that FGF is not responsible for the demonstrated biological activities, and the Ast-1 action appears to be mediated by putatively novel factor(s).