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Objectives: To conduct a geographically defined, UK-based case-control study, to examine any association between physical activity (PA) and amyotrophic lateral sclerosis (ALS)., Methods: A novel historical PA questionnaire was designed, validated, and subsequently administered in individual face-to-face interviews of 175 newly diagnosed sporadic ALS cases and 317 age- and sex-matched community controls. Historical PA energy expenditure and time spent in vigorous-intensity PA were derived from questionnaire data and compared between cases and controls., Results: Participation in an extra 10kJ/kg/day of PA (equivalent to approximately 45minutes brisk walking) was consistently associated with an increased risk of ALS, with the strongest association observed for adulthood exercise-related PA (OR 1.47, 95% CI 1.10-1.97). An extra 10mins/day of vigorous PA was also associated with the odds of ALS (OR 1.03, 95% CI 1·01-1·05). Results were slightly attenuated following adjustment for smoking and educational attainment., Conclusions: To our knowledge this is the first study to demonstrate a positive association between ALS and PA participation using a specifically designed and validated historical PA questionnaire. Despite the well-established health benefits of PA, a high activity lifestyle may also be associated with elevated risk of ALS. Large-scale prospective studies in the future may help to confirm this association.

Our objective was to review the evidence for using technology to improve access to specialist care for patients with amyotrophic lateral sclerosis (ALS) and their carers. Medline, Google Scholar and the Cochrane library were searched for articles describing technology that enabled clinical care of patients with ALS or their carers where the patient/carer and clinician were not in the same location. Two applications were identified: telemedicine to facilitate video conferencing as an alternative to outpatient consultations and telehealth monitoring for patients with respiratory failure. One randomized controlled trial using telehealth in patients with respiratory failure including 22 patients with ALS was identified. While rates of hospitalization were reduced, overall mortality was unchanged and there were too few patients with ALS in the study to detect significant benefit. In conclusion, there is limited evidence to support the use of telemedicine or telehealth in the care of patients with ALS. Future research needs to develop an understanding of the key beneficial aspects of the traditional specialist ALS service and how these factors could be delivered using technology. Successful evaluation and implementation of technologies to facilitate access to specialist care will only be possible if all the relevant impacts of an intervention are understood and measured.

Management of ALS is suboptimal. Consequently, quality improvement interventions are needed to improve ALS care. An evidence-based insight into how patients should be managed is essential when developing quality improvement interventions. Therefore, this study aimed to map, categorize and summarize international guidance on the management and care of ALS and to identify gaps in this guidance by means of a mapping review. Literature was searched for clinical practice guidelines, quality indicators and evidence-based clinical summaries. A content analysis and meta-synthesis of the included literature was performed. Interventions and outcomes used in the management and care of ALS were identified and categorized. Furthermore, the amount of guidance underpinning these interventions and outcomes was analysed. Six clinical practice guidelines, one set of quality indicators and three evidence-based clinical summaries were identified. The results demonstrated that certain domains in ALS care, mainly disease-specific domains such as breathing and swallowing, are extensively addressed in the literature whereas other subjects, such as care coordination, receive little attention. In conclusion, this mapping review provides a scientific basis for targeting and developing the clinical content of a quality improvement intervention for the management of ALS.

Background and Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition for which there is no single diagnostic test or biomarker. The level of the creatine kinase (CK) enzyme in serum may be mild to moderately elevated in some patients with ALS, the precise cause of which and its behaviour with disease progression is unknown. The aim of this study was to examine the usefulness of monitoring CK serially during the ALS disease trajectory and to determine whether CK levels mirror disease progression., Methods: This was a prospective observational cohort study, using the clinical database of the olesoxime (TRO19622) investigational medicinal product trial., Results: The baseline CK was raised in 52% of the trial participants with the mean CK ± SD being 257 ± 239 U/l. The mean CK was significantly higher in male participants than in female participants (P < 0.001) and amongst participants with limb onset ALS compared to participants with bulbar onset ALS (P < 0.001). There was no significant difference in the CK levels between upper limb and lower limb onset disease (P = 0.746). The CK level co-related positively with serum creatinine and estimated lean body mass but there was no relationship between CK and muscle scores and limb function. A higher CKlog was associated with significantly better survival, even when adjusted for prognostic co-variants (P = 0.013)., Conclusions: The serum CK level seems to be an independent prognostic factor for survival in ALS. The cellular mechanism of CK enzyme suggests that it may be upregulated to provide energy in the face of metabolic stress in ALS., (© 2016 EAN.)

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure., Objective: The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure., Design: The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy., Participants: Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation., Interventions: Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS., Main Outcome Measures: The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy., Results: In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p = 0.01)., Conclusions: Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure., Future Work: It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further., Trial Registration: Current Controlled Trials ISRCTN53817913., Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.

Background: Multimorbidity in heart failure (HF), defined as HF of any aetiology and multiple concurrent conditions that require active management, represents an emerging problem within the ageing HF patient population worldwide., Methods: To inform this position paper, we performed: 1) an initial review of the literature identifying the ten most common conditions, other than hypertension and ischaemic heart disease, complicating the management of HF (anaemia, arrhythmias, cognitive dysfunction, depression, diabetes, musculoskeletal disorders, renal dysfunction, respiratory disease, sleep disorders and thyroid disease) and then 2) a review of the published literature describing the association between HF with each of the ten conditions. From these data we describe a clinical framework, comprising five key steps, to potentially improve historically poor health outcomes in this patient population., Results: We identified five key steps (ARISE-HF) that could potentially improve clinical outcomes if applied in a systematic manner: 1) Acknowledge multimorbidity as a clinical syndrome that is associated with poor health outcomes, 2) Routinely profile (using a standardised protocol - adapted to the local health care system) all patients hospitalised with HF to determine the extent of concurrent multimorbidity, 3) Identify individualised priorities and person-centred goals based on the extent and nature of multimorbidity, 4) Support individualised, home-based, multidisciplinary, case management to supplement standard HF management, and 5) Evaluate health outcomes well beyond acute hospitalisation and encompass all-cause events and a person-centred perspective in affected individuals., Conclusions: We propose ARISE-HF as a framework for improving typically poor health outcomes in those affected by multimorbidity in HF., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS. Rarer genetic causes of ALS include mutation of optineurin (mt OPTN). Furthermore, optineurin protein has been localized to the ubiquitylated aggregates in several neurodegenerative diseases, including ALS. This study: (i) investigated the frequency of mt OPTN in ALS patients in England; (ii) characterized the clinical and neuropathological features of ALS associated with a mt OPTN; and (iii) investigated optineurin neuropathology in C9ORF72-related ALS (C9ORF72-ALS). We identified a heterozygous p.E322K missense mutation in exon 10 of OPTN in one familial ALS patient who additionally had a C9ORF72 mutation. This patient had bulbar, limb and respiratory disease without cognitive problems. Neuropathology revealed motor neurone loss, trans-activation response DNA protein 43 (TDP-43)-positive neuronal and glial cytoplasmic inclusions together with TDP-43-negative neuronal cytoplasmic inclusions in extra motor regions that are characteristic of C9ORF72-ALS. We have demonstrated that both TDP-43-positive and negative inclusion types had positive staining for optineurin by immunohistochemistry. We went on to show that optineurin was present in TDP-43-negative cytoplasmic extra motor inclusions in C9ORF72-ALS cases that do not carry mt OPTN. We conclude that: (i) OPTN mutations are associated with ALS; (ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient; and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration., (© 2015 Japanese Society of Neuropathology.)

Objectives: This study explores the experience of gastrostomy insertion from the perspective of the patients and their informal carers. Gastrostomy feeding is commonly used to support motor neurone disease (MND) patients with dysphagia. However, there is lack of information describing patient and carer experiences following gastrostomy insertion. The effect of gastrostomy on quality of life for these patients and their family is currently not well understood., Methods: Retrospective qualitative exploration using semistructured interviews with patients and their informal carers to elicit in-depth descriptions of their experiences and views following gastrostomy., Results: 27 patients consented to the study; of these, 23 underwent a successful gastrostomy. 10 patients and 8 carers were interviewed, approximately 3 months following a successful gastrostomy. Participants described clinical complications, practical issues, time restrictions imposed by strict feeding regimens and psychological issues, which adversely impacted on quality of life. However, the establishment of a safe alternative route for feeding and medication, and the reduced worry over difficult meals and weight loss, were described by all as outweighing these negative impacts. Participants also described having received education/training on gastrostomy feeding both in hospital and in the community, which helped them to cope during the transition from oral to gastrostomy feeding., Conclusions: This study highlights the challenges and benefits of gastrostomy as well as the importance of education and information provision. Emphasis should be given to education before and after insertion along with support and care in the community. While the significant impact of gastrostomy on patients and carers should not be underestimated, the potential benefits were described as outweighing these concerns., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: This study aimed at quantifying the biomechanical features of the Sheffield Support Snood, a cervical orthosis specifically designed for patients with neck muscle weakness. The orthosis is designed to be adaptable to a patient's level of functional limitation using adjustable removable supports, which contribute support and restrict movement only in desired anatomical planes., Methods: The snood was evaluated along with two commercially available orthoses, the Vista and Headmaster, in a series of flexion, extension, axial-rotation and lateral flexion movements. Characterization was performed with twelve healthy participants with and without the orthoses. Two inertial-magneto sensors, placed on the forehead and sternum, were used to quantify the neck's range of motion., Findings: In its less supportive configuration, the snood was effective in limiting movements to the desired planes, preserving free movement in other planes. The Headmaster was only effective in limiting flexion. The range of motion achieved with the snood in its rigid configuration was equivalent (P>0.05, effect size<0.4) to that achieved with the Vista, both in trials performed reaching the maximum amplitude (range of motion reduction: 25%-34% vs 24%-47%) and at maximum speed (range of motion reduction: 24%-29% vs 25%-43%)., Interpretation: The Sheffield Support Snood is effectively adaptable to different tasks and, in its most supportive configuration, offers a support comparable to the Vista, but providing a less bulky structure. The chosen method is suitable for the assessment of range of motions while wearing neck orthoses and is easily translatable in a clinical context., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There are few studies providing evidence to guide the management of oropharyngeal secretion problems in motor neuron disease (MND). There is a lack of a suitable outcome measure for evaluating management strategies. We applied several potential outcome measures for assessing excessive secretions to patients with MND who attended the Sheffield Care and Research Centre for Motor Neurone Disease between 21 November 2012 and 15 May 2013. These measures were the CSS-MND, a symptom rating scale, and the Drool and Wipe quotient, which were designed to semi-objectively measure patients' drooling. Of the 143 patients seen in clinic during the study period, 58 had symptoms of excessive secretions, and of whom 50 agreed to participate in the study. Semi-objective measures failed to effectively identify patients complaining of secretion problems. The CSS-MND had a relatively low internal consistency (Cronbach's alpha 0.539; n = 50); however, analysis of the inter-item correlations suggested the appearance of low internal consistency was because the scale was measuring a variety of saliva related symptoms that did not necessarily influence each other. The scale correlated well with patient reported symptom impact (r = 0.673, n = 50). In conclusion, the CSS-MND would be a useful outcome measure in studies assessing the management of oropharyngeal secretion problems.

Aims: Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are two syndromic variants within the motor neurone disease spectrum. As PLS and most ALS cases are sporadic (SALS), this limits the availability of cellular models for investigating pathogenic mechanisms and therapeutic targets. The aim of this study was to use gene expression profiling to evaluate fibroblasts as cellular models for SALS and PLS, to establish whether dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish the clinically defined variants of SALS and PLS., Methods: Microarray analysis was performed on fibroblast RNA and differentially expressed genes identified. Genes in enriched biological pathways were validated by quantitative PCR and functional assays performed to establish the effect of altered RNA levels on the cellular processes., Results: Gene expression profiling demonstrated that whilst there were many differentially expressed genes in common between SALS and PLS fibroblasts, there were many more expressed specifically in the SALS fibroblasts, including those involved in RNA processing and the stress response. Functional analysis of the fibroblasts confirmed a significant decrease in miRNA production and a reduced response to hypoxia in SALS fibroblasts. Furthermore, metabolic gene changes seen in SALS, many of which were also evident in PLS fibroblasts, resulted in dysfunctional cellular respiration., Conclusions: The data demonstrate that fibroblasts can act as cellular models for ALS and PLS, by establishing the transcriptional changes in known pathogenic pathways that confer subsequent functional effects and potentially highlight targets for therapeutic intervention., (© 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd. on behalf of British Neuropathological Society.)

A major problem faced by patients with amyotrophic lateral sclerosis (ALS) in respiratory failure is the inability to cough effectively. Forty eligible ALS patients were randomized to the breath-stacking technique using a lung volume recruitment bag (n = 21) or mechanical insufflator-exsufflator MI-E (n = 19) and followed up at three-monthly intervals for at least 12 months or until death. Results showed that there were 13 episodes of chest infection in the breath-stacking group and 19 episodes in the MI-E group (p = 0.92), requiring 90 and 95 days of antibiotics, respectively (p = 0.34). The mean duration of symptoms per chest infection was 6.9 days in the breath-stacking group and 3.9 days in MI-E group (p = 0.16). There were six episodes of hospitalization in each group (p = 0.64). The chance of hospitalization, in the event of a chest infection, was 0.46 in the breath-stacking group and 0.31 in MI-E group (p = 0.47). Median survival in the breath-stacking group was 535 days and 266 days in the MI-E group (p = 0.34). The QoL was maintained above 75% of baseline for a median of 329 days in the breath-stacking group and 205 days in the MI-E group (p = 0.41). In conclusion, lack of statistically significant differences due to sub-optimal power and confounders precludes a definitive conclusion with respect to the relative efficacy of one cough augmentation technique over the other. This study however, provides useful lessons and informative data, needed to strengthen the power calculation, inclusion criteria and randomization factors for a large scale definitive trial. Until such a definitive trial can be undertaken, we recommend the breath-stacking technique as a low-cost, first-line intervention for volume recruitment and cough augmentation in patients with ALS who meet the criteria for intervention with non-invasive ventilation.

Patients with ALS may have insufficientenergy substrates, due to dysphagia and hypermetabolism, which adversely affects the prognosis. Hyperlipidaemia has been reported to be associated with ALS and to represent a significant prognostic factor for survival in ALS. The aim of this study was to examine the prevalence of dyslipidaemia among a cohort of patients with ALS and how the lipid profile of patients with ALS influenced the prognosis. This was a prospective observational cohort study comprising 512 ALS patients, recruited for the TRO19622 (Olesoxime) investigational medicinal product trial. Fasting serum concentrations of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured as part of routine monitoring in the trial. Seventy-three percent of the participants had hypercholesterolaemia (defined as total cholesterol ≥ 5.1 mmol/l) at the screening visit. The prevalence of hypercholesterolaemia decreased with time and was 64% at 18 months follow-up. On unadjusted analysis total cholesterol, LDL-C and LDL/HDL ratio had a statistically significant effect on survival (p = 0.015, 0.003 and 0.027, respectively). When adjusted for prognostic covariates, however, none of the lipid measures was found to have a statistically significant effect on survival. In conclusion, prognosis in ALS is not influenced by the lipid profile of patients.

Aims: Loss of nuclear TDP-43 characterizes sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether (1) RNA splicing dysregulation is present in lower motor neurones in ALS and in a motor neurone-like cell model; and (2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts., Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurones obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS., Results: We found altered expression of spliceosome components in motor neurones and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43-depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, which were not present in fibroblasts from patients with sporadic or SOD1-related ALS., Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurones, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism., (© 2014 British Neuropathological Society.)

Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a progressive, incurable and fatal neurodegenerative disease. Few interventions significantly alter the disease course, but many symptomatic treatments exist to improve patients' quality of life. In this review, we describe our approach to symptomatic management of ALS and discuss the underlying evidence base., Recent Findings: Discussion focuses predominantly on recently published articles. We cover management settings, disease-modifying treatment, vitamin D, respiratory management including noninvasive ventilation and diaphragmatic pacing, secretions, nutrition, dysphagia and gastrostomy, communication problems, mobility, spasticity, pain, cognition, depression and emotional lability, fatigue, sleep disturbance, head drop, prevention of deep venous thrombosis and end-of-life issues., Summary: Multidisciplinary specialist care appears to improve quality of life and survival. Riluzole remains the only available disease-modifying medication and confers a survival advantage of 2-3 months. Noninvasive ventilation improves quality of life and extends survival by approximately 7 months, at least in patients without severe bulbar problems. Nutrition is an independent prognostic factor; whether gastrostomy improves survival and quality of life remains unclear and further studies are underway. Many other symptomatic treatments appear helpful to individuals in clinic, but further randomized clinical trials are required to provide a more robust evidence base.

Objectives: This study aimed to explore the decision-making process leading up to gastrostomy insertion from the perspective of the patients and their informal carers. Gastrostomy feeding is commonly used to support motor neurone disease patients with dysphagia. However, there is no robust evidence to suggest the optimal timing for gastrostomy insertion., Methods: Retrospective qualitative exploration using semistructured interviews with paired patients and carers in order to elicit their perceptions in relation to gastrostomy timing., Results: 27 patients consented to the study; of these, 23 underwent a successful gastrostomy. Approximately 3 months following a successful gastrostomy, 10 patients and 8 carers were interviewed. Decision-making in relation to the timing of gastrostomy was described as being a difficult process with individual variations and wishes. A range of factors acted as triggers for taking the decision to proceed with gastrostomy such as prolonged, tiring and effortful meals; the task of food preparation; choking and aspiration; and weight loss. Factors such as the reluctance to give up oral feeding, not realising the potential benefits and negative perceptions of gastrostomy influenced a decision to delay the procedure. A tendency for late insertion was identified despite the opposite advice by health professionals., Conclusions: The advice for early insertion does not outweigh the personal perceptions and psychosocial factors for patients and their carers. Understanding the factors which influence decision-making on an individual basis is important for information and care provision by healthcare professionals in aiding patients, and their carers, to make informed decisions in relation to gastrostomy timing.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Mutations in the superoxide dismutase gene (SOD1) are one cause of familial amyotrophic lateral sclerosis [ALS; also known as motor neuron disease (MND)] in humans. ALS is a relentlessly progressive neurodegenerative disease and, to date, there are no neuroprotective therapies with significant impact on the disease course. Current transgenic murine models of the disease, which overexpress mutant SOD1, have so far been ineffective in the identification of new therapies beneficial in the human disease. Because the human and the zebrafish (Danio rerio) SOD1 protein share 76% identity, TILLING ('targeting induced local lesions in genomes') was carried out in collaboration with the Sanger Institute in order to identify mutations in the zebrafish sod1 gene. A T70I mutant zebrafish line was characterised using oxidative stress assays, neuromuscular junction (NMJ) analysis and motor function studies. The T70I sod1 zebrafish model offers the advantage over current murine models of expressing the mutant Sod1 protein at a physiological level, as occurs in humans with ALS. The T70I sod1 zebrafish demonstrates key features of ALS: an early NMJ phenotype, susceptibility to oxidative stress and an adult-onset motor neuron disease phenotype. We have demonstrated that the susceptibility of T70I sod1 embryos to oxidative stress can be used in a drug screening assay, to identify compounds that merit further investigation as potential therapies for ALS.

This paper presents the Head-Up project, that aims to provide innovative head support to help improve posture, relieve pain and aid communication for people living with progressive neck muscle weakness. The initial focus is motor neurone disease. The case study illustrates collaborative, interdisciplinary research and new product development underpinned by participatory design. The study was initiated by a 2-day stakeholder workshop followed by early proof-of-concept modelling and patient need evidence building. The work subsequently led to a successful NIHR i4i application funding a 24-month iterative design process, patenting, CE marking and clinical evaluation. The evaluation has informed amendments to the proposed design refered to here as the Sheffield Support Snood (SSS). The outcome positively demonstrates use and performance improvements over current neck orthoses and the process of multidisciplinary and user engagement has created a sense of ownership by MND participants, who have since acted as advocates for the product.

Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians' attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety-three patients were described. Forty-two percent of patients reviewed in clinicians' last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians' preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance.

Background: The diagnosis of motor neurone disease (MND) has a profound effect on the functioning and well-being of both the patient and their family, with studies describing an increase in carer burden and depression as the disease progresses., Aim: This study aimed to assess whether patient use of noninvasive ventilation (NIV) impacted on their family carer, and to explore other sources of carer burden., Design: The study used qualitative interviews and scaled measures of carer health and well-being completed at three monthly intervals until patient end of life., Participants: Sixteen family carers were followed up over a period ranging from one month to two years., Results: NIV was perceived as having little impact on carer burden. The data however highlighted a range of sources of other burdens relating to the physical strain of caring. The Medical Outcomes Study Short Form (SF-36 Health Survey) Physical Component Summary (PCS) scores were considerably below that of the Mental Component Summary (MCS) score at baseline and at all following time points. Carers described the physical effort associated with patient care and role change; the challenge inherent in having time away; and problems relating to the timing of equipment and service delivery., Conclusions: NIV can be recommended to patients without concerns regarding increasing carer burden. The predominant source of burden described related to the physical impact of caring for a patient with MND. Services face challenges if this physical burden is to be reduced by providing equipment at an optimal time and successfully coordinating their input.

Our objective was to investigate the potential of muscle volume, measured with magnetic resonance (MR), as a biomarker to quantify disease progression in patients with amyotrophic lateral sclerosis (ALS). In this longitudinal pilot study, we first sought to determine the stability of volumetric muscle MR measurements in 11 control subjects at two time-points. We assessed feasibility of detecting atrophy in four patients with ALS, followed at three-month intervals for 12 months. Muscle power and MR volume were measured in thenar eminence (TEm), first dorsal interosseous (1DIO), tibialis anterior (TA) and tongue. Changes over time were assessed using linear regression models and t-tests. Results demonstrated that, in controls, no volumetric MR changes were seen (mean volume variation in all muscles < 5%, p > 0.1). In patients, between-subject heterogeneity was identified. Trends for volume loss were found in TEm (mean, - 26.84%, p = 0.056) and TA (- 8.29%, p = 0.077), but not in 1DIO (- 18.47%, p = 0.121) or tongue (< 5%, p = 0.367). In conclusion, volumetric muscle MR appears a stable measure in controls, and progressive volume loss was demonstrable in individuals with ALS in whom clinical weakness progressed. In this small study, subclinical atrophy was not demonstrable using muscle MR. Clinico-radiological discordance between muscle weakness and MR atrophy could reflect a contribution of upper motor neuron pathology.

Objective: To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia., Methods: DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9ORF72 expansions. α-Synuclein and p62 immunohistochemistry of the substantia nigra (SN) was undertaken in brains of 17 ALS cases with (C9ORF72+) and 51 without (C9ORF72-) the C9ORF72 expansion., Results: Only 1 of 338 cases with pathologically confirmed idiopathic Parkinson disease had a C9ORF72 expansion. Similarly, only 1 of 17 C9ORF72+ brains displayed features suggestive of α-synucleinopathy. In contrast, p62-positive, TDP-43-negative neuronal cytoplasmic inclusions within the SN were considerably more frequent in C9ORF72+ brain tissue than in the C9ORF72- brains (p = 0.005). Furthermore, there was a more marked loss of dopaminergic neurons in the SN of C9ORF72+ ALS brains than C9ORF72- ALS brains (p = 0.029)., Conclusions: SN involvement is common in C9ORF72+ ALS but can be clearly distinguished from Parkinson disease-related mechanisms by the presence of p62-positive inclusions and the absence of α-synuclein-positive Lewy bodies or Lewy neurites.

Aims: Five to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes. Mutations in the angiogenin gene, ANG, have been identified in both familial and sporadic patients in several populations within Europe and North America. The aim of this study was to establish the incidence of ANG mutations in a large cohort of 517 patients from Northern England and establish the neuropathology associated with these cases., Methods: The single exon ANG gene was amplified, sequenced and analysed for mutations. Pathological examination of brain, spinal cord and skeletal muscle included conventional histology and immunohistochemistry., Results: Mutation screening identified a single sporadic amyotrophic lateral sclerosis case with a p.K54E mutation, which is absent from 278 neurologically normal control samples. The clinical presentation was of limb onset amyotrophic lateral sclerosis, with rapid disease progression and no evidence of cognitive impairment. Neuropathological examination established the presence of characteristic ubiquitinated and TDP-43-positive neuronal and glial inclusions, but no abnormality in the distribution of angiogenin protein., Discussion: There is only one previous report describing the neuropathology in a single case with a p.K17I ANG mutation which highlighted the presence of eosinophilic neuronal intranuclear inclusions in the hippocampus. The absence of this feature in the present case indicates that patients with ANG mutations do not always have pathological changes distinguishable from those of sporadic amyotrophic lateral sclerosis., (© 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) can lead to prominent nerve hypertrophy, which can mimic other forms of neuropathy radiologically. Neuro-ophthalmological complications can also occur in CIDP, either at presentation or chronically in the disorder. This can also cause diagnostic difficulties. We report three cases of neuro-ophthalmological complications of CIDP: two cases of papilloedema and one case of proptosis. In all three cases cranial nerve hypertrophy was present. CIDP should be considered in neuro-ophthalmological presentations associated with cranial/spinal nerve root hypertrophy.

Background: Non-invasive ventilation improves quality and quantity of life in patients with motor neurone disease who have respiratory failure. Use of non-invasive ventilation may, however, result in complex clinical issues for end-of-life care, with concerns as to whether and how it should be withdrawn., Aim: This study aimed to describe carer and health professional experiences of end-of-life care of motor neurone disease patients using non-invasive ventilation., Design/participants: This article reports data from qualitative interviews with family carers and professionals following the death of patients with motor neurone disease who were using non-invasive ventilation in the final phase of the disease., Results: Ten of the 20 patients initiated on non-invasive ventilation were using it in the end-of-life phase of their disease, with 5 using it for 24 h/day. Interviews were carried out with nine family carers and 15 professionals. Nine recurring themes were identified in the data. Both carers and health-care professionals perceived that the terminal phase of motor neurone disease was unexpectedly rapid and that this often led to unplanned interactions with the emergency services. Carers of patients who used non-invasive ventilation perceived non-invasive ventilation as aiding patient comfort and anxiety at the end of life., Conclusions: The use of non-invasive ventilation was described as beneficial and was not perceived by carers or most professionals to have adversely impacted patient's end-of-life experience. This study highlights variation in patient wishes regarding usage towards the end of life, uncertainty regarding appropriate management among professionals and the importance of disseminating end-of-life wishes.

This study aimed to examine the experiences of patients with motor neuron disease and their carers following the recommendation to use non-invasive ventilation (NIV). Qualitative interviews were carried out with 20 patients and 17 carers within one month of NIV being initiated. The study identified a range of potential barriers to usage including: adverse impressions of the technology; sleep disturbance; the sensation of pressure and pulsing; dry mouth; and mask design issues. Patients/carers perceived benefits related to: increased energy; improved sleeping; enhanced carer well-being; improved breathing and increased speech clarity. A key factor described by patients and carers was the need to persevere to overcome the challenges associated with early NIV use. The study highlights the importance of patient perceptions of gains as a factor in their NIV usage decisions. While recognizing that older individuals with limb-onset disease were over-represented in the sample, key recommendations from the study are: availability of easily accessible in-person support for patients; for clinicians to pre-empt potential obstacles by discussing options such as humidification or alternative mask interfaces; the importance of discussing potential benefits in detail with patients; and optimization of secretion management prior to NIV trial.

Abstract Gastrostomy feeding is commonly used to support MND patients with dysphagia. In this paper we review three main methods of gastrostomy insertion (PEG, RIG, PIG); conduct a meta-analysis of mortality data following gastrostomy; and present a survey of current practice. A review of the literature revealed a lack of high quality evidence to indicate the optimal method and timing for gastrostomy insertion in patients with MND. A survey of 20 MND clinics demonstrated a clinic-based variability of gastrostomy practices due to factors such as clinician preference, availability of method, and patient respiratory function. The meta-analysis demonstrated that the estimate of the absolute difference in mortality rates was 2.1% higher for PEG (- 6.3%, + 11.2%), suggesting that RIG and PIG methods may be safer than PEG. These results and observations highlight the need for more research to evaluate and compare the safety of the differerent gastrostomy insertion methods in MND care.

Many centres in the UK care for patients with motor neuron disease (MND) in a multidisciplinary clinic (MDC). It has been demonstrated that such care results in better prognosis for survival than care from a general neurology clinic (GNC). Whether this is due to higher use of disease-modifying interventions or an independent factor of attendance at a specialist clinic has not been established. Hence, we performed a retrospective review of hospital notes of patients with MND who were diagnosed and followed up in a GNC between 1998 and 2002 and in an MDC between 2006 and 2010. Overall, 162 patients attended a GNC, and 255 attended the MDC. The median survival from diagnosis was 19 months for patients who attended the MDC, compared to 11 months for those attending the GNC (hazard ratio 0.51, 95% CI 0.41-0.64). The Cox hazards model identified attendance at an MDC as an independently positive prognostic factor (HR 1.93, 95% CI 1.37-2.72, p < 0.001). We concluded that care at an MDC improves survival. While this effect is augmented by the increased use of riluzole, NIV and PEG, the data suggest that coordinated care independently improves the prognosis of MND patients.

Background: Crossover in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) has been described but is poorly understood. A GGGGCC hexanucleotide repeat expansion of C9ORF72 has recently been identified in a significant proportion of patients with ALS., Methods: In approximately 650 patients diagnosed with ALS from the North of England we identified seven patients who initially presented with MS. DNA obtained from five patients with MS-ALS and 215 patients with MS alone was screened for the C9ORF72 expansion. Post-mortem material was examined from two patients with MS-ALS. Gene expression profiling was performed on lymphoblastoid cells and levels of CXCL10 were measured in cerebrospinal fluid (CSF) from patients with ALS with and without the C9ORF72 expansion and controls., Results: Concurrence of MS and ALS is higher than expected in our population. The C9ORF72 expansion was identified in 80% of patients with MS-ALS but not in those with MS alone. In the presence of preceding MS, C9ORF72-ALS was more rapidly progressive. MetaCore analysis identified alteration of the NF-кB pathway in C9ORF72-ALS and non-C9ORF72-ALS. NF-кB activation is associated with increased expression of the neuroprotective cytokine CXCL10 but, in C9ORF72-ALS, CXCL10 is downregulated and CSF levels are reduced., Conclusions: We propose that MS-associated neuroinflammation may affect penetrance and progression of the C9ORF72 expansion. In particular, the NF-кB pathway is activated in MS and appears to be dysfunctional in C9ORF72-ALS. Aberrant downregulation of CXCL10 may explain the predisposition of C9ORF72 expansion carriers to develop ALS in the context of MS and NF-кB activation, and offers a potential therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, respiratory failure being the commonest cause of death. Quality of life and survival can be improved by supporting respiratory function with non-invasive ventilation. Transcutaneous carbon dioxide monitoring is a non-invasive method of measuring arterial carbon dioxide levels enabling simple and efficient screening for respiratory failure. The aim of this study was to validate the accuracy of carbon dioxide level recorded transcutaneously with a TOSCA 500 monitor. It is a prospective, observational study of 40 consecutive patients with ALS, recruited from a specialist ALS clinic. The partial pressure of carbon dioxide (PCO(2)) in each patient was determined by both transcutaneous monitoring and by an arterialized ear lobe capillary blood sample. The carbon dioxide (CO(2)) levels obtained with these two methods were compared by Bland-Altman analysis. The results showed that the mean difference between arterialized and transcutaneous readings was - 0.083 kPa (SD 0.318). The Bland-Altman limits of agreement ranged from 0.553 to - 0.719 kPa. The difference was < 0.5 kPa in 90% of the recordings. Four of the 40 measurements had a difference of > 0.5 kPa, with a maximum recorded difference of 0.95 kPa. In conclusion, non-invasive carbon dioxide monitoring using a TOSCA monitor is a useful clinical tool in neurology practice. Users should be aware of the possibility of occasional inaccurate readings. A clinically unexpected or incompatible reading should be verified with a blood gas analysis, especially when a decision to provide ventilatory support is required.

Background: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency., Method/design: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews., Discussion: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity., Trial Registration: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.

Background: In motor neurone disease (MND), respiratory muscle weakness causes substantial morbidity, and death is usually due to respiratory failure. Non-invasive ventilation (NIV) improves symptoms, quality of life and survival, but previous surveys showed that few patients with MND received NIV., Methods: A postal survey was conducted of the clinical application of NIV in MND among consultant neurologists in the UK. The results were compared with those of a similar survey done in 2000., Findings: Over 12 months, 612 patients were referred for NIV of whom 444 were successfully established on treatment (72.5% success rate). 38% of responding neurologists assessed respiratory function at presentation and 20% routinely monitored respiratory function; 32% relied on symptoms as the only criterion for NIV referral and 43% used a combination of symptoms and physiological impairment. 75% of responding neurologists accessed specialist palliative care services for their patients towards the end of life and 69% at an earlier stage., Interpretation: Compared with 2000, there has been a marked increase in the number of patients referred for, and currently using, NIV (2.6 and 3.4-fold, respectively). The proportion successfully established on NIV has also increased, suggesting more appropriate selection and/or improvement in the methods of using NIV in this challenging group of patients. However, monitoring of respiratory function is suboptimal and uncontrolled oxygen is sometimes used inappropriately before the terminal phase.

Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.

Placement of a gastrostomy tube remains the gold standard procedure to maintain nutrition in patients with motor neuron disease (MND) and bulbar muscle weakness. Percutaneous endoscopic gastrostomy (PEG) is the most commonly used procedure in this context. Per-oral image guided gastrostomy (PIG) is a new hybrid technique used successfully in non-MND patients. We have modified the PIG technique to improve patient tolerability and have undertaken a pilot evaluation of PIG compared to PEG in MND patients. Nineteen PIG and 16 PEG procedures performed over a period of four years were evaluated. Pre-procedural forced vital capacity (FVC), procedural oxygen saturation, post-procedural complications and survival duration were recorded. Results showed that a gastrostomy tube was successfully placed in 95% of the PIG group and 80% of the PEG group. Rates of minor complications were comparable in both groups (21% in PIG, 23% in PEG). No life-threatening complications occurred in either group. Procedural mean oxygen saturations were higher in the PIG group compared to the PEG group (p < 0.001). No significant survival differences were observed. This study provides evidence for the use of the PIG procedure as a safe and well tolerated alternative to PEG in MND patients.

Background: Lifetime physical activity energy expenditure (PAEE) is an important determinant of risk for many chronic diseases but remains challenging to measure. Previously reported historical physical activity (PA) questionnaires appear to be reliable, but their validity is less well established., Methods: We sought to design and validate an historical adulthood PA questionnaire (HAPAQ) against objective PA measurements from the same individuals. We recruited from a population-based cohort in Cambridgeshire, UK, (Medical Research Council Ely Study) in whom PA measurements, using individually calibrated heart rate monitoring, had been obtained in the past, once between 1994 and 1996 and once between 2000 and 2002. 100 individuals from this cohort attended for interview. Historical PA within the domains of home, work, transport, sport and exercise was recalled using the questionnaire by asking closed questions repeated for several discrete time periods from the age of 20 years old to their current age. The average PAEE from the 2 periods of objective measurements was compared to the self-reported data from the corresponding time periods in the questionnaire., Results: Significant correlations were observed between HAPAQ-derived and objectively measured total PAEE for both time periods (Spearman r = 0.44; P < 0.001). Similarly, self-reported time spent in vigorous PA was significantly correlated with objective measurements of vigorous PA (Spearman r = 0.40; P < 0.001)., Conclusions: HAPAQ demonstrates convergent validity for total PAEE and vigorous PA. This instrument will be useful for ranking individuals according to their past PA in studies of chronic disease aetiology, where activity may be an important underlying factor contributing to disease pathogenesis.

Background: New criteria for the neurophysiological diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) were recently proposed at an international symposium in Awaji-shima, Japan. They differ from the accepted revised El-Escorial criteria by considering fasciculation potentials to be evidence of acute denervation. In addition, when assessing diagnostic certainty, the Awaji-shima criteria equate electrodiagnostic evidence of lower motor neuron dysfunction with clinical examination findings., Methods: A retrospective review of 205 consecutive sets of notes was performed, from patients who underwent neurophysiological assessment for suspected MND. The clinical signs and neurophysiological findings were combined according to the two sets of criteria (revised El-Escorial and Awaji-shima), and the diagnoses reached were compared with the interval diagnosis, to establish the sensitivities and specificities of each protocol., Results: An interval diagnosis of MND was recorded in 107 patients. The sensitivity of the Awaji-shima criteria in reaching a diagnosis of MND was 60.7% and the revised El-Escorial 28%, with a specificity of 95.9% for both criteria. The Awaji-shima criteria increased the sensitivity of diagnosis without affecting the specificity., Conclusion: Accepting EMG evidence of fasciculations as evidence of acute denervation increases the diagnostic certainty of MND, and the new criteria allow earlier diagnosis of MND without increasing the false-positive rate.

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.

Objective: To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort of amyotrophic lateral sclerosis (ALS) cases from the north of England., Design: Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented., Setting: Neurology departments of 2 university teaching hospitals in the north of England., Participants: The 15 exons of FUS/TLS were sequenced in an initial cohort of 42 familial ALS (FALS) and 117 sporadic ALS (SALS) cases. Exons 14 and 15 were subsequently screened in a larger cohort of 431 SALS cases. Regions mutated in ALS cases were also screened in 293 controls., Main Outcome Measure: Evaluation of gene-sequencing chromatographs and detailed histopathologic analysis of the central nervous system., Results: Four heterozygous mutations, 1 of which is novel, were identified in 6 patients with ALS (4 with FALS and 2 with SALS). Two of the substitutions were not found to be present in controls, and neuropathology in these cases revealed neuronal and/or glial cytoplasmic inclusions positive for the FUS/TLS protein. One of these cases is also the first reported SALS case with an FUS/TLS mutation. The other 2 substitutions identified were also identified in control cases. Neuropathology in these cases revealed typical SALS pathology, suggesting that they are likely to represent benign polymorphisms., Conclusions: FUS/TLS mutations represented approximately 5% of FALS cases screened. A FUS/TLS mutation was also identified in a single SALS case. Subsequent screening of this region in a larger cohort of SALS cases, however, did not reveal any additional mutations.

Motor neuron disease (MND) is a devastating neurodegenerative condition associated with considerable disability and a poor prognosis. Despite improvements in symptomatic management in recent years, few therapies are available which modify survival. However, the challenge to find successful treatments would be greatly assisted by clearer elucidation of the underlying pathoaetiology. Many potential exogenous risk factors have been proposed as part of a gene-environment interaction in the aetiology of MND. A growing interest in the role of vigorous physical activity in the development of MND has followed reports of a higher than expected incidence of the disease in professional sports people. Such an association is also supported by current hypotheses concerning the cellular and genetic mechanisms of MND. However, evidence from epidemiological research remains conflicting and inconclusive. This article reviews the existing literature regarding physical activity as a risk factor for MND and the potential biological and genetic plausibility for this association.

Mutations in spastin are the most common cause of hereditary spastic paraplegia (HSP) but the mechanisms by which mutant spastin induces disease are not clear. Spastin functions to regulate microtubule organisation, and because of the essential role of microtubules in axonal transport, this has led to the suggestion that defects in axonal transport may underlie at least part of the disease process in HSP. However, as yet there is no direct evidence to support this notion. Here we analysed axonal transport in a novel mouse model of spastin-induced HSP that involves a pathogenic splice site mutation, which leads to a loss of spastin protein. A mutation located within the same splice site has been previously described in HSP. Spastin mice develop gait abnormalities that correlate with phenotypes seen in HSP patients and also axonal swellings containing cytoskeletal proteins, mitochondria and the amyloid precursor protein (APP). Pathological analyses of human HSP cases caused by spastin mutations revealed the presence of similar axonal swellings. To determine whether mutant spastin influenced axonal transport we quantified transport of two cargoes, mitochondria and APP-containing membrane bound organelles, in neurons from mutant spastin and control mice, using time-lapse microscopy. We found that mutant spastin perturbs anterograde transport of both cargoes. In neurons with axonal swellings we found that the mitochondrial axonal transport defects were exacerbated; distal to axonal swellings both anterograde and retrograde transport were severely reduced. These results strongly support a direct role for defective axonal transport in the pathogenesis of HSP because of spastin mutation.

Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFH-deficient (cfh(-/-)) mice. cfh(-/-) animals exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the cfh(-/-) mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the cfh(-/-) mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina.