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This study aimed to clarify the energy requirement in patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy positive pressure ventilation with tracheostomy. Total energy expenditure (TEE) was measured in 10 hospitalized bedridden ALS patients using the doubly-labeled water (DLW) method. The mean TEE/day and TEE/fat- free mass estimated by DLW method were 934 ± 201 kcal/day and 34.8 ± 5.5 kcal/kg/day, respectively. The mean TEE/resting metabolic rate (RMR) was 0.85 when RMR was estimated by the Harris-Benedict equation, 0.91 by Dietary Reference Intake (DRI), and 0.97 by Ganpule's equation using fat-free mass (FFM). The ratios of TEE to measured RMR were 1.05, 1.15 and 1.23 in three patients. In conclusion, multiplying measured RMR by 1.1 to 1.2 is considered to be appropriate to estimate energy need. However, because it is difficult to measure RMR directly in a clinical setting, an appropriate equation for estimating RMR for ALS patient should be developed.

Malnutrition is associated with poor survival among patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate nutritional assessment by a network during first consultations in patients' homes. Patients identified by the regional ALS centre gave their informed consent. Assessment included functional, nutritional issues, evaluation of the need for help, whether personal or the use of aids, and noted any dietary supplementation and modification of the texture of food. Forty patients were seen a mean of 7.4 months after diagnosis; 52.5% had bulbar disease, 7.5% were malnourished; 29.4 ± 10.1 kcal/kg/day were consumed and protein intake was 1.3 ± 0.5 g/kg/day. Thirty-five percent of patients were anorexic, 43.8% reported taste disorders, and 70% had dysphagia, significantly associated with salivary stasis. Only 30% of dysphagic patients ate texture-modified food, and 90% of patients with problems drinking liquids did not use a thickener. In conclusion, assessment at home by a nutritional network can be conducted promptly. Malnutrition is rare in early disease, despite the fact that patients' diets are often low in energy and dysphagia is common. Unexpected taste disorders are detected. Dysphagia is very common but inadequately addressed. Consequently, home assessment by the network led several beneficial interventions.

Our objective was to measure direct (hospital and NHS) and indirect (patient/caregiver) costs of following up in-home compliance to non-invasive ventilation via wireless modem. We constructed a prospective controlled trial of 40 consecutive ALS home-ventilated patients, randomly assigned according to their residence area to G1 (nearby hospital, office-based follow-up) and G2 (outside hospital area, telemetry device-based follow-up). Total NHS direct cost encompassed costs related to outpatients' visits (office and emergency room) and hospitalizations. Hospital direct costs included transportation to/from hospital, office visit per hour cost and equipment maintenance. Non-medical costs considered days of wages lost due to absenteeism. G1 included 20 patients aged 60 ± 10 years and G2 included 19 patients aged 62 ± 13 years. Results showed that no differences were found regarding clinical/demographic characteristics at admission. NHS costs showed a 55% reduction in average total costs with a statistically significant decrease of 81% in annual costs per patient in G2. Hospital costs were found to be significantly higher in G2 with regard to total costs (64% average increase) but not annual costs (7%). No statistical difference was found with regard to expenses from absenteeism. In conclusion, at the cost of an initial financial constraint to the hospital per year (non-significant), telemonitoring is cost-effective, representing major cost savings to the NHS in the order of 700 euros/patient/year.

Our objective was to examine the pleasure derived from eating in patients with advanced ALS and how this affects advice to have a gastrostomy. Patients with advanced ALS completed a visual analogue scale indicating the pleasure they derived from eating. Data were also collected on the severity of swallow using the Hillel scale, the independent feeding status, and on whether gastrostomy was accepted or not. The findings from 38 consecutive patients indicate that pleasure derived from eating is a powerful indicator of a person's acceptance of gastrostomy. In conclusion, the study showed that a simple analogue scale is quick and practical in a clinical setting even in severely compromised people with ALS and that the eating pleasure score was a strong predictor of the final decision to accept gastrostomy placement (p = 12.2 = 10(-4)).

The literature on psychological aspects of amyotrophic lateral sclerosis (ALS) has explored quality of life, depression, anxiety, spirituality, hopelessness, and other constructs in an attempt to understand the patient's grief and other psychological responses to the disease. However, there is a lack of research on the efficacy of psychological interventions. We believe it is important to develop 'best practices' for the improvement of quality of life and the reduction of psychological distress related to ALS.

Predictable decline in ALS makes unplanned gastrostomy and tracheostomy avoidable. We determined whether gastrostomy or tracheostomy insertion during emergent hospitalization is associated with patient or hospital characteristics, changed Medicare policy in 2001, or proximity to specialized ALS care. We performed a retrospective analysis of hospitalizations and procedures for ALS/MND patients in Pennsylvania between 1996 and 2009. We identified predictors of gastrostomy/tracheostomy during emergent hospitalization and trends over time. Patients underwent 1748 gastrostomies and 373 tracheostomies. Thirty-two percent of gastrostomies and 67% of tracheostomies were placed emergently. Emergent hospitalizations involving gastrostomy were more expensive with fewer home discharges. Black patients and Medicaid patients had higher odds of emergent gastrostomy placement. Conversely, academic hospital affiliation decreased odds of emergent gastrostomy or tracheostomy placement (AOR 0.49, AOR 0.37, p < 0.001). After Medicare policy changes, gastrostomy use increased, while emergent gastrostomies decreased. Surprisingly, proximity to specialized care was associated with increased emergent gastrostomy placement. In conclusion, black patients and Medicaid patients were more likely to undergo emergent gastrostomy insertion. Patients receiving gastrostomy during emergent admissions had fewer home discharges and higher costs. Academic hospital affiliation decreased odds of emergent gastrostomy or tracheostomy. After Medicare changes broadening access, while gastrostomy use increased, the proportion of emergent procedures decreased.

The multidisciplinary approach to treatment of amyotrophic lateral sclerosis (ALS) has improved the overall care of patients suffering from this disease ( 1 , 2 ). This approach typically has included neurologists, physiatrists, occupational therapists, respiratory therapists and speech therapists. Dysphonia, dysarthria, and dysphagia are three of the most common bulbar manifestations of ALS, and are often the presenting symptoms in bulbar-onset patients. Despite this, otolaryngologists are often not included in ALS management until a tracheostomy is considered. The otolaryngologist can play an important role in early diagnosis and subsequent management of bulbar manifestations of ALS, and would be a valuable member of the multidisciplinary team.

Patients with ALS have complicated medication regimens and many questions about medications. Our multidisciplinary ALS clinic includes a clinical pharmacist, and the purpose of this study was to assess the types and outcomes of consultative interactions. This was a prospective, data collection study of patients seen by the pharmacist at a single ALS clinic visit. The following data were obtained: 1) current medications; 2) number and types of pharmacy interventions; 3) amount of time spent by the pharmacist with each patient. Thirty-seven patients were included. The average number of prescriptions used per patient was 3.59 (0-10) with 1.75 (0-9) used for ALS related indications. The average number of pharmacist interventions was two per patient, with the majority related to medication monitoring and optimizing drug therapy for ALS symptoms. The pharmacist provided education on an average of 2.5 topics per patient. The pharmacist spent an average of 21 (5-50) min with each patient. In conclusion, a clinical pharmacist contributes to the team by: 1) optimizing drug therapy for ALS symptoms; 2) providing medication-related education to patients; 3) allowing more time for the neurologist to attend to neurologic issues; and 4) discussing general medicine issues.

We have evaluated the potential role of respiratory exercise by implementing specific inspiratory muscle training in a selected population of early-affected amyotrophic lateral sclerosis (ALS) patients. We studied 26 patients with ALS with normal respiratory function using two groups of patients in a parallel, control-group, randomized, delayed-start design. Patients in the first group (G1) started the active inspiratory exercise programme at entry and were followed for eight months, while the second group (G2) of patients followed a placebo exercise programme for the first four months and then active exercise for the second four-month period. The primary outcome measure was the ALSFRS. Respiratory tests, neurophysiological measurements, fatigue and quality of life scales were secondary outcomes. Analysis of covariance was used to compare changes between and within groups. Results showed that there was no significant difference between the two patient groups. Within-group analysis suggested that inspiratory exercise promotes a transient improvement in the respiratory subscore and in the maximal voluntary ventilation, peak expiratory flow, and sniff inspiratory pressure. In conclusion, there was no clear positive or negative outcome of the respiratory exercise protocol we have proposed, but we cannot rule out a minor positive effect. Exercise regimes merit more detailed clinical evaluation in ALS.

Service providers and service users often have different perspectives on health and social care services. We have undertaken a systematic review of empirical data between 1988 and March 2011 relating to ALS service users' perspectives on health and social care services. Forty-seven texts were extracted and a narrative synthesis conducted. Few studies have explored ALS patients' experiences in relation to their satisfaction with services. Our review showed that ALS patients expect dignified care but they are often dissatisfied with health care services and have unmet expectations of their care. Most studies of decision-making and preferences for care have focused on end-of-life intervention. Various factors influence preferences for care from the service user perspective and people with ALS may adjust their use of services as they negotiate change. In conclusion, further research on the timeliness of services to meet changing needs of service users is required. The service user experience of allied health care services prior to end-of-life care also warrants investigation. Service providers need to support people with ALS as they negotiate feelings of acceptance and independence. Research to identify the key parameters of the ALS patient experience of services is required.

Non-invasive positive pressure ventilation (NIPPV) may improve health-related quality of life (HRQoL) in patients with ALS. The effect of percutaneous endoscopic gastrostomy (PEG) on HRQoL is not known. Instruments measuring QoL more broadly have not been used to assess effects of these interventions. This study was undertaken to do so via the ALS-Specific Quality of Life Instrument-revised (ALSSQOL-R). A retrospective review was carried out of ALS patients who had undergone one QoL assessment prior to NIPPV or PEG initiation and two assessments following one of these interventions. Random coefficients models were developed. Twenty-two patients met criteria for inclusion: six NIPPV, 11 PEG, and five NIPPV + PEG. The ALSSQoL-R did not change significantly following NIPPV or PEG or both. Function declined in all three groups over the same time-period. In conclusion, overall QoL in ALS does not appear to change after NIPPV or PEG. This may reflect the impact of non-health-related factors or may be due to a response shift. QoL instruments that include domains outside of health status may not be sensitive to changes from single interventions. Larger, prospective studies are needed.

Our objective was to evaluate a single-session, hands-on education programme on mechanical ventilation for ALS patients and caregivers in terms of knowledge, change in affect and to determine whether ventilator decisions made after the education sessions predict those made later in life. Questionnaires were administered to 26 patients and 26 caregivers on four separate occasions. The questionnaires assessed knowledge of ventilatory support, feedback on the nature of the education programme, as well as self-reported emotional well-being. All patients were followed until their death or until initiation of invasive ventilation. Both groups demonstrated significant improvements in knowledge as a result of the education session which was retained after one month. There was no change in patient or caregiver reports' self-reported emotional well-being. The choices of ventilatory support expressed at one month (T4) accurately predicted the real-life clinical choices made by 76% of patients. Any difference resulted from choosing palliative care. Hands-on patient and caregiver education results in improved knowledge, assists in decision-making with respect to ventilatory support, and is not associated with a worsening of affect. It also provides for an accurate prediction of real-life choices and avoids undesired life support interventions and critical care admissions.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.

A few studies suggest that non-invasive ventilation (1) and gastric tube (G-tube) may have a positive impact on survival but the effect on functional decline is unclear. Confounding by indication may have produced biased estimates of the benefit seen in some of these retrospective studies. The objective of this study was to evaluate the effects of G-tube and NIV on survival and functional decline using advanced statistical models that adjust for confounding by indications. A database of 331 subjects enrolled in previous clinical trials in ALS was available for analysis. Marginal structural models (MSM) were used to compare the mortality hazards and ALSFRS-R slopes between treatment and non-treatment groups, after adjusting for confounding by indication. Results showed that the placement of a G-tube was associated with an additional 1.42 units/month decline in the ALSFRS-R slope (p < 0.0001) and increased mortality hazard of 0.28 (p = 0.02). The use of NIV had no significant effect on ALSFRS-R decline or mortality. In conclusion, marginal structural models can be used to adjust for confounding by indication in retrospective ALS studies. G-tube placement could be followed by a faster rate of functional decline and increased mortality. Our results may suffer from some of the limitations of retrospective analyses.

Abstract Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.

Our objective was to investigate the nutritional requirements in ALS and to determine the feasibility of early intervention with NIPPV. Subjects were enrolled into one of two arms. In the nutrition arm, total daily energy expenditure (TDEE) was determined longitudinally over 48 weeks using the Doubly Labeled Water method. In the NIPPV arm, NIPPV was offered at 80% vs. 50% FVC. Additional measurements were obtained in both arms to ultimately formulate equations to predict TDEE and to estimate sample size for a phase III study of early NIPPV. Eighty subjects were enrolled in the nutrition arm and 73 in the NIPPV arm. Baseline characteristics of the participants are described. TDEE was available for 80 subjects in 249 independent determinations during disease progression. Other variables were measured simultaneously for future modeling of ALS-specific equations to predict TDEE. In the NIPPV arm, rates of progression to the criteria for NIPPV intervention (80% or 50% predicted FVC) were computed. Additional factors were obtained longitudinally to develop indices of early ventilatory insufficiency. The results of this study will allow us to model equations to predict the energy requirements in ALS and to plan a study of early intervention with NIPPV.

The construct 'meaning in life' (MiL) has become increasingly important in palliative care. Several meaning-focused interventions have been developed recently. The aim of this study was to investigate MiL in patients with amyotrophic lateral sclerosis (ALS) and compare the findings with a representative sample of the German population. In the newly developed 'Schedule for Meaning in Life Evaluation' (SMiLE), respondents first list individual areas that provide meaning to their life before rating their current level of importance and satisfaction with each area. Overall indices of weighting (IoW, range 20-100), satisfaction (IoS, range 0-100), and weighted satisfaction (IoWS, range 0-100) are calculated. Results of our study showed that 46 ALS patients completed the SMiLE: the IoS was 74.7 ± 20.2, the IoW 88.1 ± 10.1, and the IoWS 76.3 ± 20.5. Satisfaction with MiL was negatively associated with disease duration and degree of functional impairment. After adjustment for age, sex, and marital status, the representative sample (n = 977) scored significantly higher in the IoS (82.8 ± 14.7) and the IoWS (83.3 ± 14.8). Compared to the general population, ALS patients list more meaning-relevant areas, are more likely to list partner, and less likely to list health. Thus, response shift seems to be a central coping mechanism in ALS patients. Regarding their major MiL areas, they shift their focus away from decreasing health status and towards supportive relationships.

Stem cells have captured the imagination of people with ALS. The potential promise of neuronal replacement and regeneration, as well as replacement and regeneration of other neural tissues, through stem cell therapies, has become a source of great hope and expectation. While just more than a decade has passed since the discovery of human stem cells, the field has made substantial advances in the use of stem cells as tools for understanding the process of motor neuron degeneration. Although the therapeutic role of stems cells in ALS and other neurodegenerations remains to be established, recent experimental data provide grounds for considered optimism.

Currently, ALS clinical trials require large sample size and the participation of many clinical evaluators to perform the outcome measure. High variability due to testers, instruments, or patients performance errors may result in systematic bias or random error leading to erroneous or uninterpretable results. Consequently, a quality control system that aims to produce high quality data in terms of reproducibility and accuracy to ensure reliability of the primary outcome measure is essential. In this paper we report our experience in preparing and executing a prospective quality control system that was implemented in conjunction with a large multicenter, multinational randomized placebo-controlled phase III clinical trial in ALS. We have shown that a prospective quality control system is highly effective to ensure inter- and intra-rater reliability of vital capacity as a primary outcome measure during the entire trial.

Cell based therapies may be promising options for treating ALS. These therapies aim at neuronal replacement or they may prevent dysfunctional motor neurons from dying. Conflicting results on transplantation of olfactory ensheathing cells (OECs) in ALS mouse models indicate that this technique is not yet ready to progress to clinical trials. A Chinese group has nevertheless treated ALS patients with OECs. We carried out a prospective study of seven patients who underwent OEC treatment in China, following them from four months before departure until one year after treatment. Muscle strength, level of daily functioning and respiratory capacity were measured at regular intervals. Three patients reported subjective positive effects directly after treatment. No individual objective improvement was measured, and outcome measures gradually declined in all patients. Two patients had severe side-effects. Based on our findings in these ALS patients who underwent experimental OEC treatment, we conclude that there are no indications that this treatment is beneficial.

This study reviews feeding tube placement outcomes in 69 ALS outpatients seen at an outpatient interdisciplinary ALS clinic in British Columbia, Canada. The objective was to determine at which point the risks outweigh the benefits of tube placement by reviewing outcomes against parameters of respiratory function, nutritional status and speech and swallowing deterioration. The study was a retrospective review of tube placements between January 2000 and 2005, analysing data on respiratory function (forced vital capacity and respiratory status), weight change from usual body weight (UBW) and speech/swallowing deterioration using ALS Severity Score ratings (Hillel et al., 1989) at time of tube placement. Results show a statistically significant association between nutritional status and successful tube placement outcomes (p=0.003), and none between respiratory status, speech/swallowing variables, or number of deteriorated variables in each patient. Study findings were impacted by lack of available respiratory data. The only study variable that predicted successful tube placement outcome was a body weight greater than or equal to 74% UBW at time of tube placement. In the absence of access to respiratory testing, the relatively simple assessment of weight may assist patients and caregivers in appropriate decisions around tube placement.

ALS is progressive with increasing patient needs for durable medical equipment (DME) and interventions (gastric feeding tube - PEG, and non-invasive ventilation - NIV). We performed a chart review of deceased patients to determine the time-course of needs and their estimated costs. A timeline of needs was based on when clinic personnel felt an item was necessary. The point in time when an item or intervention was needed was expressed as a percentage of a patient's total disease duration. A wide range of DME and interventions was needed irrespective of site of ALS symptom onset (bulbar, upper, lower extremity), beginning at 10% of disease duration of lower extremity onset and increasing thereafter for all sites. The cumulative probability of costs of items and interventions began at 25%-50% of disease duration and increased to between $18,000 and $32,000 (USD), highest for lower extremity onset due to the cost of wheelchairs. We conclude that a high percentage of ALS patients will need a full spectrum of major DME items and interventions during the second half of disease duration. This results in a linear rise in costs over the second half of the disease duration.

Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

The human genome contains two SMN (survival motor neuron) genes: SMN1, the telomeric gene whose homozygous deletion causes spinal muscular atrophy (SMA), and SMN2, the centromeric version whose copy number modulates the phenotype of SMA. We performed a Medline search and reviewed all of the publications that focus on SMN1 and SMN2 in amyotrophic lateral sclerosis (ALS) to analyse whether these genes also act as risk factors or phenotypic modulators in ALS. While homozygous deletion of SMN1 was not associated in ALS, abnormal SMN1 copy numbers significantly increased the risk of ALS. The role of the SMN2 gene in ALS needs further clarification. The existence of abnormal SMN1 copy numbers in ALS provides additional evidence that gene copy number variants may contribute to neurodegeneration and might open new approaches to treatment.

Our objective was to estimate the economic burden of patients with amyotrophic lateral sclerosis (ALS) and to examine the effect of treatment in a multidisciplinary ALS treatment centre versus general care on costs and to describe differences in costs according to clinical characteristics. In a cross-sectional study 208 patients with ALS and their caregivers were interviewed and were asked to fill in a cost diary for six months. Patients were divided in groups according to type of treatment they received and according to clinical characteristics (site of onset, severity). The direct healthcare and non-healthcare costs were calculated according to Dutch guidelines for cost analysis in healthcare research, standardized for the year 2003. Ninety-eight patients were included when they had filled in the cost diary for at least three months and were affected for three years or less. Mean monthly costs were 1336 euros for the group receiving multidisciplinary care and 1271 euros for those receiving general care. This study shows that the costs of multidisciplinary ALS care were practically identical to the costs of general care. Earlier study showed that patients receiving multidisciplinary care had a better quality of life; therefore, the present study encourages the formation of multidisciplinary teams of professionals specialized in ALS care to further improve standards of care and QoL of patients suffering from ALS.

Current practice guidelines state that enteral feeding should be proposed and provided whenever ALS patients show significant dysphagia and/or weight loss. Percutaneous endoscopic gastrostomy (PEG) is usually available at ALS centres, but this method is not indicated in the case of patients with severe respiratory impairment. We undertook a study to assess the feasibility of applying home parenteral nutrition (PN) to ALS patients with respiratory insufficiency, to assess the complications and survival times after the procedure. PN was provided, via an implanted port, to 30 ALS patients with respiratory insufficiency requiring nutritional support. Nutritional and neurological follow-up were carried out. The results were compared with those obtained on a group of 35 patients who underwent PEG, who were subdivided into patients with respiratory insufficiency and those without respiratory insufficiency at the time of the PEG. Post-procedure survival of PEG patients with respiratory insufficiency was similar to those of the PN group. The results of the study suggest that PN is a safe and effective method, which improves the patients' nutritional status and stabilizes their weight in most cases. Home PN could be applied to patients with advanced ALS and poor respiratory function as an alternative to enteral feeding.

Although the cyanobacteria/BMAA hypothesis of the cause of ALS and other age-related neurodegenerative diseases remains to be proven, it is not too early to ask whether treatment would be possible if the hypothesis were correct. This paper reviews the possible ways that chronic BMAA neurotoxicity could be prevented or treated.

The 6th European ALS congress took place in Lisbon, Portugal from 20 to 22 June. The scientific sessions focused on disease pathogenesis and neuroprotection including genetics, proteomics, metabolomics and various disease models. In the clinical session the latest findings on nutrition, ventilation, psychological support as well as new developments in the field of imaging and neurophysiology were discussed. This review outlines the work that was presented during the meeting.

Although multidisciplinary amyotrophic lateral sclerosis (ALS) clinics are widely endorsed, there is limited evidence they improve outcome. We retrospectively assessed use of non-invasive ventilation in 37 ALS patients seen before and 40 patients seen after the addition of a respiratory therapist to our clinic. Patients undergoing respiratory therapy were more likely to try non-invasive ventilation (odds ratio 4.01; 95% confidence interval 1.42-11.35) and more likely to use it for at least four hours per night (odds ratio 9.5, 95% confidence interval 2.32-38.88). Median survival following non-invasive ventilation institution was 10 months for those using it four or more hours per night and five months for those who refused it or who used it for less than four hours per night (p<0.03). We conclude that adding a respiratory therapist to our multidisciplinary ALS clinic led to an increase in the percentage of patients willing to try BiNIV as well as to use it more than four hours per night, and confirm as in prior studies that such use leads to prolonged survival.

The purpose of the study was to assess frequency and predictors of disability measures in ALS. One hundred and fourteen newly diagnosed patients resident in eight administrative districts of Lombardy, Italy (population 4,947,554), included in a population-based registry, were followed for 2570 person-months (mean 22.5 months). The cumulative time-dependent risk of wheelchair, percutaneous endoscopic gastrostomy, and assisted ventilation was estimated according to the Kaplan-Meier method. Predictors of disability (age, sex, disease duration at diagnosis, type of onset, El-Escorial diagnosis) were assessed with the Cox proportional hazard function. During follow-up, 29 patients (25.4%) became wheelchair bound, 51 (44.7%) received gastrostomy, and 47 (41.2%) received assisted ventilation. The median time to loss of ambulation was 46.7 months (95% CI 36.5-56.8). The median time to gastrostomy and assisted ventilation was 31.1 months (95% CI 26.8-35.4) and 34.6 months (95% CI 29.6-39.6), respectively. Spinal onset ALS was the only predictor of loss of ambulation. Predictors of gastrostomy were older age, definite ALS, and shorter disease duration. Shorter disease duration was the only predictor of assisted ventilation. In conclusion, patients with ALS differ in terms of measures and predictors of disability. These factors are sources of bias and confounding in randomized clinical trials.

Two hundred and fifty-four ALS patients from British Columbia, Canada were screened for mutations in the gene encoding the enzyme superoxide dismutase type 1 (SOD1). Thirteen patients (5.1%) carried one of six missense mutations (A4V, G72C, D76Y, D90A, C111Y, I113T). Mutations were found both in sporadic and familial ALS cases. Atypical clinical features delayed diagnosis in some cases. The demographic and clinical features of the mutation carrying index cases are summarized, and compared with those of screened patients without mutations. The phenotypic variability between SOD1 mutation carrying patients in this study is dramatic, even among patients with the same mutation This underlines the hypothesis that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate to form the final clinical phenotype.

Several important design issues for clinical trials in ALS were presented at the World Federation of Neurology conference at the International Motor Neuron Disease meeting in Yokahama, Japan. We present a discussion, and critique, of the important ideas that were presented with regard to phase II trials. In particular we critique the use of 'Futility Designs' because, as presented at the meeting they will too often lead to the testing of ineffective drugs. We show that except under a highly restrictive model, the use of a 'Lead In' period has only a minor effect on trial efficiency. We show the advantage of using multi-drug phase II trials to select drugs for further study and the advantage of studies that combine phase II and III. We also describe how group sequential trials can be used to stop trials early.

A sequential trial design is an alternative for the classical trial design with a fixed sample size, that permits stopping a trial as soon as enough evidence for a treatment effect, or a lack thereof, is obtained. This study aimed to determine the difference in efficiency of time and patient number between a classical trial design and a sequential trial design. In this study we re-analysed a previously published classically designed clinical trial according to a sequential trial design. We subsequently determined the difference in total running time and patient number. We found that the sequential analysis offered a gain in time of 38%. We conclude that the sequential trial design may in certain situations be superior to the classical design.

The evidence base for diagnosis and management of ALS is still weak, and curative therapy is lacking. Nonetheless, early diagnosis and symptomatic therapy can profoundly influence care and quality of life of the patient and relatives, and may increase survival time. This review addresses the current optimal clinical approach to ALS. The literature search is complete to December 2006. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. We conclude that a diagnosis of ALS can be achieved by early examination by an experienced neurologist. The patient should be informed of the diagnosis by the consultant. Following diagnosis, a multi-diciplinary care team should support the patient and relatives. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with VC <50%: RIG may be a better alternative. Non-invasive positive pressure ventilation improves survival and quality of life but is underused in Europe. Maintaining the patient's ability to communicate is essential. During the course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be discussed early with the patient and relatives if they so wish.

Non-invasive positive pressure ventilation (NPPV) can improve survival in ALS patients with advanced respiratory impairment, but it is not known if it is beneficial earlier in the disease course. A retrospective cohort study of patients with ALS was performed comparing survival from time of diagnosis in subjects who started NPPV use when their FVC was >or=65% predicted (Early NPPV) with subjects who started NPPV when their FVC was below 65% predicted (Standard NPPV). The Early group (n = 25) and the Standard group (n = 67) were similar except for pulmonary function (mean FVC in Early NPPV group = 74.3+/-10.1% predicted and 48.3+/-11.3 in Standard group, p<0.001). The median time from ALS diagnosis to death was significantly longer in the Early NPPV group (2.7 years vs. 1.8 years, p = 0.045). This remained significant after adjustment for potential confounding factors (H.R. = 0.55, 95% CI 0.31-0.98). Survival from time of diagnosis was nearly one year longer in the Early group. Until more definitive data are available from randomized trials, our findings suggest that clinicians either encourage earlier use of NPPV or use more sensitive tests for respiratory muscle impairment than upright FVC.