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There are wider issues relating to the communication difficulties experienced by people with amyotrophic lateral sclerosis (ALS) than simply the physical problems caused by diminished oral control. In addition, existing literature on ALS rarely considers communication to be a joint interaction which depends on the strategies adopted by both communication partners, nor does it present communication in real life settings. This paper presents some of the findings from a 3-year research project which investigated the communication of people with ALS and their partners in their own homes. It discusses the purpose of human communication, and through examination of conversations in people's own homes has identified a range of strategies and techniques that families with ALS employ. For some people with ALS, although speech may deteriorate, they are still able to communicate closely and in a way that is more focused on topics that are particularly important to them. The findings from this study will be of interest to those who work with people with ALS. [ABSTRACT FROM AUTHOR]

Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs – amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied. METHODS: As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs. RESULTS: In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed. CONCLUSIONS: We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation. [ABSTRACT FROM AUTHOR]

Until fairly recently, interest in stem cells was restricted to neurobiology studies on the principles of embryonic development. This situation has changed rapidly in the last few years when neuronal stems and precursors were isolated in vitro, thus allowing expansion and controlled differentiation of selective populations of neuronal cells. This theoretically unlimited reserve would then supply specific cells for transplantation in diseases characterized by widespread degeneration of selective cell populations as motor neurons in Amyotrophic Lateral Sclerosis (ALS). The recent evidence of cell transdifferentiation has further amplified the potential therapeutic use of stem cells. Stem cell technology is at an early stage but the desperate need for a therapy in ALS patients may legitimize clinical trials in absence of conclusive scientific evidence. This paper discusses the premises for stem cell therapy in ALS. [ABSTRACT FROM AUTHOR]

The current status of evaluation and management provided by individual health-care professionals (HCP) at amyotrophic lateral sclerosis (ALS) centers and clinics needs to be analyzed. This paper describes one ALS center's experiences with the development, analysis, refinement, and utility of an interdisciplinary, HCP-driven ALS database. The purpose and conceptual framework of the database, the general data that needed to be collected, and the types of reports that needed to be generated were determined, and, in collaboration with a computer programmer, database management systems were developed. Data were collected on 234 patients between September 1996 and August 1998, and were analyzed by a data entry and biostatistician. Based on review of the biostatistician's report and discussion of problems encountered with the systems, the database was then refined. Benefits of the database system included: systematization of data collection and reporting, reduction of redundant data collection by individuals, decreased variability of evaluation methods and management decisions from patient to patient, and increased availability of a variety of uniform patient information to assist team members in making care decisions. Ongoing refinement will ensure that this HCP-driven ALS database continues to be informative, practical and effective for decision-making and enhancing delivery of care. (ALS 2001; 2: 39–46). [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of unknown etiology. Although there was a widely held belief that ALS does not cause cognitive impairment, cognitive function in patients with ALS has received more attention recently. In this paper, we discuss the clinical, neuroanatomical and neuropathological basis for cognitive dysfunction in ALS. (ALS 2000; 1: 343–347). [ABSTRACT FROM AUTHOR]

In tandem with recent progress in basic and clinical research in amyotrophic lateral sclerosis (ALS), clinical care and management has improved substantially. Key processes and practices have been established and are specified in current ALS Practice Parameters; the international ALS databases identify the current status of care and management given by physicians. A number of prospective clinical management research studies are now well underway to establish the effective utility of enteral feeding, assistive ventilatory device, and exercise in patients with ALS. One of the main research objectives in the clinical management of ALS is to improve patients' quality of life. For patients with ALS, only comprehensive multidisciplinary care can effectively improve their overall quality of life from diagnosis to death. This paper will briefly review a number of factors that must be considered if we are to improve the quality of life for these patients, including comprehensive medical management, patient education, the importance of hope, the role of the health care professional, and the patients themselves. (ALS 2000; 1: 329–336). [ABSTRACT FROM AUTHOR]

Numerous attempts have been made to visualize the motor cortex and pyramidal tract lesions in patients with ALS using magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). This paper briefly reviews the applicability of these imaging modalities in ALS. (ALS 2000; 1(suppl 2): S3-S6). [ABSTRACT FROM AUTHOR]

Electromyography (EMG) plays a key role in the diagnostic evaluation of ALS. This paper deals with the contribution of conventional needle EMG and electroneurography to the neurophysiological assessment of ALS. In addition, special EMG techniques such as single fibre EMG and macro EMG are discussed as they mirror the decline of the number of motor units during the disease process and the remodelling capacity of the surviving motor units. (ALS 2000; 1(suppl2):S33-S40). [ABSTRACT FROM AUTHOR]

The 1990s decade has seen the testing of treatments to slow disease progression in patients with ALS. Two such treatments (riluzole and myotrophin) have shown minimal or modest efficacy. Of these, riluzole has been approved for marketing in the United States, in Europe and in other countries. Patients and physicians who are trying to decide whether to use these treatments require background information: (a) to place these treatments in the context of other treatments; (b) to under stand the outcome measures used; and (c) to understand the significance of the efficacy these treatments have shown. For example, in some cases treatment efficacy has been shown by some measures, but not others. This paper attempts to assist in this process. In addition, we attempt to show how to integrate objective data with relative or subjective factors, such as patient values, economic considerations, and the role of hope. (Amyot Lat Scler 1999; 1;3–14). [ABSTRACT FROM AUTHOR]

Introduces articles published in the March 2003 issue of the 'ALS and other motor neuron disorders' journal. Stem cell therapy in amyotrophic lateral sclerosis (ALS); Importance of assisting cough in people with ALS requiring assisted ventilation; Adaptation to stress of progressive disability.

In their recent paper, Sugai et al. (1) reported a beneficial effect of valproate (VPA) in a G93A mouse model of ALS, showing a significant prolongation of disease duration, without any effect on disease onset. Although this result certainly needs to be further investigated, it is interesting to hypothesize that VPA might exert this beneficial action through a novel mechanism based on the epigenetic rearrangement of the structure of the chromatin, eventually resulting in the modulation of the disease phenotypic traits. [ABSTRACT FROM AUTHOR]

Background All are agreed that there is pressing need for an effective treatment for Amyotrophic Lateral Sclerosis (ALS; MND). Such treatment may derive from a combination of therapeutic strategies aimed at different aspects of the disorder, and might include drugs directed at the initial, intermediate or terminal cascade of events leading to cell death, as well as the use of stem cells to replace dead motor neurons, or to protect those that remain. The attraction of cell implantation or transplantation is that it might help to overcome the inability of the CNS to replace lost neurons. It is also clear that neural implantation will yield little benefit if the donor cells fail to integrate functionally into the recipient CNS circuitry. In this respect, ALS poses an especially difficult problem. The recent breakthroughs in stem cell research might nevertheless provide possibilities for neural implantation and cell replacement therapy for patients with ALS. The potential impact of these new approaches to neurodegenerative diseases has been emphasised by the many experiments using human foetal cell grafts in patients affected by Parkinson's and Huntington's disease. Clinical benefits in Parkinson's disease seem to be associated with integration of the donor cells into the recipient brain. Despite promising results, however, significant constraints have hampered the use of foetal cells for neural implantation and transplantation. Besides ethical concerns, the viability, purity, and final destiny of the foetal tissue have not been completely defined. Foetal cells are, in addition, post-mitotic and cannot be expanded or stored for long periods, necessitating close synchronisation of tissue donation and neurosurgery. [ABSTRACT FROM AUTHOR]

Announces developments concerning neurology in 2000. Holding of the 52nd Annual Meeting of the American Academy of Neurology in San Diego, California, in May 2000; Presentation of the 2000 Sheila Essey Award for Amyotrophic Lateral Sclerosis Research to Jean-Pierre Julien; Neurology association Web sites; Schedule of meetings in 2000 and 2001.

Focuses on the newcomer to the consortium of study groups known as the Great Lakes Study Group and its involvement on projects in strength testing techniques. Lists of centers that are currently eligible to start enrolment for amyotrophic lateral sclerosis study; Issue of stratification; Usage of an approach used by the National Cancer Institute for multicenter studies.

Presents ethical standards for authors contributing to the 'Journal of Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases' and for the journal itself. Guidelines; Requirement of appropriate declaration by all authors.

We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, non‐linear, or even not intuitively highly relevant to the disease. We suggest that the ALS‐FRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate. [ABSTRACT FROM AUTHOR]

Since the evaluation of vital capacity (VC) needs to be carried out every three months in patients with amyotrophic lateral sclerosis (ALS), a portable spirometer would be of value in clinical practice. Over the follow‐up of 52 ALS patients, we compared the values of slow vital capacity measured by two spirometers: a reference flow‐metered spirometer based on a Hans‐Rudolph pneumotachograph and a portable Venturi spirometer. The objectives were to analyse the overall concordance of the measurements from the two devices and determine a discordance cut‐off. The correlation between measurements was high ( r = 0.936) and significant ( p -20 ). Bland and Altman analysis showed that the measurements were concordant at a statistical risk of 5%; nevertheless, on examination of the raw differences between the measurements, two sub‐populations could be identified on either side of the 56% cut‐off where the means of the differences were significantly different ( p [ABSTRACT FROM AUTHOR]

Motor proteins link concepts of impaired axonal transport with concepts of impaired energy metabolism in motor neuron disease. Thus it is not surprising that in recent years several reports on the relevance of motor protein function in mice models for motor neuron disease as well as motor neuron patients have appeared. This article summarizes the broad spectrum of neurological phenotypes, which are caused by alterations of motor protein function. This is likely to add to the understanding of motor neuron disease and may be relevant in terms of future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Patient care and minimizing complications post gastrostomy have to date received little attention in ALS patients. We compare the complications associated with pigtail and mushroom type percutaneous radiological gastrostomy tubes in this patient group. Patients requiring PRG received either Wills‐Oglesby TM or the skin level Entristar TM . Retrospective review of the clinical notes was performed capturing demographic data, peristomal infection, tube displacement, tube failure, nutritional status, site of disease onset, and survival. Thirty‐five patients (Group 1) had the Wills‐Oglesby TM tube of which 14 (40%) tubes required replacement. The Entristar TM tube was inserted in 29 patients (Group 2) where 8 (28%) required replacement (NS). The incidence of infection was significantly lower with the Entristar TM tube, ( p [ABSTRACT FROM AUTHOR]

The article presents a discussion on primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and mutations in the alsin gene. The concepts encompassing these conditions depend upon the definition of amyotrophic lateral sclerosis (ALS), which is central to the discussion of all the other three conditions and is therefore the starting point. ALS is a disease of both upper and lower motor neurons, as identified by clinical signs, electrophysiology, and post mortem histopathology. Prospective follow-up is required to determine the variations in the natural history of uncomplicated PLS and whether it is ultimately merely a form of ALS. This determination currently depends on post mortem examination. Now that HSP and alsin have introduced molecular genetics, classification is certain to be affected, animal models will appear, and advances in theories of pathogenesis are expected.

Amyotrophic lateral sclerosis (ALS) is caused by mutations in the gene for Cu/Zn superoxide dismutase (SOD1) in 10% of familial and sporadic cases. During the SOD1 analysis of 9 FALS and 121 SALS, in only one sporadic case we found the exonic mutation N19S; in 15 SALS patients we found a 319t>a variation in IVS1 sequence, at 108 bp upstream from exon 2. This variation has an unusually high frequency of 11% and is always in linkage disequilibrium with a described polymorphism in IVS3, +34a>c. The 319t>a variation is classified in two different public databases, HGMD and The ALS Online Database, as a splicing mutation and not as a polymorphism. The unusually high frequency of this mutation in our patients prompted us to determinate its frequency in 130 age- and gender- matched healthy controls and in 54 patients with Alzheimer's disease. We found again linkage disequilibrium with the polymorphism in intron 3, and the frequency of 11% and 7.8%, respectively. These results strongly support the idea that the IVS1 +319 t>a alone is not an ALS causing mutation, and that special care must be taken in the interpretation of data from mutations databases for correct genetic counselling. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice. METHODS: As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 μg kg -1 , 3.9 μg kg -1 , 39 μg kg -1 , and 390 μg kg -1 ). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number. RESULTS: We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B. CONCLUSIONS: We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine if the publication in 1999 of the AAN Practice Parameter on ALS was associated with an improvement in the standard of management of the disease. METHODS: Data on 646 patients enrolled in the ALS CARE database and on 465 patients who died in the period May 2001 to November 2002 were compared with similar data obtained from the database from 1996 to May 1999. RESULTS: The specialty ALS clinics were the most important source of information about ALS. The internet was a source for 39%. The treatment of sialorrhea, pseudobulbar emotional lability, and failure of swallowing and breathing had all improved significantly in the period after the publication of the Practice Parameter. However many patients still did not receive a gastrostomy tube or non-invasive positive pressure ventilation when indicated by the Practice Parameter, mainly because of lack of patient compliance. Cost was the main reason why 41% of patients did not receive riluzole, though they spent a third of the cost of this medication on alternative medicines. CONCLUSIONS: The publication of the AAN Practice Parameter was associated with improvement in the standard of care. Most cases in the database come from specialized ALS centers, and further information on the community care of ALS patients is needed. [ABSTRACT FROM AUTHOR]

Presents the review of the use of rating scale in clinics to provide an assessment of rate of progression and efficacy of therapeutics in amyotrophic lateral sclerosis. Five components of scale; Mensuration of the strength of grip and lateral pinch; Goal of the rating scale.

Focuses on the impact of missing data from a randomized controlled trial (RTC) which shows efficacy and important benefit to patients with amyotrophic lateral sclerosis. Role of statistician to minimize data errors in trials; Emphasis on the importance of missing data in RTCs; Summary of the limitations in imputation procedures.

Magnetic resonance spectroscopy (MRS) allows the quantitative assessment of neuronal integrity in vivo based on the resonance intensity of N-acetylaspartate (NAA). A simple approach to quantitation that is commonly used is to quantify the resonance intensity of NAA with respect to creatine (Cr). In patients with ALS, NAA/Cr density is decreased in areas of the brain that contribute significantly to the corticospinal tract. Since MRS is non-invasive, it can be easily used to monitor the evolution of regional changes in NAA/Cr over time. The changes in NAA/Cr over a period of months are small, however, and challenge the precision of the method. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic neurodegenerative disorder. Experimental models of ALS such as the transgenic rodents expressing mutant superoxide dimutase-1 are playing a pivotal role in our understanding of ALS pathogenesis, and in our testing of new therapeutic interventions aimed at protecting against neurodegeneration. Apoptosis has emerged as a significant pathogenic factor in several neurodegenerative diseases, including ALS. Constructed of multiple interacting molecules, the apoptosis machinery offers a host of attractive targets for pharmacological and genetic interventions to be tested in experimental models of ALS. Information generated by these pre-clinical studies holds the promise to provide sound scientific basis for the development of effective neuroprotective therapies for ALS. [ABSTRACT FROM AUTHOR]

The time is now ripe for the ALS community in the United States to set up a national ALS Study Group. NIH and other granting agencies should fund a program to set up and run the ALS Study Group for five years renewable. This program should result in a competitive request for applications. The benefits likely to derive from a national ALS Study Group would include cheaper and more cost-effective clinical therapeutic trials, the development of better techniques for pilot trials, an increased number of potential new drugs brought from bench to bedside for ALS trials, increased research on biological and surrogate markers of disease, and increased physician-initiated research. [ABSTRACT FROM AUTHOR]

Examines the reliability of results from clinical trials in amyotrophic lateral sclerosis therapeutics in the U.S. Basis of modern pre-clinical therapeutics; Limitations of pre-clinical models; Excellence of transgenic rodent models as an excellent tool to reveal potential new human therapies.

We describe designs for clinical trials in ALS including two that are more efficient than the standard two-arm, parallel design. The more efficient designs incorporate a lead-in period followed by a randomized intervention (drug or placebo) period. Efficacy of the more efficient designs is based on measuring, within each patient, the difference in slope while on the new treatment compared to the lead-in period. We demonstrate, with sample size calculations, that the lead-in designs are considerably more efficient than the standard two-arm, parallel design. Sample sizes can be reduced by 44% for a 12-month study using ALSFRS rate of decline as a primary endpoint for a two-arm trial with 4 months lead-in compared to a parallel design. A sample size reduction of 70% can be realized with variable lead-in compared to a parallel design. [ABSTRACT FROM AUTHOR]

The ALSFRS-R is an attractive primary outcome measure in clinical trials of ALS because it is validated, easy to administer, minimizes dropout, reduces cost, and correlates with survival. Unlike the other standard outcome measures currently employed, the ALSFRS-R is also a measure of global function. [ABSTRACT FROM AUTHOR]

Presents the efficacy of using survival as an endpoint in amyotrophic lateral sclerosis (ALS) clinical trials. Advantages of using survivals; Reason for the difficulty in ascertaining the endpoint in ALS; Alternatives used to survival as an endpoint in ALS clinical trials.

It can be difficult to detect upper motor neuron (UMN) involvement in early amyotrophic lateral sclerosis (ALS). The present study tested the usefulness of mirror movements (MMs), i.e., contralateral coactivation of hand muscles, as a UMN sign in ALS. Thirty-seven patients with possible, probable or definite ALS and 19 patients with suspected ALS without clinical signs of UMN involvement, 21 disease controls and 15 healthy volunteers were included. MMs were studied clinically, electromyographically and by transcranial magnetic stimulation (TMS), looking for ipsilateral motor evoked potentials (IMEPs). MMs were observed clinically in 15 ALS patients (27%) and electromyographically in 28 (50%). IMEPs in the abductor pollicis brevis muscle following TMS were recorded in 34 (61%) of all ALS patients and in nine (47%) out of 19 patients with suspected ALS, but not in healthy controls. Central motor conduction times were prolonged in 15 ALS patients (27%). It is concluded that MMs, especially if studied by EMG and TMS (IMEPs) can essentially improve detection of UMN involvement, especially in early stages of ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. We report the safety and functional efficacy results of a double-blind, placebo-controlled phase II study of xaliproden, a non-peptidic compound with growth factor activities, in 54 ALS patients treated for up to 32 weeks. In order to overcome the interference of mortality with functional assessment in exploratory studies, we identified from our ALS database prognostic factors to establish a staging process for selection pf patients: age, disease duration, slopes of deterioration of the functional scores calculated during the two months prior to the inclusion, and the value at entry of the forced vital capacity (FVC). The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT). The results in the completer analysis showed a significant 43% slower rate of deterioration in FVC ( P =0.046) in xaliproden-treated patients but not in functional and MMT scores. These results support the use of a staging process to select suitable patients for phase II studies, and suggest that xaliproden may have potential effects in ALS and deserve further study. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 ( n =867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 ( n =1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P =0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS. [ABSTRACT FROM AUTHOR]

Addresses the evidence in regard to the management of nutrition for patients with motor neurone disease/amyotrophic lateral sclerosis. Impact of the symptoms and progression of motor neurone disease on patient's nutrition and hydration; Need for percutaneous endoscopic gastrostomy in the later stages of motor neurone disease; Questions to address components of nutritional management.

In November 2002, an advisory board meeting was convened by Novartis Pharma to provide recommendations and rationale for clinical trials designed to evaluate new treatments, such as TCH346, for amyotrophic lateral sclerosis (ALS). In terms of selecting appropriate outcome measures, the panel recommended the use of the ALS Functional Rating Scale (ALSFRS-R) to measure primary endpoints. A review of other key issues in this area including regional variations in the epidemiology, diagnosis and management of ALS, defining patient populations and doses of trial medication, and accommodating the likelihood of co-medication with pre-existing treatment in trial design, are discussed. [ABSTRACT FROM AUTHOR]

Literature findings on astrogliosis of the spinal cord and of the cortex of sporadic (SALS) and familial (FALS) cases of amyotrophic lateral sclerosis (ALS) and of SOD1 transgenic mice are analysed and compared with those of 50 autopsied personal cases of ALS. In the spinal cord, astrogliosis is definitely evident in the anterior horns and much less in anterior and lateral funiculi and dorsal horns. In the cortex reactive astrocytes show a distribution similar to that of ageing brains and in ischaemia and cannot be directly put in relation with neuronal loss. In the spinal cord of transgenic mice the evidence suggests a primary astrocytic response. The findings in human ALS, especially those of the cortex, are consistent with this hypothesis. [ABSTRACT FROM AUTHOR]

Discusses abstracts of studies on human cell biology and pathology in amyotrophic lateral sclerosis, presented during the 14th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Diseases held in November 2003 in Milan, Italy. Region-specific expression of intermediate filament S1teady state mRNA in ALS; Ubiquitinates inclusions in two autopsy cases of ALS; Pathology of the motor system and expression of spastin protein in hereditary spastic paraparesis.

Discusses abstracts of studies on nutritional management in amyotrophic lateral sclerosis, presented during the 14th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Diseases held in November 2003 in Milan, Italy. Issues and controversies in nutritional interventions; oropharyngeal dysphagia in ALS; Effectiveness of enteral feeding in ALS.

Discusses the paradigms for the identification of genes in motor neuron degeneration. Percentage of amyotrophic lateral sclerosis (ALS) are is familial; Gene mutations that are directly causal for motor neuron degeneration in humans; Characteristics of human genetics.

Discusses whether psychosocial factors and premorbid personality are relevant in amyotrophic lateral sclerosis (ALS). Overview of the contributions of neuropsychological and neuro-imaging studies in elucidating disease processes; Belief of health providers who care for patients with ALS; Factor in the underlying pathogenesis of ALS.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease. Mutations of the Cu/Zn superoxide dismutase gene (SOD1) are responsible for 20% of autosomal dominant familial ALS (FALS). RESULTS: We examined the clinical features of the first Italian FALS with the Leu144Phe SOD1 mutation. Seven affected members were identified in a six-generation pedigree. A slowly progressive course (20.4±14.6 years) was observed in five patients. One patient died of cardiac failure two years after the onset of the disease. The propositus is still alive. Neurological manifestations began in the legs in all patients, while bulbar signs were absent or appeared late in the course of the disease. DISCUSSION: There is evidence of a correlation between this mutation and a slowly progressive phenotype of ALS. Moreover this rare mutation might derive from a common ancestor. [ABSTRACT FROM AUTHOR]

BACKGROUND: Riluzole 100 mg probably prolongs survival in patients with amyotrophic lateral sclerosis by about two months and the safety of the drug is not a major concern. The evidence from randomized controlled trials indicates that patients taking riluzole probably survive longer than patients taking placebo. The beneficial effects are very modest and the drug is expensive. Adverse effects from riluzole are relatively minor and for the most part reversible after stopping the drug. Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was November 2002. SELECTION CRITERIA: Randomized trials of adults with diagnosis of amyotrophic lateral sclerosis (ALS), treated with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events. DATA COLLECTION & ANALYSIS: We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio. RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38). CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with ALS. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease. [ABSTRACT FROM AUTHOR]

We have shown in a mouse model of motor neuron disease, the legs-at-odd-angles ( Loa ) mutant, and that mutations in the cytoplasmic dynein heavy chain gene ( Dnchc1 ) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1 , CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86 kb genomic length. We have focused on the exons known to be mutated in Loa , and in a very similar mouse mutation, cramping 1 ( Cra1 ); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine which factors are predictive of physical and mental health one year after a first measurement of health status in amyotrophic lateral sclerosis (ALS) patients. METHODS: The Physical Component Summary (PCS) score and the Mental Component Summary (MCS) score of the SF-36 were used as the main outcome measures in patients enrolled in the European ALS Health Profile Study (ALS-HPS). Correlation and stepwise regression procedures were used to determine the relationship between patients' physical and mental health status at follow-up with baseline measures. RESULTS: A total of 1118 patients were recruited into the ALS-HPS, of which 918 (82.11%) returned fully or partially completed baseline and follow-up surveys. PCS scores declined over time. No significant changes were reported for the MCS scores over time for patients with ALS. Baseline scores were found to be significant predictors of patients' health status over time. CONCLUSIONS: Overall, patients' physical health status at the time of recruitment was the major predictor of the physical health status at both first and second follow-up time assessments. The same relationship was found between baseline and follow-up mental health status. The study also confirms the appropriateness of the use of the SF-36 in ALS patients. [ABSTRACT FROM AUTHOR]

Maximum Voluntary Isometric Contraction (MVIC) is a standardised, objective and sensitive tool for the measurement of muscle strength. The purpose of this study was to investigate different aspects of reliability of MVIC and to determine if a learning effect existed in a relatively new user of the system. Two clinical investigators participated in the study. The inter- and intra-rater reliability of MVIC of 11 muscle groups was tested on healthy subjects (n=35). Intra-class correlation co-efficients (ICCs) were calculated and the statistical methods described by Bland and Altman were applied to the data. ICCs were higher for the more experienced investigator and a learning effect was demonstrated in a relatively new user of the system. Inter-rater reliability was acceptable but lower than intra-rater reliability. Upper limb tests generally yielded higher ICCs and lower ranges of error. The ICC was similar regardless of whether the maximum or average of the two values was taken in a single session. Utilising the statistical methods proposed by Bland and Altman allows estimation of the magnitude of error of MVIC and gives additional information to the ICC. These methods may be useful in the training of investigators and in clinical interpretation of MVIC values. [ABSTRACT FROM AUTHOR]

A familial amyotrophic lateral sclerosis (FALS) patient with G37R mutation of superoxide dismutase 1 (SOD1) gene revealed an early onset and relatively slow progression. Neuropathological examination of this patient showed widespread neuronal degeneration extending to overall length of the spinal cord and the brainstem with extremely rare Lewy body-like inclusions (LBI), while there were no vacuoles in neurons, a characteristic feature in transgenic mice expressing G37R SOD1 mutation. [ABSTRACT FROM AUTHOR]

To confirm the diagnostic usefulness of muscle sympathetic nerve activity (MSNA) in differentiation between cervical spondylotic amyotrophy (CSA) and amyotrophic lateral sclerosis (ALS) with cervical spondylosis (CS), MSNA, heart rate (HR) and blood pressure (BP) were recorded in 10 patients with CSA and ALS with CS, and age-matched healthy volunteers at rest and during head-up tilting. There were no differences in age, disability scores, pulmonary function, and HR or BP at rest between ALS and CSA groups. Resting MSNA was significantly greater in patients with ALS with CS than in comparison groups (P < 0.001) with virtually no overlap between ALS and the CSA groups. During head-up tilting, changes in BP and MSNA were significantly less in patients with ALS than in patients with other subjects. MSNA at rest clearly differentiated CSA from ALS with CS, suggesting diagnostic utility. [ABSTRACT FROM AUTHOR]