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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 cognitive and psychological assessment and support in amyotrophic lateral sclerosis, presented during the 14th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Diseases held in November 2003 in Milan, Italy. Executive dysfunction in ALS; Altered emotional perception and modification of correlated neurophysiologic parameters; Longitudinal analysis of the anatomical and neuropsychological features of ALS dementia.

Discusses abstracts of studies on improving the standards of care in amyotrophic lateral sclerosis, presented during the 14th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Diseases held in November 2003 in Milan, Italy. Evidence-based treatment algorithm for the management of secretions in motor neuron diseases; Use of mobile arm support in people with ALS; Exploring loss of sexuality and intimacy.

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]

When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Previous work has not found correlations between standardized questionnaire measures of quality of life (QoL) and physical strength/functional ability in people with motor neuron disease (MND). Little is known about the relationship between ratings on an abbreviated self-generated measure of QoL, the Schedule for Evaluation of Individual Quality of Life - Direct Weighting (SEIQoL-DW), and measures of functional status such as the Sickness Impact Profile (SIP), although the former has been rated by people with MND as providing a more valid measure of their own QoL than the latter. The aim of this study was to examine whether self-generated ratings of QoL correlated with measures of physical impairment and self-reported functional status, psychological wellbeing and self-reported cognitive functioning, and with factors such as social support, which elsewhere has been reported to be a determinant of QoL in MND. DESIGN: The present cross-sectional study investigated between SEIQoL-DW ratings and SIP and the relationship ALS Severity Scale (ALSSS) scores, as well as with self-reported anxiety, depression, social support and everyday cognitive functioning in 31 people with MND. RESULTS: Overall QoL ratings on the SEIQoL-DW failed to correlate with any of the ALSSS or SIP subscale scores. This was despite the fact that health was nominated as an important QoL-related category by 64.5% of the sample. QoL scores were, however, found to correlate positively with the existence of confiding and emotional support; they also correlated negatively with the presence of self-rated everyday cognitive difficulties but not with affective state. CONCLUSIONS: Current findings support recent observations that individuals' ratings of their QoL cannot simply be equated with their physical impairment and functional limitations, and that support systems may be important. Cognitive functioning, known to be impaired in some people with MND, should also be considered when evaluating QoL. [ABSTRACT FROM AUTHOR]

Discusses the advantages and disadvantages of using survival endpoint in amyotrophic lateral sclerosis (ALS) clinical trials. Reliability and specificity; Clinical relevance and significance; Relationships with the disease processes.

INTRODUCTION: The involvement of glycation in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) was recently indicated. We previously reported the existence of an Amadori product, 1-hexitol-lysine (1-HL), which is formed in the early glycation reaction, in axonal spheroids of the anterior horn of the ALS spinal cord. OBJECTIVE: The purpose of the present study was to confirm the occurrence of the later-stage glycation reaction that follows the early glycation reaction and leads to the formation of advanced glycation end products (AGEs). METHOD: We examined whether N[sup ε]-(carboxymethyl)lysine (CML) and non-CML AGE are present in ALS spinal cords. RESULTS: Immunohistochemical staining with anti-CML antibody revealed intense positivity in the cell bodies of the remaining atrophic motor neurons and in microglia. Microglia were also positive on staining with anti-non-CML antibody. Axonal spheroids were also positive on anti-non-CML-antibody staining. Vascular endothelial cells were slightly stained by both antibodies. CONCLUSIONS: The presence of non-CML AGE in the anterior horn of the ALS spinal cord indicates that the later stage of the glycation reaction is involved in the pathology of ALS. The presence of CML in the anterior horn was also confirmed, and this may reflect augmented oxidative stress. [ABSTRACT FROM AUTHOR]

METHOD: The adapted multiple point stimulation (AMPS) method for calculating motor unit numbers (MUNE) was applied in 12 patients with amyotrophic lateral sclerosis (ALS) before riluzole therapy (T[sub 0]) and again after 4, 8 and 12 months of treatment. RESULTS: Paired Student's t-test indicated a significant decrease of thenar MUNE and compound muscle action potential (CMAP) size at each 4-monthly interval, while average surface motor unit potential (SMUP) size did not change significantly over time. The rate of motor unit (MU) loss at month 4 was more than 20% in six patients (group 1) and less than 20% in six other patients (group 2). Comparison of groups 1 and 2 by Mann-Whitney U-testing indicated that percent changes in thenar MUNE and CMAP size compared to baseline were significantly different at months 4, 8 and 12, while no difference between the two groups was found for average SMUP size variations. In the group with a slow rate of MU loss, CMAP size remained stable, while in the group with a rapid rate of MU loss, there was a dramatic reduction in size of the CMAP. A positive correlation was found between percent change in thenar MUNE at T[sub 4] and at T[sub 12] (P < 0.001). CONCLUSION: AMPS is a useful technique to document MUNE, SMUP size and CMAP size changes over time in patients with ALS. [ABSTRACT FROM AUTHOR]

OBJECT: The purpose of this study was to compare the performance of the five-item mental health dimension of SF-36 (the Mental Health Index, MHI-5) with that of the 22-item Psychological General Well-Being Index (PGWB) in patients presenting with amyotrophic lateral sclerosis/motor neuron disease, using tests of reliability and validity. DESIGN: A questionnaire-based survey of patients diagnosed with ALS across 15 European countries. SAMPLE: Patients presenting at neurological clinics for treatment of their ALS were asked to join the survey. RESULTS: 1048 patients with ALS have been recruited, of whom 861 (82.2%) have returned baseline questionnaires. There was evidence supporting the internal consistency of both instruments, and for their construct validity in distinguishing between groups, in terms of gender and age. The scores on the two instruments were highly correlated (Spearman rank correlation 0.85). CONCLUSION: Both the MHI-5 and the PGWB showed high levels of construct validity and internal reliability in this patient group. The MHI-5 has comparable psychometric performance to the PGWB, and can be used to measure and compare mental health in defined populations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The aim of this study was to determine the effect of hNT neuron transplants on motor neuron function in SOD1 (G93A) mice when motor deficits were already apparent. METHOD: The hNT neurons were implanted into L[sub 4]-L[sub 5] segments of the ventral horn spinal cord of mice at 15-16 weeks of age: either G93A mice, transgenic mice carrying the normal allele for human SOD1 gene (hTg), or control wild type mice (wt). Behavioral tests (rotorod, beam balance, extension reflex, footprint) were performed prior to transplantation and at weekly intervals afterwards. RESULTS: HNT neuron transplantation in the SOD1 mice delayed disease progression for 3-4 weeks, although lifespan was not affected. CONCLUSION: These results suggest that hNT neuron transplantation may be a promising therapeutic strategy for ALS in the later phase of the neurodegeneration. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study clinical practices and patient outcomes near the end of life in amyotrophic lateral sclerosis (ALS). BACKGROUND: Patients, families, and healthcare providers face several dilemmas in selecting and delivering care near the end of life in ALS. Published data on clinical practices and their benefits during end-of-life care for ALS patients consist of anecdotal reports based on small case series or individual case reports. METHODS: Data were obtained from 1014 American and Canadian patients with ALS who died while participating in a large observational registry (the ALS Patient Care Database) during the past four years. Following death, a caregiver or family member provided data for each patient using a standard questionnaire. Data were principally generated through American and Canadian ALS multidisciplinary centers of excellence. RESULTS: Most patients died peacefully (90.7%) and 62.4% died in a hospice-supported environment. Advance directives were in place for 88.9% of patients and were followed in 96.8%. Among the 67 patients who exhibited distress in the dying process, symptoms included breathing difficulties (82.1%), fear/anxiety (55.2%), pain (23.9%), insomnia (14.9%), and choking (14.93%). Oxygen was given to 52.6% of patients, and pain medications were given to 74%. CONCLUSION: These data suggest that palliative care at the end of life was relatively well managed for most patients with ALS who participated in this study; nevertheless, several opportunities for improvement were identified. [ABSTRACT FROM AUTHOR]

The article presents abstracts related to the Emotional and Psychological Support and Assessment for the 12th International Symposium on Amyotrophic Lateral Sclerosis and other Motor Neuron Diseases on November 18-20, 2001 in Oakland, California. They include, "Cognitive Symptoms in ALS," "'You Have Shown Me My End': Attitudes Toward Presymptomatic Testing for Familial Amyotrophic Lateral Sclerosis," and "Comparison Between the Features of Anxiety and Depression in Patients With ALS."

The article presents abstracts on Communication and Mobility for the 12th International Symposium on Amyotrophic Lateral Sclerosis and other Motor Neuron Diseases on November 18-20, 2001 in Oakland, California. They include, "Identification and Analysis of the Motor Systems at Work on Oral Language Production in Amyotrophic Lateral Sclerosis," "Novel Treatment Options for Dysphonia in Amyotrophic Lateral Sclerosis (ALS) Patients," and "Communication Issues and ALS: A Collaborative Exploration."

The article presents abstracts related to the Nutritional and Ventilatory Support for the 12th International Symposium on Amyotrophic Lateral Sclerosis and other Motor Neuron Diseases in Oakland, California. They include, "Esophageal Manometric Studies in Amyotrophic Lateral Sclerosis Patients With Dysphagia," "Oropharyngeal Dysfunction in ALS," and "Fiberoptic Endoscopic Evaluation of Swallowing (FEES): An Instrumental Procedure for Assessing and Managing Dysphagia in ALS/MND Patients."

The article presents abstracts related to the Multidisciplinary Management for the 12th International Symposium on Amyotrophic Lateral Sclerosis and other Motor Neuron Diseases on November 18-20, 2001 in Oakland, California. They include, "An Audit of ALS Services," "Utilisation of Services by ALS Patients," and "Evaluation of the Services and Support Received by the Patients With Amyotrophic Lateral Sclerosis."

The article presents abstracts related to the Multidisciplinary Team for ALS/MND care for the 12th International Symposium on Amyotrophic Lateral Sclerosis and other Motor Neuron Diseases on November 18-20, 2001 in Oakland, California. They include, "Models of Care: Creating Standards," "Use of Outcome Measures in a Multidisciplinary MND Clinic," and "Utilization of the Nursing Assessment Tool for Long-Term Care, Determination of its Feasibility in Providing Optimal Care to the ALS Patient."

The article presents abstracts related to the Practicalities of Assisted Ventilation. They include, "Decision Making and Support," "Preventing Failed Use of Noninvasive Positive Pressure Ventilation and Unplanned Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis (ALS): And When to Transition to Planned Tracheostomy," and "Domiciliary Sleep Studies in MND: Predictors of Sleep Dysfunction and Mortality in Limb and Bulbar Patients."

Numerous drugs have been tested in amyotrophic lateral sclerosis with the expectation both that they will treat patients and improve our understanding of some of the basic mechanisms of the disease. Most of these trials were considered to be negative. Careful analysis of the trials does not allow us to clearly discard any of the tested drugs, or any of the suspected mechanisms. Expectations for the future are that: a) we need to be realistic about what to expect; b) we have to define clearly our end-points; c) we have to calculate the expected power before the trials, not after; and d) we have to improve our understanding of the pharmacology. (ALS 2001; 2 (suppl 1): S15–S18). [ABSTRACT FROM AUTHOR]

The only known gene to be involved in ALS is the CuZn-superoxide dismutase (CuZn-SOD) gene. Since 1993, 89* disease-associated mutations have been found in this gene, 14 of them in cases with apparently sporadic ALS. Most frequent are the D90A (most often with recessive inheritance, but a few with dominant inheritance) and the I113T (dominant inheritance with variable penetrance). Statistical and genealogical evidence suggest that quite a number of diagnosed sporadic cases may in fact be familial cases in pedigrees with very low disease penetrance. (ALS 2001; 2 (suppl 1): S37–S41). [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 10–15% of patients has a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in 20% of FALS. We found SOD1-gene mutations in 7 of 36 unrelated FALS and in 3 of 48 SALS patients. Four FALS patients carried previously described mutations, the A4V (2 cases), the L84F mutations (1 case), and the G93D (1 case), while three FALS patients carried new missense mutations: the G12R mutation, the F45C mutation and the V47F mutation, respectively. Two SALS patients carried previously reported mutations: the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an apparently non-pathogenic SOD1 variant: the A95T mutation. Our study contributes to expand the number of ALS-associated SOD1 gene mutations. (ALS 2001; 2 (suppl 1): S43–S46). [ABSTRACT FROM AUTHOR]

Several studies have addressed the issue of a possible immunological involvement in the pathogenesis of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), particularly when the disease was associated with cancer, lymphoma or other monoclonal gammopathies or with the presence of serum antibodies to neural antigens. The hypothesis of the existence of immunologically treatable MND was reinforced by the occasional report of MND patients responding to immune or cytostatic therapies and by the identification among those with a purely lower motor neuron syndrome (LMNS) of a motor neuropathy, presently known as multifocal motor neuropathy (MMN), which almost invariably responded to immune therapies. These observations have led to several attempts to treat patients with MND or LMNS, either idiopathic or associated with the above mentioned conditions, with a number of immune or cytostatic therapies. The aim of this review is to verify whether the available data provide enough evidence to support the concept of dysimmune MND and to justify the use in these patients of potentially harmful immune cytostatic therapies. (ALS 2001; 2 (suppl 1): S23–S30). [ABSTRACT FROM AUTHOR]

In this introductory review a number of issues concerning the direction of future research in ALS are addressed in relation to current understanding of this disorder and its treatment. The importance of understanding the pathways leading to motor neuron dysfunction and death is emphasized. Contemporary epidemiology, understandably genetic markers for familial ALS, needs to be widened to include as yet undocumented susceptibility-related focussed on traits. Potential avenues for therapy are considered, and the fundamental contemporary issue of clinical measurement is discussed. Neglected aspects of contemporary research, including disturbed axoplasmic flow, are brought to attention. The role of experiment derived from clinical observation, and vice versa, is described by reference to a number of past and recent contributions to the understanding of ALS. (ALS 2001; 2 (suppl genetic 1) S3-S9). [ABSTRACT FROM AUTHOR]

The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a challenge for the neurologist. Most of the disabilities from progressive disease can be effectively relieved by symptomatic treatment. Prognosis and treatment options should be openly discussed with patient and relatives. Adequate assistance and palliative treatment in the terminal phase are of paramount importance. Unfortunately, training in communication skills for young doctors and evidence-based recommendations for palliative care are insufficient at present. In addition, new data from a randomized study question the concept of "health-related quality of life" and favor an individualized approach to the definition of quality of life in ALS. (ALS 2001: 2 (suppl 1): S31–S35). [ABSTRACT FROM AUTHOR]

Examines the treatment of amyotrophic lateral sclerosis (ALS) using anabolic steroid oxandrolone. Clinical benefits of oxandrolone; Risk for suboptimal caloric intake and weight loss of patients with ALS; Effect of oxandrolone on weight gain, wound healing and muscle function.

Discusses the role of antioxidants in the treatment of amyotrophic lateral sclerosis (ALS). Oxidative stress in ALS; Types of antioxidants; Oxidant-mediated neurotoxicity; Mechanisms of action and benefits of using antioxidants.

Explores strategies to develop mosaic chemotherapeutic approaches for amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). Inclusion of beta-2 adrenergic agonists for ALS/MND treatment; Pathogenesis-based and symptom-directed therapies in ALS/MND; Effect of beta-2 adrenergic agonists in the central nervous system and muscular system; Side-effects of beta-2 adrenergic agonists.

Cyclin-dependent kinase-5 (CDK5) is a serine-threonine protein kinase that has been implicated in a number of physiological processes in nerve and muscle cells, including neurogenesis, neuritic outgrowth, axonal transport of membrane-bound organelles and myogenesis. CDK5 has also been shown to phosphorylate the important cytoskeletal proteins, neurofilament and tau, both in vitro and in cells. The latter has prompted study into the potential role of CDK5 in the hyperphosphorylation of these proteins as part of the neuropathology seen in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. More recently, increasing evidence has suggested a role for CDK5 in cellular apoptosis. Apoptosis has been implicated as the final common pathway of cell death in a number of neurodegenerative diseases including ALS. This article sets out to review the physiological and pathological roles ascribed to CDK5 and the possible relevance thereof to the pathogenesis of ALS. (ALS 2000; 1: 319-327). [ABSTRACT FROM AUTHOR]

We describe a case of the Brown-Vialetto-Van Laere syndrome, which is a rare disorder characterized pontobulbar palsy associated with sensorineural deafness. More than 30 cases have been reported since the first case by progressive was described in 1894. We review the literature of this condition, comparing our case with those reported in the literature and emphasizing important features to improve our understanding of this syndrome. (ALS 2000; 1: 277-281). [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) has enabled us to study the human brain with unrivalled sensitivity, and has already established its place in the research of neurological conditions such as Parkinson's disease and epilepsy. PET has been used as a tool in the study of patients with motor neuron disease (MND) for well over ten years now, but its potential in diagnosis and to identify surrogate markers of disease expression (phenotype) and progression has yet to be fully realized. The early studies using 2- [sup 18]fluoro-2-deoxy-D-glucose to measure regional changes in cerebral metabolic rate for glucose gave the first clues to the more widespread involvement of the brain in MND. Later studies exploited the development of activation studies using [sup 15]O-containing tracers, which allowed correlation with neuropsychological mea sures, and the refinement of mapping techniques to delineate the extra-motor areas involved in the disease process. More recently, studies involving ligands such as [sup 11]C-flumazenil have allowed the exploration of functional reorganisation in MND, and inhibitory interneuronal pathways which may be crucial in modulation of disease expression. In the future new ligands will be applied in combination with other modalities of investigation (multimodal magnetic resonance imaging; neurophysiological studies) in order to understand the pathophysiology of this heterogeneous condition. Although the potential of PET has not yet been realized in ALS, it is likely to play a part in defining new diagnostic and surrogate markers of disease extent and severity. (ALS 2000; 1(suppl 2):S17-S22). [ABSTRACT FROM AUTHOR]

Neurodegeneration in amyotrophic lateral sclerosis (ALS) is characterized by the specific loss of central and peripheral motor neurons. While this pattern of neuronal demise gives rise to a distinct clinical syndrome, at the molecular level ALS pathology is similar to that seen in other neurodegenerative diseases. In particular, mitochondrial dysfunction in ALS is reminiscent of that observed in Alzheimer's and Parkinson's diseases. Mitochondria in persons with ALS demonstrate impaired electron transport, increased free radical generation, and an inability to adequately buffer cellular and cytosolic calcium shifts. These abnormalities are probably systemic and potentially due to mutation of mitochondrial DNA. (ALS 2000; 1:185-190). [ABSTRACT FROM AUTHOR]

The El Escorial criteria for diagnosis of amyotrophic lateral sclerosis (ALS) have been in use for almost a decade. A revised set of criteria, meant to supersede the original set, was developed at a 1998 World Federation of Neurology (WFN) ALS meeting at Airlie House in Warrenton, Virginia, USA. This revised document, nicknamed El Escorial Revisited, has been published on the WFN-ALS website. El Escorial has proven useful in standardizing diagnostic criteria for entry into research trials and it is expected that El Escorial Revisited will help to liberalize such entry requirements. However, general neurologists and neuromuscular clinicians have found El Escorial to be unwieldy and generally unhelpful in achieving an earlier, accurate diagnosis of ALS. The El Escorial Revisited document is a step toward lessening these problems, but more ‘user-friendly’ criteria may be necessary for clinicians and those not conducting research. Such ALS criteria would improve categorization of ALS patients, would allow clinicians more latitude in beginning ALS treatment, and would educate practitioners to differentiate ALS from other motor neuron and non-motor neuron diseases. Intensive education of physicians will help improve earlier patient referral and accurate ALS diagnosis. There remains a group of ‘difficult cases’ that will continue to challenge the neuromuscular specialist. Earlier diagnosis in this latter group will require significant advances in the fields of electrodiagnosis, neuroimaging, immunobiochemistry, and neurogenetics. (ALS 2000; 1 (suppl 1): S57–S60). [ABSTRACT FROM AUTHOR]

Motor unit number estimation (MUNE) techniques have evolved substantially over the past decade and have been applied, with increasing frequency, to the study of amyotrophic lateral sclerosis (ALS). As major clinical therapeutic trials in motor neuron disease continue to appear, the need for a clear quantitative method of following motor unit physiology in the living subject grows ever more pressing. In this article, we review the major modern techniques of MUNE and the data supporting their reproducibility and utility in patients with ALS, with particular attention to their role in evaluating the efficacy of new therapeutic interventions. (ALS 2000; 1:71–82). [ABSTRACT FROM AUTHOR]

Highlights the 10th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS/MND) held in Vancouver, British Columbia, from November 15-17, 1999. Scheduled meetings of various organizations concerned with ALS/MND; Molecular genetics and cell biology of ALS/MND; Challenge in improving the quality of life for patients with ALS/MND; Cognitive and psychological changes in ALS/MND.

El Escorial, a magnificent palace-monastery in central Spain, was the setting in 1990 for a meeting of ALS experts who developed a consensus document called the El Escorial ALS Diagnostic Criteria. El Escorial was originally conceived by the Spanish Habsburg monarch, Philip II (1527–1598), as an elaborate burial place for his parents, Emperor Charles V and Isabella. It soon became a symbol of the Spanish empire and Philip’s Catholic leadership of the Counter-Reformation. El Escorial included a monastery, palace, basilica, mausoleum, seminary, library, and hospital. Nothing was spared by Philip in obtaining the finest examples of religious art, architec- ture, music, and books. Philip, as absolute monarch, inherited a vast empire which stretched over Europe, Asia, North Africa, and the New World. His style of personal micro-management and poor economic planning hampered his ability to manage both national and foreign affairs. Philip had a special interest in medicine, including royal hospitals, improved government standards for physicians, medicinal plants, and the health benefits of alchemy and sacred relics. El Escorial’s grand scale has generated both illustrious praise and critical condemnation over the last four centuries. Its place in Spanish and world history is assured. (Amyot Lat Scler 1999; 1:55–62). [ABSTRACT FROM AUTHOR]

OBJECTIVES: The purpose of the study was to assess the validity and reliability of a new disease specific measure of health-related quality of life for ALS/MND: the 40-item ALS Assessment Questionnaire (ALSAQ-40). DESIGN: We carried out a longitudinal postal survey. The two administrations of the questionnaire were separated by 3 months SAMPLE: Subjects were patients diagnosed with ALS/MND and registered with the UK MND Association. RESULTS: Dimensions of the ALSAQ-40 were shown to have high levels of internal reliability. The ALSAQ-40 was found to be sensitive to changes in self reported overall health state. CONCLUSION: We concluded that the ALSAQ-40 has high levels of reliability and validity and can be used as an outcome measure in studies evaluating new treatment regimes and therapies. (Amyot Lat Scler 1999; 1:33–40). [ABSTRACT FROM AUTHOR]

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene account for 20–30% of all familial cases of ALS and for 1–2% of all ALS cases. The exact number of these mutations is, however, unknown, as is the number of individuals worldwide with them who have ALS or are at risk of developing the disease. Information on the genetic and clinical data of ALS patients with the SOD1 gene mutations is, also, only available for one-third of all families and is incomplete in some of those families. Some attempts have been made to correlate the genotype with the phenotype of the patients with SOD1 gene mutations and the available evidence suggests that only a few mutations could be linked to a consistent age of onset or pattern of survival. The ALS scientific community has recognized an urgent need for collecting the genetic and clinical information on all SOD1 individuals and the ALSOD Consortium was set up with the aim of pooling all available data into a uniform centralized database. Recent advances in information technology and the wide accessibility of the Internet have provided an ideal vehicle through which data can not only be recorded but also searched, amended and updated in real time. Here, we describe the work done so far by the ALSOD Consortium and plans for the future. (Amyot Lat Scler 1999; 1:45–49). [ABSTRACT FROM AUTHOR]

Reports on developments in amyotrophic lateral sclerosis (ALS) centers, the Eleanor and Lou Gehrig MDA/ALS Center in New York City and the King's MND Care and Research Center in London, England. Background information and aims of the medical centers; Sources of funds; Research participation; Areas of special expertise; Key publications.

Presents a discussion on patient's clinical data in assessing the extent of dysfunction and rates of progression on patients' health. Description of futility design equipments to assess the efficacy and safety of therapies; Evaluation of the use of historical database in drug trials with the futility design; Result of the usage of database in validation studies.