Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.

Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.

Pathogenesis of amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition. SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized. AREAS OF CONTROVERSY: There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease. GROWING POINTS: Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support). AREAS TIMELY FOR DEVELOPING RESEARCH: The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.

Pharmacological treatments for Friedreich ataxia.

BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012. OBJECTIVES: To assess the effects of pharmacological treatments for Friedreich ataxia. SEARCH METHODS: On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months. DATA COLLECTION AND ANALYSIS: Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion.In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence).The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low.There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. AUTHORS' CONCLUSIONS: Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

Diagnosis and management of motor neurone disease.

Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed.

Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.

OBJECTIVE: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12. METHODS: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories. RESULTS: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01). CONCLUSION: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.

Opinion: more mouse models and more translation needed for ALS.

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients. To date, we have no models for the 90% of ALS that is 'sporadic'. Potential therapies have been developed mainly using a limited set of mouse models, and through lack of alternatives, in the past these have been tested on patients regardless of aetiology. Cancer researchers have undertaken therapy development with similar challenges; they have responded by producing complex mouse models that have transformed understanding of pathological processes, and they have implemented patient stratification in multi-centre trials, leading to the effective translation of basic research findings to the clinic. ALS researchers have successfully adopted this combined approach, and now to increase our understanding of key disease pathologies, and our rate of progress for moving from mouse models to mechanism to ALS therapies we need more, innovative, complex mouse models to address specific questions.

Antioxidants and other pharmacological treatments for Friedreich ataxia.

BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis and pes cavus. Heart abnormalities cause premature death in 60% to 80% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the first update of a review published in 2009. OBJECTIVES: To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia. SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (11 July 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), AMED (January 1985 to July 2011), CINAHL Plus (January 1937 to July 2011), LILACS (January 1982 to July 2011), ORPHANET (1990 to July 2011), TRIP (1998 to July 2011) and PEDRO (October 1999 to July 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of drug treatment in people with genetically confirmed Friedreich ataxia. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. We excluded trials of shorter duration than 12 months. DATA COLLECTION AND ANALYSIS: Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. We planned to collect adverse event data from included studies. MAIN RESULTS: More than 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants, using the synthetic antioxidant idebenone 5 mg/kg, fulfilled the selection criteria for this review. Other RCTs were of insufficient duration. We identified no additional RCT when the searches were updated in 2011. In the included study, the primary outcome specified for this review, change in ICARS scale, did not reveal any significant differences with idebenone treatment compared to placebo. The secondary outcome of change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not assessed. The second secondary outcome, change in left ventricular mass as measured by echocardiography, did improve significantly; there was a 10.7% worsening after 12 months of treatment in the placebo group and a 5.6% improvement in the idebenone group. The mean difference was 16.37% (95% CI 95% 2% to 31%). There were no adverse events. We considered the included study at low risk of bias in five of the seven domains assessed. A larger trial using idebenone published an interm report in May 2010 stating that the study had failed to reach its primary endpoint, which was change in the ICARS scale. AUTHORS' CONCLUSIONS: No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but the clinical relevance of this change was not assessed in the included study.

Diagnosing and managing muscular dystrophy.

Muscular dystrophy refers to a range of muscle diseases caused by defects in muscle proteins, leading to death of the muscle cells, with loss of muscle tissue, and weakness. The development of clinical symptoms is usually gradual, and the earliest features may be difficult to identify and determine. With established disease the presence of muscle weakness and wasting is clear. In children, the presentation may be delayed walking, or poor performance in sporting activity. In children and adults presenting symptoms may include: difficulty raising from a squat; difficulty raising from a chair; difficulty lifting the arms above the head; poor balance; drooping eyelids; and joint contractures. In the presence of slowly progressive muscle weakness and wasting, an elevated serum creatine kinase would be a strong pointer to a muscle disease. Retention of limb reflexes would favour a myopathy over a neuropathy. The major differential diagnosis is an inflammatory myopathy, such as polymyositis. The muscular dystrophies have a genetic basis. There may be important genetic issues to discuss with the family, including the possibility of prenatal diagnosis. In Duchenne muscular dystrophy the inheritance is X-linked, with typically only boys affected. Many limb girdle muscular dystrophies are autosomal recessive, affecting only one generation of a family and facioscapulohumeral dystrophy is autosomal dominant.

GPs have key role in managing motor neurone disease.

Motor neurone disease (MND) is a rapidly progressive neurodegenerative condition. It affects people of all ages, but is more common with increasing age (especially over 50 years) and men are affected twice as often as women. The causes remain unknown, although around 5% of cases have a genetic basis. Survival is usually only three to five years from diagnosis. MND affects both upper and lower motor neurones, with variable contributions. The nerve involvement in MND usually has a focal onset, is asymmetrical, but tends to spread to adjacent regions of the body. If the affected region is in the legs, a common presenting feature is tripping, falls or foot drop. If it is in the arms there may be difficulty with fine tasks such as fastening buttons, or raising an arm, and if the cranial nerves are affected there may be slurring of speech, or difficulty swallowing. Key to the diagnosis is evidence of progression, and this may lead to some delay in considering and also confirming the diagnosis. When examining the patient, evidence of more widespread neuromuscular involvement should be looked for. In a patient with foot drop, and fasciculation of the tongue, MND would be a likely diagnosis. Upper motor neurone involvement may be readily determined by examining the reflexes. Brisk reflexes, in the arms, legs or jaw, in the context of features of lower motor neurone denervation are highly suggestive of MND. Suspicion of MND should lead to referral for a neurology opinion. The most useful investigation is likely to be EMG with nerve conduction studies, and probably MRI scan of relevant areas. Blood tests are arranged to screen for any other causative condition. Riluzole is a disease modifying drug licensed to extend the life of patients with MND. There is no treatment that will reverse, or halt, progression of the disease.

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Motor neuron disease: systematic reviews of treatment for ALS and SMA.

INTRODUCTION: There is no curative treatment for the common motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Nevertheless, there is an increasing volume of published studies. This review assesses the current evidence for treatment of these conditions. SOURCES OF DATA: Primarily, the systematic reviews of the Cochrane Collaboration, with additional reference to other systematic reviews and online sites. AREAS OF AGREEMENT: Riluzole remains the only medication with demonstrated efficacy and regulatory approval for the treatment of ALS. AREAS OF CONTROVERSY, GROWING POINTS, AND AREAS TIMELY FOR DEVELOPING RESEARCH: The design of clinical trials and the publication of unsatisfactory studies, in both human and animal models, continue to cause confusion in advising on patient management. Improvements in trial design, critical assessment of studies for publication and avoidance of bias towards publication of positive results are needed. A better understanding of pathogenesis should lead to more potent interventions.

Investigation of MGF mRNA expression in patients with amyotrophic lateral sclerosis using parallel in vivo and in vitro approaches.

In an animal model of ALS, intramuscular administration of MGF, the IGF-I Ec gene splice variant, improved muscle strength and increased both motor unit and motor neuron survival. Here we investigated whether there is a deficit in MGF production in the muscles of patients with ALS. We used complementary in vivo and in vitro techniques to study the IGF-I splice variant response of human muscle to exercise or mechanical stretch. We assessed the levels of MGF and IGF-IEa mRNA in muscle biopsy samples from healthy subjects and patients with ALS, before and after exercise. We used primary muscle cells to build three-dimensional collagen constructs and subjected them to a ramp stretch. Patients with ALS had similar baseline levels of MGF and IGF-IEa mRNA to healthy controls. No up-regulation was seen in either group within a short time of a single bout of low intensity exercise. Three-dimensional human muscle constructs also detected no response to a mechanical stretch from either control subjects or ALS. We conclude that the pathology of ALS does not include a deficit in baseline levels of MGF and IGF-IEa mRNA splice variants in muscle.

The sex ratio in amyotrophic lateral sclerosis: A population based study.

Replicable risk factors for ALS include increasing age, family history and being male. The male: female ratio has been reported as being between 1 and 3. We tested the hypothesis that the sex ratio changes with age in a population register covering the south-east of England. The sex ratio before and after the age of 51 years was compared using a Z-test for proportions. Kendall's tau was used to assess the relationship between age group and sex ratio using incidence and prevalence data. Publicly available data from Italian and Irish population registers were compared with results. There was a significant difference in the proportion of females with ALS between those in the younger group (30.11%) and those in the older group (43.66%) (p = 0.013). The adjusted male: female ratio dropped from 2.5 in the younger group to 1.4 in the older group using prevalence data (Kendall's tau = -0.73, p = 0.039). Similar ratios were found in the Italian but not the Irish registry. We concluded that sex ratios in ALS may change with age. Over-representation of younger patients in clinic registers may explain the variation in sex ratios between studies. Menopause may also play a role.

Scapular fixation in muscular dystrophy.

BACKGROUND: Winging of the scapula is caused by weakness of the thoracoscapular muscles, which allows the scapula to lift off the chest wall during shoulder movements. In facioscapulohumeral muscular dystrophy (and occasionally in other muscular dystrophies) there is selective weakness of the thoracoscapular muscles which may spare other shoulder muscles such as the deltoid muscle. This imbalance results in significant winging and loss of shoulder function. Historically, a number of different surgical and non-surgical interventions have been used to achieve scapular stability. This review examines the evidence available for the use of all scapular fixation techniques in muscular dystrophy, especially facioscapulohumeral muscular dystrophy. OBJECTIVES: To examine the evidence for the relative efficacy of scapular fixation techniques in muscular dystrophy (especially facioscapulohumeral muscular dystrophy) in improving upper limb function. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (20 July 2009), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009) Medline (1966 to July 2009) and EMBASE (1980 to July 2009) for randomised trials. We also contacted authors of trials and other experts in the field. SELECTION CRITERIA: All reports of scapular fixation for muscular dystrophy, including quasi-randomised or randomised controlled trials, comparing any form of scapular fixation (surgical and non-surgical) in people (of all ages and of all severity) with scapular winging due to muscular dystrophy. Our primary outcome measure was objective improvement in shoulder abduction. Our secondary outcome measures were: patient-perceived improvement in performance of activities of daily living, cosmetic results, subjective improvement in pain and proportion of patients with significant postoperative complications. DATA COLLECTION AND ANALYSIS: We collated and summarised studies on the treatment of scapular winging in muscular dystrophy. MAIN RESULTS: No randomised trials were identified. We therefore present a review of the non-randomised literature available. AUTHORS' CONCLUSIONS: There is no evidence from randomised trials to support the suggestion from observational studies that operative interventions produce significant benefits. However, these have to be balanced against postoperative immobilisation, need for physiotherapy and potential complications. We conclude that a randomised trial would be difficult, but a register of cases and the use of a standardised assessment protocol would allow more accurate comparison of the disparate techniques.

Investigation of white matter pathology in ALS and PLS using tract-based spatial statistics.

OBJECTIVE: We aimed to investigate differences in fractional anisotropy (FA) between primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) and the relationship between FA and disease progression using tract-based spatial statistics (TBSS). METHODS: Two scanners at two different sites were used. Differences in FA between ALS patients and controls scanned in London were investigated. From the results of this analysis, brain regions were selected to test for (i) differences in FA between controls, patients with ALS and patients with PLS scanned in Oxford and (ii) the relationship between FA and disease progression rate in the Oxford patient groups. RESULTS: London ALS patients showed a lower FA than controls in several brain regions. Oxford patients with PLS showed a lower FA than ALS patients and than controls in the body of the corpus callosum and in the white matter adjacent to the right primary motor cortex (PMC), while ALS patients showed reduced FA compared with PLS patients in the white matter adjacent to the superior frontal gyrus. Significant correlations were found between disease progression rate and (i) FA in the white matter adjacent to the PMC in PLS, and (ii) FA along the cortico-spinal tract and in the body of the corpus callosum in ALS. CONCLUSIONS: We described significant FA changes between PLS and ALS, suggesting that these two presentations of motor neuron disease show different features. The significant correlation between FA and disease progression rate in PLS suggests the tissue damage reflected in FA changes contributes to the disease progression rate.

Geographical clustering of amyotrophic lateral sclerosis in South-East England: a population study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that causes progressive paralysis and eventually results in death from respiratory failure. Environmental factors that trigger ALS might result in a pattern of geographical clustering of cases. We tested this hypothesis using the South-East England ALS population register, which covers south-east London, Kent and parts of neighbouring counties. METHODS: The register's catchment area was divided into postcode districts and sectors. The expected rates of ALS (adjusted for age and sex) were compared with the observed rates using a standardised residuals method and the SaTScan programme. RESULTS: There were 406 cases of ALS identified in the catchment area during the study period. Four of the 126 postcode districts, all in Greater London, had residuals >2.5 SDs from the mean. Similarly, there were 15 postcode sectors (out of 420) that had residuals >1.96 SDs from the mean. Nine of these were in Greater London. SaTScan identified an area that had a 5.61-km radius in which the relative risk of ALS was 1.70 (p = 0.012). This area overlapped with the postcode districts and some of the sectors identified using the residuals method. CONCLUSIONS: These findings suggest an excess of ALS cases in some postcode districts in south-east England.

Antioxidants and other pharmacological treatments for Friedreich ataxia.

BACKGROUND: Friedreich ataxia is a rare inherited, autosomal recessive, neurological disorder characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, pes cavus and heart abnormalities which may cause premature death in 60 to 80% of people. There is no easily defined clinical or biochemical marker and no known treatment. OBJECTIVES: To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia. SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Trials Specialized Register (17 December 2008), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2008) MEDLINE (January 1950 to December 2008), EMBASE (January 1980 to December 2008) and other sources. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised trials which examined drug treatment in people with genetically confirmed Friedreich ataxia were examined. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. DATA COLLECTION AND ANALYSIS: Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. MAIN RESULTS: Over 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants using the synthetic antioxidant, idebenone 5 mg/kg, fulfilled the selection criteria for this review. Another RCT was of insufficient duration and the other studies were open clinical trials. In the included study, the primary outcome, change in ICARS scale, did not reveal any significant differences with idebenone treatment. The secondary outcome, change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not carried out. The second secondary outcome, change in left ventricular mass, as measured by echocardiography, did improve significantly (P = 0.007). There were no adverse events. A larger RCT using idebenone is in progress, of which the primary outcome is change in the ICARS scale. However, the results are not yet available. AUTHORS' CONCLUSIONS: No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but no research on clinical relevance of this change has been done.

A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease.

Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.