Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias

Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review

Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS

Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes.

Item does not contain fulltextOBJECTIVE: To investigate the frequency of autosomal recessive paraplegin mutations in patients with sporadic adult-onset upper motor neuron (UMN) syndromes. METHODS: We analyzed the paraplegin gene in 98 Dutch patients with a sporadic adult-onset UMN syndrome. Inclusion criteria were a progressive UMN syndrome, adult onset, duration >6 months, and negative family history. Exclusion criteria were clinical or electrophysiologic evidence of lower motor neuron loss and evidence of other causes using a predefined set of laboratory tests, including analysis of the spastin gene. RESULTS: Seven patients had homozygous or compound heterozygous pathogenic paraplegin mutations: six patients had UMN symptoms restricted to the legs and one had UMN symptoms in legs and arms. No mutations were found in the 33 patients with UMN involvement of the bulbar region. Age at onset was lower in the seven patients with paraplegin mutations (37 years, range 34-42) than in the 91 patients without mutations (51 years, range 18-77, p = 0.001). Three of the seven patients with paraplegin mutations and none of the patients without mutations developed cerebellar signs during follow-up. CONCLUSIONS: Paraplegin mutations are a frequent cause of sporadic spastic paraparesis

What we truly know about occupation as a risk factor for ALS: a critical and systematic review

Occupational and environmental exposures may contribute to the risk of developing sporadic amyotrophic lateral sclerosis (ALS). To summarize the available evidence, a systematic review of the literature on occupation as a potential determinant of ALS was performed according to the MOOSE guidelines. From MEDLINE, EMBASE, CINAHL, and Cochrane databases, selected studies were methodologically appraised according to Armon's classification system for ALS risk factor studies. Each occupation studied was reclassified according to the International Standard Classification of Occupations (ISCO-88). The vote-counting method was applied to summarize the data. Of 3773 potentially relevant studies, 51 were initially included. Of these, 12 studies provided risk estimates for individual occupations--one case-control, two register-based case-control, and nine register-based cohort studies. All studies fell into Armon's level of evidence class IV, indicating methodological limitations. Due to the heterogeneity of study methodology, data could not be pooled. The vote-counting method revealed several candidate occupations: veterinarians and other health workers, athletes, hairdressers, power-production plant, electrical and military workers. However, well designed studies with standardized assessment of occupation are needed to provide a more definitive answer about exogenous risk factors of ALS

Leukocyte and complement activation by GM1-specific antibodies is associated with acute motor axonal neuropathy in rabbits

Acute motor axonal neuropathy (AMAN) in humans is associated with the presence of GM1-specific antibodies. Immunization of rabbits with GM1-containing ganglioside mixtures, purified GM1, or Campylobacter jejuni lipo-oligosaccharide exhibiting a GM1-like structure elicits GM1-specific antibodies, but axonal polyneuropathy only occurs in a subset of animals. This study aimed to dissect the molecular basis for the variable induction of AMAN in rabbits. Therefore, we analyzed the pro-inflammatory characteristics of GM1-specific antibodies in plasma samples from ganglioside-immunized rabbits with and without neurological deficits. GM1-specific plasma samples from all rabbits with AMAN were capable of activating both complement and leukocytes, in contrast to none of the plasma samples from rabbits without paralysis. Furthermore, GM1-specific IgG-mediated activation of leukocytes was detected before the onset of clinical signs. These data suggest that AMAN only occurs in rabbits that develop GM1-specific antibodies with pro-inflammatory properties

SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.

Item does not contain fulltextBACKGROUND: ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype. OBJECTIVE: To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS. METHODS: We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number). RESULTS: One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level < or = 2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate. CONCLUSIONS: SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.6 p

Lifetime occupation, education, smoking, and risk of ALS.

Objective: To investigate the association between cigarette smoking, level of education, occupation, and the occurrence of sporadic amyotrophic lateral sclerosis (ALS). Methods: A total of 364 patients and 392 controls completed a questionnaire covering smoking habits, level of education, and occupational history. Main occupations were coded according to the International Standard Classification of Occupations and compared between patients and controls. Results: The univariate analysis showed an increased risk of developing ALS among current cigarette smokers (OR = 1.7; 95% CI = 1.1 to 2.6; p = 0.01), those with a low level of education (elementary school) (OR = 2.2; 95% CI = 1.2 to 3.8; p < 0.01), and among women whose main occupation was classified as crafts and related trades workers (OR = 8.4; 95% CI = 1.0 to 70.1; p = 0.05). Multivariate analysis (with covariates age, smoking, education, and occupation) showed an increased risk for current smokers of cigarettes (OR = 1.6; 95% CI = 1.0 to 2.5; p = 0.04). Conclusions: Occupation, education, and cigarette smoking are risk factors for amyotrophic lateral sclerosis, but only smoking appeared independently associated

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis

We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy

Lifetime occupation, education, smoking, and risk of ALS.

Objective: To investigate the association between cigarette smoking, level of education, occupation, and the occurrence of sporadic amyotrophic lateral sclerosis (ALS). Methods: A total of 364 patients and 392 controls completed a questionnaire covering smoking habits, level of education, and occupational history. Main occupations were coded according to the International Standard Classification of Occupations and compared between patients and controls. Results: The univariate analysis showed an increased risk of developing ALS among current cigarette smokers (OR = 1.7; 95% CI = 1.1 to 2.6; p = 0.01), those with a low level of education (elementary school) (OR = 2.2; 95% CI = 1.2 to 3.8; p < 0.01), and among women whose main occupation was classified as crafts and related trades workers (OR = 8.4; 95% CI = 1.0 to 70.1; p = 0.05). Multivariate analysis (with covariates age, smoking, education, and occupation) showed an increased risk for current smokers of cigarettes (OR = 1.6; 95% CI = 1.0 to 2.5; p = 0.04). Conclusions: Occupation, education, and cigarette smoking are risk factors for amyotrophic lateral sclerosis, but only smoking appeared independently associated

Ganglioside-specific IgG and IgA recruit leukocyte effector functions in Guillain-Barre syndrome

The capacity of ganglioside-specific autoantibodies to recruit leukocyte effector functions was studied. Serum samples from 87 patients with Guillain–Barré (GBS) or Miller Fisher syndrome (MFS), containing GM1-, GQ1b-, or GD1b-specific IgG or IgA, were tested for leukocyte activating capacity. Ganglioside-specific IgG antibodies generally induced leukocyte activation, irrespective of specificity. The magnitude of leukocyte degranulation correlated with GM1- and GQ1b-specific IgG titers, but not with disease severity. Finally, GM1- specific IgA activated leukocytes through the IgA receptor, FcαRI (CD89). Therefore, both ganglioside-specific IgG and IgA can recruit leukocyte effector functions, which may be relevant in the pathogenesis of GBS and MFS. © 2006 Elsevier B.V. All rights reserved. Keywords: Guillain–Barré syndrome; Autoantibodies; Pathogenicity; Gangliosides; Fcγ