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Background and Objectives: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype., Methods: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis., Results: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1 , is uncertain given the absence of an associated effect on nearby gene transcription., Discussion: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS., Trial Registration Information: This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. ' Primary pathways ' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. ' Secondary pathways ' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.

In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Cerebrospinal fluid (CSF) has been implicated in amyotrophic lateral sclerosis (ALS) due to its ability to spread inflammatory proteins throughout the nervous system. We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mouse model., Methods: We filtered the CSF from 11 ALS patients via 100 kilodaltons (kD) molecular weight cut-off filters. We used mass spectrometry-based discovery proteomics workflows to compare protein abundances before and after filtration. To test the effects of CSF filtration on motor function, we injected groups of mice with saline, filtered ALS-CSF, or unfiltered ALS-CSF (n=12 per group) and assessed motor function via pole descent and open field tests., Results: We identified proteins implicated in ALS pathogenesis and showed that these were removed in significant amounts in our workflow. Key filtered proteins included complement proteins, chitinases, serine protease inhibitors, and neuro-inflammatory proteins such as amyloid precursor protein, chromogranin A, and glial fibrillary acidic protein. Compared to the filtered ALS-CSF mice, unfiltered ALS-CSF mice took longer to descend a pole (10 days post-injection, 11.14 seconds vs 14.25 seconds, p = 0.02) and explored less on an open field (one day post-injection, 21.81 m vs 16.83 m, p = 0.0004)., Conclusions: We demonstrated the ability to filter proteins from the CSF of ALS patients and identified potentially pathologic proteins that were reduced in quantity. Additionally, we demonstrated the ability of unfiltered ALS-CSF to induce motor deficits in mice on the pole descent and open field tests and showed that filtration could prevent this deficit. Given the lack of effective treatments for ALS, this could be a novel solution for patients suffering from this deadly and irreversible condition., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Venkatraman et al.)

Background: Researchers face challenges in patient recruitment, especially for rare, fatal diseases such as amyotrophic lateral sclerosis (ALS). These challenges include obtaining sufficient statistical power as well as meeting eligibility requirements such as age, sex, and study proximity. Similarly, persons with ALS (PALS) face difficulty finding and enrolling in research studies for which they are eligible., Objective: The aim of this study was to describe how the federal Agency for Toxic Substances and Disease Registry's (ATSDR) National ALS Registry is linking PALS to scientists who are conducting research, clinical trials, and epidemiological studies., Methods: Through the Registry's online research notification mechanism (RNM), PALS can elect to be notified about new research opportunities. This mechanism allows researchers to upload a standardized application outlining their study design and objectives, and proof of Institutional Review Board approval. If the application is approved, ATSDR queries the Registry for PALS meeting the study's specific eligibility criteria, and then distributes the researcher's study material and contact information to PALS via email. PALS then need to contact the researcher directly to take part in any research. Such an approach allows ATSDR to protect the confidentiality of Registry enrollees., Results: From 2013 to 2019, a total of 46 institutions around the United States and abroad have leveraged this tool and over 600,000 emails have been sent, resulting in over 2000 patients conservatively recruited for clinical trials and epidemiological studies. Patients between the ages of 60 and 69 had the highest level of participation, whereas those between the ages of 18 and 39 and aged over 80 had the lowest. More males participated (4170/7030, 59.32%) than females (2860/7030, 40.68%)., Conclusions: The National ALS Registry's RNM benefits PALS by connecting them to appropriate ALS research. Simultaneously, the system benefits researchers by expediting recruitment, increasing sample size, and efficiently identifying PALS meeting specific eligibility requirements. As more researchers learn about and use this mechanism, both PALS and researchers can hasten research and expand trial options for PALS., (©Paul Mehta, Jaime Raymond, Moon Kwon Han, Theodore Larson, James D Berry, Sabrina Paganoni, Hiroshi Mitsumoto, Richard Stanley Bedlack, D Kevin Horton. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.12.2021.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions., (© 2020 Wiley Periodicals, Inc.)

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population ( N  = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F 2t -isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r  = 0.30), percent (%) FVC ( r  = 0.20), PUA ( r  = 0.37), and 8-oxodG ( r = -0.13, all p  < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p  < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r  = 0.29, midpoint: r  = 0.23, final: r  = 0.38, all p  < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Objective: Lunasin, a soy peptide that reportedly alters histone acetylation in vitro , was associated with a single ALS reversal in the media. Following an ALSUntangled report, we sought to determine whether Lunasin altered histone acetylation and improved progression in people with ALS, and whether patient-centric trial design features might improve enrollment and retention. Methods: This single-center, year-long trial (NCT02709330) featured broad inclusion criteria, historical controls, primarily virtual data collection, and real-time results. Participants measured their own ALSFRS-R score, weight and perceived efficacy, and recorded these monthly on PatientsLikeMe. Blood tests at screening and month 1 assessed alterations in histone H3 and H4 acetylation. The protocol was published online, empowering patients outside the study to self-experiment. Results: Fifty participants enrolled in 5.5 months. Although this population had more advanced disease compared to other trials, retention and adherence were very high. There was no significant effect of Lunasin treatment on histone acetylation or disease progression. A cohort following our protocol outside the trial reported similar side effects and perceived effectiveness; however, their compliance with data entry was markedly lower. Conclusions: While Lunasin's lack of efficacy is disappointing, our novel trial design had the highest ALS trial enrollment rate ever recorded, with excellent retention and adherence. Low data density from patients who are self-experimenting outside a formal protocol casts doubt on the possibility of gathering useful information from unsupervised expanded access programs or "right to try" initiatives.

Objective: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months., Methods: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life., Results: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use., Conclusion: The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used., (© 2018 American Academy of Neurology.)

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS)., Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data., Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range., Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline., (© 2016 American Academy of Neurology.)

Objective: To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database., Methods: We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted., Results: Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months., Conclusion: ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study., (© 2015 American Academy of Neurology.)

Given the severity of their illness and lack of effective disease-modifying agents, it is not surprising that most patients with amyotrophic lateral sclerosis (ALS) consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation, and energy healing. This article reviews these in detail. The authors also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy, and shared decision making. Finally, the authors review a program called ALSUntangled, which uses shared decision making to review alternative therapies for ALS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Background: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Results from human trials, however, have been mixed. Given conflicting results regarding the efficacy of creatine, we conducted a systematic review, which was updated in 2012., Objectives: To systematically examine the efficacy of creatine efficacy in prolonging ALS survival and in slowing ALS disease progression., Search Methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 July 2012), CENTRAL (2012, issue 7 in the Cochrane Library), MEDLINE (January 1966 to July 2012) and EMBASE (January 1980 to July 2012) for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies., Selection Criteria: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and per cent predicted forced vital capacity (FVC) over time., Data Collection and Analysis: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study., Main Results: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054)., Authors' Conclusions: In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.

Amyotrophic lateral sclerosis (ALS) remains a rapidly progressive fatal degenerative disease of motor neurons for which there are few interventions to slow disease progression or improve quality of life. A diaphragm pacing system was approved by the U.S. Food and Drug Administration in September 2011 for ALS under a Humanitarian Device Exemption. News of this approval has been met with a combination of excitement and uncertainty by members of the ALS community. We review the currently available data on the diaphragm pacing system and its use in ALS. Diaphragm pacing appears to be reasonably safe in carefully selected patients, but flaws in the reporting on it thus far preclude conclusions regarding efficacy. Further study is needed., (Copyright © 2012 Wiley Periodicals, Inc.)

Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993-1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1-3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8-3.5), pyrethroids (1.4, 0.6-3.4), herbicides (1.6, 0.7-3.7), and fumigants (1.8, 0.8-3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8-5.1), dieldrin (2.6, 0.9-7.3), DDT (2.1, 0.9-5.0), and toxaphene (2.0, 0.8-4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations., (Published by Elsevier B.V.)

Enrollment in ALS research studies is surprisingly low. Here we report on two online patient surveys that help identify some of the reasons. These include failure to invite patients to enroll, especially patients who have already participated in prior studies. Also included are patient concerns about the cost of participation, and confusion about several aspects of studies being offered. Along with prior work, these data suggest specific steps that can be taken to improve enrollment.

Background: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review., Objectives: To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression., Search Strategy: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies., Selection Criteria: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time., Data Collection and Analysis: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study., Main Results: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054)., Authors' Conclusions: In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.

Our objective was to determine the interval from symptom onset to diagnosis, and to evaluate associated factors in a cohort of U.S. Veterans with motor neuron diseases. We retrospectively evaluated 1359 patients enrolled in the National Registry of Veterans with Amyotrophic Lateral Sclerosis (ALS). The main outcome measures were time from symptom onset to first diagnosis and to second opinion. Predictor variables included age at symptom onset, year of symptom onset, race, onset site, final diagnosis, number of diagnostic tests performed and clinical sites visited. Median time to first diagnosis was 11 months; median time to second opinion was two months. In a multivariable model, more recent calendar year of symptom onset, younger age, bulbar onset and a diagnosis of ALS versus non-ALS motor neuron disease were all significantly associated with a shorter time to first diagnosis. Later year of symptom onset and white race were significantly associated with a shorter time to second opinion. While the interval from symptom onset to diagnosis, and many of the associated factors are similar between our large cohort of U.S. Veterans with ALS and other smaller published cohorts, we found that the diagnostic interval among U.S. Veterans has significantly decreased over time.

Lyme disease is sometimes part of the differential diagnosis for amyotrophic lateral sclerosis (ALS). Herein we report on 414 individuals with ALS at the Massachusetts General Hospital who underwent laboratory testing for Lyme disease. Twenty-four (5.8%) were seropositive, but only 4 (0.97%) had confirmed past immunoreactive infection. Two of these patients received ceftriaxone for 1 month without clinical improvement. Lyme disease was rare in 414 patients with ALS and is not likely to be causative.

The clinical course of patients with ALS is highly variable. While the median survival time from symptom onset is 2-4 years, there are reports of survival ranging from less than a year to more than 40 years. Such variability makes planning difficult for patients and physicians, and complicates clinical trial design. We sought to validate previous predictors of survival and search for new ones using a large group of ALS patients in the National Registry of Veterans with ALS. We were especially interested in how various aspects of military service might affect survival. Subjects were those in the National Registry of Veterans with ALS who had probable or definite ALS (according to El Escorial criteria). A multivariable Cox proportional hazard regression model was used to examine variables for statistical association with ventilator-free survival time (determined from date of first diagnosis). Subjects who had not died or started ventilation by 31 October 2006 were censored. Our group of 1085 US military veterans with ALS was primarily male (98%) and white (94%), with mostly sporadic (95%) and extremity-onset (76%) ALS. Symptom onset occurred at a mean age of 59.3 years (60.6 years for diagnosis). Median survival time from symptom onset was 4.7 years (3.3 years from diagnosis). In our multivariable model, older age at diagnosis (HR 1.41 (95% CI 1.27-1.55) per 10-year increase), non-extremity site of onset (HR 1.55 (1.24-1.94)), and past deployment to Vietnam (HR 1.73 (1.36-2.19)) were all associated with shortened survival. A longer time to diagnosis was associated with better survival (HR 0.77 (0.70-0.84) per one year increase in diagnosis time). In this unique cohort of veterans with ALS, traditional factors of reduced survival remained important. In addition, past deployment to Vietnam was found to be associated with shortened survival as well. This finding could be due to a common exposure, a shared characteristic, an unmeasured confounder, or an enrollment bias. More research will be needed to understand the reasons behind this new finding.

Cramps and spasticity impair quality of life and function in patients with motor neuron diseases, and there are no proven treatments for these problems. We conducted a pilot trial to determine if treatment with levetiracetam was associated with a reduction in cramp severity, cramp frequency, tonic or phasic spasticity. We used an open-label repeated measures pilot trial of 20 patients, comparing cramp and spasticity scores over a 3-month baseline versus nine months on treatment. Cramp and spasticity scores were stable over a 3-month baseline. Shortly after starting levetiracetam, there was a significant reduction in cramp severity and frequency, which persisted for the duration of this year-long study. There was also a reduction in phasic but not tonic spasticity. Levetiracetam was well tolerated. Our results justify a placebo-controlled study of levetiracetam for treatment of cramps and spasticity in patients with motor neuron diseases, and suggest that this can be accomplished with a small number of subjects followed for a short time.

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

Enrollment in ALS trials has not been systematically studied. We surveyed the ALS Research Group (ALSRG) to learn their impressions of enrollment at ALS clinics across North America. We also reviewed completed ALS trials to determine an enrollment rate (subjects per site per month), its variability across trials, whether it is changing over time, and whether it is influenced by 'trial factors'. ALSRG members were polled via an online survey. ALS trials were identified by literature review and investigator contact. Enrollment rate versus publication year was plotted for each trial. Models were created to examine how 'trial factors' were associated with enrollment rate. By survey, percent enrollment is 25% and highly variable (range 0-75%). By literature review, enrollment rate is 2.2 participants/site/month and highly variable (range 0.1-7.5). Enrollment is not improving over time; no 'trial factor' explains the variability in enrollment across trials. Behaviors among clinic directors and patients were identified that may influence enrollment. In conclusion, ALS trial enrollment rate is low, highly variable and not influenced by trial design factors. 'Patient factors' and 'physician factors' may play more important roles in influencing enrollment, as in oncology trials. Our survey data support this idea, and provide potential mechanisms for improving enrollment.

Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.

Background: The Department of Veterans Affairs (VA) Cooperative Studies Program has established a National Registry of Veterans with Amyotrophic Lateral Sclerosis (ALS). This article describes the objectives, methods, and sample involved in the registry., Methods: United States military veterans with ALS were identified through national VA electronic medical record databases and nationwide publicity efforts for an enrollment period of 4 1/2 years. Diagnoses were confirmed by medical record reviews. Registrants were asked to participate in a DNA bank. Follow-up telephone interviews are conducted every 6 months to track participants' health status., Results: As of September 30, 2007, 2,400 veterans had consented to participate in the registry, 2,068 were included after medical record review, 995 were still living and actively participating, and 1,573 consented to participate in the DNA bank. 979 participants had been enrolled in the registry for at least 1 year, 497 for at least 2 years, and 205 for at least 3 years. Fourteen studies have been approved to use registry data for epidemiological, observational, and interventional protocols., Conclusion: This registry has proven to be a successful model for identifying large numbers of patients with a relatively rare disease and enrolling them into multiple studies, including genetic protocols., ((c) 2008 S. Karger AG, Basel)

Background: Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS)., Methods: We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723., Findings: ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score., Interpretation: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.

It has been > 130 years since the first description of the upper and lower motor neuron disease called amyotropic lateral sclerosis (ALS). Sadly, there has been little change in the long interval over which this disease is diagnosed, or in its poor prognosis. Significant gains have been made, however, in understanding its pathophysiology and in symptomatic care. Disease-causing mutations have been identified and used to create animal models. Other identified mutations may increase susceptibility and cause disease only in a particular environment and at a particular age. A number of 'downstream' molecular pathways have been implicated, including transcriptional disturbances, protein aggregation, excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, cytoskeletal and axonal transport derangements, growth factor dysregulation and apoptosis. This knowledge has led to an impressive pipeline of candidate therapies that offer hope for finally being able to alter ALS disease progression. These are described and prioritized herein, and suggestions are offered for efficiently sifting through them.

Context: Clinicians must be able to diagnose myasthenia gravis, since delays in establishing the diagnosis may put patients at risk for complications from this treatable disease., Objective: To determine if items in the history and examination or results of simple tests change the likelihood of myasthenia gravis as a diagnosis., Data Sources: MEDLINE search of English-language articles (January 1966-January 2005) using the terms myasthenia gravis, diagnosis, and test, and a search of bibliographies of retrieved articles., Study Selection: Studies evaluating a particular symptom or sign in patients both with and without myasthenia gravis. Of 640 articles retrieved, 33 were eligible for review. Of these, 15 met inclusion criteria and form the basis of this review., Data Extraction: Two authors independently reviewed each study to determine eligibility, abstracted data using a standardized instrument, and classified study quality using previously published criteria., Data Synthesis: A history of "speech becoming unintelligible during prolonged speaking" and the presence of the peek sign increase the likelihood of myasthenia gravis (likelihood ratio [LR], 4.5; 95% confidence interval [CI], 1.2-17.0 and LR, 30.0; 95% CI, 3.2-278.0, respectively). Their absence does not significantly reduce the likelihood of myasthenia gravis. The identified studies only assessed 1 other historical feature and sign each ("food remaining in the mouth after swallowing" and quiver eye movements, respectively), and neither of these significantly changes the likelihood of myasthenia. The ice test is useful when the response is abnormal (summary positive LR, 24.0; 95% CI, 8.5-67.0) and diminishes the likelihood of myasthenia gravis when the response is normal (summary negative LR, 0.16; 95% CI, 0.09-0.27). A positive response to an anticholinesterase medication (mainly edrophonium test) increases the probability of a diagnosis of myasthenia gravis (summary positive LR, 15.0; 95% CI, 7.5-31.0), and a negative response reduces the diagnostic probability of myasthenia (summary negative LR, 0.11; 95% CI, 0.06-0.21). An abnormal sleep test result is useful in confirming the diagnosis (LR, 53.0; 95% CI, 3.4-832.0). The rest and sleep tests make the probability of myasthenia unlikely when results are normal (LR, 0.52; 95% CI, 0.29-0.95 and LR, 0.01; 95% CI, 0.00-0.16, respectively)., Conclusions: Items in the history and physical examination along with results of certain simple tests performed in the office (ice test, sleep test, and edrophonium test) are useful in predicting the likelihood of myasthenia gravis. These results must be interpreted with caution, however, given the high prevalence of disease in the populations reported in clinical studies. This review is limited by the small number of signs and symptoms scientifically studied and reported in the literature. Future studies evaluating the value of common historical features and easy maneuvers commonly known and practiced by experts in the clinical diagnosis of myasthenia are needed.

We report five patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who had demyelinating peripheral neuropathy. The MNGIE neuropathy had clinical and electrodiagnostic features typical of acquired, rather than inherited, etiologies. In fact, three patients were actually treated for chronic inflammatory demyelinating polyneuropathy (CIDP). We discuss findings that may help distinguish patients with MNGIE from those with CIDP.

This article reviews controversies surrounding the concept of myasthenic crisis. Literature review and our own experience demonstrate that there is disagreement about how a crisis should be defined, what the implications of a crisis are, whether crises are preventable, and how crisis incidence should be calculated. We propose that crisis be defined as weakness from acquired myasthenia gravis that is severe enough to necessitate intubation or delayed extubation following surgery. We argue that crisis need not "doom" a myasthenic patient to a different prognosis or response to therapy compared with myasthenic patients with severe generalized weakness. Finally, we argue that crisis is preventable and that crisis incidence, calculated in a standardized fashion, could be a useful outcome measure.

Molecular mechanisms that alter the incidence and rate of neuromuscular disease progression are, in many cases, only partially understood. Several recent studies have asked whether apolipoprotein E (apoE for the protein, APOE for the gene) influences these aspects of specific neuromuscular disorders, as it does in central nervous system disorders such as Alzheimer disease. Although these studies are open to methodological criticism, several interesting trends have emerged. First, the APOE4 allele seems to be associated with an increased risk for developing certain neuromuscular diseases, including diabetic neuropathy and human immunodeficiency viral neuropathy. Second, this allele appears to be associated with faster progression of some neuromuscular diseases, including diabetic neuropathy and possibly motor neuron disease. Third, the APOE2 allele seems to confer protection against developing certain neuromuscular diseases, including the amyotrophic lateral sclerosis (ALS)/parkinsonism/dementia complex of Guam. Finally, this allele is associated with a better prognosis in neuromuscular diseases such as motor neuron disease. The effect of various APOE alleles on neuromuscular diseases therefore parallels their influence on central nervous system diseases. Arch Neurol. 2000;57:1561-1565