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The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design., (© 2024 Wiley Periodicals LLC.)

Background: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS)., Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available., Results: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management., Conclusions: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS., Methods: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression., Results: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10 -12 ), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10 -7 ). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10 -4 )., Discussion: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS., Competing Interests: AA-C was a consultant for Mitsubishi-Tanabe Pharma, GSK, and Chronos Therapeutics, and chief investigator for clinical trials for Cytokinetics and OrionPharma. JvV reports to have sponsored research agreements with Biogen. VS was a consultant for Novartis and Biogen. LB reports grants from Netherlands ALS Foundation, grants from Netherlands Organization for Health Research and Development (Vici Scheme), grants from The European Community’s Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR)], grants from Netherlands Organization for Health Research and Development) the STRENGTH project, funded through the EU Joint Programme—Neurodegenerative Disease Research, JPND), during the conduct of the study; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. AA-C also serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denali Pharma, Cytokinetics, Lilly, and Amylyx research. CS reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. JL was a member of the scientific advisory board for Cerevel Therapeutics, a consultant for ACI Clinical LLC sponsored by Biogen, Inc. or Ionis Pharmaceuticals, Inc. JL was also a consultant for Perkins Coie LLP and may provide expert testimony and also supported by funding from NIH/NINDS (R01NS073873 and R56NS073873). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al Khleifat, Iacoangeli, Jones, van Vugt, Moisse, Shatunov, Zwamborn, van der Spek, Cooper-Knock, Topp, van Rheenen, Kenna, Van Eijk, Kenna, Byrne, López, Opie-Martin, Vural, Campos, Weber, Smith, Fogh, Silani, Morrison, Dobson, van Es, McLaughlin, Vourc’h, Chio, Corcia, de Carvalho, Gotkine, Panades, Mora, Shaw, Landers, Glass, Shaw, Basak, Hardiman, Robberecht, Van Damme, van den Berg, Veldink and Al-Chalabi.)

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability., (© 2022. The Author(s).)

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

The removal of non-brain signal from magnetic resonance imaging (MRI) data, known as skull-stripping, is an integral component of many neuroimage analysis streams. Despite their abundance, popular classical skull-stripping methods are usually tailored to images with specific acquisition properties, namely near-isotropic resolution and T1-weighted (T1w) MRI contrast, which are prevalent in research settings. As a result, existing tools tend to adapt poorly to other image types, such as stacks of thick slices acquired with fast spin-echo (FSE) MRI that are common in the clinic. While learning-based approaches for brain extraction have gained traction in recent years, these methods face a similar burden, as they are only effective for image types seen during the training procedure. To achieve robust skull-stripping across a landscape of imaging protocols, we introduce SynthStrip, a rapid, learning-based brain-extraction tool. By leveraging anatomical segmentations to generate an entirely synthetic training dataset with anatomies, intensity distributions, and artifacts that far exceed the realistic range of medical images, SynthStrip learns to successfully generalize to a variety of real acquired brain images, removing the need for training data with target contrasts. We demonstrate the efficacy of SynthStrip for a diverse set of image acquisitions and resolutions across subject populations, ranging from newborn to adult. We show substantial improvements in accuracy over popular skull-stripping baselines - all with a single trained model. Our method and labeled evaluation data are available at https://w3id.org/synthstrip., Competing Interests: Declaration of competing interest Bruce Fischl has a financial interest in CorticoMetrics, a company whose medical pursuits focus on brain imaging and measurement technologies. This interest is reviewed and managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. The authors declare that they have no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype., (© 2022. The Author(s).)

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001., Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity., Results: A significant survival benefit of 25 months ( p  = 0.037) and 47% reduced risk of death ( p  = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib ( n  = 45) versus placebo ( n  = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001., Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015)., Competing Interests: Conflict of interest statement: Masitinib is under clinical development by the study funder, AB Science. AM, OH and CDM are employees and shareholders of AB Science. JSM has received research funding from AB Science. All remaining authors have no competing interests. AL, an Associate Editor of Therapeutic Advances in Neurological Disorders, is an author of this paper, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process., (© The Author(s), 2021.)

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients ( N  = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( p  = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p  = 0.09; muscle strength mega-score, p  = 0.31). Post hoc analyses pooling all active reldesemtiv -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib ( n  = 99) showed significant benefit over placebo ( n  = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes skeletal muscle weakness, including muscles involved with respiration. Death often results from respiratory failure within 3-5 years. Monitoring respiratory status is therefore critical to ALS management, as respiratory/pulmonary function tests (PFTs) are used to make decisions including when to initiate noninvasive ventilation. Understanding the different respiratory and PFTs as they relate to disease progression and survival may help determine which tests are most suitable., Methods: This review describes the tests used to assess respiratory muscle and pulmonary function in patients with ALS and the correlations between different respiratory measures and clinical outcomes measures., Results: The most commonly used measurement, forced vital capacity (VC), has been shown to correlate with clinical milestones including survival, but also requires good motor coordination and facial strength to form a tight seal around a mouthpiece. Other tests such as slow VC, sniff inspiratory pressure, or transdiaphragmatic pressure with magnetic stimulation are also associated with distinct advantages and disadvantages., Conclusions: Therefore, how and when to use different tests remains unclear. Understanding how each test relates to disease progression and survival may help determine which is best suited for specific clinical decisions.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Adaptation of the ECAS to the Spanish population., Methods: The ECAS test was adapted and implemented in a random sample of 102 ALS patients. A test-retest reliability of the instrument and internal consistency assessment were carried out. Its convergent validity was determined by comparing the ECAS screen with the ALS Cognitive Behavioural Screen (ALS-CBS), another standard tool., Results: The Spanish adaptation of the ECAS scale preserves the statistical characteristics of the original version. Its analysis revealed a high internal consistency, similar to that of the original version. A significant correlation was found between the ECAS scale and the ALS-CBS, with the highest degree of correlation values shown at the Executive and Lack of empathy domains scales. Additionally, significant differences were observed between the scores obtained in ALS patients and healthy individuals. Furthermore, the analysis of the screen discrimination ability resulted acceptable., Conclusion: The results of this study prove that the Spanish adaptation of the ECAS scale preserves the internal consistency and construct validity of its original version.

Background: To ascertain which countries in the world have retinopathy of prematurity (ROP) screening programmes and guidelines and how these were developed., Methods: An email database was created and requests were sent to ophthalmologists in 141 nations to complete an online survey on ROP screening in their country., Results: Representatives from 92/141 (65%) countries responded. 78/92 (85%) have existing ROP screening programmes, and 68/78 (88%) have defined screening criteria. Some countries have limited screening and those areas which have no screening or for which there is inadequate knowledge are mainly Southeast Asia, Africa and some former Soviet states., Discussion: With the increasing survival of premature babies in lower-middle-income and low-income countries, it is important to ensure that adequate ROP screening and treatment is in place. This information will help organisations focus their resources on those areas most in need., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Objective: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a "reverse" round-robin with 15 centers across Europe/U.S., Methods: Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories., Results: CSF pNfH was increased (p < 0.05) in ALS in 10 out of 15 centers and NfL in 5 out of 12 centers. The coefficient of variation (CV%) of pNfH measurements between laboratories was 18.7 ± 19.1%. We calculated a diagnostic cut-off of >568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%)., Conclusion: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up.

Background and Purpose: To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole., Methods: A double-blind, randomized, placebo-controlled, multicenter trial of 18 months' duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) ≥70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months' survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed., Results: At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan-Meier analysis was 67.5% (95% CI 61.0%-73.1%) in the placebo group and 69.4% (95% CI 63.0%-74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months' treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns., Conclusions: Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole., (© 2014 The Author(s) European Journal of Neurology © 2014 EFNS.)

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Background: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease., Methods: In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189., Findings: Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43-468·08) and those in the placebo group (438·84, 412·81-464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13·34 in the dexpramipexole group vs -13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75-1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups., Interpretation: Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis., Funding: Biogen Idec., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: ALS is a neurodegenerative disease of the entire motor system that most frequently ends with respiratory arrest in few years. Its diagnosis and the rapid progression of the motor dysfunctions produce a continued emotional impact. Studies on this impact are helpful to plan adequate psychotherapeutic strategies., Objective: To assess and analyze: First: How the patients with ALS perceive their emotional health. Second: The emotional impact of their physical disabilities. Third: The physical disabilities with highest emotional impact. Fourth: The feelings with highest emotional impact., Methods: Up to 110 Spanish patients with ALS were assessed less than 1 year from diagnosis, then twice more at 6 month intervals, using the ALS Quality of Life Assessment Questionnaire (ALSAQ-40) validated for use in Spanish. Descriptive analysis and correlation between variables were obtained., Results: Worries about the future, of lack of freedom, and of being a burden were prevalent feelings. On average depression was felt only "sometimes." Only 25% of the variations in the emotional state were explained by changes in the physical state at first evaluation, and 16% at the last one. Emotional functioning correlated significantly with the physical disabilities at first and second evaluation, less so at third. Communication disabilities always had the highest impact. Depression at first evaluation and hopelessness at the next two evaluations had the highest emotional impact. Hopelessness did not correlate with any physical disability at the third evaluation. On the whole, emotional dysfunction was self perceived as intermediate (between none and worst), and remained stable at 1 year follow up, in both bulbar and spinal onset patients., Conclusions: Physical dysfunctions per se have a limited role in patients´ emotional distress. Communication disabilities, as well as feelings of depression at early stages of illness, and of hopelessness later on, had the most impact. This requires their careful therapeutic attention. On average, Spanish patients with ALS cope with their disease, overcoming depression, which is not felt often, and with just mid levels of emotional dysfunction.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes., (© 2012 Wiley Periodicals, Inc.)

To compare the relative efficacy of trabeculectomy surgery with 90-s and 5-min intraoperative exposure time to 5-fluorouracil. This was a retrospective, non-randomized comparative study. 41 eyes of 33 consecutive patients in the study group were compared to 40 eyes of 30 consecutive patients in the historical control group. Both groups were exposed to 5-fluorouracil (50 mg/ml) during trabeculectomy surgery. The exposure time was 90 s for the study group and 5 min for the control group. Three criteria were used to define surgical success: IOP (intraocular pressure) less than 21 mmHg; IOP less than 21 mmHg with more than 30% reduction in pressure; and IOP less than 15 mmHg with more than 30% reduction. The number of antiglaucoma medications, visual acuity, complications, and interventions were recorded at regular intervals. Mean preoperative IOP was 21.6 +/- 4.8 in the 90-s group and 21.2 +/- 4.9 in the 5-min group. Mean follow-up was 28.2 +/- 5.1 months in the 90-s group and 48.0 +/- 4.9 months in the 5-min group. During the first 30 postoperative months, there were no statistically significant differences in IOP and requirement for antiglaucoma medications between the two groups. The 90-s group had shorter survival rates using the 1st success criteria, but no significant difference was detected when the more stringent 2nd and 3rd criteria were applied. Choroidal effusions were significantly less common in the 90-s group (P = 0.0076). The results of this small study suggest that a 90-s application of 5-fluorouracil may be as effective as a 5-min one in trabeculectomy.

Purpose: 5-Fluorouracil (5-FU) is used intraoperatively to improve the success of trabeculectomy Common practice is a 5-min application of 5-FU delivered via a Weck Cel sponge. The aim of this study was to determine if shorter exposure times were as effective in inhibiting Tenon's capsule fibroblast proliferation., Methods: Samples of Tenon's capsules, obtained from young patients undergoing strabismus surgery, were immersed In vitro in 5-FU (50 mg/mL) for periods ranging from 1 to 10 min. Control samples were exposed either to growth medium (M 199) or 5-FU vehicle alone. Explants were cultured for up to 7 days and analysed for cell density, cell viability using fluoroprobe detection, and cell proliferation determined by proliferating cell nuclear antigen (PCNA)-staining., Results: Exposure to 5-FU for 1 and 5 min resulted in a similar and significant inhibition of the culture-induced increase in stromal cell density (P < 0.01), a significant reduction in the percentage of viable cells (P < 0.02), and reduced PCNA indices, compared with controls. Exposure times of 3 and 10 min produced similar results., Conclusions: In vitro, under conditions of organ culture, a 1-min exposure to 5-FU had a significant antiproliferative effect on fibroblasts of Tenon's capsule, and was similar to 5 min of exposure. Optimal intraoperative 5-FU exposure time may be as little as 1 minute.

Purpose: To assess a single dose of intraoperative beta radiation used to enhance the success rate of trabeculectomy in a population of low-risk glaucoma patients in whom antimetabolites might not be indicated., Methods: A prospective randomized trial of 65 eyes was designed, with 31 eyes receiving 750 rads of intraoperative beta radiation (group 1), and 34 eyes receiving no supplementation (group 2)., Results: Mean follow-up time was 24 months. Mean postoperative intraocular pressure was 12.2 mmHg in group 1, and 13.7 mmHg in group 2 (P = 0.16). Mean decrease in intraocular pressure was 10.3 mmHg in group 1, and 9.3 mmHg in group 2 (P = 0.49). The two groups were not significantly different in terms of surgical complications., Conclusion: For this population of low-risk patients, there was no significant difference in outcome after applications of a single intraoperative dose of beta radiation.

Introduction: To determine whether 5-fluorouracil is effective in reducing scarring after strabismus surgery we used rectus muscle surgery in experimental animals to compare a single intraoperative dose of 5-fluorouracil with mitomycin C and to compare results in similarly treated controls not receiving these antimetabolites., Methods: Muscle resections were performed on eight rabbits (16 eyes). Four eyes had 5-fluorouracil (50 mg/ml), and four eyes received mitomycin C (0.2 mg/ml), each of which was applied during surgery on an ophthalmic sponge for 5 minutes. Eight eyes served as controls. Six weeks after surgery conjunctival vascularity, muscle length-tension curves, muscle disinsertion force, and the histologic degree of scarring were assessed., Results: The mitomycin C-treated eyes clearly had more conjunctival avascularity and a lower disinsertion force. Both treated groups had flatter length-tension curves and less scarring on histologic examination than the control eyes., Conclusions: Antifibroproliferative therapy with intraoperative sponge 5-fluorouracil appears as effective as, and is possibly safer than, mitomycin C. It may be a useful adjunct in recurrent strabismus surgery or in other situations where a risk of excessive postoperative scarring exists.

Background and Objective: Endoscopic diode laser cyclophotocoagulation with a limbal approach was reviewed retrospectively. The delivery system and procedure used as well as the role of this procedure in the management of glaucoma are discussed., Patients and Methods: An 810-nm pulsed continuous-wave diode laser capable of 1.2-W output was used. The maximum treatment area is 7 to 8 clock hours with a single limbal incision. Generally, 800 mW were used for less than 1 second, for a total of 0.8 J per treatment., Results: Eight eyes of 6 patients were treated. The mean follow-up time for each procedure was 3.2 months (range 1 to 8 months) and for each eye was 5.1 months (range 2 to 8 months). Pre- and postoperative intraocular pressures were determined. Postoperative inflammation was the most common complication., Conclusion: One reason for the failure of transscleral cyclophotocoagulation, particularly in congenital glaucoma, may be displacement of the ciliary processes. This displacement does not permit the indirect treatment to reach the appropriate area. Because endoscopic laser cyclophotocoagulation allows direct visualization, treatment can be accurately applied to individual ciliary processes.

Purpose: To determine whether microorganisms are able to survive in a solution of 50 mg/ml of 5-fluorouracil (5-FU) and, therefore, whether there is a risk of vial contamination with multiple use., Methods: Ten common nosocomial pathogens were tested. Minimal inhibitory concentrations (MICs) of 5-FU were determined for each organism. Organisms were then inoculated into 1 ml of 5-FU (50 mg/ml) and, after timed periods of exposure, were plated onto blood agar and incubated at 37 degrees C. Plates were checked daily for the presence or absence of growth., Results: The MICs of Klebsiella pneumoniae and Pseudomonas cepacia were within one log unit of the 10 mg/ml concentration of 5-FU used by some clinics. After incubation in 5-FU for 1 h, all species survived; after 24 h of exposure, five of the 10 species-Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, K. pneumoniae, and Proteus mirabilis-were still viable., Conclusion: 5-FU has limited bactericidal activity, and there is a risk of contamination if 5-FU vials are used in multiple dose fashion.

Background and Objective: This is a follow-up report on 103 THC:YAG (holmium) sclerostomies ab externo performed on 87 eyes of 81 patients., Patients and Methods: The patients received pulse energies of 0.06 to 0.13 J (mean total energy 4.4 +/- 3.3 J, range 0.6 to 17.1 J)., Results: The estimated success rates with or without medication, and allowing a second procedure, were 44% at 2 years and 36% at 4 years. The mean preoperative intraocular pressure (IOP) was 29.7 +/- 11.4 mm Hg, and the mean postoperative IOP in the successful patients was 13.6 +/- 4.6 mm Hg (P < .01). Hypotony and iris incarceration were the most frequent early complications., Conclusions: Although holmium laser sclerostomy is a relatively straightforward procedure and offers some advantages over standard trabeculectomy in select cases, it currently has a number of drawbacks that limit its use.

Purpose: To assess the prevalence of occludable angles in a Vietnamese population., Methods: The authors retrospectively reviewed the angle status in 482 Vietnamese patients who presented to a general ophthalmology practice. All angles were graded by a glaucoma specialist according to the Shaffer method. Patients were excluded if they had known glaucoma or narrow angles, or a history of trauma or intraocular surgery., Results: A total of 29.5% of all patients surveyed and 47.8% of those 55 years of age or older had grade 0 to 2 angles. In the Framingham study, 3.8% of white patients 55 years of age or older had grade 0 to 2 angles. Of the patients in our study population, 8.5% had grade 0 to 1 angles and were considered at high risk for occlusion., Conclusions: Vietnamese patients have a much higher prevalence of narrow angles and a greater risk of angle-closure glaucoma than white patients.

Purpose: To retrospectively assess the outcome of trabeculectomy surgery performed using intraoperative sponge 5-fluorouracil (5-FU) (50 mg/ml)., Methods: Trabeculectomy with intraoperative sponge 5-FU was performed on 140 eyes of 119 patients. The reduction in intraocular pressure (IOP), the number of supplementary postoperative injections, and any treatment complications were noted., Results: The mean preoperative IOP was 25.7 +/- 8.6 mmHg. The mean postoperative IOP was 12.5 +/- 5.7 mmHg with a mean IOP reduction of 52 percent (P < 0.0001). One hundred twenty-one (86.4 percent) eyes required no postoperative glaucoma medications, with the mean number of glaucoma medications dropping from 2.5 +/- 1.1 before operation to 0.3 +/- 0.8 after operation (P < 0.001). One hundred five eyes received a mean of 5.3 +/- 2.7 postoperative 5-FU injections. There was no significant difference in final IOP or success rate between low- and high-risk eyes, but high-risk eyes seemed to require supplementary postoperative 5-FU. Corneal epithelial damage arose in 52 (37 percent) eyes and correlated strongly with postoperative 5-FU supplementation., Conclusion: Intraoperative sponge 5-FU is a reasonably safe and effective adjunct to trabeculectomy surgery.

Reports of several large series of patients with superior oblique palsy (SOP) published in 1986 or before set forth important guidelines for both diagnosis and treatment of this condition. Newer information about the anatomy, physiology, and pathophysiology of the superior oblique has accrued over the past decade. This paper reviews our experience with diagnosis and treatment of SOP over the past 5 years in light of this new information. Charts of patients treated for SOP over 5 year (1990 to 1995) were reviewed for male or female sex, age, symptoms, refraction, vision, stereo acuity, head posture, facial asymmetry, intraoperative superior oblique traction test, diagnostic position prism and cover test, torsion, surgery performed, and results of treatment. The charts of 190 patients were reviewed. In 181, postoperative examinations were performed by us. The etiology of the SOP was congenital in 137 and acquired in 53. Twenty-nine acquired cases were due to trauma and 24 arose from other causes. Fifty-six patients had facial asymmetry, 51 of whom had congenital SOP. Ninety-five had a lax tendon, 83 (87%) of whom had congenital SOP. Sixty-six had a normal tendon, 29 (44%) of whom had acquired SOP. Seventy-seven percent of patients had Knapp class I, III, or IV palsy. An average of 1.26 surgeries was performed per patient. Inferior oblique weakening was performed in 177 (93%), while 68 vertical rectus recessions were done. Thirty-five patients had superior oblique tuck or resection, all on lax tendons, and 15 had Harada Ito procedures for torsion. Six patients had mild Brown syndrome postoperatively, none of which required a takedown. A cure, defined as relief of symptoms or elimination of strabismus and head tilt, was achieved in 166 of 181 (92%) of patients. Successful treatment of SOP can be accomplished in the majority of cases by selective surgery usually beginning with inferior oblique weakening plus additional vertical rectus and horizontal surgery as needed, with superior oblique strengthening used only for lax tendons or when torsion is the main problem.

Purpose: To determine the long-term efficacy of noncontact transscleral neodymium:YAG (Nd: YAG) cyclophotocoagulation., Methods: A retrospective analysis was made of 167 patients (173 eyes) with intractable glaucoma treated with noncontact Nd:YAG cyclophotocoagulation between December 1987 and November 1993, reviewing the treatment parameters, complications, and pre- and posttreatment intraocular pressure (IOP). The IOP was compared using a Student's t test, and the results were subjected to a Kaplan-Meier life-table analysis. Success was defined as an IOP of 22 mmHg or lower in the absence of phthisis and without having undergone any additional surgical procedures., Results: Mean follow-up was 30.5 +/- 22.8 months. Mean preoperative IOP was 40.0 +/- 12.9 mmHg. Mean postoperative IOP was 19.8 +/- 11.4 mmHg (P < 0.05). The mean number of treatment sessions was 1.8 +/- 1.3 (range, 1-8) with 95 eyes (55%) having only one treatment. Kaplan-Meier survival analysis showed a probability of continued success at 3 years of approximately 73% and at 5 years of 45%. Complications included loss of two or more lines of Snellen visual acuity or one or more categories in the low-vision range (40%), phthisis (6.9%), epithelial defects (1.9%), and hyphema (0.6%)., Conclusion: This study suggests that Nd:YAG transscleral cyclophotocoagulation provides a useful long-term reduction of IOP in eyes with advanced or complicated glaucoma, but there is a significant risk of visual loss associated with the procedure.

Two patients, one of them with myasthenia gravis, presented symptoms of continuous muscle fiber activity syndrome before discovery of a thymoma. Peripheral neuropathy was present in both patients, with axonal and demyelinating lesions in sural nerve biopsy. The syndrome remained unchanged or worse after thymectomy. Both patients died of associated complications.

Ten patients with amyotrophic lateral sclerosis were given intrathecal injections of natural interferon alpha, 1 million units weekly for 7 to 24 weeks. Six patients completed the trial. Four voluntarily withdrew after 7 to 13 injections. The slopes of deterioration for 40 quantitative tests of neuromuscular function for the control and treatment periods were compared by paired t test in the six patients who completed the trial and in the patient who withdrew after 13 injections. No significant differences were found. The patients tolerated treatment well. The CSF reaction was modest and spontaneously reversible. Indomethacin and ibuprofen blocked interferon side effects.

We conducted a double-blind controlled study of the effect of brain gangliosides in amyotrophic lateral sclerosis. Nineteen patients received intramuscular gangliosides (40 mg/d) for 6 months, and 21 received placebo. The deterioration rates for approximately 120 clinical and electrophysiologic parameters of neuromuscular function were analyzed, but no statistically significant beneficial effect of the drug was demonstrated. However, the large coefficient of variation for each item indicated that a sample size of several hundred patients would have been necessary to exclude the possibility that the drug produced a 25% slowing of progression of the disease.

A 13-year-old boy developed closely spaced episodes of recurrent febrile meningitis that persisted for 22 months despite antibiotic therapy. During exacerbations the cerebrospinal fluid contained up to 2,500 leukocytes per cubic millimeter, including up to 20% activated monocytoid cells, with high IgM and IgG levels. No cause for the disorder was found, but steroids improved the condition and colchicine therapy apparently cured it.

A patient with ankylosing spondylitis developed a neurological disorder suggesting multiple sclerosis. An increased level of gammaglobulin was detected in the analysis of the cerebro spinal fluid. The response to steroid therapy, however, was unusual to that of multiple sclerosis since clinical manifestations disappeared shortly after, recurred some months later after discontinuance of the treatment, and subside again when the administration of corticosteroids was repeated. On the other hand, the patient developed an acute right peroneal neuritis with slowness of the conduction velocity. Although the association of a clinical picture resembling multiple sclerosis with ankylosing spondylitis has been reported, there are a few, and sometimes poorly documented, published cases. The literature is reviewed and the possibility of a relationship between the isolated peripheral neuritis and the underlying disease is suggested.