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Objective: Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results: Fixed‐effects meta‐analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT‐O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta‐analysis results. Finally, several tail in‐frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. Interpretation: We showed that NEFH tail missense and in‐frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP). Methods: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients. Results: We included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p =.012) more frequent in LL‐spinal onset subgroup, tongue spasticity in bulbar‐onset subgroup (p =.021), and Hoffman sign in UL‐spinal onset subgroup (p =.024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p =.037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p <.001) and UL spasticity (44.1% vs. 0.0%, p <.001). Asymmetric distribution of UMN signs was present in PLS and not in HSP. Discussion: In PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS‐R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS‐R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS‐R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS‐R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS. [ABSTRACT FROM AUTHOR]

Introduction/Aims: In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre‐ and post‐synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS. Methods: We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos). Results: Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p =.036; H'Pre 1.0 vs. 5.0, p =.001; H'Pos 0.0 vs. 2.5, p =.031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition. Discussion: Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS. [ABSTRACT FROM AUTHOR]

Background and purpose: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. Methods: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised [ALSFRS‐R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t‐test, χ2, or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan–Meier analysis assessed survival. p < 0.05 was considered significant. Results: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS‐R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2mean (p = 0.014). Conclusions: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups. [ABSTRACT FROM AUTHOR]

Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease‐modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater. Methods: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey. Results: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non‐neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior—which impacts diagnostic delay—and their site of symptom onset. Limb‐onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy. Conclusion: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease‐modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non‐neurologists and unnecessary diagnostic workup. [ABSTRACT FROM AUTHOR]

Background and purpose: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R). The association of respiratory test alterations with respiratory symptoms is unclear. Methods: Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS‐R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO2mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. Results: We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS‐R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO2mean. Independent predictors for G2 were MIP and SpO2mean; for G3, the only independent predictor was PhrenAmpl. Conclusions: These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS‐R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3. [ABSTRACT FROM AUTHOR]

Background and purpose: Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate. Methods: In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS‐R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and C9orf72) and dynamic (ALSFRS‐R scores and sub‐scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables. Results: Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub‐score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub‐score has little influence in all groups. ALSFRS‐R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively. Conclusions: The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Age can affect hand muscles non‐uniformly. We investigated the influence of age on the compound muscle action potential (CMAP) amplitude of the hand muscles and the derived split‐hand index (SHI). Methods: We studied 244 subjects investigated for suspected myasthenia gravis but without neuromuscular disorders. Abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) CMAPs were obtained by supramaximal stimulation at the wrist, recording with surface electrodes while checking the best recording site. We applied Tukey's HSD and Kruskal–Wallis one‐way analysis of variance for comparing age groups defined by median and interquantile ranges (IQRs). Spearman's rank correlation coefficient and linear regression were used for testing age‐dependence of measurements. Results: Median age was 61.5 y (first IQR, 44.5; third IQR, 72.0; range 18–89). Age and neurophysiological measurements were similar between genders. APBCMAP, FDICMAP, ADMCMAP, and SHI were correlated with age (P <.001). Median and cutoff values were significantly different between age groups. APBCMAP, FDICMAP, and ADMCMAP decreased by 0.8/0.7/0.3 mV/y, respectively, and SHI decreased 0.15/y. Discussion: The CMAP amplitudes of hand muscles and derived SHI were strongly age‐dependent, although this effect was less in ADM. This represents a physiological phenomenon. Future studies using the SHI should consider age effects. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known whether MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response to reinnervation after motor unit loss. Methods: Fifty‐seven patients with ALS were assessed at 3‐month intervals for 12 months in four centers. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii, and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without increases. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential amplitude, and Medical Research Council strength score were investigated. Results: One hundred thirty‐three muscles were examined. Fifty‐nine percent of the muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (58% decline in MUNIX at 12 months, P <.001) than muscles that did not increase MUSIX (34.6% decline in MUNIX at 12 months, P <.001). However, longitudinal changes in muscle strength were similar. When motor unit loss was similar, the absence of a MUSIX increase was associated with a significantly greater loss of muscle strength (P =.002). Discussion MUSIX increases are associated with greater motor unit loss but relative preservation of muscle strength. Thus, MUSIX appears to be measuring a clinically relevant response that can provide a quantitative outcome measure of reinnervation in clinical trials. Furthermore, MUSIX suggests that reinnervation may play a major role in determining the progression of weakness. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Fasciculations can be symptomatic, yet not progress to amyotrophic lateral sclerosis (ALS), a condition categorized as benign fasciculation syndrome (BFS). We aimed to assess electrodiagnostic changes and clinical course over time in patients with BFS. Methods: This was a retrospective review of medical records of patients who were referred because of a suspicion of ALS or who had directly asked for a consultation because of a personal concern regarding ALS. All clinical and electromyography (EMG) investigations were performed by the same neurologist, following an established protocol. In addition, laboratory testing and imaging studies were performed as determined to be clinically necessary. Results: We included 37 subjects (mean age 46 ± 14.7 y, 29 male, 7 healthcare professionals). Most patients had experienced fasciculations in both upper and lower limb muscles (62.2%); the remaining patients had fasciculations only in their lower limbs. EMG in seven subjects showed chronic neurogenic potentials in addition to fasciculation potentials; all of these were older men. Follow‐up data were available in 24 patients (median 4.7 y), 21 with repeat EMGs, including all those with neurogenic EMG changes at baseline (median 6.5 y). Two‐thirds of patients reported symptomatic improvement: 57.1% of those with abnormal EMG and 61.1% with normal EMG. The EMG changes were stable. Discussion: Prognosis of BFS is favorable, regardless of minor EMG abnormalities. The latter do not necessarily imply progression to ALS. [ABSTRACT FROM AUTHOR]

Background and purpose: Short‐interval intracortical inhibition by threshold tracking (T‐SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A‐SICI). This study compared A‐SICI and T‐SICI for sensitivity and clinical usefulness as biomarkers for ALS. Methods: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow‐up. T‐SICI and A‐SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age‐matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. Results: Motor neuron disease patients had significantly reduced T‐SICI and A‐SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T‐SICI and A‐SICI respectively at 1–3.5 ms). Paradoxically, T‐SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10−6). Conclusions: Amplitude‐based measure of cortical inhibition and T‐SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T‐SICI most abnormal before UMN signs have developed. The gradation in T‐SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation. [ABSTRACT FROM AUTHOR]

Introduction: Immobility of the upper limbs has been associated with reduction of F-wave frequency. However, there are no similar studies on lower limb (LL) F-waves. We investigated the impact of LL rest on F-wave and H-reflex parameters.Methods: The LLs of 14 healthy participants were studied after 90 minutes rest. F-waves (frequency, latencies, chronodispersion, and mean amplitude) and H-reflexes (latency and recruitment curve) were investigated bilaterally. In seven participants the protocol was repeated, but the temperature of one limb was reduced.Results: Immobility only changed F-wave latencies, which increased significantly (mean value of 2 ms, P < .01). Limb cooling did not influence results.Discussion: Contrary to what occurred in cervical lower motor neurons (LMN), LL LMNs did not show a reduced F-wave response to immobility, but their latency increased significantly. This could have been due to reduced Renshaw inhibition of small LMNs, thus facilitating their response to antidromic stimulation and causing delayed late responses. [ABSTRACT FROM AUTHOR]

Introduction: Fasciculations are a marker for the diagnosis of amyotrophic lateral sclerosis (ALS) and reflect increased lower motor neuron (LMN) excitability.Methods: We investigated modulation of fasciculation frequency in the first dorsal interosseous (FDI) muscle of the right hand following peripheral sensory nerve electrical stimulation, and vibration over the muscle-tendon region (50 and 100 Hz), in patients with ALS, spinal muscular atrophy, and benign fasciculation syndrome. FDI muscles of ALS patients were classified by the presence or absence of neurogenic changes on needle electromyography.Results: Both sensory nerve electrical stimulation and vibration significantly increased the frequency of fasciculations in neurogenic FDI muscles of ALS patients, but not in the remaining groups.Discussion: Our results favour increased excitability of LMNs when affected by the disease process in ALS. We found that some fasciculations originating in these neurons in ALS are susceptible to modulation by sensory input. Muscle Nerve 59:688-693, 2019. [ABSTRACT FROM AUTHOR]

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide. HIGHLIGHTS: Optimal terminology in neuromuscular electrodiagnosis and ultrasound has been revisited. A team of international experts have revised and expanded a standardized glossary. This list of terms serves as standard reference for clinical practice, education and research. [ABSTRACT FROM AUTHOR]

However, we completely agree with Dr Gazulla et al.'s assumption that PLS, like ALS, is not a pure motor neurone disease but rather a multisystem neurodegenerative disease defined by a predominant motor system injury. Moreover, Bede's team has demonstrated the existence of cerebellar atrophy in sporadic ALS and in ALS linked to I C9orf72 i abnormal G4C2 expansion [5,6]. We read with great interest the letter of Drs Gazulla and collaborators, who suggested that the continuum between primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) is not straightforward [1]. [Extracted from the article]

Introduction: In this study we performed a longitudinal investigation to assess the impact of early introduction of assistive communication devices (ACDs) on quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients and their caregivers.Methods: Patients were followed for 7-10 months (3 evaluation periods). Bulbar-onset ALS patients (N = 27) and paired caregivers (N = 17) were included. Fifteen randomly selected patients received early support in ACD use. Patients were assessed using the ALS Functional Rating Scale-revised (ALSFRS-R), the McGill QoL (MQoL), the Communication Effectiveness Index (CETI), and performance in writing; and caregivers were assessed with the MQoL and World Health Organization Quality of Life questionnaire (WHOQOL-BREF).Results: Patients with early support had higher MQoL Psychological and MQoL Existential well-being domains; caregivers had higher MQoL Support domain and their MQoL Psychological domain positively associated with patient CETI. Most patients could communicate using a touchscreen keyboard to write, even when handwriting and speech were not possible.Conclusion: Early intervention with an ACD seems to have a positive impact on QoL and gives patients the opportunity to improve skills for communication in later disease stages. [ABSTRACT FROM AUTHOR]

Data mining has been widely applied in biomarker discovery resulting in significant findings of different clinical and biological biomarkers. With developments in technology, from genomics to proteomics analysis, a deluge of data has become available, as well as standardized data repositories. Nonetheless, researchers are still facing important challenges in analyzing the data, especially when considering the complexity of pathways involved in biological processes and diseases. Data from single sources appear unable to explain complex processes, such as those involved in brain-related disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, thus raising the need for a more comprehensive perspective. A possible solution relies on data and model integration, where several data types are combined to provide complementary views. This in turn can result in the discovery of previously unknown biomarkers by unraveling otherwise hidden relationships between data from different sources, and/or validate such composite biomarkers in more powerful predictive models. WIREs Syst Biol Med 2015, 7:357-379. doi: 10.1002/wsbm.1310 For further resources related to this article, please visit the . [ABSTRACT FROM AUTHOR]

Introduction: Some patients with amyotrophic lateral sclerosis (ALS) die suddenly despite normal nocturnal pulse oximetry (NPO), possibly due to dysautonomia. Methods: Forty-four ALS patients without other medical conditions were studied. Heart rate variability was assessed through finger oximetry. The heart rate coefficient of variation (HR CV) was evaluated during nocturnal sleep. All patients were investigated at study entry (T1); 13 were tested 4 months later (T2), and 21 patients were investigated a further 24 months after entry (T3). Only recordings obtained from patients with normal NPO were accepted. Results: HR maximal, minimum, and median values remained stable. HR CV was similar between T1 and T2, but it decreased significantly at T3 ( P < 0.01). Very low values were observed in 4 patients at T3 (HR CV <0.20), and 3 died suddenly within the following 2 months, despite normal NPO. Conclusions: Low HR CV is a potential marker of prognosis in ALS. Muscle Nerve 46: 341-345, 2012 [ABSTRACT FROM AUTHOR]

Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background. [ABSTRACT FROM AUTHOR]

By following a group of amyotrophic lateral sclerosis (ALS) patients longitudinally using lower motor neuron (LMN) and upper motor neuron (UMN) markers of dysfunction it may be possible to better understand the functional relationships between these motor systems in this disease. We used neurophysiological techniques to follow UMN and LMN dysfunction in a group of 28 patients with ALS, in comparison with the ALS functional rating scale (ALS-FRS) score and the forced vital capacity (FVC). We used motor unit number estimation (MUNE), compound muscle action potential (CMAP) amplitude, and the Neurophysiological Index (NI) to quantify the LMN disorder, and transcranial motor stimulation to study cortical motor threshold, motor-evoked response amplitude, central motor conduction time, and cortical silent period (CSP). The patients were studied shortly after diagnosis and then 6 months later, using both abductor digiti minimi muscles (ADM); ADM strength was initially >MRC 3 (Medical Research Council, UK). The NI and MUNE changed more than any other variable. CSP increased by about 30%, a change more marked than the slight increase observed in the cortical motor threshold (9%). The normal increase of CSP after acute muscle fatigue was preserved during disease progression. The CSP increase correlated with the MUNE rate of decay but not to the NI reduction, perhaps because NI includes F-wave frequency in itscalculation. There was no definite correlation between UMN and LMNdysfunction or progression, but there was a link between CSP and LMN changes in ALS. The CSP may be a useful variable in following UMN dysfunction in clinical practice and in clinical trials. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

In 38 amyotrophic lateral sclerosis (ALS) patients and 28 controls, we performed motor unit potential (MUP) analysis in the C-6 and T-5 paraspinal and biceps muscles. In ALS cases, we found similar abnormalities in MUPs in paraspinal and limb muscles. Fasciculation potentials (FPs) were more frequent in biceps than in paraspinal muscles, but fibrillation potentials and positive sharp waves (fibs-sw) were equally frequent in all three muscles. These results confirm the value of paraspinal MUP analysis in the diagnosis of ALS. © 2009 Wiley Periodicals, Inc. Muscle Nerve 39: 83-86, 2009 [ABSTRACT FROM AUTHOR]

The sternocleidomastoid muscle (SCM) is an accessory inspiratory muscle, but it is not investigated systematically in patients with amyotrophic lateral sclerosis (ALS). We aimed to study the involvement of the SCM and to evaluate the role of the diaphragm and SCM on respiratory tests performed in ALS patients. We studied 45 patients (mean age ± SD: 60.6 ± 13 years). In all patients we evaluated: neck flexion strength; forced vital capacity (FVC); maximal inspiratory pressure (PImax); sniff nasal inspiratory pressure (SNIP); ALS functional scale (ALS-FRS-R); SCM and diaphragm compound muscle action potential (CMAP) amplitudes (SCM Ampl and Diaphr Ampl) and latencies (SCM Lat and Diaphr Lat). In ALS patients, SCM Lat is increased and SCM Ampl is smaller in patients with neck weakness. The subgroup of patients with neck weakness had more abnormal respiratory function tests and lower clinical scores. There is a significant correlation between SCM Amp and Diaphr Ampl, FVC, PImax, and SNIP. Hence, there is a parallel loss of motor units in the SCM and diaphragm. On multiple regression analysis both PImax and SNIP are dependent on SCM Ampl and Diaphr Ampl, but FVC is not. PImax and SNIP determination mostly depend on SCM and diaphragm function, but the FVC is also dependent on expiratory muscle function. We conclude that neck weakness is a clinical sign that indicates a poor prognosis, and the SCM CMAP can contribute to respiratory function evaluation in ALS patients. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

See article on pages 598–603 in this issue. [ABSTRACT FROM AUTHOR]

Introduction: Chorea-acanthocytosis (ChAc) is a rare autosomal recessive disease characterized by involuntary movements, seizures, cognitive changes, myopathy, and axonal neuropathy. Methods: We report a patient who presented with gait impairment and dysarthria. Clinical and neurophysiological assessment disclosed upper and lower motor neuron signs suggestive of motor neuron disease (MND). Results: Later observation of involuntary movements prompted further investigation. Acanthocytes were identified, and the patient's chorein level was low. Genetic studies identified a novel double heterozygous mutation of the chorein gene involving an exon-stop mutation associated with another mutation that can affect the normal splicing of the RNA. Conclusions: We speculate that this genetic mutation could cause the atypical presentation. ChAc should be included in the differential diagnosis of atypical MND. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

To test for interside differences and ipsilateral correlation of compound muscle action potentials (CMAP) from muscles of the cervical region according to El Escorial criteria, we stimulated the phrenic, axillary, and ulnar nerves bilaterally in 67 patients with amyotrophic lateral sclerosis. The diaphragm CMAP was symmetric, but it did not correlate with deltoid or abductor digiti minimi (ADM) CMAPs. The deltoid CMAP in all groups and ADM CMAP in bulbar- and lower-limb-onset patients showed significant interside correlation. The ADM CMAP is asymmetric in upper-limb-onset patients. Unilateral stimulation is sufficient to monitor the phrenic nerve response; its degree of CMAP decrease does not correlate with other cervical muscle involvement. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

We compared early- with late-onset cases in 86 patients with familial amyloidotic polyneuropathy type I (FAP). Among these patients, 43 presented before age 50 (early-onset) and 43 after this age (late-onset). Sex and geographical distribution were similar, although a family history of the disorder was more frequent in early-onset cases. In late-onset disease, autonomic dysfunction was less frequent, but organ involvement and severe neuropathic pain were more frequent. Neurophysiological measurements were similar. FAP is a cause of neuropathy in elderly patients, in particular in those presenting with neuropathic pain. Muscle Nerve, 2006 [ABSTRACT FROM AUTHOR]

A correction to the article "Integrative biomarker discovery in neurodegenerative diseases" published in the previous issue of the journal is presented.

A letter to the editor discussing about steroid-responsive demyelinating motor neuropathy with conduction block associated with hepatitis C infection and treatment with interferon alpha is presented.