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Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups. The authors proposed ClusTric, a temporal stratification approach to find disease progression groups. Applied to Amyotrophic Lateral Sclerosis, the method identifies four progression groups with distinguished characteristics. [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]

Motor Neuron Diseases (MND) have a large clinical spectrum, being the most common amyotrophic lateral sclerosis (ALS) but there is significant clinical heterogeneity. Our goal was to investigate this heterogeneity and any potential changes during a long period. We performed a retrospective cohort study among a large Portuguese cohort of MND patients (n = 1550) and investigated changing patterns in clinical and demographic characteristics over the 27-year period of our database. With that aim, patients were divided into three 9-year groups according to the date of their first visit to our unit: P1, 1994–2002; P2, 2003–2011; P3, 2012–2020. The overall cohort's clinical and demographic characteristics are consistent with clinical experience, but our findings point to gradual changes over time. Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, the proportin of patients using respiratory support with noninvasive ventilation (NIV), time to NIV, and survival. Across time, in the overall cohort, we found an increasing age at onset (p = 0.029), a decrease of two months in diagnostic delay (p < 0.001) and a higher relative frequency of progressive muscular atrophy patients. For ALS patients with spinal onset, from P1 to P2, there was a more widespread (54.8% vs 69.4%, p = 0.005) and earlier (36.9 vs 27.2 months, p = 0.05) use of NIV and a noteworthy 13-month increase in median survival (p = 0.041). Our results probably reflect better comprehensive care, and they are relevant for future studies exploring the impact of new treatments on ALS patients. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and myopathy have been already described as part of a common genetic syndrome called multisystem proteinopathy. They may occur together or not, and can be associated with other clinical features such as frontotemporal dementia and Paget's bone disease. In addition, primary skeletal muscle involvement has been also reported in inherited forms of lower motor neuron disease, in spinal–bulbar muscular atrophy and in spinal muscular atrophy. We aim to characterize three sporadic, spinal-onset ALS patients, one with a concurrent non-specific myopathy, and two with a previous diagnosis of myopathy before upper and lower motor neuron signs emerged. Perhaps our sporadic ALS cases associated with myopathy share a common, but still unknown, pathogenic background. These cases raise the paradigm of a possible interplay between skeletal muscle degeneration and motor neuron damage. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 2--5 years. An early diagnosis is essential for providing ALS patients the finest management possible. Studies from different countries report a similar median diagnostic delay of around 12 months, which is still far from desirable. We analyzed the diagnostic pathway in different countries in order to identify the major challenges. Methods: We studied a cohort of 1,405 ALS patients fromfive different centers, in four different countries (Turkey, Germany, Poland, and Portugal), which collaborated in a common database. Demographic, disease and sociocultural factors were collected. Time from first symptom onset to first medical evaluation and to diagnosis, the specialist assessment and investigations requested were analyzed. Factors contributing to diagnostic delay were evaluated by multivariate linear regression. Results: Themedian diagnostic delay fromfirst symptomonset was 11months and was similar between centers. Major differences were seen in the time from symptom onset to first medical evaluation. An earlier first medical evaluation was associated with a longer time to diagnosis, highlighting that ALS diagnosis is not straightforward in the early stages of the disease. The odds for ALS diagnosis were superior when evaluated by a neurologist and increased over time. Electromyography was decisive in establishing the diagnosis. Conclusions: We suggest that a specific diagnostic test for ALS-- a specific biomarker--will be needed to achieve early diagnosis. Early referral to a neurologist and to electromyography is important for early ALS diagnosis. [ABSTRACT FROM AUTHOR]

We describe three unrelated patients with sporadic motor neuron disease (MND) and hereditary amyloid transthyretin (ATTRv) amyloidosis family history, who were asymptomatic carriers of the pVal50Met mutation of transthyretin (TTR) gene. Patients 1 and 2 were a 43-year-old man with a spinal-onset of ALS and a 37-year-old woman with a bulbar-onset of ALS, who died due to respiratory complications five and two years after disease onset, respectively. Patient 3 is a 52-year-old woman, with a two-year history of a probable primary lateral sclerosis, and a frontotemporal dysfunction. Imaging, cerebrospinal fluid (CSF) and nerve conduction and small fiber tests were normal in all. Genetic testing for ALS was negative in the two patients tested. Previous studies in MND patients have identified reduced TTR levels in CSF and neuronal gene overexpression, suggesting a neuroprotective role of TTR. The association of MND in patients with TTR gene mutations has not yet been described. [ABSTRACT FROM AUTHOR]

Objective: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset. Methods: 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival. Results: Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4–18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of C9orf72 hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients. Conclusions: MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction. [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]

VRK1 encodes a serine/protein kinase possibly involved in pathways related to amyotrophic lateral sclerosis (ALS) pathogenesis. Pathogenic variants in VRK1 have been related to different phenotypes. We describe the clinical phenotype of two unrelated Portuguese patients with different VRK1 variants. Both patients presented a bilateral distal weakness in lower limbs beginning in childhood slowly progressing to upper limbs, associated with pyramidal signs, without bulbar, respiratory or cognitive involvement, according to probable ALS. Imaging and nerve conduction studies were unremarkable in both patients. Genetic testing in patient 1 identified two VRK1 variants in heterozygosity: c.265C > T, p.(Arg89*) and c.769G > A, p.(Gly257Ser), classified as pathogenic and variant of uncertain significance, respectively. In patient 2, two probably pathogenic variants in VRK1 were identified in heterozygosity: c.710-14T > C in intron 8 and c.721C > T, p.(Arg241Cys) in exon 9. We report two unrelated patients with different variants in VRK1 displaying a similar childhood-onset motor neuron disease/ALS, further expanding the phenotypic spectrum associated to VRK1 variants. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence and incidence of amyotrophic lateral sclerosis (ALS) is not fully established, and this varies depending on the studied population. Objective: To estimate the prevalence/incidence of ALS patients in Antioquia-Colombia. Methodology: Observational/descriptive study by reviewing clinical records from 2010 to 2014. Cases with possible, probable and definite ALS were included. To estimate the prevalence/incidence, capture-recapture method was used. Results: Point prevalence in December 2014 was 4.9/100,000 (95% CI 2.0–7.8), and the incidence was 1.4/100,000/year (95% CI 0.5–2.2). The median survival was 4 years. Spinal-onset was observed in 62.4% of the included patients. Conclusion: Prevalence, incidence and clinical presentation of ALS in Antioquia are similar to most studies reported worldwide. However, prevalence in Antioquia seems to be slightly higher than in other studies from Latin -American countries. This may derive from the inclusion criteria and case detection methodology adopted, but sociodemographic and genetic factors should be considered. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a fast-progressing disease with no cure. Nowadays, needle electromyography (nEMG) is the standard practice for electrodiagnosis of ALS. Surface electromyography (sEMG) is emerging as a more practical and less painful alternative to nEMG but still has analytical and technical challenges. The objective of this work was to study the feasibility of using a set of morphological features extracted from sEMG to support a machine learning pipeline for ALS diagnosis. We developed a novel feature set to characterize sEMG based on quantitative measurements to surface representation of Motor Unit Action Potentials. We conducted several experiments to study the relevance of the proposed feature set either individually or combined with conventional feature sets from temporal, statistical, spectral, and fractal domains. We validated the proposed machine learning pipeline on a dataset with sEMG upper limb muscle data from 17 ALS patients and 24 control subjects. The results support the utility of the proposed feature set, achieving an F 1 score of (81.9 ± 5.7) for the onset classification approach and (83.6 ± 6.9) for the subject classification approach, solely relying on features extracted from the proposed feature set in the right first dorsal interosseous muscle. We concluded that introducing the proposed feature set is relevant for automated ALS diagnosis since it increased the classifier performance during our experiments. The proposed feature set might also help design more interpretable classifiers as the features give additional information related to the nature of the disease, being inspired by the clinical interpretation of sEMG. • We proposed a set of novel features for sEMG based on signal morphology. • A validation study with sEMG with 17 ALS patients and 24 control subjects. • A practical data collection setup with promising results for ALS diagnosis. • Features based on sEMG morphology might improve the classifiers' interpretability. • The features might have potential as novel biomarkers of ALS disease progression. [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]

In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN’s, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Background: Motor Unit Number Index (MUNIX) is a neurophysiological measure that provides an index of the number of lower motor neurons in a muscle. Its performance across centres in healthy subjects and patients with Amyotrophic Lateral Sclerosis (ALS) has been established, but inter-rater variability between multiple raters in one single subject has not been investigated. Objective: To assess reliability in a set of 6 muscles in a single subject among 12 examiners (6 experienced with MUNIX, 6 less experienced) and to determine variables associated with variability of measurements. Methods: Twelve raters applied MUNIX in six different muscles (abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibialis anterior (TA), extensor dig. brevis (EDB), abductor hallucis (AH)) twice in one single volunteer on consecutive days. All raters visited at least one training course prior to measurements. Intra- and inter-rater variability as determined by the coefficient of variation (COV) between different raters and their levels of experience with MUNIX were compared. Results: Mean intra-rater COV of MUNIX was 14.0% (±6.4) ranging from 5.8 (APB) to 30.3% (EDB). Mean inter-rater COV was 18.1 (±5.4) ranging from 8.0 (BB) to 31.7 (AH). No significant differences of variability between experienced and less experienced raters were detected. Conclusion: We provide evidence that quality control for neurophysiological methods can be performed with similar standards as in laboratory medicine. Intra- and inter-rater variability of MUNIX is muscle-dependent and mainly below 20%. Experienced neurophysiologists can easily adopt MUNIX and adequate teaching ensures reliable utilization of this method. [ABSTRACT FROM AUTHOR]

Background Surgery is not a recognised potential amyotrophic lateral sclerosis (ALS) risk factor that might modify the onset or course of ALS. Methods We studied our database of ALS patients, which includes questions concerning surgical procedures. We defined surgery as an operative procedure requiring general or regional anaesthesia, but not local anaesthesia. Patients were classified as G1--no surgery; G2--surgery performed =3 months before disease onset; G3--surgery <3 months before disease onset; and G4--surgery after disease onset. The ALS-FRS score was evaluated every 3 months from presentation. The maximal ALS-FRS score was ascribed to disease onset, itself defined as symptom onset. Results 657 patients with ALS were studied. In G3 there was a positive correlation between onset-region and surgery-region (p=0.032). In G4, 35 (57.6%) patients had surgery, probably due to initial misdiagnosis. The rate of functional change (%) in G4 was significantly greater in the 3-month period immediately after surgery as compared with the 3-month period before (1.46%±1.35 vs 6.30%±8.10, p=0.005) and the following 3 months (3.30%±3.10, p=0.006). Conclusions The site of surgery before ALS onset correlates with the region of onset of ALS. Patients with slower disease progression are at an increased risk of undergoing surgery, probably as part of initial difficulty in diagnosis. We noted accelerated disease progression during the 3-month period after surgery. Definite diagnosis is important to avoid unnecessary surgical trauma and subsequent more rapid deterioration. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Motor unit recruitment order and firing rate was investigated in healthy subjects, and in small numbers of patients 50years ago. We aimed to investigate firing rate in different disorders, testing the same target muscle with normal strength, to evaluate possible application in diagnosing upper motor neuron (UMN) lesion. Methods: We studied motor unit firing in the tibialis anterior muscle in six groups of subjects; normal subjects (n =45), patients with amyotrophic lateral sclerosis (ALS) (n =36), primary lateral sclerosis (PLS) (n =21), progressive muscular atrophy (PMA) (n =14), various upper motor neurone lesions (n =16) and polyneuropathy (n =42). In all these subjects the tibialis anterior muscle was of normal strength. Motor units were recruited during slight contraction in order to study 2–5 motor units at each recording site, using a standard concentric needle electrode, so that 20–22 motor units were recorded in each muscle. We analysed the coefficient of variation (CV) for amplitude, area, duration and firing rate in these motor units, and the correlation between motor unit potential size and recruitment order. Results: The mean MU firing rate in this task was similar in each group. No recruitment order was disclosed within the limits of the study task. The CV of firing rate was decreased in UMN and PLS groups. ALS patients with marked spasticity showed a lower CV of motor unit firing rate. The CV of amplitude, area and duration was similar between groups. Conclusions: These results in tibialis anterior indicate that physiological modulation of lower motor neuron (LMN) firing rate is decreased in patients with lower limb spasticity. The variability of MU discharges tends to be greater in diseases affecting the LMN. Significance: These results suggest that, notwithstanding the simplicity of the task we have used, the physiological variability of motor unit firing may be a useful variable in assessing UMN involvement in motor system disorders. [Copyright &y& Elsevier]

Abstract: Flail-leg syndrome or lower limb diplegia is a form of motor neuron disease characterized by a slower progression rate. The differential diagnosis with motor neuropathy is important. We present two patients with a previous diagnosis of amyotrophic lateral sclerosis (ALS)–flail-leg syndrome, in whom neurophysiological studies suggested proximal conduction block. Both patients responded to immunomodulatory therapy, which suggested an immunologically mediated, treatable flail-leg syndrome phenotype. We stress the importance of fasciculations in the diagnosis of ALS, and the study of nerve root conduction in the differential diagnosis. [Copyright &y& Elsevier]

Our objective was to analyse how patients with amyotrophic lateral sclerosis (ALS) are examined neurophysiologically at different European centres in order to identify possible areas with variation or disagreement in the neurophysiological examination of ALS. Ninety-three prospectively collected examinations from six out of seven neurophysiologists in the European ESTEEM project were analysed. All examinations were peer reviewed with an electromyographic consensus diagnosis of motor neuron disease and the diagnosis of ALS confirmed by clinical follow-up. The examinations were analysed for differences among the physicians in EMG techniques and number and distribution of examined and abnormal muscles and nerve segments. Considerable variation was found among the physicians regarding the average numbers of performed and abnormal EMG and nerve conduction studies per patient, the EMG techniques used, and the topographical distribution of the examined muscles. The existence of two different examination approaches, one with quantitative EMG analyses and relatively few muscles studied, and one with more muscles studied using qualitative methods was clearly confirmed in the present study. The large variation among the physicians indicates that different criteria were used, or that criteria were used inconsistently. [ABSTRACT FROM AUTHOR]

Abstract: A consensus meeting was held to determine the best use and interpretation of electrophysiological data in the diagnosis of ALS. The utility of needle EMG and nerve conduction studies was affirmed. It is recommended that electrophysiological evidence for chronic neurogenic change should be taken as equivalent to clinical information in the recognition of involvement of individual muscles in a limb. In addition, in the context of a suspected clinical diagnosis of ALS, fasciculation potentials should be taken as equivalent to fibrillation potentials and positive sharp waves in recognising denervation. The importance of searching for instability in fasciculation potentials and in motor unit potentials in ALS is stressed. These changes in the interpretation of electrophysiological data render obsolete the category Probable Laboratory-Supported ALS in the modified El Escorial diagnostic criteria for ALS. Methods for detection of upper motor neuron abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor neuron lesion are uncertain. [Copyright &y& Elsevier]

Progressive muscular atrophy (PMA) is a form of motor neuron disease, but its outcome is not well defined, and the aim was to study the pattern of clinical progression in PMA. We studied 10 patients prospectively for 12 months. None showed clinical signs of upper motor neuron involvement at presentation or during follow-up, and all had normal transcranial magnetic stimulation studies. Four had upper limb onset, four lower limb onset and two axial onset. We used neurophysiological and strength measurements and a clinical rating scale (ALS-FRS). Seven other patients presenting with a PMA syndrome developed upper motor neuron signs during a one-year period of observation and were excluded from the study. The rate of progression was variable. At six months, only motor unit number estimation (MUNE) and ALS-FRS had decreased significantly. The Neurophysiological Index (NI) and M-wave amplitude measurements decreased at 12 months. Two patients with axial-onset disease progressed rapidly to respiratory failure. Overall the pattern of change resembled that of ALS, although some patients progressed very slowly. Axial onset, however, predicts the early onset of respiratory failure, and a poor prognosis. [ABSTRACT FROM AUTHOR]

Primary lateral sclerosis (PLS) is a very rare disease characterized by pure upper motor neuron findings. Although a number of previous reports have evaluated this condition, no study has addressed the respiratory function in PLS. Six patients meeting previously proposed diagnostic criteria for PLS were submitted to a number of respiratory tests: forced vital capacity, maximal pressures, phrenic nerve responses, needle electromyography of the respiratory muscles, percutaneous nocturnal oximetry (PNO) and polysomnography (two patients). Our results show that the diaphragm is not affected in this condition, but some respiratory function tests (RFT) and PNO had abnormal values. Voluntary muscular activation to perform RFT may be limited in these patients. PNO and polysomnography suggest that respiratory central drive dysfunction can occur when upper motor neurons are severely affected, in PLS. Howeve`r, we did not verify progression on follow-up. [ABSTRACT FROM AUTHOR]

INTRODUCTION: It is suggested that early in ALS the corticomotor threshold (CMT) is low, but increases with increasing duration of the disease. POPULATION AND METHODS: We compared CMT, central conduction time and motor-evoked response/M-wave amplitude in two populations of ALS patients: one with disease duration shorter than 6 months (Group A, 11 patients) and another who had had the disease for more than 24 months (Group B, 14 patients). These two groups were compared with a control group of 30 subjects. In all the ALS patients, abductor digiti minimi (ADM) strength was greater than MRC 3. RESULTS: M-wave amplitude was comparable in the three groups. We found no difference between the three groups in these transcranial magnetic stimulation studies and there was no correlation between disease duration time and CMT. CONCLUSION: We did not confirm a relation between CMT and disease duration. An increased CMT late in the disease progression is associated with greater lower motor neuron loss, and greater corticospinal tract degeneration with dispersion of the descending motor volley. [ABSTRACT FROM AUTHOR]

Different forms of motor neuron disease occurring in association with HIV infection have been described. We present two patients with pseudobulbar syndrome and HIV infection, with no clinical or electromyographic signs of lower motor neuron loss. In patient 1, on follow-up, focal seizures led to additional investigations that identified unsuspected HIV infection and progressive multifocal leucoencephalopathy (PML). In patient 2, all investigations excluded an active HIV infection or central nervous system involvement, and the disease progression made primary lateral sclerosis (PLS) with pseudobulbar onset the most likely diagnosis. ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patient 1 shows that PML is a possible cause for pseudobulbar syndrome, and our second patient demonstrates that ALS may also occur by chance in patients with HIV infection. [ABSTRACT FROM AUTHOR]

• Non-invasive brain and spinal stimulation techniques have been investigated as a potential treatment in motoneuron disease. • Stimulation methods aim at counteracting glutamate-mediated excitotoxicity leading to motoneuron degeneration. • Targeted, individualized and home-deliverable treatments are critical challenges for future advancements. Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives. [ABSTRACT FROM AUTHOR]

• Onset latency of cutaneous silent period (CSP) is delayed in patients with motor neuron disease. • Patients with progressive muscular atrophy (PMA) have delayed onset latency of the CSP. • Delayed onset latency can be shortened by transcallosal ipsilateral corticospinal tract activation in PMA. To investigate the cutaneous silent period (CSP) by measuring its onset latency, duration and amount signal suppression in patients with motor neuron disease (MND) grouped according to the intensity of upper motor neuron involvement (UMN), and to test the effect of contralateral hand contraction. Painful stimulation was applied at the V finger, and contraction recorded from the abductor digiti minimi (ADM) muscle (baseline condition). Afterwards, CSP was studied during strong contralateral ADM contraction (test condition). 10–15 consecutive traces were recorded for each condition, signals were rectified, averaged, and analyzed offline. 46 patients were investigated, 15 with progressive muscular atrophy (PMA), 16 with typical amyotrophic lateral sclerosis (ALS), 15 with primary lateral sclerosis/predominant UMN-ALS (PLS+UMN-ALS), and 28 controls. In the baseline condition, all MND groups showed delayed onset latencies (p = 0.001). There was no significant difference in the CSP duration. Suppression was lower in the PLS + UMN-ALS group (p = 0.004). In the control group, contralateral contraction did not change CSP, but onset latency shortened significantly in the PMA group. CSP onset latency is delayed in all investigated groups of MND, including in PMA, indicating subclinical UMN involvement. Changes in CSP can indicate UMN lesion in MND. CSP should be explored to identify UMN involvement in MND. [ABSTRACT FROM AUTHOR]

The article focuses on the ethical issues governing the provision of non-invasive methods of ventilatory assistance for amyotrophic lateral sclerosis (ALS). Invasive ventilation in ALS improves the quality of life of ventilated patients, while having a negative impact on the quality of life of their caregivers. The author recommends the application of invasive ventilation in the management of ALS in developed countries.

Progressive muscular atrophy (PMA) refers to motor neuron disease presenting with weakness and wasting of muscles of the limbs and trunk without evidence of upper motor neuron lesion. The onset and progression are typically slow. This article focuses on a patient with PMA who had an abrupt presentation after heavy cocaine consumption and physical exercise. This patient had an abrupt onset of motor neuron loss, characterized by unusual electrical spontaneous activity on electromyography, following cocaine abuse and strenuous physical exertion.

A letter to the editor is presented about the frequency rates of dropped head syndrome (DHS) in patients with amyotrophic lateral sclerosis.

Abstract: Objective: To evaluate sensory nerve conduction studies in ALS in a prospective multicentre study involving 7 neurophysiologists from 6 European countries. Methods: Bilateral sural potentials were obtained in 35 ALS patients and 35 age-matched controls according to a standardised examination protocol using antidromic surface technique. The recordings from the right sural nerve of the controls were used for reference values. A reduction from the mean of controls greater than 2 SDs was considered abnormal. Results: Reduced sensory nerve action potential (SNAP) amplitude or reduced conduction velocity (CV), or both, was found in 6 ALS patients (17%). Decrease in CV was the most frequent finding, and was observed in 8 nerves from 5 patients. Reduced SNAP amplitude was found in 2 nerves from 2 patients. All changes were minor ranging from −2.1 to −3.2 SDs. Conclusions: This is the first standardised multicentre study on sensory potentials in ALS. It confirms that although normal sensory findings should be expected in the majority of ALS patients, minor abnormalities are not uncommon. Significance: Mild sensory abnormalities do not necessarily exclude a diagnosis of ALS. [Copyright &y& Elsevier]