Limb-onset Amyotrophic Lateral Sclerosis Research Articles

102P Clinical profiles bulbar and limb onset amyotrophic lateral sclerosis patients: a retrospective cohort study

102P Clinical profiles bulbar and limb onset amyotrophic lateral sclerosis patients: a retrospective cohort study

Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei

Objective: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs). Methods: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson’s correlation, with p < 0.05 considered significant. Cohen’s d was reported to compare the standardized mean difference (SMD) of QSM. Results: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = −0.845), right CN (SMD = −0.851), whole CN (SMD = −1.016), and left subthalamic nucleus (STN) (SMD = −1.000). Susceptibility in the left putamen (SMD = −0.857), left thalamus (SMD = −1.081), and whole thalamus (SMD = −0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration. Conclusions: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.

Analysis of the characteristics of patients with amyotrophic lateral sclerosis with neuromuscular junction dysfunction prior to motor neuron degeneration

Objective: To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS. Methods: The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects. Results: At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] (P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m2] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) (P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions: Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.

The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis: a retrospective observational study.

JOURNAL/nrgr/04.03/01300535-202505000-00032/figure1/v/2024-07-28T173839Z/r/image-tiff Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons. Early bilateral limb involvement significantly affects patients' daily lives and may lead them to be confined to bed. However, the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear. To address this issue, we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022. A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis. We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients. Multiple factor analyses revealed that higher upper motor neuron scores (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.09, P = 0.018), onset in the left limb (HR = 0.72, 95% CI = 0.58-0.89, P = 0.002), and a horizontal pattern of progression (HR = 0.46, 95% CI = 0.37-0.58, P < 0.001) were risk factors for a shorter interval until bilateral limb involvement. The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients. These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.

Veterans with familial ALS and bulbar and respiratory presentations at onset had shorter survival.

We sought to characterize the clinical prognostic factors in veterans with amyotrophic lateral sclerosis (ALS) followed in our ALS clinic. ALS is a rare, progressive neurodegenerative condition associated with decreased survival compared to that in the normal population. The electronic medical records of 105 veterans diagnosed with ALS who are followed in our ALS clinic between 2010 and 2021 were reviewed. Approval from the institutional review board was obtained from the study protocol. Demographic and clinical variables included age at symptom onset, age at initial evaluation, survival (from symptom onset to death), gender, site of onset (appendicular, bulbar, and respiratory), initial amyotrophic lateral sclerosis functional-related score-revised (ALSFRS-R), total functional independence measure (TFIM) scores, initial forced vital capacity (FVC), and interventions (Riluzole, gastrostomy, noninvasive ventilation [NIV], and tracheostomy). Normally distributed data was expressed as mean ± standard deviation. Fischer's exact analysis of the distribution differences of categorical data. The Kaplan-Meier plot analyzed the time-to-event. The mean (SD) age at symptom onset was 62.0 (11.1) years, age at diagnosis was 65 (11) years, with 72% of the patients being over 60 years at diagnosis. The median survival time from symptom onset was 4.12 (3) years. Limb-onset ALS (appendicular) was the most frequent (52%) followed by bulbar-onset ALS (43%). The mean ALSFRS-R and TFIM scores were 31 (8) and 91 (25), respectively. Family history (familial), bulbar, and respiratory presentation at diagnosis were associated with shorter survival times. This study suggests that of the clinical prognostic factors veterans with familial ALS, bulbar, and respiratory onset at presentations had shorter survival. The presence of Agent Orange, PEG placement, and NIV did not affect survival.

Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?

Currently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS). This study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb-onset ALS. Consecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups. Among 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. ThefrequencyofHSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74%vs. 50%) in patients with upper limb-onset (UL-ALS), compared to patients with lower limb-onset (LL-ALS; p < .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL-ALS, compared to UL-ALS (p < .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS-r sub-score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS-r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP. Our findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease.

Amyotrofik lateral skleroz erken tanısında sinir iletim çalışmaları ve ayrık el bulgusunun önemi

Aim: The heterogeneity of the Amyotrophic Lateral Sclerosis (ALS) clinical phenotypes leads to difficulties in early diagnosis. The ‘split hand’ sign is defined as the thenar muscles that are more prominently affected by hypothenar. In this study, the results of the initial nerve conduction study of the patients were compared with those of the controls in order to increase the findings supporting early diagnosis.&#x0D; Material and Method: Seventy-five patients who were diagnosed with ALS in our clinic were included in the study. The initial ENMG findings of the patients were compared with those of 70 healthy controls: Distal motor latency (DML), the compound muscle action potential (CMAP) amplitude, velocity in the motor conduction of median, ulnar, peroneal and tibial nerves; distal latency, amplitude, velocity in sensorial conduction were evaluated. Ulnar/median DML and ulnar/median CMAP amplitude ratios were examined.&#x0D; Results: In ALS group, DMLs of the median, ulnar, peroneal, and tibial nerves were significantly longer, and CMAP amplitudes were significantly smaller than those of the controls. The sensory conductions of the median, ulnar, and sural nerves were not statistically different between the groups. The ulnar/median DML ratio of the patients was lower than the ratio of controls (0.73/0.80;p=0.003); while the ulnar/median CMAP amplitude ratio was greater (1.40/1.11; p=0.002).&#x0D; Conclusion: Prolonged DML and reduced amplitudes were observed in the motor nerve conduction of ALS patients in the early period. The results of the present study also support the presence of split-hand phenomenon even in early period of limb-onset ALS (both upper and lower). These findings suggest that nerve conduction studies and electrophysiologically detected split-hand sign are important clues for the early diagnosis of ALS in case of heterogeneous clinical phenotype.

Network diffusion model predicts neurodegeneration in limb-onset Amyotrophic Lateral Sclerosis.

ObjectiveEmerging evidences suggest that the trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS.MethodsWe measured degeneration in limb-onset ALS patients (n = 14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n = 12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. In order to investigate whether network spread on the brain connectome derived from healthy individuals were significant findings, we compared our findings against network spread simulated on random networks.ResultsThe cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Network spread simulated on the random networks showed that the findings using healthy brain connectomes are significantly different from null models.InterpretationOur findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.

Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype.

BackgroundFlail leg syndrome (FLS) is a regional variant of amyotrophic lateral sclerosis (ALS) with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. However, FLS may not be easily differentiated from typical ALS.ObjectiveThe objective of the study was to determine a cutoff time of disease progression that could differentiate FLS from the typical lower limb onset ALS.MethodsA cutoff point analysis was performed with maximally selected log–rank statistics in patients with lower limb onset ALS registered from 2009 to 2013. Based on the cutoff duration from the lower limb onset to second region significantly involved (SRSI), all patients were divided into the slowly progressive subtype of lower limb onset ALS group and the typical lower limb-onset ALS group. Patients with the slowly progressive subtype of the lower limb onset ALS, who had the flail leg phenotype, were classified as patients with FLS. Differences between groups were analyzed.ResultsAmong the 196 patients recruited, 157 patients with a duration <14 months from lower limb onset to SRSI were classified as having typical lower limb onset ALS. Twenty-nine patients with a duration more than or equal to 14 months and the flail leg phenotype were classified as having FLS. Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to SRSI, a forced vital capacity abnormity rate of 12.5% at the first visit to our department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset ALS (p < 0.001, p < 0.001, p = 0.024, p < 0.001). The 5-year survival rate of the FLS group (79.3%) was much higher than that of the other group (1.9%).ConclusionsA crucial feature in differentiating FLS from typical lower limb onset ALS in Chinese patients may be symptoms confined to the lumbosacral region for at least 14 months, which may be better than 12 or 24 months used in the previous studies. The FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset ALS.

Clinical and electrophysiological characteristics of respiratory onset amyotrophic lateral sclerosis: a single-centre study.

We compared the clinical characteristics of patients with respiratory, bulbar and limb onset amyotrophic lateral sclerosis (ALS) who visited a single tertiary centre for 8years. Total of 115 ALS patients with respiratory, bulbar and limb onset ALS, including sex, body mass index (BMI), presence of lung disease, age at diagnosis, disease duration after initial symptoms, ALS Functional Rating Scale (ALSFRS-R) and progression rate (Delta-FS), pulmonary function, amplitude and distal latency (DL) of the phrenic nerves and blood creatine kinase (CK) and uric acid levels were collected. The prevalence of respiratory, bulbar and limb onset ALS were 5.2%, 28.7% and 66.1%, respectively. The mean age at diagnosis and ALSFRS-R were 67.8 ± 5.5, 63.8 ± 10.1 and 59.2 ± 11.7 in the descending order. The mean amplitude (0.18 ± 0.10mV) and DL (9.5 ± 1.7ms) of the phrenic nerves were significantly decreased and prolonged in respiratory onset ALS compared with other types of ALS patients. Patients with respiratory onset ALS had normal creatine kinase (CK) levels, whereas patients with other types of ALS had increased CK levels. Although rare, respiratory onset ALS may occur and should be considered during the initial differential diagnosis. In this study, patients with respiratory onset ALS were characterised by male predominance, with a higher baseline ALSFRS-R, lower BMI and phrenic nerve study well discriminated respiratory onset ALS from bulbar or limb onset ALS patients.

Lack of an association between SCFD1 rs10139154 polymorphism and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Through a genome-wide association study (GWAS), the Sec1 family domain-containing protein 1 (SCFD1) rs10139154 variant at 14q12 has emerged as a risk factor gene for ALS. Moreover, it has been reported to influence the age at onset (AAO) of patients with ALS. The aim of the present study was to assess the association of the SCFD1 rs10139154 polymorphism with the risk of developing ALS. For this purpose, 155 patients with sporadic ALS and 155 healthy controls were genotyped for the SCFD1 rs10139154. The effect of the SCFD1 rs10139154 polymorphism was then examined on the following parameters: i) The risk of developing ALS; ii) the AAO of ALS; iii) the site of ALS onset (patients with bulbar onset ALS vs. healthy controls; and patients with limb onset ALS vs. healthy controls); and iv) the AAO of ALS onset with subgroup analyses based on the site of onset (bulbar and limb, crude and adjusted for sex). The analysis of all the outcomes was performed assuming five genetic models. Crude and adjusted analyses were applied. The threshold for statistical significance was set at 0.05. The results revealed no association between SCFD1 rs10139154 and any of the examined phenotypes in any of the models examined. On the whole, based on the findings of the present study, SCFD1 rs10139154 does not appear to play a determining role in the risk of developing ALS.

Plateaus and reversals evaluated by different methods in patients with limb-onset amyotrophic lateral sclerosis

ObjectiveTo determine the difference in frequency of amyotrophic lateral sclerosis (ALS) reversals and plateaus in limb-onset patients evaluated with different methods. MethodsOne hundred and eighteen patients with limb-onset ALS were prospectively recruited. ALS Functional rating scale-revised (ALSFRS-R) score, total Medical Research Council (MRC) muscle strengthscore and clinical global impression (CGI) score were followed up every three months for at least 1 year. The changes between two follow-up points in scores were analyzed. ResultsReversal and plateau in ALSFRS-R score were detected in 26.14% patients between initial and 3-month, 21.19% between 3-month and 6-month, 23.73% between 6-month and 9-month, 19.49% between 9-month and 12-month, respectively. For total MRC muscle score, the percentages were 28.81%, 21.19%, 16.95%, 13.56%, respectively. For CGI score, the percentages were 74.57%, 64.41%, 66.10%, 66.95%, respectively. There was significant difference in the frequency of plateau or reversal between ALSFRS-R scale and total MRC scale over 3-month interval visit (P < 0.05), while no significant difference was revealed between CGI scale and ALSFRS-R scale or total MRC scale. The frequency of reversal and plateau were 8.47% at 6-month, 4.24% at 9-month, 3.34% at the last follow-up in both ALSFRS-R score and total MRC score, respectively. ConclusionPlateaus and reversals in ALSFRS-R score, total MRC score and CGI score are not uncommon in limb-onset patients during follow-up. The combination of ALSFRS-R score and total MRC score could better reflect the relentless progression of ALS. The importance of long-interval follow-up should be stressed in clinical practice.

The frequency of ALSFRS-R reversals and plateaus in patients with limb-onset amyotrophic lateral sclerosis: a cohort study.

Although amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, ALS patients might show reversals or plateaus of ALS Functional rating scale-revised (ALSFRS-R) scores during follow-up, which might cast the doubt on the diagnosis. The study aims to determine the frequency of reversals and plateaus of ALSFRS-R score in patients with limb-onset ALS. One hundred and fifty four patients with limb-onset ALS were prospectively recruited. ALSFRS-R scores were followed up every 3 months for at least 1year. The changes between two follow-up points in ALSFRS-R score were compared. Totally 95 (61.7%) participants showed 85 times plateau and 69 times reversal in ALSFRS score during the 12-month follow-up when compared the ALSFRS-R score between two adjacent follow-up points. Reversal and plateau in ALSFRS-R score were detected in 31.8% patients between initial and 3 months, 18.8% between 3 and 6 months, 22.7% between 6 and 9 months, 22.7% between 9 and 12 months, respectively. When comparing with the ALSFRS-R score in the baseline, reversal and plateau in ALSFRS-R score were detected in 31.8% patients at 3 months, 14.9% at 6 months, 6.5% at 9 months, 5.8% at 12 months, respectively. Plateaus and reversals in ALSFRS-R score were common in limb-onset ALS patients during follow-up. A relatively stable or reversal in the ALS-FRS-R score does not exclude the diagnosis of ALS. Limitations of ALSFRS-R score as an outcome parameter in clinical trial should be further evaluated.

The\xa0Gold Coast criteria increases the diagnostic sensitivity for amyotrophic lateral sclerosis in a Chinese population

ObjectivesThe aim of this study was to assess and compare the diagnostic utility of a new diagnostic criteria for amyotrophic lateral sclerosis (ALS), abbreviated as the ‘Gold Coast Criteria’, with the revised El Escorial (rEEC) and Awaji criteria.MethodsClinical and electrophysiological data of 1185 patients from January 2014 to December 2019 in the Peking Union Medical College Hospital ALS database were reviewed. The sensitivity of the Gold Coast criteria was compared to that of the possible rEEC and Awaji criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS).ResultsA final diagnosis of ALS was recorded in 1162 patients. The sensitivity of the Gold Coast criteria (96.6%, 95% confidence interval [CI] = 95.3%–97.5%) was greater than that of the rEEC (85.1%, 95%CI = 82.9%–87.1%) and Awaji (85.3%, 95%CI = 83.2%–87.3%). In addition, the sensitivity of the novel criteria maintained robust across subgroups, and the advantage was more prominent in limb-onset ALS patients and those who completed electromyographic tests. In those who did not achieve any of the rEEC diagnostic categories, the sensitivity of Gold Coast criteria was 84.4%.ConclusionsThe current study demonstrated that the Gold Coast criteria exhibited greater diagnostic sensitivity than the rEEC and Awaji criteria in a Chinese ALS population. The application of the Gold Coast criteria should be considered in clinical practice and future therapeutic trials.

P-NU006. Longitudinal evaluation of fasciculation through ultrasonography in amyotrophic lateral sclerosis

Introduction . Muscle fasciculation in amyotrophic lateral sclerosis (ALS) is typically evaluated through needle electromyography. In recent years, ultrasound has been increasingly used to detect fasciculation particularly as this procedure is non-invasive. We aimed to longitudinally evaluate muscle fasciculation in ALS patients through neuromuscular ultrasound. Methods . ALS patients fulfilling the revised El-Escorial and Awaji criteria presenting to University Malaya Medical Centre were consecutively recruited. Neuromuscular ultrasound was performed at 6-monthly intervals. Two sets of 30-second recordings were obtained from three cervical region muscles (biceps brachii, brachioradialis, first dorsal interosseus) and two lumbosacral region muscles (vastus medialis, tibialis anterior). Fasciculation was considered present when there were ≥ two involuntary contractions. These findings were correlated with disease duration and the revised ALS Functional Rating Scale (ALSFRS-R). Results . A total of 40 patients were recruited. The diagnosis of ALS was definite in 42.5%, probable in 40.0% and possible in 17.5%. The mean onset age was 56.5±8.8 years. Most patients were limb-onset ALS (77.5%). The mean ALSFRS-R was 33.7±9.7 (baseline) and 28.3±11.0 (6 months). At baseline, 17/40 (42.5%) patients had fasciculations in one region, 19/40 (47.5%) in two regions while 4/40 (10.0%) had none. At 6 months, the regions affected remained unchanged in 21 (52.5%) patients. In eight (20.0%) patients, fasciculation was further detected in additional region/s. In five (12.5%) patients, fasciculation could no longer be detected. The disease duration was negatively correlated with the number of muscles with fasciculation detected (R=-0.319 p=0.045 at baseline, R=-0.361 p=0.020 at 6 months). There was, however, no correlation between ALSFRS-R and the number of muscles with fasciculation. Conclusion . Our findings support the role of neuromuscular ultrasound as a diagnostic tool in detecting fasciculation in ALS. However, its role as a prognostic biomarker remains less clear as fasciculation can be less frequently detected with progressive motor neurons loss.

Split-hand index: A diagnostic and prognostic marker in amyotrophic lateral sclerosis across varying regions of onset

ObjectiveThe split-hand index (SI), a reliable diagnostic marker of amyotrophic lateral sclerosis (ALS), was prospectively assessed for differences across ALS subtypes and between the onset side of clinical symptoms or the dominant and contralateral sides. In addition, the prognostic utility of the SI was longitudinally assessed. MethodsTwo hundred and forty-five ALS patients underwent measurement of SI on both sides compared with 126 neuromuscular mimic disorders (NMD). A subset of patients (N = 45) underwent longitudinal assessment of SI. ResultsThe SI was significantly reduced (SI RIGHT ALS 5.47(4.2), SINMD 9.0 (5.0); P < 0.001; SILEFT ALS 5.5 (4.1), SI NMD 9.4 (5.0), P < 0.001) on both sides in all ALS patients with prominent reduction on the onset side in upper limb onset ALS (SI RIGHT P < 0.001; SI LEFT P < 0.05) and in Awaji definite/probable diagnostic category (SI RIGHT P < 0.05; SI LEFT P < 0.05). Longitudinal studies disclosed that the rate of SI decline correlated with the decline in ALSFRS-R (r = 0.21, P < 0.05). ConclusionThe SI is reduced in all ALS subtypes most prominently in upper limb onset disease, on the side of clinical onset, and in patients with Awaji definite/probable diagnostic category. SignificanceThe split-hand index is a reliable diagnostic and outcome biomarker across ALS subtypes and may have potential utility in a clinical trial setting, although further multicenter studies are required to confirm this.

Staging model for amyotrophic lateral sclerosis in Singapore.

Introduction:A clinical-based staging model would guide physicians in the prompt management of the evolving symptoms and functional needs of patients with amyotrophic lateral sclerosis (ALS).Methods:We aimed to delineate the clinical trajectory of ALS in Singapore and test the degree of congruity of King's College staging for ALS (King's staging) among Singapore patients. In this retrospective cohort study, clinical milestones used for staging were identical to King's staging: stage 1 corresponded to symptom onset; stage 2A corresponded to diagnosis; stage 2B corresponded to two central nervous system (CNS) regions; stage 3B corresponded to three CNS regions; stage 4A corresponded to requirement of supportive enteric feeding; and stage 4B corresponded to requirement of non-invasive ventilation, of which bulbar, diaphragmatic, upper and lower limb pyramidal involvements each constituted one CNS region. Standardised timings from disease onset (0) to death (1) among Singapore patients with ALS were measured.Results:46 patients with ALS were reviewed. Results were largely congruous with King's staging. Results for patients with limb-onset ALS were: diagnosis (0.35); two CNS region involvement (0.42); three CNS region involvement (0.63); diaphragmatic involvement (0.81); and bulbar involvement (0.73). Results for patients with bulbar-onset ALS were: diagnosis (0.14); two CNS region involvement (0.28); three CNS region involvement (0.42); diaphragmatic involvement (0.62); and bulbar involvement (0.67).Conclusion:King's staging can be used to model ALS trajectory in Singapore due to the large degree of congruity seen. Easily remembered and accessible knowledge of ALS staging will allow prompt management of the evolving needs of patients with ALS.

Patterns of grey and white matter changes differ between bulbar and limb onset amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a high heterogeneity in patients’ disease course. Patients with bulbar onset of symptoms (b-ALS) have a poorer prognosis than patients with limb onset (l-ALS). However, neuroimaging correlates of the assumed biological difference between b-ALS and l-ALS may have been obfuscated by patients’ diversity in the disease course. We conducted Voxel-Based-Morphometry (VBM) and Tract-Based-Spatial-Statistics (TBSS) in a group of 76 ALS patients without clinically relevant cognitive deficits. The subgroups of 26 b-ALS and 52 l-ALS patients did not differ in terms of disease Phase or disease aggressiveness according to the D50 progression model. VBM analyses showed widespread ALS-related changes in grey and white matter, that were more pronounced for b-ALS. TBSS analyses revealed that b-ALS was predominantly characterized by frontal fractional anisotropy decreases. This demonstrates a higher degree of neurodegenerative burden for the group of b-ALS patients in comparison to l-ALS. Correspondingly, higher bulbar symptom burden was associated with right-temporal and inferior-frontal grey matter density decreases as well as fractional anisotropy decreases in inter-hemispheric and long association tracts. Contrasts between patients in Phase I and Phase II further revealed that b-ALS was characterized by an early cortical pathology and showed a spread only outside primary motor regions to frontal and temporal areas. In contrast, l-ALS showed ongoing structural integrity loss within primary motor-regions until Phase II. We therefore provide a strong rationale to treat both onset types of disease separately in ALS studies.

Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: a retrospective case-control study.

Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015.

Noninvasive Ventilation Use Is Associated with Better Survival in Amyotrophic Lateral Sclerosis.

Rationale: Noninvasive ventilation (NIV) is standard of care in amyotrophic lateral sclerosis (ALS), yet few data exist regarding its benefits.Objectives: We sought to identify whether the use of NIV was associated with survival in ALS.Methods: This was a single-center retrospective cohort study of 452 patients with ALS seen between 2006 and 2015. We matched one or more NIV subjects (prescribed NIV) to non-NIV subjects (never prescribed NIV) without replacement. The outcome was time from NIV prescription date (NIV subjects) or matched date (non-NIV subjects) until death. We performed a multivariable Cox proportional hazards model with NIV hourly usage as a time-varying covariate and stratified by matched groups.Results: After creating 180 matched groups and adjusting for age, body mass index, ALS Functional Rating Scale Revised dyspnea score, and hourly NIV use, NIV was associated with a 26% reduction in the rate of death compared with non-NIV subjects (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.98; P = 0.04). Among those with limb-onset ALS, NIV subjects had a 37% lower rate of death compared with non-NIV subjects (HR, 0.63; 95% CI, 0.45-0.87; P = 0.006). Among NIV subjects, we found that NIV use for an average of ≥4 h/d was associated with improved survival.Conclusions: NIV use was associated with significantly better survival in ALS after matching and adjusting for confounders. Increasing duration of daily NIV use was associated with longer survival. Randomized clinical trials should be performed to identify ideal thresholds for improving survival and optimizing adherence in ALS.