Bulbar-onset Patients Research Articles

Clinical and epidemiological features of amyotrophic lateral sclerosis in eastern Turkey

Aim: The number of studies on the epidemiological and clinical data of amyotrophic lateral sclerosis (ALS) patients in Turkey is quite low and the studies on this subject reflect the data of western regions of Turkey. In this study, we aimed to present the demographic, clinical and mortality features of ALS patients diagnosed in the last 10 years in a large reference hospital in the Eastern Anatolia region of Turkey.
 Material and Method: 42 ALS patients diagnosed between January 2011 and January 2021 in ………., Faculty of Medicine, Department of Neurology were included in the study. The data of the patients were obtained by retrospectively scanning the patient electronic files registered in the database of our hospital. The age, gender, examination findings, clinical course, treatments they received and the cause of death of the patients were recorded.
 Results:26 of ALS patients were men and 16 were women. The mean age of onset was 53.4 ± 12.3 and the mean diagnostic delay was 13.6 ± 6.9 months. 64.2% of the patients had onset in the spinal region, and 35.7% in the bulbar region. Weakness/atrophy of the upper extremity muscles and swallowing difficulty were the most common onset symptoms. All ALS patients were using riluzole. 11 ALS patients died. The mean time between diagnosis and death in patients who died was 27.2 ± 18.6 months. The most common causes of death in ALS patients were pneumonia and sepsis.
 Conclusion: Age of onset of ALS was low in our patients. The number of patients in the clinically definite ALS group was the highest. Weakness/atrophy of the upper extremity muscles and swallowing difficulty were the most common onset symptoms. Approximately 2/3 of the patients had spinal, and 1/3 bulbar region onset. There was no significant difference between spinal and bulbar onset patients in terms of gender, age of disease onset, mortality, and life expectancy of patients with death. The rate of using riluzole was high. The most common causes of death in ALS patients were pneumonia and sepsis.

Motor neuron disease beginning with frontotemporal dementia: clinical features and progression

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.

Swallowing Safety and Efficiency Impairment Profiles in Individuals with Amyotrophic Lateral Sclerosis.

Dysphagia is common in individuals with amyotrophic lateral sclerosis (ALS) and associated with reductions in quality of life and health-related outcomes. Despite the high prevalence of dysphagia in ALS, functional impairment profiles of swallowing safety and efficiency have not been comprehensively examined. We therefore aimed to determine the relative prevalence of unsafe and inefficient swallowing in a large cohort of individuals with ALS. We further sought to examine the impact of global and bulbar disease progression (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised "ALSFRS-R" total and bulbar scores, respectively), disease duration, and onset type on swallowing impairment profiles.One hundred individuals with ALS completed a standardized videofluoroscopic swallowing examinationTwo independent and blinded raters performed validated ratings of safety (Penetration-Aspiration Scale, PAS) and efficiency (Analysis of Swallowing Physiology: Events, Kinematics, and Timing, ASPEKT % residue). Binary classifications of safety (unsafe: PAS ≥ 3), efficiency (inefficient: total residue ≥ 3% of C2-42) and global swallowing status were derived. The ALSFRS-R was completed to derive ALSFRS-R total and bulbar subscale scores.Demographic data (disease duration and onset type) for each participant was also recorded.Descriptives, 2 × 2 contingency tables with Fishers exact test, and independent samples t-tests were performed (α = 0.05). Prevalence of unsafe and inefficient swallowing was 48% and 73%, respectively. Global swallowing profiles were, in rank order: unsafe and inefficient (39%), inefficient but safe (34%), safe and efficient (18%), and unsafe but efficient (9%). There were no differences in global disease progression or disease duration across swallowing impairment profiles. ALSFRS-R bulbar subscale scores were significantly lower in unsafe versus safe swallowers, p<0.05. Spinal onset patients had a greater proportion of safe swallowers as compared to bulbar onset patients (p=0.000, Fisher's exacttest). Both spinal and bulbar onset patients demonstrated a higher prevalence of inefficient swallowers as compared to efficient swallowers (p=0.04, Fisher's exact test).Dysphagia was prevalent in this group of individuals with ALS. Approximately half demonstrated safety impairments and two-thirds had impairments in swallowing efficiency. Inefficient swallowing was approximately four times more likely to be the initial functional impairment in patients with one pathophysiologic functional impairment. A longitudinal study is needed to examine the temporal evolution of dysphagia in ALS.

Non-Motor Features of Amyotrophic Lateral Sclerosis

Introduction:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons. Spread of pathology to other brain areas leads to development of non-motor symptoms (NMSs). These usually remain undiagnosed because of overwhelming motor problem and are responsible for significant distress to the patient. Our objective was to explore the burden of various NMSs of patients with ALS, compare between limb-onset and bulbar-onset patients, and to correlate with severity and duration of disease.Methods:Fifty patients with ALS diagnosed according to revised El Escorial Criteria and 50 healthy controls were included in this study. They were assessed with NMS Questionnaire, Beck's Depression Inventory, Center for Neurologic Study-Lability Scale, Drooling Frequency and Severity Scale, Epworth Sleepiness scale, Bengali Mental State Examination, and Frontal Assessment Battery and relevant statistical analyses were carried out.Results:The patients with ALS had significantly increased prevalence of almost all NMSs compared to controls. There was also significant increase in depression, suicidal ideation, pseudobulbar affect, and daytime sleepiness in patients with ALS. The bulbar onset subgroup had significantly increased daytime drooling, dysphagia, nausea and vomiting, whereas the limb onset subgroup reported increased frequency of leg swelling. Executive dysfunction was detected in 24% of patients with ALS and 9.8% had mild cognitive impairment. Weight loss, frequency of falling, insomnia, unpleasant nocturnal leg sensations, difficulty having sex, depression, and cognitive impairment increased significantly with an increase in severity of the disease.Conclusion:NMSs were significantly more prevalent in patients with ALS. Some NMSs worsened with advancement of the disease.

Multidisciplinary care in Amyotrophic Lateral Sclerosis: a systematic review and meta-analysis.

Multidisciplinary care (MDC) has been the most recommended approach for symptom management in amyotrophic lateral sclerosis (ALS) but there is conflicting evidence about its effectiveness on survival and quality of life (QoL) of ALS patients. We conducted a systematic review to determine the effects of multidisciplinary care compared to general neurological care in survival and quality of life of ALS patients. A comprehensive literature search using Scopus, MEDLINE-PubMed, Cochrane, Web of Science, PEDro, and Science Direct was undertaken. Studies related to multidisciplinary care or general neurological care in ALS patients that assessed survival and quality of life and were published in the period up to and including January 2020 were included. A total of 1192 studies were initially identified, but only 6 were included. All studies that investigated survival showed and advantage of MDC over NC, and this benefit was even greater for bulbar onset patients. A meta-analysis was performed and showed a mean difference of 141.67 (CI 95%, 61.48 to 221.86), indicating that patients who received MDC had longer survival than those who underwent NC (p = 0.0005). Concerning QoL, only one study found better mental health scores related to QoL for patients under MDC. Multidisciplinary care is more effective than general neurology care at improving survival of patients with ALS, but only improves mental health outcomes related to quality of life of these patients.

The spectrum of language impairments in amyotrophic lateral sclerosis

Language disorders are increasingly recognised in Amyotrophic lateral sclerosis (ALS), supporting the view of ALS as a multi-system disorder, impacting cognitive and motor function. However, the language impairments are heterogeneous and recent focus has been on determining the language profile across the ALS spectrum with little focus on spontaneous speech. The current study systematically investigated a wide range of language abilities in an unselected ALS sample (N = 22), including spontaneous speech. We analysed the ALS patients' performance as a group, compared to age-, education- and IQ-matched healthy controls (N = 21), and as a case series to identify dementia and specific language profiles. The ALS group was impaired on measures of spontaneous speech, word fluency and action naming. By contrast, object naming, semantic memory (object and actions), sentence comprehension and repetition (word and sentences) were comparable to healthy controls. In line with recent suggestions, our ALS patients’ action naming (but not action semantic) deficit does not support the notion that action processing may be selectively impaired in ALS. The case series demonstrated that 14% of patients had probable dementia, 31% showed significant cognitive and/or language impairment and 55% were unimpaired, consistent with the spectrum of cognitive and language impairments reported in the literature. In addition, 36% of ALS patients produced significantly fewer words per minute on a spontaneous speech task than the control group, with this difference remaining when the ALS patients with frontotemporal dementia were excluded from the analysis. This pattern was observed across the ALS spectrum and in both limb and bulbar onset patients. The pattern of performance observed in the present study suggests that spontaneous speech is reduced across the ALS spectrum even in those with intact core language abilities.

Information Needs and Preferences of Family Caregivers of Patients With Amyotrophic Lateral Sclerosis.

The aim of this study was to explore the information needs and preferred sources of information of Korean family caregivers of patients with amyotrophic lateral sclerosis (ALS). Family caregivers of patients with ALS (n = 108) completed a structured questionnaire to assess their information needs and preferred sources of information. Most of the caregivers obtained health information from Internet searches (89.8%) and healthcare professionals (85.2%). The source rated most helpful was healthcare professionals, and that rated least helpful was broadcast media. Family caregivers who were younger than 50 years and well educated and caregivers of bulbar-onset ALS patients had higher scores of information needs. Providing information through healthcare professionals and self-support groups could enhance family caregiver satisfaction. Family caregivers who are older and less educated need to be more empowered to be involved in information-based caring, and caregivers of patients with bulbar-onset ALS have substantial information needs.

CSF neurotoxic metals/metalloids levels in amyotrophic lateral sclerosis patients: comparison between bulbar and spinal onset

IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the central nervous system (CNS) that causes progressive and irreversible damage in motor neurons. Different causal hypotheses include genetic, viral, traumatic and environmental mechanisms, such as exposure to heavy metals. The aim of this study was to compare metal/metalloid levels in cerebro-spinal fluid of ALS subtypes (spinal vs bulbar clinical onset). Material and methodsThis observational study consecutively screened all ALS patients referring to the Neurology Clinic of the University of Catania (Italy). Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify magnesium (Mg), cuprum (Cu), selenium (Se), iron (Fe), manganese (Mn), vanadium (V), zinc (Zn), alluminium (Al), arsenic (As), cobalt (Co), nickel (Ni), mercury (Hg), lead (Pb), cadmium (Cd) and palladium (Pd) levels. ResultsThirty-seven patients were enrolled (62.2% females), median age of 65 years (IQR: 59–71 years). Thirty-one (83.8%) patients had a spinal onset and 6 (16.2%) a bulbar onset. Se and As levels were higher compared to the reference values (RV) both in spinal and bulbar onset, while Cu was higher than RV only in bulbar onset. Moreover, Cu (129.8 μg/L vs 29.8 μg/L), Fe (54.5 μg/L vs 33.3 μg/L), Mn (3.4 μg/L vs 1.8 μg/L), Zn (46.1 μg/L vs 35.7 μg/L), Al (12.2 μg/L vs 6.7 μg/L), Ni (2.80 μg/L vs 1.40 μg/L), and Pb (0.60 μg/L vs 0.30 μg/L) levels were higher in bulbar than in spinal onset, conversely As was slightly higher in spinal than in bulbar onset (1.40 μg/L vs 1.10 μg/L). Overall, Cu (129 μg/L vs 31 μg/L), Fe (92.2 μg/L vs 32.9 μg/L), Mn (3.35 μg/L vs 1.80 μg/L), Zn (56.5 μg/L vs 35.2 μg/L), Al (14.45 μg/L vs 6.70 μg/L), and Cd (0.40 μg/L vs 0.08 μg/L) levels were higher in patients with disease duration less than 19 months. ConclusionOur results supported the hypothesis that metals/metalloids with neurotoxic effects could be involved in the etiology of ALS, showing higher levels of Cu, Se and As. Relevant differences in Cu and Mn levels were found between bulbar and spinal onset patients.

Diagnostic delay among ALS patients: Egyptian study

Introduction: In the current study, we are going to look at different factors responsible for the diagnostic delay of ALS patients among the sample of Egyptian patients. Method/patients: This is a cohort study. ALS patients were recruited from December 2018 to January 2020 from the ALS clinic at the international medical center (IMC) (Cairo, Egypt). We analyzed the site of onset, the time from symptom onset to diagnosis, age and sex differences among these ALS patients. Results: Thirty patients were included in the study. Seventy percent of the patients had limb onset ALS with a mean age of onset of 50 ± 12.1 vs 58.6 ± 2.1 years for the patients with bulbar onset (p = 0.02). Bulbar-onset patients were diagnosed earlier than limb onset patients (mean lag of 8.2 ± 2.57 months vs 22.95 ± 17.6 months respectively, p < 0.05). The average diagnosis time for women was slightly longer than that of men with a mean lag of 20.7 ± 21.1 vs. 17.6 ± 13.6 months, respectively, p > 0.05. Diagnostic delay and age at onset of symptoms were negatively correlated, however, this was not statistically significant. Discussion: To our knowledge, this the first population-based study from Egypt about predicting factors of diagnostic delay among Egyptian patients. Limb onset, female gender and young age are correlated with increased mean time to diagnosis. Statistically insignificant results could be attributed to a small sample. Larger population-based studies are needed from Egypt.

Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK levels were assayed for 16 months every 4 months in an observational case-control cohort study with prospective data collection conducted in Italy. CK was also measured at baseline in 88 CIDP patients with secondary axonal damage and in two mouse strains (129SvHSD and C57-BL) carrying the same SOD1G93A transgene expression but showing a fast (129Sv-SOD1G93A) and slow (C57-SOD1G93A) ALS progression rate. Higher CK was found in ALS slow progressors compared to fast progressors in T1, T2, T3, and T4, with a correlation with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Higher CK was found in spinal compared to bulbar-onset patients. Transgenic and non-transgenic C57BL mice showed higher CK levels compared to 129SvHSD strain. At baseline mean CK was higher in ALS compared to CIDP. CK can predict the disease progression, with slow progressors associated with higher levels and fast progressors to lower levels, in both ALS patients and mice. CK is higher in ALS patients compared to patients with CIDP with secondary axonal damage; the higher levels of CK in slow progressors patients, but also in C57BL transgenic and non-transgenic mice designs CK as a predisposing factor for disease rate progression.

Early weight loss in amyotrophic lateral sclerosis: outcome relevance and clinical correlates in a population-based cohort

ObjectivesTo assess the role of body mass index (BMI) and of the rate of weight loss as prognostic factors in amyotrophic lateral sclerosis (ALS) and to explore the clinical correlates...

Testing the diagnostic accuracy of [18F]FDG-PET in discriminating spinal- and bulbar-onset amyotrophic lateral sclerosis

The role for [18F]FDG-PET in supporting amyotrophic lateral sclerosis (ALS) diagnosis is not fully established. In this study, we aim at evaluating [18F]FDG-PET hypo- and hyper-metabolism patterns in spinal- and bulbar-onset ALS cases, at the single-subject level, testing the diagnostic value in discriminating the two conditions, and the correlations with core clinical symptoms severity. We included 95 probable-ALS patients with [18F]FDG-PET scan and clinical follow-up. [18F]FDG-PET images were analyzed with an optimized voxel-based-SPM method. The resulting single-subject SPM-t maps were used to: (a) assess brain regional hypo- and hyper-metabolism; (b) evaluate the accuracy of regional hypo- and hyper metabolism in discriminating spinal vs. bulbar-onset ALS; (c) perform correlation analysis with motor symptoms severity, as measured by ALS-FRS-R. Primary motor cortex showed the most frequent hypo-metabolism in both spinal-onset (∼57%) and bulbar-onset (∼64%) ALS; hyper-metabolism was prevalent in the cerebellum in both spinal-onset (∼56.5%) and bulbar-onset (∼55.7%) ALS, and in the occipital cortex in bulbar-onset (∼62.5%) ALS. Regional hypo-and hyper-metabolism yielded a very low accuracy (AUC<0.63) in discriminating spinal- vs. bulbar-onset ALS, as obtained from single-subject SPM-t-maps. Severity of motor symptoms correlated with hypo-metabolism in sensorimotor cortex in spinal-onset ALS, and with cerebellar hyper-metabolism in bulbar-onset ALS. The high variability in regional hypo- and hyper-metabolism patterns, likely reflecting the heterogeneous pathology and clinical phenotypes, limits the diagnostic potential of [18F]FDG-PET in discriminating spinal and bulbar onset patients.

A pilot study assessing T1-weighted muscle MRI in amyotrophic lateral sclerosis (ALS).

The authors set out to study the role of T1-weighted muscle MRI in the diagnostic phase of ALS, comparing images from ten patients and nine age-matched healthy controls (HCs). All subjects underwent MRI of 68 muscles in the hands, paraspinal regions and lower limbs; the images were semi-quantitatively scored. Atrophy was more frequent in muscles of ALS patients than HCs (p < 0.0001); fatty infiltration was particularly marked in iliopsoas (p = 0.046), anterior (p = 0.020) and posterior (p = 0.047) calf muscles in patients. A trend towards agreement was found between MRI and clinic-EMG data for the first dorsal interosseous, paraspinal, and tibial anterior muscles. Muscle T1-weighted MRI can distinguish ALS patients from HCs for specific regions (i.e., legs). MRI abnormalities could be found in pauci-symptomatic spinal muscles in bulbar-onset patients. Muscle MRI may be a useful diagnostic tool in ALS, in particular for muscles difficult to investigate using clinical-EMG methods.

Clinical Staging of Amyotrophic Lateral Sclerosis in Chinese Patients.

Objective: It is important to explore the utility of clinical staging systems in the management of amyotrophic lateral sclerosis (ALS). Our aim was to assess the validity of King's College in a Chinese ALS cohort, by evaluating the duration and informativeness of each stage and examining the association between stage and prognosis.Methods: From May 2008 to December 2016, patients with a likely diagnosis of ALS were registered. We prospectively assessed the progression of the patients through the stages and calculated the duration of each stage.Results: The median duration in Stage 1 was 12.00 months, Stage 2 7.50 months, Stage 3 6.50 months, and Stage 4 4.10 months. Subset analysis revealed that the spinal-onset and early-onset patients had a longer median time in Stage 1 compared to bulbar-onset and late-onset patients, respectively. Riluzole treatment extended the durations of Stages 1 and 2, and the effect was maintained in patients with long-term use of riluzole (>6 months). Patients who initiated long-term riluzole therapy early, in Stage 1 or 2, had a longer Stage 2. Patients who received percutaneous gastrostomy endoscopy (PEG) or non-invasive positive-pressure ventilation (NIPPV) showed longer durations of Stage 4. The differences in survival time measured from each stage to death or censor date were significant.Conclusions: We validated the King's College staging system in a Chinese population, and showed this system to be useful in clinical practice. Patients with bulbar-onset or an age of onset>45 years tended to have rapidly progressing ALS. Riluzole may be more effective when initiated in an early disease stage and continued long-term. PEG and NIPPV treatments can extend disease duration of Stage 4.

Sniff nasal inspiratory pressure (SNIP) in amyotrophic lateral sclerosis: Relevance of the methodology for respiratory function evaluation

ObjectivesWe investigated two different methodological approaches for determining nasal inspiratory pressure during a sniff (SNIP) in patients with Amyotrophic Lateral Sclerosis (ALS). Patients and MethodsWe included 37 ALS patients and 11 controls. SNIP was measured in the sitting position, performed in each nostril with (SNIPocclud) and without (SNIPopen) closing the contralateral nostril. The best of 3 consistent results was considered for analyses. Patients were also assessed with MIP and the revised functional ALS rating scale (ALSFRS-R). Mann-Whitney U test, Wilcoxon test and Spearman's rank correlation coefficient with Bonferroni correction were applied. Coefficient of variation (CV) was calculated. ResultsSNIP was significantly lower in patients than controls, either for SNIPopen (p = 0.011) or SNIPocclud (p = 0.002). SNIPopen values were significantly lower both in ALS patients and controls than SNIPocclud (p < 0.001 and p = 0.007, respectively). SNIPopen CV was 8.14% and 8.51%, while SNIPocclud CV was 4.98% and 6.37%, respectively for controls and patients. SNIPopen and SNIPocclud were strongly correlated in both groups (r = 0.761 for controls; r = 0.768 for patients). In ALS, both methods were moderately correlated with MIP (respectively r = 0.525, p = 0.006 and r = 0.685, p < 0.001) and the respiratory subscore of ALSFRS-R (respectively r = 0.525, p = 0.001 and r = 0.64, p < 0.001). Although bulbar and spinal onset patients presented no differences for SNIPopen (p = 0.157), significant differences were found for SNIPocclud (p = 0.018). ConclusionSNIPocclud should be considered when evaluating ALS patients as its values present lower variability and favor longer follow-up.

The Primitive Palmomental Reflex in Amyotrophic Lateral Sclerosis

Background and Purpose: The palmomental reflex (PMR) is a primitive reflex that might be released due to inhibition in adulthood. It has been associated with several neurodegenerative conditions. The aim of the present study was to evaluate the frequency of PMR in amyotrophic lateral sclerosis (ALS). Patients and Methods: Non-demented ALS patients (n = 179) were recruited. Two groups of disease controls were enrolled: (a) non-demented patients with other neurological disorders (NC; n = 86, mean age 60 ± 14 years); (b) healthy subjects, healthy controls (HC; n = 175, mean age 61 ± 12 years). PMR was elicited by a brisk stroke along the thenar eminence of the right hand with a key or a pen. Results: The PMR could be elicited in 46% of the ALS patients, compared to 29% of NC and 16% of HC (p < 0.001). A multivariate analysis showed that bulbar-onset and female gender are associated with an increased risk of PMR. Conclusion: We demonstrate a higher frequency of the PMR in ALS patients compared to NC or HC. Its expression increases with age, being higher in bulbar-onset patients. Given that the reflex circuit is located in the brain stem, its release due to inhibition might be associated to the presence of a cortico-bulbar tract dysfunction in ALS.

10. Phenotypic variability in motor neuron disease: Site of onset and patterns of disease spread

Background The clinical heterogeneity across motor neuron disease (MND) is well known, and largely attributed to differences in the relative mix of upper (UMN) and lower motor neuron (LMN) dysfunction, site of onset, and rate of disease progression. These differences hold prognostic significance and clues to patterns of disease spread. Objective understanding of motor dysfunction across these clinical phenotypes is thus pivotal for unravelling disease pathogenesis and mechanisms underpinning disease spread. Aims To investigate the sites of origin and patterns of disease spread across MND phenotypes using multimodal clinical and neurophysiological tools in all 4 limbs. Methods Patients were prospectively recruited from the Forefront Neurology Clinic (Brain and Mind Centre, Sydney) and diagnosed according to Awaji Criteria. Detailed clinical assessments were performed including classification by phenotype and site of onset. Neurophysiological studies were conducted in all 4-limbs. LMN dysfunction was investigated by recording CMAP and MUNIX responses, while UMN dysfunction was assessed using threshold tracking transcranial magnetic stimulation (TT-TMS). Results Lower limb TT-TMS techniques were first established in healthy subjects (n = 40). The clinical cohort consisted of 52 MND patients (31 males, 21 females, mean age 59.3 ± 6.8 yrs). Upper limb analysis showed evidence of cortical hyperexcitability with a significant reduction of averaged short interval intracortical inhibition (SICI) over both motor hemispheres, most prominently over the motor cortex contralateral to the affected upper-limb (controls 11.27 ± 1.12%; MND 3.6 ± 1.5%, p 0.01 ). Bulbar-onset patients had the greatest cortical hyperexcitability (SICI 2.6 ± 1.4%, p 0.01 ). For all phenotypes, there was a positive correlation between UMN and LMN dysfunction in the affected limbs and in faster disease progressors. This relationship was not observed in non-affected limbs (R2 = 0.03, p = 0.3) or slower progressors (R2 = 0.004, p = 0.7). Conclusion Cortical hyperexcitability was evident globally but there was heterogeneity amongst phenotypes, with bulbar-onset patients showing the greatest degree of hyperexcitability. In addition, a difference in the interplay of the two motor compartments was seen, lending pathophysiological insight into the prognostic differences between patients. Through deep phenotyping and novel testing across all compartments of the nervous system, differences in the prognosis and patterns of neuronal vulnerability in MND subtypes are thus evident. This multimodal analysis lends potential to develop robust biomarkers and offer new pathophysiological insights.

Cortical Thinning Pattern of Bulbar- and Spinal-onset Amyotrophic Lateral Sclerosis: a Surface-based Morphometry Study.

Objective The precise cortical thinning pattern has not been elucidated for onset subtypes of amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the altered cortical thickness signatures of the bulbar-onset and spinal-onset ALS using surface-based morphometry, and the correlation between the cortical thickness of positive brain regions and clinical variables of the patients.Methods MR structural images were obtained from 65 ALS patients (15 bulbar-onset, 50 spinal-onset) and 65 normal controls (NCs) on a 3.0T MRI system. The structural images were segmented into gray matter and white matter based on DARTEL method and the central cortical surfaces were reconstructed using projection-based thickness method. The surface-based morphometry was performed to identify the alteration of cortical thickness in overall ALS patients, bulbar-onset ALS patients and spinal-onset ALS patients comparing to the NCs. The correlation analysis was applied between the clinical variables and the mean cortical thickness of the abnormal brain regions with age and sex as covariates.Results The cortex thinning of ALS patients was located in the left precentral gyrus, left postcentral gyrus, right gyrus rectus and right medial precentral gyrus. The bulbar-onset ALS (ALS-bulbar) presented motor cortex thinning of left precentral gyrus and right supplementary motor cortex, and the spinal-onset ALS (ALS-spinal) suffered from extra-motor cortex thinning of left posterior insula and right gyrus rectus. In ALS patients, the thickness of right gyrus rectus was negatively correlated to disease duration (r=-0.311, P=0.013), the thickness of right precentral gyrus was positively correlated to the score of ALS functional rating score-revise (ALSFRS-R) (r=0.271, P=0.032). The thickness of motor cortices in ALS-bulbar were not correlated to disease duration and ALSFRS-R score; the thickness of extra-motor cortices in ALS-spinal were negatively correlated to the disease duration (left insula, r=-0.409, P=0.004; right gyrus rectus, r=-0.351, P=0.014).Conclusion The findings suggested that bilateral motor cortex thinning presented in bulbar-onset ALS and extra-motor cortex thinning presented in spinal-onset ALS. The motor cortex thinning may be the intrinsic pathophysiological change that associated to the disease disability, and extra-motor cortex thinning may be secondary pathophysiological change that associated to disease duration.

Overview and audit against Motor Neurone Disease (MND) Association guidelines of a MND consultant’s practice over the last 3 years at the [Hospital

Background: Motor neurone disease (MND) is an incurable neurodegenerative condition. Recent guidelines from the MND Association UK (MNDA) emphasise prompt diagnosis and monitoring of quality of life (QOL). However, primary literature indicates that diagnosis is often delayed through several factors, including unawareness of how MND presents and delays through multiple secondary referrals. The [hospital] operates an internationally-recognised MND clinic whose service has not been audited against the MNDA UK guidelines for the last 3 years.Aim: To assess how well the MND consultant’s service ensures prompt diagnosis and the provision of end-of-life care or appropriate respiratory or nutritional support.Methods: Using the [hospital’s] database, records from 77 patients consulted consecutively in the MND clinic were obtained. Service parameters were compared against reference standards for diagnostic delay and treatment provision.Results: 84.4% of referrals came from neurologists outside of the MND service, with only 13% from general practitioners. On average, it took 14.7 months for patients to be seen in the MND clinic following symptom onset. Riluzole and percutaneous endoscopic gastrostomy (PEG) were prescribed faster in bulbar-onset versus limb-onset patients, by 4 times and 9 times respectively. End-of-life care discussion was recorded for 26% of patients.Conclusion: Diagnosing MND remains challenging for primary care physicians, which may be alleviated by disseminating recent Red Flag Committee guidelines. Investigation and treatment provision differed between MND subtypes, given the poorer prognosis associated with bulbar-onset. End-of-life care documentation remains low, which is an issue for the multi-disciplinary team (MDT) to resolve through incorporating palliative services.

Alterations in the Masticatory System in Patients with Amyotrophic Lateral Sclerosis.

To determine the effect of amyotrophic lateral sclerosis (ALS) on aspects of masticatory function and to assess the relationship between ALS and the prevalence of traumatic mucosal lesions caused by oral self-injury. A total of 153 ALS patients and 23 control subjects participated in this cross-sectional study. Clinical characteristics including site of onset, medication, type of feeding, and use of noninvasive mechanical ventilation were recorded. The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol and a specific questionnaire to assess aspects of masticatory dysfunction and frequency of self-injury of the oral mucosa were applied to all participants. Maximum mandibular range of motion, maximum bite force, and maximum finger-thumb grip force were determined and tested with Mann Whitney, Kruskal-Wallis, or chi-square tests. P < .05 was considered significant. Maximum unassisted and assisted mouth opening, protrusion, left laterotrusion, and finger-thumb grip force were significantly reduced in both spinal- (n = 102) and bulbar-onset (n = 40) patients compared to the control group; however, bite force was reduced only in bulbar-onset patients. ALS patients with tube feeding (n = 16) had the greatest reduction in maximum bite force and mandibular opening. There was no relationship between TMD and ALS. Oral self-injury due to biting was more frequent in the ALS group (29.9%) than in the control group (8.7%) and in the bulbar-onset group (55.0%) compared to the spinal- (20.8%) and respiratory-onset (18.2%) groups. Of the ALS patients in the study, 10% sought dental treatment related to the condition. The ALS patients in this study had a reduction in finger-thumb grip force that was twice as great as the reduction in bite force. The maximum range of mandibular movement was also reduced, especially in bulbar-onset patients. ALS patients did not have a higher prevalence of TMD but did have more traumatic mucosal injury than controls. The dentist should be an integral part of the multidisciplinary team to manage ALS patients.