scholarly journals A systematic review of non-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Emily Beswick ◽  
Deborah Forbes ◽  
Zack Hassan ◽  
Charis Wong ◽  
Judith Newton ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Sleep Disturbances ◽  
Neuropsychiatric Symptoms ◽  
Behavioural Change ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Behavioural Changes ◽  
Non Motor Symptoms ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva. Aim/hypothesis We aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments. Methods We reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied. Results 237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms. Conclusions Non-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs. PROPSERO registration CRD42020223648.

#3080 A systematic review of extra-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis

2021 ◽  
Vol 92 (8) ◽  
pp. A5.1-A5
Author(s):  
Emily Beswick ◽  
Deborah Forbes ◽  
Zachary Hassan ◽  
Charis Wong ◽  
Siddharthan Chandran ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Outcome Measures ◽  
Sleep Disturbances ◽  
Neuropsychiatric Symptoms ◽  
Behavioural Change ◽  
Assessment Tools ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Lateral Sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with extra-motor symptoms which arise secondary to motor degeneration or are indicative of wider pathophysiology. Extra-motor symptoms such as cognitive impairment, behavioural change, neuropsychiatric symptoms, sleep disturbances, fatigue, sialorrhea, and pain are common in, and impactful upon, people with ALS.Aim/HypothesisWe aimed to systematically review historical clinical trials in ALS to identify if extra-motor features of ALS were explored as outcome measures and if so describe the tools used. We hypothesise that assessment of extra-motor symptoms has been largely neglected in trial design and that where evaluated, it has been with assessment tools which are not designed to evaluate these symptoms in people with ALS.MethodsWe reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied. We evaluated the use of assessment tools to investigate extra-motor symptom as outcome measures.Results237 clinical trials were included in this review for use of outcome measures. These trials evaluated cognitive impairment (16 trials, 6.8%), behavioural change (38, 16%), neuropsychiatric symptoms (75, 32%), sleep disturbances (12, 5%), fatigue (18), 8%, saliva (182, 77%) and pain (55, 23%). 29 trials (12%) did not include any assessment of extra-motor symptoms. 51 versions or combinations of assessment tools were utilised in these trials. The most commonly used primary outcome measure in ALS trials, the ALS-FRS(R), is a physical functioning assessment with one sub-domain item assessing saliva. The ALS-FRS accounted for the full number of trials assessing saliva in this review. 6 instruments used were ALS-specific (designed and validated specifically for people with ALS), 14 were symptom-specific, 4 were both, and 9 were generic (evaluated the symptom within a general measure, eg QoL).ConclusionsExtra-motor symptoms have been under-evaluated in trials for people with ALS. Where evaluated, this has been primarily using assessment tools which are not specific to ALS or the extra-motor symptom, which may affect the validity of conclusions drawn regarding the impact of candidate drugs.

Cortical correlates of behavioural change in amyotrophic lateral sclerosis

2018 ◽  
Vol 90 (4) ◽  
pp. 380-386 ◽  
Author(s):  
Monica Consonni ◽  
Stefano F Cappa ◽  
Eleonora Dalla Bella ◽  
Valeria Elisa Contarino ◽  
Giuseppe Lauria
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Orbitofrontal Cortex ◽  
Behavioural Change ◽  
Principal Component ◽  
Behavioural Changes ◽  
The Core ◽  
Behavioural Profile ◽  
The Right ◽  
Item Scale ◽  
Lateral Sclerosis

BackgroundBehavioural changes in amyotrophic lateral sclerosis (ALS) are heterogeneous. The study aim was to identify the behavioural profiles of non-demented patients with ALS and their neuroimaging correlates and to elucidate if they are comparable to those reported in studies of the behavioural-variant of frontotemporal dementia (bvFTD).MethodsBehavioural changes of 102 non-demented patients with ALS were assessed through the Frontal Behavioural Inventory (FBI), a 24-item scale assessing different behavioural modifications, mainly chosen from the core clinical features of FTD. Principal component analysis (PCA) was used to detect distinct clusters of behavioural changes based on FBI subscores. The cortical thinning related to each behavioural profile was analysed in 29 patients with ALS. Cronbach’s α was used to test the reliability of bvFTD-related FBI clustering in our cohort.ResultsSixty patients with ALS had FBI score≥1. PCA identified three phenotypic clusters loading on disinhibited/hostile, dysexecutive and apathetic FBI subscores. Imaging analyses revealed that the thinning of bilateral orbitofrontal cortex was related to apathy, the right frontotemporal and cingular cortex to the disinhibited/hostile profile and the left precuneus cortex to the dysexecutive behaviours. The bvFTD-associated aggressive profile reliably applied to our cohort.ConclusionsIn non-demented patients with ALS, different behavioural profiles could be identified. The right frontotemporal and cingular cortex thinning was the hallmark of the behavioural profile mostly overlapping that described in bvFTD. Our findings provide the unbiased identification of determinants relevant for a novel stratification of patients with ALS based on their behavioural impairment, which might be useful as proxy of cognitive decline.

Non-Motor Symptoms of Amyotrophic Lateral Sclerosis: A Multi-Faceted Disorder

2021 ◽  
pp. 1-15
Author(s):  
Yuval Nash ◽  
Michal Sitty
Keyword(s):  
Quality Of Life ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Symptoms ◽  
Motor Pathways ◽  
Progressive Degeneration ◽  
Wide Range ◽  
Growing Body ◽  
Non Motor Symptoms ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients’ quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.

scholarly journals Prevalence of non-motor symptoms in Parkinson’s disease

2019 ◽  
Vol 7 (5) ◽  
pp. 1459
Author(s):  
Shakthi C. ◽  
Sritharan B. ◽  
Muthuveeran M. ◽  
Manivannan M. R. ◽  
Justin C. ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sleep Disturbances ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Nocturnal Sleep ◽  
Males And Females ◽  
Non Motor Symptoms

Background: Parkinson’s disease is a common neurodegenerative movement disorder characterised by motor symptoms of rest tremor, bradykinesia, rigidity and postural instability and non-motor symptoms (NMS) which include neuropsychiatric symptoms, sleep disturbances, autonomic symptoms, sensory symptoms and symptoms of mixed aetiology. Parkinson’s Disease Non Motor Group (PD-NMG) devised a comprehensive clinic-based self-completed NMS questionnaire that allows easy identification of NMS by the physician. Most NMS have a poor response to dopaminergic therapy as it is due to dysfunction of the serotonergic and noradrenergic pathways. Treatment of these nonmotor symptoms help in improving the quality of life in patients with Parkinson’s disease.Methods: There were 100 patients with Parkinson’s disease who had presented to our neuromedicine movement clinic were included in the study. Patients were diagnosed as PD based on UK Parkinson’s disease brain bank criteria. The inclusion criteria were diagnosis as PD, age >18 yrs, inclusion of both males and females and consent for the study. Patients with atypical parkinsonism and secondary parkinsonism, stroke, intake of antipsychotics were excluded from the study. Non motor symptom questionnaire was given to the study group and frequency of occurrence of each non motor symptoms and their predominance in both males and females were studied. The frequency of each NMS was calculated by computing the number of yes response and calculating the percentage related to the number of patients in the sample. Analysis was done to calculate the frequency of all NMS among the enrolled patient.Results: Nocturnal sleep disturbances (43%) were most common followed by constipation (29%).The most common non motor symptoms in males were constipation (20%), urinary urgency (18%) and nocturia (11%).The most common non motor symptoms in females were nocturnal sleep disturbance (25%), feeling sad (19%), unexplained pains (17%) and being anxious (13%).Conclusions: Non motor symptom questionnaire helps in screening patients with Parkinson’s disease of non-motor symptoms and aims at providing holistic treatment improving the quality of life.

scholarly journals A systematic review of neuropsychiatric and cognitive assessments used in clinical trials for amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Emily Beswick ◽  
Emily Park ◽  
Charis Wong ◽  
Arpan R. Mehta ◽  
Rachel Dakin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Cognitive Impairment ◽  
Outcome Measures ◽  
Neuropsychiatric Symptoms ◽  
Secondary Outcome ◽  
Secondary Outcome Measure ◽  
Exclusion Criteria ◽  
The Impact ◽  
Lateral Sclerosis

Abstract Background Up to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning. Methods We reviewed the past 25 years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted. Results 216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (n = 6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (n = 8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials. Conclusions Trials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS. PROPSERO registration CRD42020175612.

scholarly journals Sleep disturbances and gastrointestinal dysfunction are associated with thalamic atrophy in Parkinson’s disease

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Flavia Niccolini ◽  
Heather Wilson ◽  
Beniamino Giordano ◽  
Konstantinos Diamantopoulos ◽  
Gennaro Pagano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gastrointestinal Tract ◽  
Cortical Thickness ◽  
Sleep Disturbances ◽  
Sensory Information ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Subcortical Nuclei ◽  
Non Motor Symptoms

Abstract Background Non-motor symptoms are common aspects of Parkinson’s disease (PD) occurring even at the prodromal stage of the disease and greatly affecting the quality of life. Here, we investigated whether non-motor symptoms burden was associated with cortical thickness and subcortical nuclei volume in PD patients. Methods We studied 41 non-demented PD patients. Non-motor symptoms burden was assessed using the Non-Motor Symptoms Scale grading (NMSS). Cortical thickness and subcortical nuclei volume analyses were carried out using Free-Surfer. PD patients were divided into two groups according to the NMSS grading: mild to moderate (NMSS: 0–40) and severe (NMSS: ≥ 41) non-motor symptoms. Results Thalamic atrophy was associated with higher NMSQ and NMSS total scores. The non-motor symptoms that drove this correlation were sleep/fatigue and gastrointestinal tract dysfunction. We also found that PD patients with severe non-motor symptoms had significant thalamic atrophy compared to the group with mild to moderate non-motor symptoms. Conclusions Our findings show that greater non-motor symptom burden is associated with thalamic atrophy in PD. Thalamus plays an important role in processing sensory information including visceral afferent from the gastrointestinal tract and in regulating states of sleep and wakefulness.

scholarly journals MNCD: A New Tool for Classifying Parkinson’s Disease in Daily Clinical Practice

Diagnostics ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 55
Author(s):  
Diego Santos García ◽  
María Álvarez Sauco ◽  
Matilde Calopa ◽  
Fátima Carrillo ◽  
Francisco Escamilla Sevilla ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sleep Disturbances ◽  
Tnm Classification ◽  
Neuropsychiatric Symptoms ◽  
Motor Symptoms ◽  
Simple Classification ◽  
Axial Symptoms ◽  
Stage 1 ◽  
Non Motor Symptoms

Background and objective: Parkinson’s disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.

Current clinical trials in amyotrophic lateral sclerosis

2007 ◽  
Vol 16 (8) ◽  
pp. 1197-1207 ◽  
Author(s):  
Jaydeep M Bhatt ◽  
Paul H Gordon
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

scholarly journals Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open-Access ALS clinical trials database

2017 ◽  
Vol 57 (3) ◽  
pp. 430-434 ◽  
Author(s):  
Sabrina Paganoni ◽  
Katharine Nicholson ◽  
James Chan ◽  
Amy Shui ◽  
David Schoenfeld ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Open Access ◽  
Lateral Sclerosis
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