Non-motor symptoms in motor neuron disease: prevalence, assessment and impact

Abstract People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as ‘severe’ by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.


Introduction Non-motor symptoms
][3] Although motor neuron disease is increasingly recognized as a multi-system disorder, these symptoms remain underexplored, with only 1% of motor neuron disease-related publications focusing on non-motor symptoms. 4The prevalence of these symptoms has previously been evaluated using adapted assessment tools validated for other neurological conditions 5 and symptom-specific studies. 6The types of non-motor symptoms evaluated vary across studies, 5,7 with limited exploration of participant-reported feedback from people with motor neuron disease on the importance and impact of these symptoms. 3on-motor symptoms can occur due to motor neuron disease pathology, and as a result of motor degeneration, symptoms may be associated with pathology affecting different neuroanatomical regions, 5 broadening understanding of the aetiopathogenesis of motor neuron disease and providing insights into wider neuroanatomical dysfunction. 8ymptoms such as cognitive and behavioural change, manifestation due to the pathology of the disease, which includes frontotemporal cerebral dysfunction. 9Inefficient saliva clearance from bulbar motor dysfunction, pain and gastrointestinal issues from inability to move regularly and disturbed sleep due to pain or anxiety, may considered as results of the impact of motor decline.Additional symptoms, such as low mood, anxiety, fatigue and sexual dysfunction, may be more complex aetiologically, occurring directly as a result of motor neuron disease pathology for some people, but result of receiving a difficult diagnosis and experiencing progressive disability for others.
Motor neuron disease is a multi-system disorder with non-motor symptoms that are poorly understood, and their impact upon the individual is not yet well established.An overview of the symptoms, which will be explored in this study, and their reported prevalence from prior research, is provided in Table 1.The prevalence and progression of these symptoms have also been shown to vary depending on disease characteristics 16 and increase in frequency as the disease progresses 5 ; we will investigate the associations between clinical and demographic features with the number of non-motor symptoms participants report.
This study explores how frequently people with motor neuron disease report non-motor symptoms, co-occurrence across symptoms and respondents' perception of the clinical care they receive regarding these issues.The impact of the presence of these symptoms on the individual was also evaluated, with symptoms defined as impactful if they were reported as significant to respondents, a definition encompassing both the perceived severity and burden of the symptom on the individual.It also considers how important people with motor neuron disease report it is to address these non-motor symptoms in clinical trial design, whether this is to explore potential additional therapeutic benefit of candidate drugs or to provide a complete picture of potential side-effects.

Assessment in clinical care
In a condition such as motor neuron disease, where no cure is currently available, the primary focus of clinical care is to provide symptomatic relief and improve an individual's quality of life. 17The broad range of non-motor symptoms previously reported, 18 and their significant effect on quality of life, 17 has highlighted the need for further research into the presence and impact of a broad range of non-motor symptoms in motor neuron disease.
In the UKL, evidence-based management of people affected by motor neuron disease is supported by the National Institute of Clinical Excellence 2016 guidelines. 19Approaches for some non-motor symptoms' diagnosis and management are included in these guidelines, but a clear focus on the motor features of respiratory failure, muscular weakness and bulbar symptoms remains.Key challenges for the identification of non-motor symptoms in clinical practice are the emerging awareness of these symptoms' association with motor neuron disease, from both the clinician and patient perspective, and the lack of validated disease-specific screening tools available. 4is is further confounded by the inconsistency in published literature relating to which non-motor symptoms are associated with motor neuron disease. 20he Trajectories of Outcomes in Neurological Conditions study is multi-phase exploration of quality of life determinants in motor neuron disease; the Trajectories of Outcomes in Neurological Conditions study reported the prevalence of pain, depression and anxiety and the resulting negative impact on an individual's quality of life. 21Despite evidence from the Trajectories of Outcomes in Neurological Conditions group that people with motor neuron disease and their clinical team believe that several of these symptoms can affect the quality of life, 22 non-motor symptoms are often under-reported by patients in clinical consultations more generally, perhaps due to a lack of awareness that they are related to motor neuron disease progression. 23he National Institute of Clinical Excellence clinical guidance 19 directly addresses cognitive and behavioural change as symptoms of motor neuron disease that may precede motor dysfunction and as aspects of functioning that need to be continually monitored.Guidelines for managing the psychological and social impact of motor neuron disease, changes relating to sexual symptoms and intimacy and problematic saliva are also provided.Problematic sleep and fatigue are considered as secondary effects of respiratory dysfunction.Guidelines on symptom-focused treatment 24 encourage a broader conceptualization of motor neuron disease as a multi-system disorder with nonmotor symptoms as areas that also require effective management and treatment.

Evaluation of non-motor symptoms in clinical trials
Guidelines on designing and running trials for people with motor neuron disease have also encouraged the exploration of non-motor symptoms as additional outcome measures.The Airlie House recommendations on trial design highlight the potential for cognitive or behavioural assessments to be included as primary or secondary outcome measures. 25he European Medicines Agency ALS Trial Guidelines also indicate the importance of also evaluating mood. 26ncluding assessment of non-motor symptoms as additional outcome measures in clinical trials enables researchers to provide a more complete picture of the potential side-effects and additional benefits of prospective disease-modifying treatments.Expanding our concept of treatment when evaluating a candidate drug, to include the potential for beneficial impact on non-motor symptoms, may identify drugs that have a significant impact on the quality of life and disability experienced by people with motor neuron disease. 27,28Despite this guidance, we have recently reported that non-motor symptoms have been insufficiently addressed in trial design, 29,30 and where these symptoms were evaluated, it was often with assessments that were not designed to evaluate non-motor symptoms in people with a progressive physical decline or communication impairment. 29,30

Aims
The aims of this study were (i) to explore how frequently people with motor neuron disease report symptoms of low mood, anxiety, cognitive complaints, behavioural change, fatigue, pain, disturbed sleep, problematic saliva, sexual dysfunction and gastrointestinal issues occurring and the clinical characteristics associated with a number of symptoms reported; in addition, (ii) to investigate how impactful these symptoms are for people with motor neuron disease and how many individuals reporting a symptom report it to be significant to them; also (iii) to explore how frequently people with motor neuron disease report that non-motor symptoms are assessed in clinical care; and (iv) to understand if people with motor neuron disease feel these symptoms are important to consider in clinical trial design.

Objectives
The objective of this study was to establish the frequency and impact of non-motor symptoms by inviting people with motor neuron disease to complete questionnaires on how their disease affects them.These questionnaires were designed specifically for this study with input from people with motor neuron disease and their clinical team.Data from these questionnaires will be combined with clinical data from participants' records on the Scottish Motor Neuron Disease register.

Hypotheses
We hypothesize that non-motor symptoms will be frequently reported by people with motor neuron disease, often co-occur and • Sleep quality, length of sleep and rapid eye movement duration can be improved in people with motor neuron disease utilizing non-invasive ventilation. 13tigue • Up to 44% of person with motor neuron disease • Co-occurs with depression in 15% of individuals. 14 Sleepiness is a key aspect of fatigue in people motor neuron disease, along with reduced alertness, loss of stamina and lack of energy. 7uropsychiatric • 19.7%, 70% of which were mood disorders and 31.67%neurotic disorders (inclusive of anxiety, stress-related and somatoform disorders) 15 • Elevated in comparison with rates in the general population, 6.9% of whom fulfil diagnostic thresholds for major depressive disorder and 14% an anxiety disorder. 50,51gnitive complaints • Experienced by 30-50% of person with motor neuron disease • Detrimental to an individual's quality of life and prognosis. 52,53haviour change • 28% indicated abnormally high levels of apathy 54 • 50% experience emotional lability 54 • Apathy is the most commonly reported behavioural change, measured with the Dimensional Apathy Scale. 55 Emotional lability is characterized by some changes in emotionality and emotion regulation. 54oblematic saliva • 37.5% of people with motor neuron disease 56 • Problematic saliva production and handling in motor neuron disease is characterized by thickened saliva and sialorrhoea.• Detrimental to an individual's well-being, increase the risk of respiratory complications and exacerbate dysarthria.57 Gastrointestinal • 16-83%, depending on the specific symptom 7 • Symptoms such as constipation, nausea, vomiting, acid reflux or excessive flatulence. 58 May occur as a response to interventions (particularly new drug treatments or non-invasive ventilation), secondary to increasingly physical disability or as indicative of wider nervous system degeneration.7,59 Sexual dysfunction • Interest in sex reported to decrease 28% after an motor neuron disease diagnosis 60 • Not directly affected by motor neuron disease but the impact of an motor neuron disease diagnosis on sexuality, intimacy and libido remain relevant to exploring the a more holistic impact of non-motor symptoms of the condition on the individual 61 • Changes in sexual behaviour can have on an individual's quality of life 61,62 ; sexuality is often not discussed in routine clinical consultations or included in research design.
be more common in individuals with worse physical function and older in age.In addition, we hypothesize that people with motor neuron disease may not find the frequency that these nonmotor symptoms are assessed in clinical care, or evaluated in trial design, to be sufficient.As a result, we hypothesize that people with motor neuron disease may be supportive of including nonmotor symptom assessment in future clinical trial design.

Participant recruitment
The  31 No additional exclusion or inclusion criteria were applied.

Patient consent
All participants in this study provided written consent alongside their questionnaires; the consent was obtained according to the Declaration of Helsinki.Ethical approval was provided for this study on 19 October 2021 (Yorkshire and The Humber, South Yorkshire Research Ethics Committee: 21/YH/0226).

Data collection
Source data from participant-completed questionnaires were collected using paper questionnaires or an online survey, depending upon participant preference, to ensure participants with physical disability, speech impairment or inexperience with technology were not alienated from participating.Within the questionnaire pack was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALS-FRS(R)), a questionnaire-based assessment, evaluating the presence and resulting disability, of physical symptoms commonly affecting people with motor neuron disease. 32The participant-reported version of the ALS-FRS(R) demonstrated high inter-rater and intra-rater reproducibility 33 and was shown to be suitable for remote digital assessment. 34In addition to data collection through questionnaires, this project involved a data request to CARE of motor neuron disease for clinical information on participants.

Non-motor symptom selection
The pre-specified list of 11 symptoms explored in this study was selected based on current literature, with input from motor neuron disease clinical specialists, people with motor neuron disease and their caregivers.An opportunity to highlight any symptoms that were impactful to each individual, but not included in the pre-specified list, was also provided in the questionnaire.The 11 aspects of health explored were pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction.Table 1 reports data from previous literature, where available, on the prevalence and features of these symptoms in people with motor neuron disease.
In addition, we asked participants their preference on how these symptoms were assessed.Participants were asked to indicate if they found five types of assessment methods 'acceptable', or if they would 'prefer not to', 'not sure' was also available to offer a neutral response option too.These response options were assigned a numerical code, 'acceptable' = 3, 'not sure = 2', and 'prefer not to' = 1, or in order for responses to be ranked by preference.

Study questionnaire
The questionnaire was developed specifically for this study, and a full copy is provided in the appendices.The questionnaire content was designed with input from members of the multi-disciplinary care team for people with motor neuron disease, expert neurologists and a motor neuron disease nurse consultant.In addition, people with motor neuron disease attending routine National Health Service clinics provided feedback on the early design.The selection of pre-specified potential non-motor symptoms was based on previous literature. 2,3People with motor neuron disease, and their caregivers, provided feedback on the questionnaires in the final stages to ensure the symptom list was comprehensive.

Statistical analysis plan
Descriptive statistics were used to explore the characteristics of the sample, considering demographic, phenotypic and clinical data followed by ascertainment of the total number of nonmotor symptoms reported (defined as a 'yes' response to the list of 11 pre-specified symptoms) are associated with age at participation, age at diagnosis, years since diagnosis and ALS-FRS(R) score using a series of linear regression models.Analysis of variance and t-tests were used to explore the same association of the total number of non-motor symptoms with categorical variables: long survivorship (defined as greater than 7 years since diagnosis), use of interventions, gender and disease sub-type.Missing data will be represented as not available values and the variable excluded from the analysis of that variable; respondents with over half of their data points missing will be excluded from the analysis.
A binary logistic regression was used to explore if the number of non-motor symptoms an individual reported is associated with their response to the questionnaire item 'Is it important to you that trials for new drug treatments also consider symptoms like these [non-motor symptoms] as well?'.
Preference for the assessment method was represented using descriptive statistics, to consider the number of responses to each preference level for the options of assessment.

Sample characteristics
A total of 120 people with motor neuron disease completed the questionnaires between 13 November 2021 and 23 February 2022, 109 in paper format and 11 online.This sample represents 23% of the 532 people living with motor neuron disease in Scotland during the recruitment period and 39% of the group (n = 311) who provided consent to be approached for recruitment to research studies such as this.
Despite a potential for responder bias, the sample characteristics appear to be generally representative of the wider motor neuron disease population 35 ; Table 2 provides an overview of the demographic and clinical characteristics of study participants.The gender divide of participants and the frequency of bulbar symptom onset were akin to previous registry studies in the Scottish 36 and American motor neuron disease populations. 37The use of riluzole, 36 noninvasive ventilation 38 and gastrostomy insertion 13 in study participants was also representative of the wider motor neuron disease population in Europe.
Age at diagnosis of participants was lower than Scottish 36 and English 14 ; motor neuron disease registries have previously indicated, which may be explained by the greater prevalence of people with the progressive lateral sclerosis sub-type in this cohort, as progressive lateral sclerosis often presents at a younger age and is slower to progress than the amyotrophic lateral sclerosis sub-type. 39The greater representation of long survivors in the study cohort, defined as individuals with survival from diagnosis greater than 8 years, 1 than the wider motor neuron disease population may also partially explain the younger age of study participants as long survivorship is associated with younger age at onset. 40

Total number of non-motor symptoms reported Presence, frequency and impact
Ninety-nine per cent of participants experienced at least one non-motor symptom, with 72% reporting five or more nonmotor symptoms.The presence, impact and reported frequency of these symptoms are shown in Table 3.
The most frequently reported non-motor symptoms were fatigue and pain, each affecting 76% of participants; 40% of participants who reported that they experienced pain described that their pain occurred 'every day' in the previous fortnight.
To ensure a more complete picture of the symptoms, experienced participants were also asked to report any additional symptoms that were impactful to them, including any non-motor symptoms not included in the pre-specified list and motor symptoms.A summary of the most frequently reported symptoms is presented in Table 4, with the full data available in Supplementary Table 1, as this includes the frequency with which these symptoms were reported.
There was no significant difference in number of non-motor symptoms reported between men (M = 5.6, SD = 2.4) and women (M = 5.4,SD = 2.2), t(119) = −0.48,no data on sub-type) were removed from this section of the analysis to improve power to detect an effect.We explored the influence of riluzole, non-invasive ventilation and feeding tube use (never taken, currently taking and discontinued) on the prevalence of non-motor symptoms.The use of riluzole (F(3, 117) = 0.22, P = 0.91), noninvasive ventilation (F(3, 117) = 0.62, P = 0.54) or a feeding tube (F(3, 117) = 0.35, P = 0.70) was not associated with the number of non-motor symptoms an individual reported (Table 6).

Management and assessment of non-motor symptoms
Of the sub-group (n = 109) who responded to this question, 73% were satisfied with the frequency with which these symptoms were discussed with their clinical team, reporting that they felt able to raise concerns where needed.
Eighty per cent of all participants indicated that they believe non-motor symptoms are important and should be included in future clinical trials, either to be explored in secondary outcome measures as potential additional therapeutic benefits for candidate drugs or as areas to consider as possible side-effects.
The total number of non-motor symptoms participants personally reported did not have a significant association with the likelihood of a participant indicating 'yes' to the question 'Is it important to you that trials for new drug treatments also consider symptoms like these as well?', (odds ratio = 1.03, 95% confidence interval = 0.82-1.28,P = 0.79).This suggests that the participants' personal experience of non-motor symptoms was not associated with their view that these symptoms are important to include in trial design.
The potential side-effects most frequently raised as concerning by respondents were concerns that a prospective new treatment would cause, or worsen, nausea/vomiting, gastrointestinal issues or fatigue.Ten per cent of respondents stated that any side-effects would inform their decision-making process, and 10% reported that no side-effects would prevent them from taking a drug.

Assessment methods
The most acceptable method of data collection to participants was completing questionnaires themselves remotely, with 91% (n = 108) reporting this as acceptable.This was   Note that due to missing data patterns, frequency of identification may be greater than frequency of occurrence or impact and percentages may not total 100%.b Represented as a percentage of the number of people who reported this symptom as occurring to them.
followed by completing questionnaires with the support of the research team, with 71% (n = 83) reporting as acceptable or using wearable devices to provide data, 68% (n = 79).After these methods, participants indicated a lesser preference for data collection using specialized websites or entering their data into apps.The full exploration of assessment method preference is reported in Table 7.

Findings summary
This study presents the results from a structured questionnairebased study of people living with motor neuron disease in Scotland and identifies that 99% report experiencing a nonmotor symptom, with 72% reporting five or more non-motor symptoms.The high prevalence and frequency of these symptoms are consistently reported in systematic reviews of prior literature, 3 symptom-focused research 41 and interventional studies. 12This study used a questionnaire-based methodology to collate feedback directly from people with motor neuron disease on their experience with a broad list of potential nonmotor symptoms and suggests that these symptoms are more widely experienced and more frequently co-occur than previously suggested in symptom-specific studies. 10,15ain and fatigue were the symptoms participants reported to be the most frequently occurring and most impactful on daily life, aligning with previous research findings on the multi-factorial nature and added burden of pain and fatigue for people living with motor neuron disease. 6,42,43In particular, the finding that pain is a frequently occurring and impactful symptom of motor neuron disease echoes findings presented by the Trajectories of Outcomes in Neurological Conditions group, who in a larger sample of 636 found 69% individuals reported pain and significantly reduced a person's quality of life. 21The prevalence of non-motor symptoms also varied with the clinical characteristics of participants, with those who were long survivors and those with worse physical function (as indicated by lower ALS-FRS(R) scores) more likely to report more non-motor symptoms.
To our knowledge, this is the first study to directly ask participants about their current experience of the evaluation of non-motor symptoms in clinical care and towards the inclusion of non-motor symptoms in clinical trials.
Although symptom-focused trials in motor neuron disease are beneficial to identify treatments, our recent systematic review suggests that the additional potential benefits or side-effects of candidate drugs in motor-focused trials are under-evaluated. 29,30The findings from the current study indicate that people affected by motor neuron disease are also supportive of exploring the holistic impact of motor neuron disease treatment options when choosing outcome measures, irrespective of their personal experience of such symptoms.
The vast majority of people with motor neuron disease supported the consideration of non-motor symptoms when evaluating new drug treatments, aligning with pre-existing expert guidelines, 25 which encourage a more holistic perspective of the impact, management and treatment of motor neuron disease.By focusing on the participant perspective, findings from this study inform of the broad range of symptoms that can be experienced in addition to, or as a result of, motor degeneration in motor neuron disease.

Non-motor symptoms reported
Understanding the frequency and impact of non-motor symptoms experienced by people with motor neuron disease continues to challenge the narrative of motor neuron disease as a primarily motor disorder.A greater understanding of these symptoms can provide an insight into the heterogeneity of motor neuron disease and inform decisions regarding prospective therapeutic targets.Evaluating the importance of these symptoms to people with motor neuron disease enables us to better understand the holistic impact of motor neuron disease on the individual and the disability and impact on quality of life that occur as a result of motor degeneration.
An example of this is the improved understanding over the past decade of cognitive and behavioural change as a common aspect of motor neuron disease progression, particularly the diagnostic overlap with frontotemporal dementia. 44In line with clinical care guidelines, the multi-disciplinary team now routinely screens for cognitive impairment and behavioural symptoms in people with motor neuron disease, with the opportunity to use specifically developed assessment tools such as the Edinburgh Cognitive and Behavioural ALS Screen. 45nderstanding of the frequency of these cognitive and behavioural issues has enabled early intervention so people with motor neuron disease and their supporters can implement management strategies and adapt care plans accordingly. 46

Evaluation of non-motor symptoms
Integration of non-motor symptoms into the trial design is key to offering holistic evaluation of disease progression and effective treatment options.Including non-motor symptoms either as additional outcome measures, potential therapeutic targets or side-effects of investigative medicinal products is supported by the overwhelming majority of respondents and aligns with current trial design guidance. 25,26his study is the first to offer feedback from people affected by motor neuron disease on integrating non-motor symptoms into trial design, indicating that the majority of respondents are supportive.Holistic assessment of non-motor symptoms is also crucial in clinical care.Providing space within the multi-disciplinary team, and time within the clinical appointment schedule, is essential to ensure people with motor neuron disease feel able to discuss their changing health.Non-motor symptoms may not be reported by people with motor neuron disease, so the clinician must lead discussions in this area, prompting their patient to consider symptoms beyond their motor dysfunction and explain the various ways motor neuron disease can present. 23wareness that these symptoms may also be more common in certain groups of people with motor neuron disease may also help shape clinical discussions and offer areas of focus for future research.The current study and previous research indicate that non-motor symptoms increase as the disease progresses and physical function worsens, 5,16 with more symptoms reported by long survivors.
In designing effective research and delivering efficient clinical care, the way in which all symptoms of motor neuron disease are assessed must be a balance between patient preference and data quality.Respondents indicated a clear preference for remote data collection through at-home questionnaires, reducing the burden of travelling to appointments and enabling people with motor neuron disease to respond at their own pace.A preference for remote assessment has been indicated in larger surveys considering self-monitoring and device use as remote options for clinical care and trial delivery. 47

Strengths and limitations
A key strength of this study is the relatively large populationbased sample size for a condition classified as a rare disorder based on prevalence data. 36,48A total of 120 people with motor neuron disease completed the study questionnaires, with demographics and clinical features generalizable to the wider motor neuron disease population.A secondary strength is the focus on exploring the participant perspective using prospective data, in addition to a pre-defined list of potential non-motor symptoms participants were encouraged to consider how they were affected by motor neuron disease and list symptoms that were impactful to them.
A limitation of this general area of research is the difficulty of defining non-motor symptoms, and the subjectivity of how these symptoms can affect, and be reported by, people with motor neuron disease.Different people may report the presence and impact of these symptoms differently, and this impacts their measurement.Quantification of nonmotor symptoms as present versus absent, to enable comparison across participants, may be reductionist.Complex concepts such as mood and fatigue are difficult to define and often overlap, and results must be interpreted cautiously with this in mind.Some of the included symptoms may be more complex and multi-dimensional than others, affecting how participants acknowledge and report their presence.
The availability of disease-specific measurement tools is limited, 29 and current studies use assessments designed for other neurological conditions adapted for motor neuron disease. 4However, these are often reliant on self-reporting of symptoms or clinical judgement, which may be flawed or subjective in their interpretation.An additional limitation of this study is a reliance on self-reporting of symptoms, which may lead to an over (or under) estimation of symptom prevalence and impact.Self-reporting also raises the issue of insight, particularly in relation to cognitive and behavioural changes, that the person affected by motor neuron disease may not report due to lack of awareness of these issues, and as a result, these may be under-represented in the current study.

Future research
Future research in this area may focus on the benefits of assessing non-motor symptoms within current multi-disciplinary care teams and evaluating the suitability of new symptomfocused interventions as potential avenues to improve the quality of life for those currently living with motor neuron disease.This may be a particularly impactful area in individuals in the earlier stages of the condition, and exploring the pattern of nonmotor symptoms in those individuals with a recent diagnosis offers the opportunity to evaluate the benefit of early intervention and the impact of symptoms on care planning decisions.
In addition, studies could explore how these non-motor symptoms can be explored as additional outcome measures in clinical trials.In previous reviews, 29,30 we have reported that non-motor symptoms have been under-evaluated in trial design and the current study provides evidence of support from prospective participants to include additional assessments.More randomized controlled trials focusing on the impact of interventions and medication regimens on non-motor symptoms in motor neuron disease will enable clinicians to make informed, evidenced-based, management decisions that consider the holistic impact of the condition.Considering the effectiveness of interventions for the nonmotor symptoms is a key direction to explore, and the findings will have implications for clinical care.

Conclusion
Ninety-nine per cent of people with motor neuron disease experience at least one non-motor symptom and 72% report five or more; these symptoms affect the vast majority of people with motor neuron disease and often co-occur.The most frequently occurring symptoms are pain and fatigue, reported by 76% of participants respectively, and symptoms that have the most significant impact, where reported, are pain and problematic saliva.Evaluation of the impact of these symptoms on function and quality of life is necessary to understand, manage and ultimately treat the individual.The frequency of reporting non-motor symptoms increases in long survivors and for those with worsened physical function.
The key novel aspect of this study was the exploration of the attitudes of people with motor neuron disease towards including the evaluation of non-motor symptoms in clinical trials.Findings indicated that people with motor neuron disease, prospective participants in these trials, were supportive of including non-motor assessments in trials, in line with clinical 19 and trial 25

Assessment of symptoms
If you were being asked about your motor neuron disease symptoms in clinical or research appointments, there are many different ways that we can collect this information.We would like to know your preferences on how to collect information on motor neuron disease symptoms.
Below is a list of ways that we can collect information, please use the tick boxes to indicate if you would find these options acceptable or not acceptable.There is a change in my speech that people (either yourself or others) have noticed.

3.
People can understand me when I speak but I have to repeat myself often (around a quarter of the time, or more).4.
I can speak but I also need to use technology or writing to be understood.

5.
I can no longer speak.

Saliva
How is your saliva?Please tick 1.I do not have any excessive saliva (please still tick this option if you have a dry mouth).2.
I feel I have excessive saliva and there may be some drooling at night, but I do not usually have to mop up saliva with a tissue.

3.
I need a use a tissue to mop up excessive saliva, but not often (less than a quarter of the time).4.
I experience drooling and have to use a tissue to mop up excessive saliva often, but not all the time. 5.
I need to use a tissue, or suction device, to mop up excessive saliva all of the time.

Swallowing
How is your swallowing?Please tick 1.
I have no problem eating food and having drinks the same as I did before my motor neuron disease diagnosis.

2.
I have some issues with food sticking in my throat or coughing/choking when I eat.Sometimes I have to cut food up small, but I never have to mash or liquidize food.

3.
I need to have food mashed or liquidized, or my drinks need thickeners in.I avoid tougher and drier foods.4.
I struggle to eat food and I need to have gastrostomy to add to my calories intake (please tick yes if you need gastrostomy, regardless of if you have one or not). 5.
I only take in calories through gastrostomy or other supported feeding.

Handwriting
Thinking about your dominant hand, are you able to hold a pen?Please tell us about your handwriting.

1.
My handwriting is normal there has been no change.

2.
My handwriting is slower and sloppier but all words are legible, or sometimes I use writing aids or specialized pen grips.

3.
Not all of my words are legible when I write.

4.
I can grip a pen, but my words are not legible.5.
I am unable to grip a pen.

A. Cutting food and handling utensils-without gastrostomy
Please complete this section if you do not use gastrostomy as your only source of calories.If you only use gastrostomy, please move on to question 5B below.How are you with cutting food or handling cutlery? 1.
There has been no change in my ability to cut up my food and I have not changed the utensils I use to eat. 2.
I am a little slow and clumsy, but I do not need help from others.

3.
Occasionally I need help from others to eat, but usually I can do it alone.4.
I need someone else to cut up my food, but I am able to eat independently. 5.
I need some to cut up my food and help me with eating.I need some help from others with the closures and fasteners.4.
I need someone else to do most of the setting up. 5.
I am unable to do the task alone, someone else has to do it for me.

Dressing and hygiene
How are you with dressing or washing? 1.
There has been no change since my motor neuron disease began.2.
I am a little slower but I do not need other people or supportive devices (e.g.button hook) to help me.3.
I need some assistance at some stages from other people, or supportive devices, when I am getting dressed or washing, but I can do most of it myself.4.
I need assistance when I am getting dressed or washing, but I can do some parts myself.5.
I cannot dress or bathe myself and need support from others.

Turning in bed and adjusting bed clothes
Can you turn in bed and adjust the bed clothes?(pillow/blankets) 1.I can do this as normal.

2.
I am a little slower and clumsy but I can do this without help.

3.
I can turn, or adjust the bed sheets, alone but with great difficulty.4.
I can begin to turn or adjust the bed sheets but I need someone to help me. 5.
I cannot turn or adjust the bedsheets.

Walking
How is your walking? 1.I can walk as normal.

2.
I am have some issues with walking slowly, tripping or balance but I do not need help from others or a walking aid.

3.
I can walk with help from others or a walking aid. 4.
I can stand up and weight bear.

5.
I can no longer walk.

Climbing up stairs
Are you able to climb up stairs?Please only think about going up, not down.

1.
I have no problems going up stairs.2.
I am a little slower but I do not feel unsteady or need to rest between steps.

3.
I need to rest between steps and I feel unsteady.4.
I need support from another person or a handrail to be able to climb stairs.5.
I cannot climb stairs.

Breathlessness
Do you become breathless?If you are using non-invasive ventilation please choose the final option.

1.
No I do not become breathless.2.
I get breathless when I am walking (walking at a good speed on a flat route).

3.
I get breathless when I am eating, bathing or dressing.4.
I get breathless when I am sitting or lying down. 5.
I have significant difficulty breathing and I either currently use, or am considering using, a ventilation system.

Lying down
Can you sleep lying down flat or do you need to be propped up? 1.I do not need to be propped up.

2.
I have some difficulty sleeping at night due to shortness of breath, but I do not routinely use more than two pillows.

3.
I need more than two pillows to sleep, or I need to be angled at 45° or more.4.
I can only sleep sitting up in bed or a chair.5.
I can only sleep with non-invasive mechanical ventilation on for most, or all, of the night.

Respiratory insufficiency
Do you use non-invasive ventilation?1.I do not use.2.
I use ventilation occasionally.

3.
I use ventilation during the night only.4.
I use ventilation during the day and night.5.
I have permanent invasive ventilation by intubation or tracheostomy.

Table 2 Characteristics of non-motor symptoms in motor neuron disease participants Characteristics Overall (%) (N = 120)
P = 0.63, or between the two largest disease sub-types in the sample, amyotrophic lateral sclerosis (n = 67) and progressive lateral sclerosis (n = 21) (F(1, 87) = 0.003, P = 0.96).Rarer sub-types under-represented in this study's sample (including motor neuron disease amyotrophic lateral sclerosis, SOD1 amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy and those with

Table 5 Linear regressions to explore ALSFRS(R), years since diagnosis and age with total number of non-motor symptoms reported
*Indicates significance at P < 0.05.**Indicates significance at P < 0.01.***Indicates significance at P < 0.00.

Table 6 Analysis of variance to explore intervention use and disease sub-type with total number of non-motor symptoms reported
a ANOVA uses disease sub-types of amyotrophic lateral sclerosis and progressive lateral sclerosis only.

Table 7 Assessment methods ranked by preference Assessment method N
guidance encouraging a broader conceptualization of treatment.What types of side-effects would concern you most about new treatments being investigated in a drug trial?If a drug being investigated in a clinical trial led to side-effects, which side-effects would stop you from wanting to take a new drug?Please 'list up to five symptoms' that you experience, which affect your life the most.If you cannot think of this many, please leave lines blank.You can use symptoms already mentioned in the questionnaire or new ones of your own.Please indicate how often this symptom occurs for you, and how much of a problem it is for you.
Non-motor symptoms motor neuron disease BRAIN COMMUNICATIONS 2024: Page 15 of 17 | 15 B. Cutting food and handling utensils-with gastrostomy If you do not have gastrostomy, or still have some food, please complete 5A instead.How are you with handling the gastrostomy fastenings and fixtures?1.I have no difficulty with setting up the fastenings and fixtures.2. I am a little slower and clumsy but I can do it myself.3.