This information is for health professionals and service providers.
More than 50% of people with MND will experience changes in cognition, language, behaviour and personality. These changes may be classified as ALS with cognitive impairment, ALSci, ALS with behavioural impairment, ALSbi, and ALS with cognitive and behavioural impairment, ALScbi.
Most people experience relatively mild changes. However, a small proportion will show more significant changes and will receive a diagnosis of ‘motor neurone disease with frontotemporal dementia’ or ALS-FTD.
While the nature of changes in cognition and behaviour will vary from person to person, some of the most common symptoms are listed below:
Changes in language can include:
Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder which includes a broad spectrum of non-motor symptoms that can dominate the clinical presentation. Cognitive and behavioral symptoms include impaired executive function, deficits in social and emotional cognition, apathy, disinhibition, and perseveration similar to that seen in frontotemporal dementia (FTD). Frontotemporal dysfunction of varying severity can affect more than 50% of ALS patients, with ~8–14% meeting full diagnostic criteria for FTD. As such, early detection and timely management of cognitive and behavioral symptoms is widely acknowledged as an important aspect of contemporary ALS care. However, fully assessing cognitive and behavioral symptoms in ALS is made difficult by the fact that these symptoms must be distinguished from psychological reactions to a terminal diagnosis and the progressive physical loss that comes alongside it (Caga et al 2019).
Of the 797 patients included in the study, 163 (20.5%) had ALS–frontotemporal dementia (FTD), 38 (4.8%) cognitive and behavioral impairment (ALScbi), 132 (16.6%) cognitive impairment (ALSci), 63 (7.9%) behavioral impairment (ALSbi), 16 (2.0%) nonexecutive impairment, and 385 (48.2%) were cognitively normal. According to King staging, the frequency of cases with ALS-FTD progressively increased from 16.5% in stage 1–44.4% in stage 4; conversely, the frequency of ALSci, ALSbi, and ALScbi increased from King stage 1 to King stage 3 and decreased thereafter. A similar pattern was observed with the MiToS staging. ALS-FTD was more frequent in patients with bulbar involvement at time of cognitive testing. Patients with C9ORF72 expansion (n = 61) showed more severe cognitive impairment with increasing King and MiToS stages.
Our findings suggest that ALS motor and cognitive components may worsen in parallel, and that cognitive impairment becomes more pronounced when bulbar function is involved. Our data support the hypothesis that ALS pathology disseminates in a regional ordered sequence, through a cortico-efferent spreading model” (Chiò et al 2019).
Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).
These revised criteria (Table 2) have addressed the issue of genetic testing more critically, in part driven by the explosion in knowledge of genetic mutations that are either causally associated with ALS, or identified as modifiers of the disease process (Strong et al 2017).
Recent discoveries have highlighted the ‘non-motor’ aspects of the disease, with increasing awareness of cognitive dysfunction in patients with MND. There is a spectrum of cognitive impairment marked by behavioural changes such as apathy and disinhibition, mood changes, and executive dysfunction, with a minority of patients progressing to a diagnosis of coexistent frontotemporal dementia (Simon et al 2015).
Ideally, consultation with a neuropsychologist for cognitive assessment is beneficial if cognitive involvement is suspected. Regular and timely review and assessment of changes in cognition and behaviour is an important aspect of the multidisciplinary care of people living with MND. Early identification is important in supporting decision making and advance care planning.
Dementia in ALS Patients—ALS-FTD Variants
ALS-FTD diagnosis is made upon the presence of an ALS phenotype associated with behavioural or cognitive defects that fulfil FTD diagnostic criteria: (1) progressive impairment of behavioural/cognitive functions and observation of at least three behavioural symptoms defined by Rascvosky et al.; or (2) loss of insight and/or presence of psychotic features associated with at least two Rascvosky et al. symptoms; or (3) language impairment combined with semantic dementia.Cognitive Changes in Non-Demented ALS Patients—ALSci and ALSbi Variants
Non-demented ALS patients presenting with behavioural impairment are classified as ALSbi-variant, while ALS patients experiencing cognitive impairment including language defects are considered to be ALSci variant. Based on the revised diagnostic criteria from Strong et al., ALS patients can be diagnosed as ALSci variant if either executive impairment (social cognition), or language dysfunction, or a combination of the two features are evident during diagnosis. Diagnostic criteria for ALSbi variant require apathy with or without other behavioural symptoms, or two or more behavioural changes, such as disinhibition, loss of sympathy/empathy, perseverative/stereotypic/compulsive behaviour, hyper orality/dietary change, loss of insight and psychotic symptoms” (Connolly et al 2020).
There is general consensus that an extensive neuropsychological battery is required to confirm the presence of cognitive impairment, and in particular to assess which cognitive domains are affected. In clinical practice, however, it is not always feasible for all ALS patients to undergo such a broad assessment, because it is time-consuming, expensive, requires qualified personnel, and fatigues patients. Moreover, ALS patients may not be capable of completing a full neuropsychological battery due to motor and/or speech impairment. Therefore, several brief cognitive screeners have been developed, specifically designed for testing ALS patients. The current systematic review provides an overview of cognitive and behavioral screening instruments used in ALS patients, based on information gathered from 99 articles (Gosselt et al 2020).
This systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards (6). The main aim was to evaluate the validity of six ALS-specific screening tools referred to by Strong et al. (4). Box 1 describes the screening tools in terms of who usually completes them and what they measure (Simon and Goldstein 2018).
Assessment and management of cognitive and behavioral symptoms forms the larger goal of preservation of quality of life in both ALS patients and caregivers. Timely assessment of cognitive and behavioral symptoms has important prognostic and therapeutic implications. The presence of dysexecutive symptoms is not only likely to impact on patient and caregiver psychological well-being but also decision-making, adherence to life-sustaining interventions, and capacity to engage and benefit from non-pharmacological interventions. Additionally, cognitive and behavioral symptoms may exist before full blown motor symptoms and, therefore, the ability to make informed decisions may be effected early in the disease course.
While treatments for symptomatic management in ALS is often most beneficial if initiated early and clinicians value proactive decisions, failure to identify cognitive and behavioral symptoms may mean that patients are not fully supported by their health care team and caregivers to undertake informed decision-making that is in accordance with their current personal philosophy and values” (Caga et al 2019).
As such, beyond expanding the nature of neuropsychological and neuropsychiatric deficits that characterise ALS- FTSD, a key advance in this revision is the inclusion of three levels of complexity or depth of assessment: criteria which can be applied in everyday clinical use (Level I), those which can be utilised for prognostic stratification in clinical trials (Level II), and those which are considered as research intensive with the goal of better defining the nature and extent of FTSD in ALS (Level III) (Figure 1).
The criteria are intentionally hierarchical. Level I incorporates tools that can be easily applied at the bedside and are of low statistical complexity, require the least amount of effort to implement, rely upon well-validated tools that have already been applied in the ALS population, and while not requiring neuropsychological support for implementation, would benefit from neuropsychological support for interpretation. Level III are the most advanced criteria and contain the core elements of the Level I testing but are of high statistical complexity, require a maximum amount of time and effort to complete, include research tools not yet validated in a broader ALS population, and would be considered research grade. Level II criteria are anticipated to be applicable to clinical trials where a moderate amount of effort could be expended. Level II criteria also would consist of a minimum dataset for inclusion in case publications. In contrast to Level I, Level II criteria require the engagement of either neuropsychologists or speech-language pathologists to evaluate the testing paradigms, to oversee or manage test administration and to interpret results ” (Strong et al 2017).
A complete family history of neurological disease is critical, as families in which young-onset cognitive impairment (often mistakenly labelled as Alzheimer disease), Parkinson disease and psychiatric disorders cluster with MND, suggesting the presence of the recently identified hexanucleotide expansion mutation in the C9orf72 gene. Cognitive symptoms are particularly important to consider when constructing multidisciplinary management plans, as they may result in barriers to effective intervention if not addressed (Simon et al 2015).
Management and treatment for frontotemporal dysfunction and cognitive change in motor neurone disease is an emerging area of research. There are currently no evidence-based treatments available to manage cognitive and behavioural symptoms. Early recognition, timely information and a multidisciplinary team approach to support the person living with MND and their carer is therefore the mainstay of treatment.
Management of cognitive and behaviour change (ALSci and ALSbi) includes:
It is also essential to recognize the importance of caregivers in the management of ALS from an early stage, informing them about the possibility of burden, offering them health care support, and monitoring their well-being over time. Weisser et al. showed that the needs of ALS caregivers were multiple, including practical, social, and psychological needs. A model of coping was subsequently proposed integrating resilience, burden, needs, and rewards. An intervention to reduce maladaptive coping strategies has also been found to improve well-being in caregivers of patients with ALS. Furthermore, the use of technological approaches (e.g., telemedicine) for ALS patients and their caregivers that live in remote and rural areas which have reduced access to health care services may be especially beneficial. Provision of training for health care professionals to help patients and caregivers during the advanced stages of the disease would also ensure that important factors such as fatigue, stress, and ethical challenges related to end-of-life care are adequately addressed (Caga et al 2019).
Most of the time, interventions and treatment in ALS are focused on quality of life and safety. For the person with cognitive and/or behavioral challenges, it is important to identify advanced directives as early as possible in the course of disease. Caregivers, family members, and even providers on the team should be educated about appropriate expectations for the person with ALS. When a caregiver or team member is reporting that a person with ALS/MND is having difficulty following or responding to recommendations, the neuropsychologist can use information from the cognitive and behavioral evaluation to educate team members about the most effective ways to work with the person, using his/her strengths or environmental strengths to meet challenges. Arguably, the neuropsychological evaluation of the person with ALS/MND provides some of the most powerful data for informing interventions and addressing functional recommendations (Woolley and Rush 2017).
There are five types of strategies used with patients and families in managing negative behaviors: environmental, behavioral, pharmacological, physical, and those internal to the family caregiver. Environmental strategies focus on modifications to the person's environment. Examples include limiting access to bank accounts or altering aspects of the patient's environment such as access to cars, dangerous tools or even food. Behavioral strategies focus on changing the person's behavior and can include actions such as rewarding positive behaviors. Pharmacological strategies involve medications. The selective serotonin reuptake inhibitors (SSRIs) and related compounds remain the mainstay of treatment for treating bvFTD, however, there are limitations to pharmacologic management and not all behaviors can be medicated. Physical strategies include any action that blocks the person's movement or access, e.g. restraint vests or belts. This category is rarely employed, as the use of restraint devices is usually associated with adverse consequences.
A fifth type of intervention is internal to the caregiver and involves aspects of psychological coping and acceptance for the symptoms. It entails assisting the caregiver to change their reaction and response to the negative behavior(s). Some families struggle with providing exemplary care, yet despite their hard work and deep concern, the disease progresses and the patient worsens. Although it can be difficult for family caregivers to ask for assistance or feel comfortable taking time away from caregiving, these are appropriate strategies for managing the hardships of patient care and behavioral/cognitive symptoms. Table 1 provides a few examples of possible interventions for negative behaviors (Merrilees et al 2010).
Upper motor neurone involvement is associated with pseudobulbar palsy. This is a troubling symptom that occurs in as many as half of all people living with motor neurone disease. It may involve excessive laughing or crying, or involuntary emotional expression and/or facial spasticity. This is referred to as pseudobulbar affect (PBA) and is also known as known as 'involuntary emotional expression disorder' or emotional lability. Emotional lability is not a mood disorder but abnormal affective display. It is often confused with depression and people living with MND and their carer may not recognise or report it as a symptom. Careful review and assessment is therefore required.
These symptoms can cause severe distress, embarrassment, social disruption and isolation adding to the burden of communication and cognitive difficulties with which patients and their carers must cope.
Management includes:
NOTE: Nuedexta, a combination of dextromethorphan and quinidine, has shown to be effective in some trials and has been approved by the FDA for use in ALS patients in the USA to manage emotional lability. This medication is not approved by the TGA in Australia.
The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Fig. 2). When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli ( Brown and Al-Chalabi 2017).
Also referred to as emotional lability, this symptom is common in ALS, particularly for those with greater bulbar involvement. Spontaneous crying or laughing episodes of pseudobulbar affect (PBA) can be difficult to control and may occur without provocation. For those who are tearful, caregivers may mistakenly describe the patient as depressed. Careful questioning can help differentiate depressive symptoms from PBA.
In PBA, the FDA has approved the use of Nuedexta, a dextromethorphan-quinidine sulfate compound that attenuates disproportionate laughing, crying, or increased emotional reactivity. In situations for which excessive psychomotor agitation, fall risk, impulsive gait or transfers, or disinhibited behavior create challenge, other psychotropic medications such as low-dose SSRIs or even very low dose atypical antipsychotics can be considered (Woolley and Rush 2017).
Pseudobulbar affect (PBA) affects 20%–50% of patients with ALS, especially in patients with bulbar onset. (14 McCullagh) The characteristics of PBA include uncontrolled laughter or crying, often with minimal or no provocation. Episodes are often sudden, involuntary outbursts of emotion inappropriate to the context of the situation. Patients experiencing uncontrolled crying are more common than those with uncontrolled laughter, however, the symptoms can result in significant disability, limiting social interactions and impairing quality of life (QoL).
Although it is not a mood disorder, selective serotonin reuptake inhibitors, tricyclic antidepressants and some serotonin-norepinephrine reuptake inhibitors have been used for treatment of PBA (Table 2).
A novel combination of dextromethorphan (20mg) and quinidine sulfate (10mg) (Nuedexta™) has been shown to be effective in a large phase three multicenter randomized trial. Nuedexta patients reported significantly less emotional lability, improved QoL and improved quality of relationship scores. Side effects included dizziness, nausea, and somnolence. These side effects can be minimized by initiating the dose at 1 tablet at bedtime for 7 days followed by twice a day dosing. The AAN Practice Guidelines recommend that if side effects are acceptable, dextromethorphan/quinidine should be considered for symptoms of pseudobulbar affect in patients with ALS (Level B)” (Jackson et al 2015).
Approximately half of patients experience emotional lability, pathological laughter or crying and this is more common in those with bulbar onset ALS. A selective┽serotonin reuptake inhibitor (fluvoxamine) and amitriptyline have been associated with reduced emotional outbursts in small observational studies. More recently two randomised controlled trials of Nuedexta, a combination of dextromethorphan and quinidine, including 333 patients with ALS found a significant reduction in emotional events. Side effects include dizziness and somnolence which led to 24% of patients to stop taking the drug in one study. Nuedexta should be avoided in those with a risk of cardiac arrhythmia as it can prolong the QT interval. It is licensed for use in the United States and is awaiting European license (Hobson and McDermott 2016).
Emotional lability occurs in at least 50% of patients with ALS irrespective of the presence or absence of bulbar motor signs. Emotional lability does not correlate with cognitive impairment. Prominent pseudobulbar features such as pathological weeping, laughing or yawning can be socially disabling and affect patients’quality of life. The most commonly used agents are tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), which were effective in small placebo-controlled studies or case series (Class IV). Two randomized controlled trials of a fixed dose combination of dextrometorphan and quinidine have shown efficacy in improving emotional lability and quality of life (Class I). This medication has been approved by the US FDA (Andersen et al 2012).
Recent research, conducted by the Department of Developmental Disability Neuropsychiatry (3DN) at UNSW, Sydney looked at the physical and mental health needs of people with MND to see whether people with MND use mental health services more or less than the general population and people with other neurological disorders (such as Alzheimer’s disease and Parkinson’s disease). This project also examined whether mental health is associated with going to hospital for physical health conditions, and the information needs of this cohort and mental health services caring for people with MND.
Compared with the general NSW population, people with MND* had a:
*After adjusting for age and sex (a statistical procedure to adjust for any differences in age and sex between the groups)
Compared with people with other neurological disorders, people with MND* had a:
*After adjusting for sex, age, remoteness of area (metropolitan area or rural and remote), socioeconomic status of area, and the Charlson Comorbidity Index (measure of comorbid, or other, medical conditions).
The use of mental health services was highest in the year after people’s first admission for MND. Fact sheets have been developed for people with MND; their families, friends, and carers; and for health professionals.
Regular review and monitoring of person with MND, as well as their carer, for signs of depression and anxiery, especially in the weeks and months following diagnosis, should be included in their management plan.
Based on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, the “gold standard” for assessment of depression, the rate of clinical depression ranges between 9 and 12% in ALS. Perhaps not surprisingly, self-report measures of depression tend to show more variable rates of depression ranging from 20 to 64%. Similarly, the prevalence rates of anxiety vary widely, with rates ranging as low as 8% to as high as 88% among patients with ALS. The severity of symptoms appear to be predominantly in the mild range. Despite the low rates of clinical depression and anxiety, patients with ALS have been shown to be at increased risk of being diagnosed with depression, anxiety and other neurotic or stress-related disorders following diagnosis, however this may be attributable to the clinicopathological overlap between ALS and FTD (Caga et al 2019).
Several classes of medications are used for the treatment of depression in ALS and are used depending on their side effect profile. There have been no controlled clinical studies of these medications in ALS patients. Tricyclic antidepressants like amitriptyline can be prescribed if anticholinergic effects are desired simultaneously for treating sialorrhea, pseudobulbar affect or insomnia.
Prevalence rates for anxiety in patients with ALS range from 0–30%. (93 Kurt 2007) The early disease phase, especially during the diagnostic period, has been reported to be associated with a higher level of stress and anxiety. (96 Vignola 2008) Anxiety is usually treated with anxiolytics like benzodiazepines, but again there have been no systematic studies of these drugs in patients with ALS. Treatment of depression and anxiety can involve both cognitive behavioral therapy and pharmacological intervention. There are no clinical trials that allow a recommendation of pharmacotherapy over psychotherapy. A positive patient-physician relationship and easy access in communicating with their physician reduces levels of anxiety in patients. Patients may benefit from a range of approaches, including relaxation strategies such as meditation and biofeedback. Cognitive behavioral therapy equips patients with the skills to overcome maladaptive thought patterns and encourages emotional readjustment (Jackson et al 2015).
The incidence of depression ranges from 11% (interview studies) to 75% (self┽ reported measures) and is associated with a poorer quality of life. There have been no trials of specific ALS treatment, so standard therapies (selective-serotonin reuptake inhibitors, amitriptyline or mirtazapine) are recommended (Hobson and McDermott 2016).
Depression and anxiety occur frequently in patients with ALS and their caregivers. Anxiety is particularly prevalent during the diagnostic and terminal phases. No formal studies with antidepressants have been conducted in patients with ALS, but empirically tricyclic antidepressants (e.g. amitriptyline) and SSRIs such as escitalopram may be effective. Mirtazapine may be better tolerated in the later stages than SSRIs or amitriptyline. The choice may be guided by additional symptoms (e.g. sialorrhoea, insomnia, apathy, appetite loss), which are differently affected by the various antidepressants. There are no systematic studies on anxiolytics in ALS. Some antidepressants, such as escitalopram, exert anxiolytic effects, but additional oral diazepam or sublingual lorazepam, may be necessary (Andersen et al 2012).
Shoesmith et al 2021, Canadian best practice recommendations for the management of amyotrophic lateral sclerosis
See table 1: symptom management recommendations
National Institute for Health and Clinical Excellence (2016) NICE Guideline: Motor Neurone Disease Assessment and Management – see recommendation:
1.3 Cognitive assessments
Andersen et al 2012, EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task force - Cognition in ALS Recommendations:
Being a syndrome with low incidence and short survival, most recommendations are good clinical practice principles (GCPPs) based on the consensus of experts in the field of ALS. Further randomized and double‐blind clinical trials are urgently needed to improve the management of ALS.
Miller et al 2009, Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom managment and cognitive/behavioural impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology:
See also: Summary of Evidence Based Guideline for Clinicians
The Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a brief multidomain assessment originally designed for people with Amyotrophic Lateral Sclerosis (ALS/Motor Neurone Disease) - downloads and guidelines
Andersen et al 2012, EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task force - Pseudobulbar emotional lability recommendations:
Miller et al 2009, American Academy of Neurology (AAN) update: The management and care of the patient with amyotrophic lateral sclerosis (ALS): Multidisciplinary care, symptom management, and the treatment of cognitive/ behavioral impairment:
Recommendations:
For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.
National Institute for Health and Clinical Excellence (2016) NICE Guideline: Motor Neurone Disease Assessment and Management – see recommendation:
1.6 Psychological and social care support
Andersen et al 2012, EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task force - Depression and anxiety recommendations:
MND Aware e-training program MND Hub – online training course for health professionals and service providers developed by MND NSW – Session 16: Symptom Management –Cognition
The Southern Metropolitan Region Palliative Care Consortium (SMRPCC), Robyn Reid, MND Shared Care Worker- MND podcasts - Fronto temporal dementia
International Alliance of ALS/MND Associations,18th Allied Professionals Forum, 2020:
International Alliance of ALS/MND Associations,16th Allied Professionals Forum, 2018:
International Alliance of ALS/MND Association, 15th Allied Professionals Forum 2017:
MND NSW, Special Interest Group meeting 2017:
International Alliance of ALS/MND Association, 14th Allied Professionals Forum 2016:
Professor Sharon Abrahams, Personal Chair in Neuropsychology, The University of Edinburgh delivers her inaugural lecture entitled: Mind Matters in Motor Neurone Disease, 2015
ALS Association, Professionals Guide, Cognitive impairment and dementia
MND Association England, Wales and Northern Ireland, Cognitive Change and frontotemporal dementia and MND
MND Australia, Motor Neurone Disease: More Facts - for people living with MND
MND Australia Fact Sheet series for people living with MND:
Cognitive and behaviour change in MND
MND Australia 4th MND Connect 2018:
Health Talk - healthtalk.org - stories collected by academic researchers who interview people in their own homes, using their own words: