Assessment of suspected motor neuron disease
BMJ 2022; 379 doi: https://doi.org/10.1136/bmj-2022-073857 (Published 23 November 2022) Cite this as: BMJ 2022;379:e073857- Colin J Mahoney, consultant neurologist1,
- Richard Sleeman, freelance journalist and person living with motor neuron disease2,
- Will Errington, general practitioner3
- 1Forefront Motor Neuron Disease Clinic, Brain and Mind Centre, University of Sydney, Australia
- 2Sydney, Australia
- 3Rose Bay Family Medical Centre, Sydney, Australia
- Correspondence to C J Mahoney colin.mahoney{at}sydney.edu.au
What you need to know
Amyotrophic lateral sclerosis (ALS, a form of motor neuron disease) was previously considered rare, but incidence is expected to increase by 30% by 2040
ALS is a multisystem disease that commonly causes cognitive and behavioural changes; up to one quarter of patients meet the criteria for dementia
Diagnostic delay may reduce access to treatment and support that could improve survival and quality of life; refer urgently for expert assessment patients with asymmetrical painless progressive weakness or unexplained changes to swallowing
Motor neuron disease (MND) represents a group of neurodegenerative disorders that feature progressive motor weakness of limb or bulbar muscles (ie, those innervated by the lower brain stem). Classically, three distinct MND phenotypes are described, and these present along a spectrum of upper and lower motor neuron dysfunction,1 with increasing recognition of non-motor features.2
Amyotrophic lateral sclerosis (ALS) represents 85% of all MND cases, and features a combination of upper and lower motor neuron dysfunction.1 Primary lateral sclerosis (PLS) presents with upper motor neuron dysfunction, with substantial muscle spasticity. Primary muscular atrophy (PMA) presents with lower motor neuron dysfunction, with flaccid weakness and muscle atrophy. ALS is typically associated with rapid clinical decline, with survival typically 3-4 years from symptom onset, but PMA and more so PLS are associated with longer survival.3 This article focuses primarily on ALS.
Why should non-neurologists know about ALS?
People with ALS often experience challenges in getting the right diagnosis (box 1). Most patients visit their general practitioner first, typically with mild symptoms such as cramps, balance disturbance, reduced dexterity, or subtle cognitive changes including apathy. The time from symptom onset to diagnosis ranges from 10 to 16 months, and signs often go unrecognised, with patients referred to other specialists, or given misdiagnoses.5 Despite attempts to improve awareness in primary care, many doctors remain unfamiliar with the core features of ALS.6 Patients are often given a diagnosis of degenerative spinal disease, with 12% of ALS patients undergoing inappropriate surgery,7 which may lead to accelerated functional decline,8 increased levels of distress and anxiety for patients and their carers,9 and higher costs for health systems.10 Guidelines from the National Institute for Health and Care Excellence,11 European Academy of Neurology,12 and American Academy of Neurology13 emphasise early recognition and priority referral to an experienced centre for assessment. This allows early access to disease modifying therapies, clinical trials, and multidisciplinary support, which may improve survival and quality of life. Primary care doctors, as the gateway to medical contact, can be critical in reducing delays.
2020 Gold Coast Criteria for ALS4
Criteria for diagnosis of ALS
Progressive motor impairment documented by history or repeated clinical assessment, preceded by normal motor function, and
Presence of upper and lower motor neuron* dysfunction in at least one body region,** (with upper and lower motor neuron dysfunction noted in the same body region if only one body region is involved) or lower motor neuron dysfunction in at least two body regions, and
Investigations excluding other disease processes.***
*May be either clinical examination findings or features of active and chronic denervation using needle electromyography (EMG)
**Body regions are bulbar, cervical, thoracic, and lumbosacral
***Table 1 lists suggested investigations to exclude other disease processes
How common is ALS?
MND/ALS is a rare disease with a global prevalence of around 4.5 cases per 100 000, increasing to 12 to 15 per 100 000 in high income settings,14 comparable to the prevalence of glioblastoma multiforme, the most common malignant brain tumour.15 ALS presents most commonly in the sixth and seventh decades of life and is 1.3 times more common in men than women.16 In 2016, global deaths from ALS increased by 8%, rising to 14% in countries with a high sociodemographic index (SDI), and 22% in nations with a moderate SDI.14 By 2040, global incidence of ALS is estimated to increase by 31%, and by 50% in China and Iran.17
What causes ALS?
For most people, ALS occurs sporadically. Around 10% develop it as a result of mutations in chromosome 9 open reading frame 72 (C9ORF72), or less commonly the superoxide dismutase 1 (SOD1) gene.1 In approximately 15% of patients with no reported family history, the cause is eventually determined to be genetic, highlighting the need to consider routine genetic testing in people with apparently sporadic disease.18 The cause of sporadic ALS remains unclear, although it has been suggested that ALS results from a multistep process requiring six “hits” prior to disease onset.19 Two of these “hits” are from gene mutations, but the other four are unknown. Some “hits” may occur because of multiple risk genes, such as UNC13A, and ALS is more common in families with a history of significant neuropsychiatric or neurodevelopmental disorders.20 Environmental risks may be another contributing factor. One systematic review suggests that some individuals with high lifetime levels of physical activity (notably those playing professional sports with recurrent concussive or cervical traumas) are at an increased risk of disease.21
How does ALS present?
ALS is a syndrome of initially localised, typically painless and progressive weakness, though different patterns of upper and lower motor neuron dysfunction may occur (fig 1).1 Limb onset ALS occurs in around 60% of patients, with asymmetric muscle weakness and atrophy occurring, often in the dominant limb,22 before spreading to the contralateral limb. Seventy per cent of patients present with limb weakness, approximately half with shoulder girdle and intrinsic hand muscle weakness, and half with asymmetric lower limb weakness.22 Around 30% of individuals present with bulbar onset ALS with a combination of progressive dysphagia and dysarthria, sometimes referred to as progressive bulbar palsy.1 Dysphagia for dry crumbly food or thin liquids is common; however, subtle symptoms may include unexplained weight loss or increased eating time. Dysarthria may manifest as a change in diction or pitch, with hypernasality depending on the extent of upper or lower motor neuron involvement. A recognised molecular link exists between frontotemporal dementia (FTD) and ALS, resulting in 10-15% of patients presenting with significant behavioural and cognitive disturbances either before or alongside their motor weakness.2
What examination findings should prompt consideration of ALS?
The combination of upper and lower motor neuron findings in a limb or the bulbar region (eg, a wasted tongue and presence of a jaw jerk) should prompt consideration of ALS. The presence of a split hand (fig 2) has a high specificity (around 95% compared with healthy controls) for ALS,23 and is characterised by wasting of the lateral (thenar) side of the hand and preservation of the medial (hypothenar) side. Patients may develop widespread fasciculations, often more obvious proximally, though fasciculations in the absence of weakness should be interpreted with caution as this is common in healthy individuals.24 Upper motor neuron dysfunction may manifest more subtly, with spastic (“high pitched”) dysarthria, slower walking, and impaired fractioned finger movements, accompanied by clonus, hyper-reflexia, and extensor plantar responses.25 Cognitive and behavioural disturbance is increasingly recognised in ALS, and combined with motor dysfunction, substantial apathy, disinhibition, or emotional lability is linked with frontal lobe dysfunction associated with ALS-FTD spectrum disorder.2
Does ALS only affect muscles?
Up to half of those with ALS develop some cognitive impairment, with 25% eventually meeting the criteria for FTD.26 The commonest cognitive and behavioural abnormalities are executive dysfunction and apathy, respectively, both being associated with poorer survival.26 Eighty per cent of patients experience significant anxiety and 20% develop psychosis.26 Screening for these symptoms should be routinely considered; the Edinburgh cognitive and behavioural ALS screen takes around 10 minutes to complete.27 Other non-motor symptoms may include hypermetabolism associated with weight loss, sleep disruption, and autonomic dysfunction.
What other conditions should be considered?
Up to two thirds of patients receive an alternative diagnosis prior to ALS5; however, only 6% of those with ALS subsequently receive an alternative diagnosis.28 In those without a combination of upper and lower motor neuron signs, an alternative diagnosis should always be considered. The list of disorders that may mimic ALS is extensive29; however, several of the disorders are treatable or less aggressive than ALS, and these often have distinguishing clinical features (table 1, fig 3).
What tests should be considered when suspecting ALS?
The 2020 Gold Coast diagnostic criteria (box 1) emphasise that ALS is a clinical diagnosis.4 These criteria have a sensitivity greater than 90% for diagnosing ALS30 and stress that appropriate investigations should be undertaken to exclude other causes.12 Other investigations should be guided by the clinical history and examination.
What is the role of the non-neurologist in caring for those with ALS?
Management of ALS is complex, with patients relying on a range of health professionals to provide care. An ALS multidisciplinary clinic has a central role in facilitating care, and can provide a survival benefit of around eight months.126 The configuration of these services varies, but often involves physiotherapy, speech and occupational therapists, respiratory medicine, and palliative care. Specialist nurses provide a link with community services and general practice. Specific therapies delivered by non-neurologists include non-invasive ventilation, with one cohort study showing that, in treated patients, median tracheostomy-free survival was 28 months compared with 15 months in untreated patients, with the greatest benefits seen in bulbar onset ALS.31 Improved nutritional support with high calorific fatty diets offered survival benefits in those with fast progressing disease.32 A combination of disease modifying and supportive therapies represent best practice in improving survival and quality of life for those with ALS; however, further well designed trials are needed to confirm the benefits.
Future developments
A major research focus in neurodegenerative disease is to identify prodromal or early disease, the hypothesis being that earlier disease modification will improve outcomes. The updated Gold Coast diagnostic criteria enable earlier diagnosis and access to emerging therapies.4 In future, non-motor features may also be incorporated. Biomarkers, such as serum neurofilament light chain, are elevated early in the disease and may also have a role in early diagnosis.33 ALS is a heterogeneous disease, and it is likely that analysis of a variety of clinical, genetic, and other biomarker profiles will lead to a more individualised approach to both prognosis and treatment. Until these techniques are translated into the clinic we will continue to rely on clinicians’ recognition of ALS. We propose a simple clinical algorithm (fig 4) to highlight core clinical features to aid non-neurologists in recognising ALS and lead to prompt onward referral to an appropriate diagnostic service. The move towards precision medicine in ALS is being supported by global consortiums, such as the European Network to Cure ALS and the Northeast ALS Consortium in the US. The box “Resources for patients” lists national organisations that can provide support to patients and healthcare providers for care and developments in ALS research. With prompt diagnosis, patients have increasing opportunities to engage with these networks, whose ultimate aim is to identify disease modifying therapies to slow or halt disease progression.
Education into practice
A 62 year old man presents with several months of progressive swallowing difficulties, weight loss, and difficulty doing up shirt buttons. What first steps will you take to explore his symptoms and condition?
You are notified that a patient has received a diagnosis of ALS. What key areas will you prioritise for their future care?
The author’s experience of diagnosis
The first indication for me of what would much later be an MND diagnosis was trying to run for the train. I was suddenly frozen, unable to put one foot in front of the other, like in the common nightmare: being chased, but stuck there. As it happened more often, I sought advice from GPs—four in six months. I was told it was just old age or arthritis: get some physiotherapy, here are some anti-inflammatories. I was 62. Only when I saw a neurosurgeon on a completely unrelated matter—for a pinched nerve in my neck—was something more sinister suspected. He was concerned about my right foot shuffle and shake, ordered a brain scan, and made a neurology appointment. There I was told: “I think I know what it is. You’ll need tests. Are you stoic?”
Resources for patients
International support groups for those living with ALS/MND
ALS Association (USA): www.als.org
MND Association (UK): www.mndassociation.org
MND Australia: www.mndaustralia.org.au
Patient involvement
RS provided a personal reflection as a patient and supplied guidance as to the priorities of those living with motor neuron disease. He provided critical review and revision of the manuscript.
How this article was created
The authors searched PubMed and Web of Science to identify contemporary (within the past 10 years) literature relating to diagnosis and management of motor neuron disease. Particular attention was paid to recent epidemiological studies, non-motor dysfunction, and multidisciplinary management, given both recent advances in these areas and importance to the non-neurologist. Relevant societal guidelines were also reviewed.
Footnotes
Contributorship: CM conceived the article and is the guarantor. All authors contributed to the drafting and final revision of the article, including revision of figures and tables.
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.
Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests
Provenance and peer review: commissioned; externally peer reviewed.