PRACTICE
1 Forefront Motor Neuron Disease
Clinic, Brain and Mind Centre,
University of Sydney, Australia
2 Sydney, Australia
3 Rose Bay Family Medical Centre,
Sydney, Australia
Correspondence to C J Mahoney
colin.mahoney@sydney.edu.au
Cite this as: BMJ 2022;379:e073857
http://dx.doi.org/10.1136/bmj-2022-073857
Published: 23 November 2022
the bmj | BMJ 2022;379:e073857 | doi: 10.1136/bmj-2022-073857
PRACTICE POINTER
Assessment of suspected motor neuron disease
Colin J Mahoney, 1 Richard Sleeman, 2 Will Errington3
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.
Box 1: 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
1
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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
Fig 1 | Different clinical phenotypes and examination findings across the spectrum of motor neuron disease. Green=greater involvement of lower motor neurons; blue=greater
involvement of upper motor neurons. PMA=progressive muscle atrophy; ALS=amyotrophic lateral sclerosis; PLS=primary lateral sclerosis. *A flail-arm variant is displayed,
a flail-leg variant may also present
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
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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
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
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Fig 2 | The split hand sign in ALS. Circles indicate wasting within the first dorsal interosseous muscle (top) and thenar muscles (bottom). Broken line highlights the discrepancy
between the wasted thenar side of the palm and the more preserved hypothenar side. Muscle is preserved on the contralateral side, typical of the initial asymmetric
presentation of ALS

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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).

Table 1 | Differential diagnoses of ALS, with clinical features and suggested investigations
Differential diagnosis
Multifocal motor neuropathy
Cervical spondylotic myeloradiculopathy
Immune/inflammatory myopathy
Myasthenia gravis
Inclusion body myositis
Kennedy’s disease (spinobulbar muscular atrophy)
Peripheral nerve hyper-excitability syndrome
Toxic/heavy metal neuropathy
Clinical phenotype
Highly asymmetric and upper limb wasting with distal weakness
Significant sensory symptoms +/- urinary dysfunction
Very high creatine kinase
Symptoms worsen as day progresses, periods of symptom
remission.
Bulbar weakness with ptosis
Weakness of finger flexors (typically spared in ALS)
Male sex
Fasciculations and wasting of tongue
Gynaecomastia/testicular atrophy
Prominent cramps and fasciculations without substantial
weakness
Wrist and finger flexor weakness
Helpful test
• Nerve conduction study (conduction block)
• Anti-ganglioside antibodies
• Magnetic resonance imaging cervico-thoracic spine
• Myositis associated antibody panel
• EMG
• Muscle biopsy
• Anti-acetylcholine receptor antibodies
• Muscle specific kinase antibodies
• Repetitive nerve stimulation
• Muscle biopsy
• Anti-NT5C1A antibodies
• EMG
• Gene testing for mutation in androgen receptor (AR) gene
• Voltage gated potassium channel antibodies
• EMG to assess for spontaneous motor unit activity
• Heavy metal studies
• Nerve conduction studies

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Fig 3 | Left, coronal view of the brain in a patient with ALS. Green chevrons indicate the presence of increased signal (brightness) within the corticospinal tract, which may
be seen in around 50% of ALS patients. Right: compression of the cord at C6/7 resulting in cervical myeloradiculopathy. This may mimic ALS with potentially lower motor
neuron signs in the upper limbs and upper motor neuron signs in the lower limbs. This highlights the importance of obtaining spinal neuroimaging (preferably magnetic
resonance imaging) in those with suspected ALS
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.1 26 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.
the bmj | BMJ 2022;379:e073857 | doi: 10.1136/bmj-2022-073857
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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.
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Fig 4 | Proposed algorithm for prompt consideration of ALS as a diagnosis. UMN=upper motor neuron; LMN=lower motor neuron; B12=vitamin B12; NCS=nerve conduction
studies; EMG=electromyography

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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.
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/re-
sources-authors/forms-policies-and-checklists/declaration-competing-interests
Provenance and peer review: commissioned; externally peer reviewed.
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