Motor Neurone Disease (Amyotrophic Lateral Sclerosis)

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Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder and the most common form of motor neurone disease (MND).¹

It is characterised by degeneration of upper motor neurones (UMN) and lower motor neurones (LMN) within the cortex, brainstem and spinal cord, with a significant extra-motor (frontotemporal and frontostriatal) component.¹

ALS is now recognised as a spectrum disorder, with up to half of patients experiencing cognitive or behavioural change. The most severe form is frontotemporal dementia (FTD).²

ALS accounts for around 80-90% of MND cases. The annual incidence is around 2 per 100,000, with a prevalence of around 5-7 per 100,000 in populations of European ancestry. Lower rates are reported in more genetically diverse populations.³ ALS typically presents between 50 and 70 years and is slightly more common in men.

This article focuses on ALS as the prototypical and most common form of MND, while acknowledging other clinical subtypes.

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Aetiology

ALS is typically classified as sporadic (around 80-95%), with no clear family history. The remainder are considered familial ALS, often linked to mutations in genes such as C9orf72, SOD1, TARDBP and FUS.⁴

Population-based studies suggest that heritability may account for up to 50% of overall risk.⁴

Pathophysiology

ALS is characterised by progressive degeneration of both UMN and LMN:

• UMN degeneration: loss of motor cortex neurones and their corticospinal projections, leading to spasticity, brisk reflexes and pathological UMN signs (e.g. Hoffmann’s sign, Babinski response, jaw jerk, pectoral reflex and crossed adductor reflex)
• LMN degeneration: particularly anterior horn cell loss in the spinal cord, resulting in muscle wasting, fasciculations and flaccid weakness

Several mechanisms are thought to contribute to ALS pathogenesis, based on genomic studies and animal models. Protein misfolding and aggregation are key features, with abnormal protein accumulation, such as TDP-43 and SOD1, observed in affected neurones.

Altered RNA signalling disrupts cellular metabolism. Oxidative stress and mitochondrial dysfunction impair energy metabolism and contribute to neuronal injury. Neuroinflammation may exert both harmful and potentially protective effects. Defective axonal transport and RNA metabolism further disrupt cellular communication and repair.⁵

Together, these mechanisms result in progressive motor neurone degeneration and the characteristic combination of UMN and LMN features.

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Risk factors

ALS likely arises from an interplay between genetic susceptibility and environmental triggers.⁷ Over 40 ALS-associated genes have been identified. Mutations in genes such as C9orf72 and SOD1 have higher penetrance and are more likely to cause disease, while other variants may increase risk in combination with additional factors.⁷

Risk increases with age, with peak onset between 50 and 70 years, and there is a slight male predominance (around 1.5:1).

Environmental exposures implicated include military service, pesticides, solvents, heavy metals, and cyanotoxins. Lifestyle factors such as smoking are associated with increased risk. Associations with elite athleticism have been proposed, but remain an area of ongoing research.⁷

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Clinical features

ALS is usually a clinical diagnosis based on a combination of history and examination findings. Patients may present with asymmetric limb weakness, bulbar dysfunction or respiratory symptoms, often accompanied by fasciculations and, in some cases, cognitive or behavioural change.

History

Typical symptoms of ALS can vary depending on the presentation:

• Spinal onset ALS (most common): progressive (often asymmetric) weakness in the arms or legs, clumsiness, tripping or difficulty with fine motor tasks
• Bulbar onset ALS: slurred or nasal speech, dysphagia, sialorrhoea, emotional lability (involuntary laughing or crying)
• Respiratory onset ALS (rare): exertional dyspnoea, orthopnoea or early morning headaches due to nocturnal hypoventilation
• Cognitive or behavioural onset: executive dysfunction or behavioural change, sometimes preceding motor symptoms

Note: Patients may present with any combination of the above features.

Associated symptoms may include muscle cramps, fasciculations, and cognitive/behavioural changes.²

Other important areas to cover in the history include:

• Past medical history: neurological disorders or systemic conditions that can mimic ALS (e.g. thyroid disease, autoimmune neuropathies or prior neuromuscular disorders)
• Drug history: medications that can cause weakness or neuropathy (e.g. corticosteroids, statins or chemotherapy)
• Family history: MND, dementia or early unexplained neurological deaths
• Social history: occupational exposures (e.g. military service, welding, farming), smoking, alcohol use, support network and living situation

Clinical examination

The clinical hallmark is the coexistence of UMN and LMN signs within the same body region.

Upper motor neurone (UMN) signs may include:

• Spasticity
• Hyperreflexia, clonus
• Babinski response and Hoffmann’s sign
• Crossed adductor reflex and pectoral reflex

Lower motor neurone (LMN) signs may include:

• Muscle wasting
• Fasciculations (including tongue fasciculations)
• Weakness
• Hyporeflexia in affected muscles (may coexist with brisk reflexes elsewhere)

Other findings may include tongue wasting, dysarthria, dysphagia, pseudobulbar affect and respiratory signs (weak cough, paradoxical breathing and reduced chest expansion).

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Differential diagnoses

ALS must be distinguished from other conditions that can mimic progressive weakness and UMN or LMN signs.⁸

Table 1. Important ALS mimics and distinguishing features

Condition	Key distinguishing features
Primary lateral sclerosis (PLS)	Pure UMN signs, slower progression
Multifocal motor neuropathy (MMN)	Asymmetric weakness, no UMN signs, conduction block on nerve conduction studies, slow progression
Cervical myelopathy	UMN signs with sensory deficits and possible bowel or bladder involvement, imaging shows cord compression
Peripheral neuropathies (e.g. CIDP, CMT)	Prominent sensory loss, often symmetric weakness, slowed nerve conduction
Myasthenia gravis	Fluctuating weakness, ocular and bulbar involvement, preserved reflexes
Inclusion body myositis	Distal and proximal weakness, no UMN signs, creatine kinase elevated
Kennedy disease	X-linked, LMN weakness with sensory involvement, gynaecomastia
Structural CNS lesions	Brain or spinal cord tumour or stroke, sensory or sphincter involvement common
Post-polio syndrome	History of paralytic poliomyelitis, slow progression, limited UMN signs
Vitamin B12 deficiency	Prominent sensory symptoms and dorsal column signs
Severe hypothyroidism	Proximal weakness and fatigue with systemic features

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Investigations

ALS is primarily a clinical diagnosis, but investigations are important to support the diagnosis and to exclude mimics.

Bedside investigations

Relevant bedside investigations include:

Laboratory

There is no blood test that confirms ALS, but blood tests help exclude alternative diagnoses:

• Baseline blood tests (full blood count, urea & electrolytes, glucose and thyroid function tests): to exclude metabolic or systemic causes of weakness
• Serum vitamin B12 and folate: to exclude neuropathy mimics
• Autoimmune and inflammatory markers: when neuropathy is suspected
• Creatine kinase (CK): may be mildly elevated in ALS, but markedly raised CK suggests myopathy rather than ALS

Electrophysiology

Nerve conduction studies and electromyography (EMG) are key supportive investigations.

EMG may show denervation, fasciculations and chronic reinnervation, supporting the diagnosis and helping exclude mimics (e.g. MMN, neuropathies and myopathies)

Imaging

MRI of the brain and spinal cord is used to exclude structural lesions or demyelination that may cause UMN or LMN signs (e.g. cervical myelopathy or tumours).

Genetic testing

Genetic testing may be considered in suspected ALS, particularly when there is a family history, early onset, or when results may affect management or trial eligibility. Testing commonly includes C9orf72, SOD1, TARDBP and FUS.

Genetic results can support counselling and may enable access to emerging gene-specific therapies (e.g. tofersen for SOD1-associated ALS).¹²

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Diagnosis

Diagnostic frameworks include the El Escorial criteria and the Gold Coast criteria.^10,11

El Escorial criteria

• Clinically definite ALS: UMN and LMN signs in the bulbar region and at least two spinal regions, or UMN and LMN signs in three spinal regions
• Clinically probable ALS: UMN and LMN signs in at least two regions with UMN signs rostral to LMN signs (may be subgrouped as laboratory-supported)
• Clinically possible ALS: UMN and LMN signs together in only one region, or UMN signs alone in two or more regions, or LMN signs rostral to UMN signs without supportive neurophysiology
• Clinically suspected ALS: diagnostic uncertainty remains such that the patient would not meet criteria for inclusion in research studies

Gold Coast criteria

The Gold Coast criteria is an alternative diagnostic framework for ALS.¹¹

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Management

There is no cure for ALS.

Management focuses on slowing progression where possible, optimising symptom control, maintaining quality of life and supporting patients and families via a multidisciplinary team.

Medical

The only disease-modifying therapies currently licensed for ALS in the UK and Ireland are

• Riluzole is a glutamate release inhibitor that modestly prolongs survival and is usually well-tolerated
• Tofersen is an antisense oligonucleotide targeting SOD1 and is relevant for the small proportion of patients with SOD1-associated ALS.

Medications for managing symptoms may include:

• Amitriptyline: for sialorrhea, depression, sleep disturbance, pain
• Anticholinergics (e.g. glycopyrronium, hyoscine patches): for sialorrhea
• Spasticity agents (e.g. baclofen, tizanidine)
• SSRIs/SNRIs/mitrazapine: for mood or sleep disturbance

Respiratory support

Respiratory muscle weakness is the leading cause of morbidity and mortality in ALS. Early identification and intervention are essential:

• Pulmonary function testing is commonly repeated at regular intervals (e.g. every 3 months) and sooner if new symptoms develop (e.g. orthopnoea, dyspnoea or fatigue)
• Non-invasive ventilation (NIV): improves survival and quality of life in chronic respiratory failure or sleep-disordered breathing, with settings individualised
• Overnight oximetry or polysomnography can guide NIV initiation
• Airway clearance: secretion management, mechanical cough assist devices, and suction can be helpful for selected patients

Transition to invasive home ventilation is complex, rarely pursued and should be guided by patient preferences and shared decision making.

Nutritional and swallowing support

• Dietetic input: early involvement to optimise caloric intake and hydration
• Gastrostomy feeding: may be considered with significant weight loss (e.g. around 10%) or problematic dysphagia, ideally before severe respiratory compromise. Evidence for survival benefit is very limited, but it may improve comfort and quality of life
• Speech and language therapy (SALT): supports communication strategies (including voice banking where appropriate) and swallowing techniques

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Complications

As ALS progresses, patients develop increasing disability and complications across respiratory, nutritional, motor, cognitive and psychological domains:

• Respiratory failure: progressive diaphragmatic and accessory muscle weakness leads to hypoventilation, recurrent chest infections and ultimately respiratory failure, the most common cause of death in ALS
• Dysphagia and aspiration: bulbar involvement causes impaired swallowing, weight loss, malnutrition and aspiration pneumonia
• Communication difficulties: dysarthria can progress to anarthria, often requiring assistive communication devices
• Nutritional compromise: reduced oral intake and increased metabolic demand contribute to weight loss
• Spasticity and cramps: stiffness and weakness contribute to pain, immobility and secondary complications
• Cognitive and behavioural impairment: ranges from mild executive dysfunction to FTD and has important implications for decision making and care planning²
• Psychological impact: anxiety and depression are common in patients and carers and should be actively screened for and supported

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Reviewer

Professor Orla Hardiman

Consultant Neurologist

Beaumont Hospital, Dublin, Ireland

Internationally recognised leader in ALS research.

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References

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6. Vidovic M, et al. Current state and future directions in the diagnosis of amyotrophic lateral sclerosis. Cells. 2023;12(5):736. 
7. Ingre C, Roos PM, Piehl F, Kamel F, Fang F. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015;7:181-193.
8. Ghasemi M. Amyotrophic lateral sclerosis mimic syndromes. Iran J Neurol. 2016;15(2):85-91.
9. Cedarbaum J. Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). MDCalc. Available from: [LINK]
10. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299. 
11. Turner MR; UK MND Clinical Studies Group. Diagnosing ALS: the Gold Coast criteria and the role of EMG. Pract Neurol. 2022;22(3):176-178. 

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