Motor Neurone Disease (MND/ALS)
Motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disorder characterized by selective degeneration of both upper and lower motor neurons. It leads to progressive muscle weakness, wasting, and ultimately respiratory failure. Sensation, cognition (in pure ALS), and ocular movements are typically preserved. The disease affects approximately 2-3 per 100,000 people annually, with a median survival of 2-4 years from symptom onset. While currently incurable, multidisciplinary care and disease-modifying therapies can extend survival and improve quality of life.
Clinical Pearls:
- Most common motor neuron disease in adults
- Progressive bulbar palsy has worst prognosis (median survival 1-2 years)
- Ocular muscles and sphincters typically spared until late disease
- Frontotemporal dementia occurs in 15-20% of patients
- 5-10% of cases are familial (FALS), 90-95% sporadic (SALS)
Red Flags:
- Respiratory muscle weakness: FVC less than 50% predicted, orthopnea, morning headaches
- Dysphagia: Risk of aspiration, weight loss, dehydration
- Rapid progression: Loss of >1 ALSFRS-R point per month
- Bulbar onset: Poorer prognosis, earlier respiratory involvement
- Cognitive decline: Frontotemporal dementia in 15-20%
MND/ALS is a rare but devastating condition with significant geographic and demographic variation. Understanding epidemiology aids in diagnosis and resource planning.
Key Statistics:
- Annual incidence: 1.5-2.7 per 100,000 population worldwide
- Prevalence: 4-6 per 100,000 (increasing due to improved survival)
- Peak age: 60-70 years, rare before age 40
- Gender: Slight male predominance (1.2-1.5:1), equalizes after age 70
- Lifetime risk: 1 in 400 for men, 1 in 500 for women
Geographic Variation:
- Western Pacific: Higher incidence (Guam, Kii Peninsula)
- Europe/North America: 1.5-2.5 per 100,000
- Asia: Lower reported rates, possibly underdiagnosed
- Familial clusters: Certain regions show higher FALS rates
Risk Factors:
- Age: Risk increases with age, peak 60-70 years
- Gender: Male predominance in younger patients
- Genetics: 5-10% familial, C9orf72 most common (40% of FALS)
- Military service: 1.5-2x increased risk (veterans)
- Physical activity: Controversial, some studies suggest increased risk
Mortality and Survival:
- Median survival: 2-4 years from symptom onset
- 5-year survival: 20-30%
- 10-year survival: 5-10%
- Respiratory failure: Most common cause of death (70-80%)
MND/ALS results from complex interactions between genetic, environmental, and cellular factors leading to motor neuron death. Multiple pathogenic mechanisms contribute to the disease process.
Pathophysiology Steps:
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Genetic Susceptibility: Mutations in >40 genes identified (C9orf72, SOD1, TARDBP, FUS). C9orf72 hexanucleotide repeat expansion causes toxic gain-of-function, RNA foci formation, and dipeptide repeat protein production
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Protein Aggregation: Misfolded proteins (TDP-43, FUS, SOD1) aggregate in motor neurons, forming inclusions that disrupt cellular function and trigger stress responses
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Excitotoxicity: Excessive glutamate signaling causes calcium overload in motor neurons. Reduced EAAT2 (glutamate transporter) expression impairs glutamate clearance, leading to chronic excitotoxic damage
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Mitochondrial Dysfunction: Impaired mitochondrial function reduces ATP production, increases reactive oxygen species, and triggers apoptosis pathways in motor neurons
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Neuroinflammation: Activated microglia and astrocytes release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), contributing to motor neuron damage and disease progression
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Axonal Transport Disruption: Impaired anterograde and retrograde axonal transport prevents proper protein and organelle distribution, leading to synaptic dysfunction and neuronal death
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Motor Neuron Death: Progressive loss of upper and lower motor neurons results in denervation, muscle atrophy, weakness, and ultimately respiratory failure
Non-Modifiable Risk Factors:
- Age: Risk increases with age, peak 60-70 years
- Gender: Male predominance (1.2-1.5:1) in younger patients
- Genetics: 5-10% familial, multiple gene mutations identified
- Ethnicity: Slight variations in incidence rates
Modifiable Risk Factors:
- Military service: 1.5-2x increased risk in veterans
- Physical activity: Some studies suggest increased risk with intense exercise
- Smoking: Modest increase in risk (1.2-1.5x)
- Head trauma: Possible association, requires further study
Genetic Factors:
- C9orf72: Most common genetic cause (40% FALS, 5-10% SALS)
- SOD1: 20% of FALS, various mutations with different phenotypes
- TARDBP: 5% of FALS, TDP-43 proteinopathy
- FUS: 5% of FALS, aggressive phenotype
- Other genes: >35 additional genes identified
Protective Factors:
- No clearly established protective factors
- Early diagnosis: Enables earlier intervention and planning
- Multidisciplinary care: Improves survival and quality of life
Clinical presentation varies by subtype and site of onset. Classic ALS shows mixed upper and lower motor neuron signs, while variants may show pure UMN or LMN involvement.
Classic ALS (Mixed UMN and LMN):
Limb-Onset ALS:
Bulbar-Onset ALS:
Progressive Muscular Atrophy (PMA):
Primary Lateral Sclerosis (PLS):
Cognitive Features:
Comprehensive neurological examination identifies UMN and LMN signs, assesses bulbar function, and monitors respiratory status. Serial examinations track progression.
Motor Examination:
- Weakness: Asymmetric, progressive, both proximal and distal
- Wasting: Muscle atrophy, most prominent in hands and tongue
- Fasciculations: Visible muscle twitching, widespread
- Tone: Spasticity (UMN) or flaccidity (LMN)
- Power: MRC grading, track progression
Reflexes:
- Hyperreflexia: Brisk reflexes, clonus (UMN signs)
- Hyporeflexia: Reduced in wasted muscles (LMN)
- Babinski: Extensor plantar response (UMN)
- Jaw jerk: Hyperactive in bulbar involvement
Cranial Nerve Examination:
- Facial weakness: Lower motor neuron type, bilateral
- Bulbar: Tongue wasting, fasciculations, weak palate
- Extraocular: Usually spared until late disease
- Speech: Spastic dysarthria, nasal quality
Sensory Examination:
- Intact: Sensation preserved throughout
- No sensory loss: Distinguishes from other neuropathies
Respiratory Assessment:
- FVC: Serial measurements, less than 50% indicates need for NIV
- NIF: Maximal inspiratory pressure, less than 60 cmH2O concerning
- Orthopnea: Symptom of respiratory muscle weakness
- Morning headaches: Suggest nocturnal hypoventilation
Functional Assessment:
- ALSFRS-R: Functional rating scale, tracks progression
- Swallowing: Videofluoroscopy if dysphagia present
- Communication: Assess speech intelligibility
Diagnostic evaluation confirms MND/ALS and excludes mimics. El Escorial/Awaji criteria guide diagnosis. Genetic testing identifies familial cases.
Essential Investigations:
- Nerve conduction studies: Normal sensory, reduced motor amplitudes
- EMG: Widespread denervation, fasciculations, reduced recruitment
- MRI brain/spine: Excludes structural causes, may show corticospinal tract hyperintensity
- Blood tests: CK mildly elevated, exclude mimics
Electrodiagnostic Studies:
- EMG: Active denervation (fibrillations, positive sharp waves), chronic denervation (large motor units), fasciculations
- NCS: Reduced CMAP amplitudes, normal SNAP, normal conduction velocities
- Pattern: Widespread, not confined to single nerve or root
Neuroimaging:
- MRI brain: Corticospinal tract hyperintensity on T2/FLAIR
- MRI spine: Excludes structural causes (disc disease, tumors)
- Atrophy: Motor cortex and anterior horn cell loss in advanced disease
Laboratory Tests:
- Creatine kinase: Mildly elevated (2-3x normal)
- Genetic testing: C9orf72, SOD1, TARDBP, FUS if familial or young onset
- Exclude mimics: Vitamin B12, thyroid function, paraneoplastic panel
Diagnostic Criteria (El Escorial/Awaji):
- Clinically definite: UMN + LMN signs in 3 regions
- Clinically probable: UMN + LMN signs in 2 regions
- Clinically possible: UMN + LMN signs in 1 region
- Laboratory-supported: EMG evidence in clinically affected or unaffected regions
3. Surgical Atlas: Gastrostomy (PEG vs RIG)
"Feeding the Bulbar Patient." Gastrostomy is a critical intervention for nutritional support and medication administration.
- The Dilemma: When to insert?
- Too early: Unnecessary procedure.
- Too late: Respiratory function (FVC) too poor to tolerate sedation/procedure.
- Rule of Thumb: Discuss when FVC > 50%. Insert before FVC < 50%.
- Techniques:
- PEG (Percutaneous Endoscopic Gastrostomy):
- Method: Endoscope passed down oesophagus. Light shines through stomach wall. Needle puncture from outside. Tube pulled through.
- Requirement: Patient must be able to swallow the scope (difficult in severe bulbar palsy) and lie flat (difficult in severe respiratory weakness).
- RIG (Radiologically Inserted Gastrostomy):
- Method: Stomach inflated with air via NG tube. Punctured under X-ray/US guidance. Retained with sutures/balloon.
- Pro: No endoscope needed. Safer for severe bulbar/respiratory patients.
- Con: Higher risk of peritonitis/displacement initially.
- PEG (Percutaneous Endoscopic Gastrostomy):
- Post-Procedure:
- Tube feeding can stabilize weight.
- Does NOT prevent aspiration of saliva.
- Does NOT prolong survival significantly (except by preventing starvation).
4. Deep Dive: Genetics of MND
"The C9orf72 Expansion." 90% of MND is sporadic. 10% is familial.
- C9orf72 (Chromosome 9 Open Reading Frame 72):
- Mutation: Hexanucleotide repeat expansion (GGGGCC).
- Prevalence: 40% of Familial ALS. 5-10% of Sporadic ALS.
- Phenotype: Associated with Frontotemporal Dementia (FTD).
- Pathology: Accumulation of toxic RNA foci and dipeptide repeats.
- SOD1 (Superoxide Dismutase 1):
- Prevalence: 20% of Familial ALS.
- Pathology: Toxic gain of function (misfolding).
- Therapy: Targetable by Tofersen (Antisense Oligonucleotide).
- TDP-43 (TARDBP):
- The pathological protein found in inclusions in 95% of ALL ALS cases (even sporadic). Mutations in the gene itself are rare (5% familial).
MND Subtype Classification:
| Subtype | UMN Signs | LMN Signs | Features | Prognosis |
|---|---|---|---|---|
| Classic ALS | Yes | Yes | Most common | 2-4 years |
| Progressive Bulbar Palsy | Yes | Yes | Bulbar onset | 1-2 years |
| Progressive Muscular Atrophy | No | Yes | Pure LMN | 3-5 years |
| Primary Lateral Sclerosis | Yes | No | Pure UMN | 5-10 years |
| Flail Arm Syndrome | Yes | Yes | Upper limb onset | 3-4 years |
| Flail Leg Syndrome | Yes | Yes | Lower limb onset | 3-4 years |
3. Deep Dive: Non-Invasive Ventilation (NIV)
"The only life-prolonging intervention?" While Riluzole adds 2-3 months, NIV adds 7-12 months and massively improves Quality of Life.
- Indication:
- FVC < 50% predicted.
- SNP (Sniff Nasal Pressure) < 40 cmH2O.
- Morning headache (CO2 retention).
- Weak cough.
- Mechanism:
- Supports the weak diaphragm during sleep (when it is most vulnerable).
- Rests the respiratory muscles.
- Improves sleep quality (less daytime somnolence).
- The Device: BiPAP (Bilevel Positive Airway Pressure). IPAP supports breath in, EPAP keeps airway open.
4. Ethics: End of Life Decisions
"The Good Death." MND is the archetype for Assisted Dying debates.
- Advance Directives (AD):
- "Living Will". Must be signed when patient has capacity.
- Specifies refusal of life-sustaining treatment (e.g. antibiotic for pneumonia, PEG feeding, Invasive ventilation).
- DNACPR: Essential discussion early in the disease.
- The "Choking" Fear:
- Patients fear choking to death.
- Reality: Most die peacefully from CO2 narcosis (Respiratory Failure).
- Anticipatory Meds: Opioids (Morphine) and Benzodiazepines (Midazolam) for dyspnoea/anxiety.
Management focuses on disease-modifying therapy, symptom control, respiratory support, nutrition, and multidisciplinary care. Early intervention improves outcomes.
MOTOR NEURONE DISEASE MANAGEMENT ALGORITHM
==========================================
Patient diagnosed with MND/ALS
|
v
Multidisciplinary Team Assessment
|
+-------------------+-------------------+
| | |
Disease-Modifying Symptomatic Care Supportive Care
Therapy | |
| | |
- Riluzole 50mg bd - Spasticity: - Physiotherapy
- Edaravone (if Baclofen, tizanidine - Occupational therapy
indicated) - Sialorrhea: - Speech therapy
- Tofersen (SOD1) Hyoscine, glycopyrrolate - Dietitian
- Genetic counseling - Cramps: Quinine - Social work
- Pain: Analgesics - Psychology
- Pseudobulbar: - Palliative care
Dextromethorphan/
quinidine
RESPIRATORY MANAGEMENT
|
+-------------------+-------------------+
| | |
FVC Monitoring NIV Indication Ventilator Options
| | |
- Baseline and q3-6m - FVC less than 50% predicted - NIV (BiPAP)
- More frequent if - Orthopnea - Invasive ventilation
declining - Morning headaches - Tracheostomy
- SNIP less than 40 cmH2O (if desired)
NUTRITIONAL MANAGEMENT
|
+-------------------+-------------------+
| | |
Swallow Assessment Weight Monitoring Feeding Options
| | |
- Videofluoroscopy - Monthly weights - Modified diet
- Regular review - BMI tracking - Thickened fluids
- Nutritional - NG tube (short-term)
supplements - PEG/RIG (long-term)
ADVANCE CARE PLANNING
|
v
Discuss preferences early
- NIV use and limits
- Invasive ventilation
- Feeding tube
- End-of-life care
- Legal documents (POA, will)
Disease-Modifying Therapy:
Riluzole:
- Dose: 50mg twice daily
- Mechanism: Glutamate antagonist, reduces excitotoxicity
- Efficacy: Extends survival by 2-3 months
- Monitoring: LFTs at baseline and monthly for 3 months
- Contraindications: Severe hepatic impairment
Edaravone:
- Indication: Early-stage ALS (ALSFRS-R >2, less than 3 years from onset)
- Administration: IV infusion cycles
- Efficacy: Slows functional decline in selected patients
- Limitations: Expensive, requires IV access
Tofersen (SOD1-ALS):
- Indication: SOD1 mutation-associated ALS
- Administration: Intrathecal injection
- Efficacy: Reduces SOD1 protein, slows progression
- Monitoring: Requires regular lumbar punctures
Symptomatic Management:
Spasticity:
- Baclofen: 10-80mg daily, titrate gradually
- Tizanidine: 2-24mg daily
- Dantrolene: Less commonly used
- Botulinum toxin: For focal spasticity
Sialorrhea:
- Hyoscine patches: 1-3 patches, change every 72 hours
- Glycopyrrolate: 1-2mg tds
- Amitriptyline: 10-50mg nocte, also helps sleep
- Botulinum toxin: Salivary gland injection
Cramps:
- Quinine: 200-300mg nocte
- Magnesium: 200-400mg daily
- Baclofen: May help if spasticity present
Pseudobulbar Affect:
- Dextromethorphan/quinidine: 20/10mg bd
- Amitriptyline: 25-75mg daily
- SSRI: May help in some cases
Respiratory Management:
- FVC monitoring: Baseline and every 3-6 months
- NIV indication: FVC less than 50%, orthopnea, morning headaches
- NIV benefits: Extends survival 6-12 months, improves quality of life
- Invasive ventilation: Discuss preferences early
Nutritional Support:
- Swallow assessment: Regular videofluoroscopy
- Weight monitoring: Monthly, aim to maintain BMI
- PEG/RIG: Consider when FVC >50%, before severe bulbar weakness
- Timing: Early insertion improves outcomes
MND/ALS causes progressive complications affecting multiple systems. Proactive management prevents morbidity and improves quality of life.
Respiratory Complications:
Respiratory Failure:
- Incidence: 70-80% of deaths from respiratory failure
- Onset: Progressive, may be sudden with intercurrent illness
- Symptoms: Dyspnea, orthopnea, morning headaches, fatigue
- Management: NIV, invasive ventilation if desired
- Prevention: Early NIV initiation improves outcomes
Aspiration Pneumonia:
- Risk: High with bulbar weakness
- Prevention: Swallow assessment, modified diet, PEG
- Management: Antibiotics, supportive care
- Recurrence: Common without feeding tube
Nutritional Complications:
Weight Loss:
- Causes: Dysphagia, hypermetabolism, reduced intake
- Impact: >10% weight loss associated with worse prognosis
- Management: Nutritional supplements, PEG/RIG
- Monitoring: Monthly weights, BMI tracking
Dehydration:
- Risk: High with dysphagia
- Prevention: Thickened fluids, PEG if severe
- Management: IV fluids if needed, consider PEG
Neurological Complications:
Frontotemporal Dementia:
- Incidence: 15-20% of ALS patients
- Features: Executive dysfunction, behavioral changes, language impairment
- Impact: Affects decision-making, care planning
- Management: Supportive, family education
Pain:
- Causes: Immobility, spasticity, cramps, joint contractures
- Management: Multimodal approach, regular analgesics
- Types: Musculoskeletal, neuropathic, spasticity-related
Other Complications:
- Constipation: From immobility, medications
- Pressure sores: From immobility
- Contractures: From spasticity and immobility
- Depression: 30-50% prevalence
- Anxiety: Common, especially around progression
Prognosis is generally poor, but varies significantly by subtype, site of onset, and access to care. Multidisciplinary management improves survival and quality of life.
Survival Statistics:
- Median survival: 2-4 years from symptom onset
- 1-year survival: 70-80%
- 3-year survival: 40-50%
- 5-year survival: 20-30%
- 10-year survival: 5-10%
Prognostic Factors:
- Site of onset: Bulbar worse than limb (1-2 vs 2-4 years)
- Age: Younger age associated with longer survival
- Gender: Women may have slightly better prognosis
- ALSFRS-R: Higher score at diagnosis predicts longer survival
- FVC: Higher FVC at diagnosis predicts longer survival
- Multidisciplinary care: Improves survival by 6-12 months
Subtype Prognosis:
- Progressive bulbar palsy: 1-2 years (worst)
- Classic ALS: 2-4 years
- Progressive muscular atrophy: 3-5 years
- Primary lateral sclerosis: 5-10 years (best)
Quality of Life:
- Multidisciplinary care: Improves quality of life
- NIV: Improves quality of life and survival
- PEG: Improves nutrition, may extend survival
- Early intervention: Better outcomes with proactive management
Major Guidelines:
- NICE Guidelines (NG42, 2016): Motor neurone disease assessment and management
- AAN Practice Parameter (2009): Care of patient with ALS
- EFNS Guidelines (2012): Management of amyotrophic lateral sclerosis
- EAN Guidelines (2021): Evidence-based recommendations for ALS care
Landmark Clinical Trials:
-
Riluzole Trial (1994): First disease-modifying therapy
- Riluzole extends survival by 2-3 months
- 50mg bd dosing, well-tolerated
- Established riluzole as standard of care
- PMID: 7916642
-
Edaravone Trial (2017): Antioxidant therapy
- Slows functional decline in early-stage ALS
- Requires IV administration
- Benefit in selected patient population
- PMID: 28522181
-
Tofersen Trial (2022): SOD1-targeted therapy
- Reduces SOD1 protein in CSF
- Slows functional decline in SOD1-ALS
- First gene-specific therapy for ALS
- PMID: 36351295
-
NIV Trial (2006): Non-invasive ventilation
- Extends survival by 6-12 months
- Improves quality of life
- Should be offered to all with respiratory compromise
- PMID: 16476929
-
PEG Trial (2006): Percutaneous endoscopic gastrostomy
- Improves nutrition and may extend survival
- Better outcomes with early insertion
- Reduces aspiration risk
- PMID: 16476930
Meta-Analyses:
- Riluzole: Consistent survival benefit across trials (Miller, 2012)
- Multidisciplinary care: Improves survival and quality of life (Traynor, 2003)
- NIV: Significant survival and quality of life benefit (Bourke, 2006)
Systematic Reviews:
- ALS treatment: Comprehensive review of evidence (Hardiman, 2017)
- Symptomatic management: Evidence-based recommendations (Andersen, 2012)
- Respiratory management: NIV and invasive ventilation (Benditt, 2001)
"What is motor neurone disease?" Motor neurone disease (MND), also called ALS or Lou Gehrig's disease, is a condition where the nerve cells that control your muscles gradually stop working. This causes progressive weakness and muscle wasting. It's a serious condition, but there are treatments and support available to help manage symptoms and maintain quality of life.
"What causes it?" In most cases (90-95%), we don't know the exact cause. It's thought to be a combination of genetic and environmental factors. About 5-10% of cases run in families. The disease affects the motor neurons - the nerves that send messages from your brain to your muscles.
"What symptoms will I notice?" Symptoms depend on where it starts, but common early signs include:
- Weakness in your hands or legs
- Muscle twitching (fasciculations)
- Cramps and stiffness
- Difficulty speaking or swallowing (if it starts in the throat area)
- Tripping or dropping things
The weakness gets worse over time and spreads to other parts of your body.
"How is it diagnosed?" Your doctor will examine you and do tests including:
- Nerve and muscle tests (EMG)
- Brain and spine scans (MRI)
- Blood tests to rule out other conditions
- Sometimes genetic testing if it runs in your family
The diagnosis can take time because other conditions need to be ruled out first.
"Is there a cure?" Unfortunately, there's no cure yet. However, there are treatments that can:
- Slow down the disease (riluzole extends life by a few months)
- Help with symptoms (medications for cramps, stiffness, saliva)
- Support breathing (non-invasive ventilation)
- Help with nutrition (feeding tubes)
"What about my breathing?" As the disease progresses, breathing muscles can weaken. Your doctor will monitor this regularly. Non-invasive ventilation (a mask that helps you breathe) can:
- Extend your life by 6-12 months
- Improve your quality of life
- Help you sleep better
- Reduce fatigue
"Will I be able to eat?" Swallowing can become difficult. Your team will:
- Assess your swallowing regularly
- Suggest diet modifications
- Consider a feeding tube (PEG) if needed, which can be inserted before swallowing becomes too difficult
"How long do people live?" This varies a lot. On average, people live 2-4 years from when symptoms start, but:
- Some people live much longer (5-10% live over 10 years)
- It depends on where it starts and how fast it progresses
- Good care and support can make a difference
"What support is available?" You'll have a team including:
- Neurologist (specialist doctor)
- Nurse specialist
- Physiotherapist (for movement and exercises)
- Occupational therapist (for daily activities and equipment)
- Speech therapist (for communication and swallowing)
- Dietitian (for nutrition)
- Social worker and psychologist (for emotional support)
"What can I do to help myself?"
- Stay as active as you can (with guidance from your physiotherapist)
- Eat well and maintain your weight
- Use equipment and aids to help with daily tasks
- Communicate your wishes about treatment early
- Connect with support groups
- Take medications as prescribed
"What about my family?" This affects families too. Your team can help with:
- Information and education
- Support for caregivers
- Genetic counseling if it might run in families
- Planning for the future
"Is there hope?" Yes. While there's no cure, research is ongoing and new treatments are being developed. The care you receive can make a real difference to your quality of life and how long you live. Many people with MND/ALS live meaningful lives with good support and management.
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Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. PMID: 28980624
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Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007;(1):CD001447. PMID: 17253460
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Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505-512. PMID: 28522181
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Miller TM, Cudkowicz ME, Genge A, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110. PMID: 36351295
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Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5(2):140-147. PMID: 16426990
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Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74(9):1258-1261. PMID: 12933930
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van den Berg LH, Sorenson E, Gronseth G, et al. Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials. Neurology. 2019;92(14):e1610-e1623. PMID: 30850440
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National Institute for Health and Care Excellence. Motor neurone disease: assessment and management. NICE guideline [NG42]. 2016. Available at: https://www.nice.org.uk/guidance/ng42
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Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1226. PMID: 19822872
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Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) - revised report of an EFNS task force. Eur J Neurol. 2012;19(3):360-375. PMID: 21914052
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Chio A, Logroscino G, Hardiman O, et al. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009;10(5-6):310-323. PMID: 19922118
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Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-955. PMID: 21296405
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Zoccolella S, Beghi E, Palagano G, et al. Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy. Eur J Neurol. 2007;14(3):262-268. PMID: 17355546
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de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008;119(3):497-503. PMID: 18164242
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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. PMID: 11464847
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Strong MJ, Abrahams S, Goldstein LH, et al. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3-4):153-174. PMID: 28054827
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Genge A, Jackson C, Rosenfeld J, et al. An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(sup1):88-97. PMID: 28872912
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Matamala JM, Moreno-Roco J, Acosta I, et al. Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis. Rev Med Chil. 2022;150(12):1633-1646. PMID: 37906785
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Lovett A, Chary S, Babu S, et al. Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis. Muscle Nerve. 2025;71(6):1006-1015. PMID: 40017137
The "Holy Grail" for clinical trials, though often criticized for being too retrospective for clinical practice. Requires presence of:
- LMN signs (clinical, electrophysiological, or neuropathological).
- UMN signs (clinical).
- Progression.
Categories:
- Definite ALS: UMN + LMN signs in 3 regions (Bulbar, Cervical, Thoracic, Lumbosacral).
- Probable ALS: UMN + LMN signs in 2 regions (with UMN signs rostral to LMN signs).
- Possible ALS: UMN + LMN signs in 1 region OR UMN signs alone in 2 regions.
- Suspected ALS: LMN signs alone in >2 regions.
The "Awaji" Modification: Incorporates EMG findings as equivalent to clinical LMN signs, allowing earlier diagnosis (especially in Bulbar cases).
"The difficult conversations." Advance Care Planning (ACP) should start early, when the patient still has communication ability.
- Communication: As dysarthria progresses, voice banking (recording voice) and Eye Gaze technology are vital.
- Secretions:
- Thin/Watery: Hyoscine patches, Glycopyrronium, Atropine drops (sublingual), Amitriptyline.
- Thick/Tenacious: Carbocisteine, Nebulised Saline, Pineapple juice (contains papain enzymes).
- Breathlessness:
- Opioids (Morphine): Reduces the sensation of air hunger and anxiety. Do not fear respiratory depression in the terminal phase.
- Benzodiazepines (Lorazepam): For panic/anxiety associated with choking.
- The End: Usually peaceful CO2 narcosis. Sleep -> Coma -> Death.
Common Exam Questions
1. MRCP / PLAB:
- Q: A 60-year-old man presents with a wasted, fasciculating tongue and brisk jaw jerk. What is the diagnosis?
- A: Motor Neurone Disease (Bulbar onset). The combination of LMN (wasting) and UMN (brisk jaw jerk) in the bulbar territory is pathognomonic.
2. Palliative Care:
- Q: An MND patient on NIV becomes increasingly confused and drowsy in the mornings. Why?
- A: CO2 retention (Type 2 Respiratory Failure). The NIV pressures may need adjusting, or the disease has progressed.
3. Neurology:
- Q: What are the sensory findings in ALS?
- A: NONE. Sensation is clinically normal. If there is sensory loss, look for a mimic (e.g. Cervical Myelopathy, Kennedy's Disease).
Viva Points
- "Split Hand Sign": Preferential wasting of the APB (Abductor Pollicis Brevis) and FDI (First Dorsal Interosseous) with sparing of the ADM (Abductor Digiti Minimi). Highly specific for ALS.
- "Head Drop": Weakness of neck extensors. Often an early sign. Requires a collar.
- "Pseudobulbar Affect": Emotional lability (inappropriate laughing/crying) due to UMN disconnect from limbic control. Treated with Dextromethorphan/Quinidine.
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