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A 59-year-old bank manager has an 8-month history of progressive painless right-hand weakness. He first had difficulty fastening buttons and began dropping coins; his right forearm then became thinner and his wife noticed fasciculations. During the past 3 months his right foot has begun to drag.[1]
Examination shows right thenar, first-dorsal-interosseous and forearm wasting, visible fasciculations and weakness. Right upper-limb reflexes are pathologically brisk, Hoffman sign is present and the right plantar response is extensor. The left hand has early wasting with brisk reflexes; both legs are hyperreflexic, with right ankle clonus. Pinprick, vibration and joint-position testing are normal. There is no ocular or sphincter complaint and no bulbar sign. Upright FVC is 78% predicted and SNIP is 55 cmH2O; he denies orthopnoea, morning headache, sleep disruption or daytime somnolence. CK is mildly raised.[1][3]
Questions and marking scheme
a) Give the diagnosis and the examination pattern that supports it. (2 marks)
The most likely diagnosis is classical limb-onset amyotrophic lateral sclerosis (ALS) within the MND spectrum.[1]
Award exactly 2 marks:[1]
- 0.5 — ALS/MND named.[1]
- 0.5 — progressive focal weakness with spread from one limb region to another.[1]
- 0.5 — mixed LMN signs (weakness, wasting, fasciculations) and UMN signs (brisk reflexes, Hoffman/clonus/extensor plantar).[1]
- 0.5 — no prominent early sensory, ocular-motor or sphincter abnormality; the candidate must call this a supportive classical pattern or mimic screen, not an absolute lifetime exclusion.[1]
b) Outline the diagnostic approach: Gold Coast criteria, EMG/NCS and exclusion of mimics. (3 marks)
Award exactly 3 marks:[2]
- 1 mark — Gold Coast: progressive motor impairment after previously normal motor function, plus UMN and LMN dysfunction in at least 1 body region or LMN dysfunction in at least 2 regions, plus investigations excluding another disease process. LMN dysfunction may be clinical or EMG; do not require EMG as a compulsory fourth criterion and do not reattach El Escorial definite/probable/possible categories.[2]
- 1 mark — EMG/NCS: needle EMG samples multiple regions for chronic neurogenic change with ongoing denervation and may disclose subclinical LMN disease; fasciculations alone are not diagnostic. NCS looks for motor conduction block/demyelination and a prominent sensory neuropathy. EMG supports localization but neither proves nor excludes ALS by itself.[2][3]
- 1 mark — pattern-directed mimic exclusion: chooses imaging, laboratory, CSF or neuromuscular testing to test a plausible alternative raised by the patient’s age, tempo, distribution, atypical features, exposure history or electrophysiology. There is no universal ALS imaging or laboratory panel. Offer ALS genetic testing after counselling—at minimum C9orf72 repeat expansion plus SOD1, FUS and TARDBP.[1][2][4]
No named laboratory test is required if the candidate gives a coherent pattern-directed mimic strategy and one appropriate example linked to this presentation.[1][2]
c) State standard disease-modifying therapy and one current therapy update. (2 marks)
Award exactly 2 marks:[5]
- 0.5 — riluzole 50 mg orally twice daily.[5]
- 0.5 — reduces glutamatergic excitotoxicity and provides a modest aggregate survival benefit, commonly taught as about 2–3 months; do not award the false hybrid “HR 0.80, 95% CI 0.70–0.99.”[5]
- 0.5 — baseline and regular early liver-function monitoring, continued through the first year then periodically according to the current local label; clinically important hepatic injury or label-defined marked transaminase elevation requires stopping/specialist review.[3][5]
- 0.5 — any 1 of the following current updates:[3]
- edaravone has FDA/PMDA authorization but highly selected pivotal evidence and is not recommended by EAN 2024 outside trials; this patient’s FVC of 78% does not meet the pivotal trial’s FVC-at-least-80% entry criterion[3][6]; or
- tofersen is SOD1-genotype-specific; VALOR missed the week-28 ALSFRS-R primary endpoint despite biomarker reduction, and FDA approval is accelerated on the neurofilament surrogate[7]; or
- sodium phenylbutyrate/taurursodiol (AMX0035; Relyvrio/Albrioza) failed PHOENIX, left the US/Canadian market in 2024 and is not current routine therapy; FDA’s formal approval withdrawal took effect in 2025 (Federal Register).[3]
Award the final 0.5 once only, even if more than 1 update is given.[3]
d) Does an upright FVC of 78% settle the NIV decision? State your assessment and the evidence. (2 marks)
No. FVC alone is not a safe gate: symptoms, supine VC/FVC, SNIP/MIP, gas exchange and nocturnal assessment may disclose respiratory insufficiency despite a relatively preserved upright result. In this asymptomatic patient, repeat standardized respiratory assessment, compare sitting with supine VC/FVC, interpret the SNIP in context and obtain nocturnal oximetry/capnography or gases if concern persists; do not declare him permanently “below threshold.” Offer NIV when symptoms, signs or investigations support respiratory insufficiency, irrespective of bulbar status.[3]
Award exactly 2 marks:[3]
- 1 mark — states that FVC 78% neither automatically starts nor rules out NIV, and gives at least 2 of: respiratory symptoms, sitting/supine VC/FVC, SNIP/MIP, gases, nocturnal oximetry/capnography.[3]
- 0.5 — Bourke RCT: NIV improved quality of life and produced a survival advantage in participants with better bulbar function; severe bulbar dysfunction modified tolerance/survival evidence but is not an automatic exclusion.[8]
- 0.5 — the BTS oxygen guideline treats neuromuscular disease as a hypercapnia-risk condition: if oxygen is required, it should be controlled and titrated with prompt blood-gas assessment and repeat monitoring, while ventilatory support is escalated when hypoventilation persists; do not give uncontrolled oxygen alone.[9]
e) Name a treatable motor mimic and the most useful discriminator. (1 mark)
Multifocal motor neuropathy (MMN) is the key treatable mimic.[1]
Award exactly 1 mark:[3]
- 0.5 — MMN named.[1]
- 0.5 — motor NCS showing conduction block or an equivalent correct discriminator: absence of UMN signs with an asymmetric motor syndrome; anti-GM1 may support but cannot exclude MMN because sensitivity is limited. Do not require the words “pathognomonic” or “never in ALS.”[3]
Mark reconciliation
Total = 2 + 3 + 2 + 2 + 1 = 10 marks. Every fractional element is explicit; alternatives that can earn a mark are listed, and no element can be scored twice.[1]
References9ShowHide
- [1]Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis Nature Reviews Disease Primers, 2017.PMID 28980624
- [2]Shefner JM, Al-Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for ALS Clinical Neurophysiology, 2020.PMID 32387049
- [3]Van Damme P, Al-Chalabi A, Andersen PM, et al. European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) European Journal of Neurology, 2024.PMID 38470068
- [4]Roggenbuck J, Eubank BHF, Wright J, et al. Evidence-based consensus guidelines for ALS genetic testing and counseling Annals of Clinical and Translational Neurology, 2023.PMID 37691292
- [5]Miller RG, Mitchell JD, Moore DH Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) Cochrane Database of Systematic Reviews, 2012.PMID 22419278
- [6]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 The Lancet Neurology, 2017.PMID 28522181
- [7]Miller T, Cudkowicz M, Shaw PJ, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS New England Journal of Medicine, 2022.PMID 36129998
- [8]Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial The Lancet Neurology, 2006.PMID 16426990
- [9]O'Driscoll BR, Howard LS, Earis J, Mak V BTS guideline for oxygen use in adults in healthcare and emergency settings Thorax, 2017.PMID 28507176