Motor Neuron Disease (ALS) — SAQ

Stem

A 59-year-old bank manager presents to the neurology outpatient department with an 8-month history of progressive painless weakness of his right hand. He first noticed difficulty doing up shirt buttons and dropping coins, then his grip weakened and his right forearm "thinned". His wife has noticed intermittent twitching under the skin of his right arm and around his right shoulder. Over the past three months his right foot has begun to drag, and he has tripped on stairs twice. [1]

On examination: in the right upper limb there is marked wasting of the thenar eminence, the first dorsal interosseous and the forearm muscles, with fasciculations visible at rest. Power is Medical Research Council grade 4 minus distally and 4 proximally. Reflexes are pathologically brisk at the right biceps, triceps and supinator, and there is a positive Hoffman sign. The right plantar response is extensor (Babinski). The left upper limb shows mild wasting of the thenar eminence with brisk reflexes. Both lower limbs have brisk reflexes, sustained clonus at the right ankle, and an extensor right plantar. Sensation is normal to pinprick, vibration and joint position sense throughout. Cranial nerves are normal; the tongue is normal. Blood pressure 138/86, pulse 78, oxygen saturation 98 percent on room air. Forced vital capacity is 78 percent predicted; sniff nasal inspiratory pressure is 55 cmH2O. Creatine kinase 320 U per litre (mildly raised). [1]

Questions

a) What is the most likely diagnosis, and which three features of the examination are most diagnostic? (2 marks) [1]

The most likely diagnosis is amyotrophic lateral sclerosis (motor neuron disease) — a progressive neurodegenerative disorder of both upper and lower motor neurons. The three most diagnostic features are: (1) the coexistence of lower motor neuron signs (wasting, weakness, fasciculations of the right thenar eminence, first dorsal interosseous and forearm) with upper motor neuron signs in the same limb (pathologically brisk reflexes at the biceps, triceps and supinator; positive Hoffman; extensor plantar) — the signature of ALS; (2) the spread to a second body region (the left upper limb and both lower limbs, demonstrated by brisk reflexes, clonus and the Babinski) confirming progressive multifocal motor neuron degeneration; and (3) the preserved sensation to pinprick, vibration and joint position sense — the absence of sensory loss is essential to the diagnosis of ALS.[1][3]

b) Outline your diagnostic approach, naming the criteria you would apply, the role of EMG, and the imaging and laboratory tests you would order to exclude mimics. (3 marks) [1]

ALS is a clinical diagnosis supported by EMG and by exclusion of mimics — there is no single confirmatory test. The diagnostic criteria I would apply are the Gold Coast 2020 criteria (Shefner et al), the current international standard, which require: (1) progressive motor impairment (clearly present over 8 months), (2) UMN and LMN signs in at least one body region, OR LMN signs in at least two regions (satisfied — UMN and LMN in the right upper limb), (3) exclusion of mimics by imaging and laboratory testing, and (4) confirmation of LMN degeneration by EMG in at least one region.[3]

Electromyography would be performed in muscles of multiple regions (bulbar, cervical, thoracic including paraspinal, lumbosacral) looking for active denervation (fibrillations, positive sharp waves, fasciculations) plus chronic reinnervation (large-amplitude, long-duration, polyphasic motor unit potentials with reduced recruitment) — this combination, in at least two regions, confirms widespread LMN degeneration. Nerve conduction studies are essential to confirm that sensory conduction is normal (excluding a sensory neuropathy) and to exclude conduction block (the electrophysiological hallmark of multifocal motor neuropathy, the treatable mimic that must not be missed).[1]

MRI of the cervical spine (and brain) is mandatory to exclude cervical myelopathy with radiculopathy — a cord compression producing UMN signs below and LMN signs at the level can closely mimic combined UMN and LMN disease and is treatable by decompression. I would also request blood tests to exclude mimics and treatable causes: creatine kinase (already mildly raised — consistent with ALS; a markedly raised value would prompt reconsideration), full blood count, electrolytes, glucose, renal and liver function, thyroid-stimulating hormone, vitamin B12 with methylmalonic acid (B12 deficiency causes a combined UMN and LMN myeloneuropathy), calcium and copper, HIV and HTLV-1, anti-GM1 antibodies (if multifocal motor neuropathy is suspected), and serum and urine immunoelectrophoresis. Genetic testing for the C9orf72 hexanucleotide repeat expansion is offered to all patients given the rise of gene-targeted therapy.[1][3]

c) State the disease-modifying drug therapy with dose, route, mechanism, monitoring and survival benefit; and the role of edaravone. (2 marks) [1]

The disease-modifying drug of choice is riluzole, an inhibitor of presynaptic glutamate release that targets the glutamate-excitotoxicity mechanism of motor neuron death. The dose is 50 mg orally twice daily, started at diagnosis. The Cochrane meta-analysis of four randomised trials (Miller et al 2012) showed a hazard ratio of 0.80 (95 percent CI 0.70 to 0.99) for tracheostomy-free survival, equivalent to extending median survival by about 2 to 3 months. Monitoring requires liver function tests (ALT and AST) at baseline, monthly for the first three months, then three-monthly; riluzole should be discontinued if transaminases exceed five times the upper limit of normal. Common adverse effects are asthenia, nausea and stomatitis; leucopenia is rare but warrants a full blood count if fever develops. Contraindications are significant hepatic impairment (Child-Pugh C) and pregnancy.[5]

Edaravone is a free-radical scavenger given as 60 mg intravenously daily for 14 days, then 10 of 14 days in subsequent 4-week cycles. The Writing Group trial (Lancet Neurology 2017) showed a 2.49-point benefit on the ALS Functional Rating Scale-Revised over 24 weeks in a narrow subgroup of early-stage patients with definite or probable ALS by revised El Escorial criteria, FVC 80 percent or more and disease duration 2 years or less. It is FDA-approved in the United States but was refused by the European Medicines Agency on benefit-cost grounds — a classic regional delta. This patient (8 months of symptoms, FVC 78 percent, no UMN-only disease) would meet the subgroup criteria if his El Escorial category is definite or probable.[6]

d) The patient's FVC is 78 percent predicted. At what threshold would you initiate non-invasive ventilation, and what is the evidence for its benefit? (2 marks) [1]

Non-invasive ventilation is initiated when there is symptomatic respiratory insufficiency (orthopnoea, morning headaches, daytime somnolence) OR the forced vital capacity falls to 50 percent predicted or less OR the sniff nasal inspiratory pressure falls to 40 cmH2O or less OR a postural drop in FVC of greater than 25 percent from sitting to lying OR nocturnal oximetry showing oxygen saturation under 90 percent for more than 5 percent of the night.[2][7]

At his current FVC of 78 percent and SNIP of 55 cmH2O he is not yet at the threshold for NIV, but he should be monitored at every clinic visit with FVC (lying and standing), SNIP and overnight oximetry, so that NIV is initiated at the threshold. The evidence is the Bourke randomised controlled trial (Lancet Neurology 2006): in patients with normal or only mildly impaired bulbar function (this patient has no bulbar signs), NIV improved both survival (a median benefit of about 205 days, roughly 7 months) and quality of life across multiple measures; in those with severe bulbar impairment, NIV improved sleep-related symptoms but did not extend survival. NIV is therefore the single most effective intervention in ALS — more impactful than riluzole.[7]

e) Name the one treatable mimic that must be excluded before a diagnosis of ALS is confirmed, and how you would exclude it. (1 mark) [1]

The mimic that must be excluded is multifocal motor neuropathy (MMN) — a pure lower motor neuron disorder that looks exactly like limb-onset ALS but responds dramatically to intravenous immunoglobulin. Missing it condemns a treatable patient to the prognosis of ALS. I would exclude it by: (1) nerve conduction studies looking specifically for conduction block (pathognomonic for MMN and never present in ALS) in multiple motor nerves; (2) anti-GM1 antibodies (present in about half of MMN cases, rare in ALS); and (3) clinical features — MMN is typically pure lower motor neuron, asymmetric, upper-limb predominant, with sparing of bulbar muscles and no UMN signs. The presence of brisk reflexes, clonus and an extensor plantar in this patient makes MMN unlikely, but the exclusion is still mandatory.[1]

References

1. [1]Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nature Reviews Disease Primers, 2017.PMID 28980624
2. [2]Radunovic A, Mitsumoto H, Leigh PN Clinical care of patients with amyotrophic lateral sclerosis. Lancet Neurology, 2007.PMID 17884681
3. [3]Shefner JM, Al-Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for ALS (Gold Coast criteria). Clinical Neurophysiology, 2020.PMID 32387049
4. [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
5. [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. Lancet Neurology, 2017.PMID 28522181
6. [7]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. Lancet Neurology, 2006.PMID 16426990