11th August 2024

Neuromuscular junction disorders

Myasthenia gravis (MG)

Overview of MG

The most common disorder of the neuromuscular junction (NMJ) (incidence 7-23 per million), myasthenia gravis has a bimodal age distribution with peaks at 20-30 years, predominantly in females, and 60-80 years, predominantly in males.

It is caused by antibody-mediated disruption of signalling at the acetylcholine receptor (AChR), with 80-90% of patients having direct IgG antibodies to the AChR. Other antibodies that may be identified are anti-muscle-specific receptor tyrosine kinase (MuSK) and, more rarely, LRP4 antibodies. In some cases however, no antibodies are identified. Those with generalised disease are more likely to have identifiable antibodies than those with purely ocular disease, only half of whom are antibody positive.

Clinical features of MG

Patients most commonly present with ocular symptoms including ptosis or diplopia, along with muscle weakness. Symptoms typically worsen throughout the day and show fatigue. Fifteen percent present with bulbar symptoms such as difficulty chewing and weakness or fatigability of the voice. Fewer than 5% present with limb weakness alone.

Common drugs that may exacerbate MG include the following:

Abbreviations: PD-1 (Programmed cell death protein 1)

Management of MG

The mainstay of MG treatment are the acetylcholinesterase inhibitors, such as pyridostigmine. Many patients will also require additional treatments such as glucocorticoids or steroid-sparing agents (azathioprine or mycophenolate). Thymectomy is another important modality in management and may be considered in those with or without thymoma in certain cases.

Side effects of acetylcholinesterase inhibitors are largely cholinergic and can be managed by dose reduction, taking doses with food, or with the addition of propantheline or another anticholinergic.

Myasthenic crisis is a medical emergency characterised by life-threatening compromise of respiratory muscle function. All patients should be admitted and closely monitored, with vital capacity (VC) the most important modality. For those with falling VC or respiratory distress, intubation should be urgently considered. Plasma exchange and IVIG have similar efficacy in the acute treatment of MG so are both used, often in combination with steroids.

Lambert-Eaton myasthenic syndrome (LEMS)

LEMS is caused by antibodies to voltage-gated calcium channels (VGCC) on the presynaptic membrane, leading to decreased release of acetylcholine into the synapse. It can occur as a primary autoimmune disorder, but the majority of cases are paraneoplastic, with more than half related to small cell lung cancer (SCLC). Most (60-75%) patients are male, with mean age of onset in the 6ᵗʰ decade.

It is characterised by predominantly proximal muscle weakness which improves with exercise (post-exercise facilitation). Oculobulbar symptoms are common – diplopia, ptosis, dysarthria and dysphagia are all seen. Autonomic symptoms are also prominent, with constipation, dry mouth, altered perspiration and erectile dysfunction in men reported. Reflexes are typically absent.

In addition to antibody testing, EMG may be carried out demonstrating increasing compound muscle action potentials (CMAPs).

The mainstay of treatment should be identification and treatment of the underlying malignancy. Symptomatic relief may be afforded by 3,4-diaminopyridine (amifampridine) and immunosuppression.

Botulism and tetanus

The toxin released by Clostridium botulinum also works at the NMJ by blocking acetylcholine release. Exposure leads to an acute-onset descending flaccid paralysis.

Tetanus toxin also binds to the NMJ but is transported up the neuron to the CNS where it blocks neurotransmitter release from spinal inhibitory interneurons, thereby causing a spastic rather than flaccid paralysis.

References

• Bird SJ. Diagnosis of myasthenia gravis [Internet]. Shefner JM (Ed). UpToDate. 2021 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/diagnosis-of-myasthenia-gravis
• Jayarangaiah A, Theetha Kariyanna P. Lambert Eaton Myasthenic Syndrome [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020. [Accessed 2022 Feb 09]. Available from:  https://www.ncbi.nlm.nih.gov/books/NBK507891/
• Bird SJ. Overview of the treatment of myasthenia gravis. UpToDate [Internet]. Shefner JM (Ed). UpToDate. 2021 [cited 2022 Feb 14]. Available from: https://www.uptodate.com/contents/overview-of-the-treatment-of-myasthenia-gravis
• Manji H. Oxford Handbook of Neurology. Oxford Medical Publications; 2020
• Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Clementi F, Fesce R, Meldolesi J, Valtorta F, editors. Philosophical Transactions of the Royal Society of London Series B: Biological Sciences [Internet]. 1999 Feb 28;354(1381):259–68. [Accessed 2022 Feb 09]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1692495/
• Wendell LC, Levine JM. Myasthenic Crisis. The Neurohospitalist [Internet]. 2011 Jan;1(1):16–22. [Accessed 2022 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726100/
• Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI, Hilton-Jones D. The Association of British Neurologists’ myasthenia gravis guidelines. Annals of the New York Academy of Sciences. 2017 Nov 9;1412(1):166–9