a Myasthenia gravis

Myasthenia gravis¹ epitomises diseases of the neuromuscular junction, and is an autoimmune disease with antibodies directed against the acetylcholine receptors on skeletal muscles in approximately 90% of those with generalised myasthenia gravis and about half those with ocular myasthenia. Should these antibodies not be identified then the muscle-specific kinase antibodies (MuSK antibodies) are found in about half the remaining patients with myasthenia gravis. Those with MuSK antibodies tend to have a slightly atypical presentation of their myasthenic picture with more oculo-bulbar and neck extensor involvement and more respiratory symptoms.

Myasthenia may occur at any age, with male to female ratio of 1 : 3 with an earlier onset in women and girls (10–40 years) as compared to men (often 50–70 years). After the age of 40 years, the male : female ratio is approximately equal. There is a neonatal form of myasthenia, thought to be secondary to placental transmission of the acetylcholine receptor antibodies. This presents with impaired sucking, weak cry and ‘floppy’ limbs. This presents within the first two days of life. It generally only requires supportive treatment for the lifespan of the antibodies. There is also an autosomal recessive congenital form with infantile onset, and a drug-induced form consequent to the use of D-penicillamine.

The usual presentation of myasthenia gravis is with ptosis (see Table 16.1) together with fatiguable muscle weakness, diplopia and possible dysarthria, dysphagia, dyspnoea or fatiguable proximal limb weakness. Almost any skeletal muscle may be involved, as may be respiratory muscles, and myasthenia gravis may mimic other diseases. Purely ocular myasthenia often presents with ptosis and diplopia without other muscle group involvement.

When examining the patient with suspected myasthenia gravis, fatiguability is demonstrated by asking the patient to look up at a fixed object or spot and to maintain the upward gaze (see Fig 16.1).

FIGURE 16.1 Testing for fatiguable ptosis.

Alternative methods for testing for fatiguability include asking the patient to count aloud to 100, and listening to the quality of articulation to recognise the development of a dysarthric and nasal quality to enunciation as the counting proceeds. Testing muscles of mastication, the patient is asked to bite down on a wooden tongue depressor while at the same time the doctor pulls on the spatula and observes the decline in the strength of the bite. Peripheral muscle fatiguability may be tested by asking the patient to repeatedly perform a muscle task with intervening relaxation, and recording the evolving weakness over time (see Fig 16.2).

FIGURE 16.2 (i) Testing for fatiguability of shoulder abduction; (ii) Testing for fatiguability of wrist dorsiflexion.

What presents as purely ocular myasthenia may often progress to become generalised myasthenia, possibly consequent to an intercurrent infection. As with all neurology, the diagnosis requires a high index of suspicion with the differential diagnosis including: brainstem lesions and other causes of ptosis (see Table 16.1); multiple sclerosis; Graves’ disease (thyrotoxicosis) with ophthalmo-paresis; and other inflammatory myopathies, most of which causes elevation of creatine kinase (CK).

While diagnosis usually relies on specialist involvement, the suspicious general practitioner can start the ball rolling, having ordered acetylcholine receptor antibodies and a chest CT scan, looking for thymoma. Repetitive nerve stimulation or single fibre electromyography are clearly the domain of a neurophysiologist. Double-blind edrophonium (Tensilon) testing is best performed within the hospital setting with cardiac monitor and facility for resuscitation, which is rarely required. The general practitioner may perform an ‘ice test’ in which the application of ice produces strengthening of muscles. This is rarely, if ever, used these days as a referral to the consultant has supplanted such simple testing with Tensilon test. The ‘ice’ test really was only used in ocular myaesthenia.

Patients with myasthenia gravis may have concomitant other organ specific autoimmune diseases with up to 10% having associated thyroid disease, be it hyperthyroidism or hypothyroidism, that may be identified by the astute general practitioner who will treat this in their usual fashion, with possible referral.

Thymectomy is advocated in young patients with myasthenia (below the age of 50 years) and all those with thymoma. It is not usually advocated in those older than 65 years, those with pure ocular myasthenia or with MuSK antibodies.²

Pharmacological treatment of myasthenia is with pyridostigmine (Mestinon®) and/or the use of immunosuppression, be it with steroids or more aggressive, but this is usually the domain of the specialist.

Mestinon® is started at 60 mg b.d. or t.d.s. in mild cases, often complemented with slow release ‘Time Span’ (180 mg) at night. Adverse events may include excess salivation, abdominal cramping and possible diarrhoea; the latter may require anticholinergics. It should be remembered that Mestinon® may exacerbate glaucoma. A cholinergic crisis must be considered in patients with respiratory failure. These patients may also experience dilated pupils, together with the above adverse symptoms plus fasciculations. When this occurs the anticholinesterases should be withdrawn and the patient maintained in an intensive care environment with possible intubation. This represents a medical emergency, which may be provoked following the initiation of Mestinon® therapy.

Steroids, at a dosage of 1.0–1.5 mg/kg/day (usually 60–100 mg per day), may exacerbate weakness in the first one to two weeks so caution must be exercised when starting steroids, particularly in outpatients. Additional treatment with myclophenalate, azathioprine or possibly even cyclosporins has been used as steroid-sparing agents. In more severe cases plasmapheresis or IV immunoglobulin may be required, but this again is the domain of the consultant rather than the general practitioner.

b Lambert-Eaton myasthenic syndrome (LEMS)

This is usually a paraneoplastic, auto-immune, myasthenic condition.³ It is caused by antibodies to calcium channels on the presynaptic nerve terminals of skeletal muscles and autonomic ganglia. The myasthenic syndrome usually precedes the diagnosis of the tumour, which is usually a small cell lung cancer.

The symptoms often start in the proximal leg and shoulder girdle muscles without ocular features. There may be parasympathetic symptoms of dryness, including mouth, constipation, urinary retention and impotence.

The diagnosis relies on neurophysiology with post-exercise potentiation of the compound muscle action potential, but this is definitely the precinct of the specialist. Ultimate treatment is directed towards managing the underlying malignancy, although treatment specific to myasthenia gravis may have limited efficacy.

c Botulism

The toxin produced by Clostridium botulinum blocks the release of acetylcholine from the autonomic and motor nerve endings, causing nausea, vomiting, anorexia, constipation, blurring of vision, diplopia, dysarthria, dysphagia, dyspnoea and limb weakness 12–36 hours after consuming contaminated food.⁴

Diagnosis requires a high index of suspicion plus identifying the toxin in serum. Treatment is the application of appropriate anti-serum, by which stage the patient will usually be in hospital.