Introduction

The most common adult-onset disorders of neuromuscular transmission are myasthenia gravis (MG)1 and the Lambert–Eaton myasthenic syndrome (LEMS). Both conditions are antibody mediated and arguably the best understood of all neurological autoimmune diseases. The membrane ion channels and receptors at the neuromuscular junction (NMJ) seem particularly vulnerable to attack from circulating autoantibodies, perhaps because these structures lie outside the blood–nerve barrier. The most common, but not exclusive, target antigen in MG is the postsynaptic muscle nicotinic acetylcholine receptor (AChR) and in LEMS the targets are presynaptic neuronal voltage-gated calcium channels. In addition, antibodies to neuronal voltage-gated potassium channels are the most common cause of the neuromyotonia clinical variant of peripheral nerve hyperexcitability (PNH) and are also responsible for a non-paraneoplastic limbic encephalitis.

Myasthenia Gravis

Clinical Features

MG was possibly first described by Thomas Willis in the seventeenth century (De Anima Brutorum, 1672), but was only named as such by Jolly in 1895. The overall incidence of MG is between 2 and 10 per 100 000 people. It affects all races and can begin at any age after the first year of life. However, incidence is markedly age dependent, with about half of patients presenting after the age of 40 years. The condition is markedly underdiagnosed in people over the age of 75 years.2 There are peaks of incidence at both 10–30 years and over the age of about 60 years in patients not harbouring an underlying thymoma, whereas onset of MG with thymoma is most common between the ages of 40 and 60 years. Men predominate in the over-60 age group, whereas women outnumber men 3:1 in the under-40 age group.

Symptoms and Signs

The clinical hallmark of MG is painless fluctuating skeletal muscle weakness that worsens with exercise and improves with rest. There is a characteristic diurnal pattern of weakness, gradually worsening throughout the day and improving with rest or sleep. Some individuals find that symptoms improve in a cold ambient temperature.

Any skeletal muscle may be affected in MG, but certain muscles and muscle groups are especially susceptible, notably those supplied by the motor cranial nerves. More than 90% of patients have peri- and extraocular muscle involvement, with ptosis and diplopia being common symptoms. Typically there is asymmetric weakness of several muscles of both eyes accompanied by weakness of eye closure. Eye movements resembling internuclear ophthalmolegia (pseudo-INO) and one-and-a-half syndrome (pseudo-one-and-a-half syndrome) are described. Patients often attempt to correct partial ptosis by contracting the frontalis muscle, causing a characteristic wrinkled brow appearance. Repeated blinking causing diagnostic confusion with blepharospasm has been reported.3 A twitching of the upper eyelid seen a moment after the eyes are moved from downgaze to the primary position, Cogan’s lid twitch sign, is said to be a characteristic sign of ocular myasthenia, but sensitivity and specificity are relatively low, as it may be seen in other oculomotor brainstem disorders.4 In 15–20% of patients, weakness is confined to the ocular muscles, ocular MG, whereas others present with or will develop the generalized form of MG.

The muscles of facial expression, mastication, swallowing and speech are the next most commonly affected group. Relatives may notice that a lack of facial movement makes the patient look depressed and that the smile has a transverse or snarling quality (‘myasthenic snarl’). Jaw weakness may interfere with chewing; in extreme cases, the jaw hangs open and has to be supported by the patient’s hand. Palatal weakness can result in dysarthria with a nasal quality and in reflux of liquids through the nose when drinking. Dysphagia and choking reflect involvement of pharyngeal and tongue musculature and hoarseness and dysphonia caused by laryngeal weakness are frequently seen.

Neck muscle weakness is common and the head may droop forwards in severe cases; MG is one of the most common causes of the ‘dropped head syndrome’.5 In generalized MG, the proximal limb muscles are typically most affected, but predominantly distal6 and sometimes very focal weakness are described.7 Tendon reflexes are normal or brisk and sensation is intact.

Clinical examination should pay particular attention to shoulder abduction, elbow extension, wrist and finger extension, finger abduction and hip extension, as these are frequently weaker and fatigue more quickly than their antagonistic limb movements. In severe cases, all muscles can be involved, including the diaphragm and intercostal muscles, causing dyspnoea and hypoventilation. Muscle wasting may be seen on occasion in chronic, poorly controlled disease. Muscle strength should be quantified (MRC grading) as serial assessment may give an objective early warning of deterioration, and also help to monitor treatment efficacy. Measurements should include vital capacity (VC), timed elevation of the eyes and eyelids and forward abduction of the arms. A rapid decline in VC or a reading below 1 l are signs of imminent respiratory failure.

Muscle weakness can be worsened by a wide range of conditions, including intercurrent diseases, especially infections, fever, extremes of temperature and emotional upset. In addition, many drugs may adversely affect myasthenia8 and should be used with caution in poorly controlled patients (Table 66.1). If possible, neuromuscular blocking agents should not be used during general anaesthesia. Sufficient muscle relaxation can usually be provided by inhalation anaesthetics alone. Many other drugs may increase weakness and it is a useful rule to monitor carefully all MG patients when starting a drug that is new to them.

Table 66.1 Drugs that may worsen MG.

Neuromuscular blockers, including D-tubocurarine, pancuronium, curare and succinylcholine

Aminoglycosides, including gentamicin, streptomycin, kanamycin, neomycin and viomycin

Polymixins, including polymixin B and colistin

Beta-blockers

Calcium channel antagonists

Quinine, quinidine and procainamide

Chloroquine and hydroxychloroquine

Whether cardiac function is impaired in MG remains uncertain. Although there is no evidence for an increased risk of heart-related deaths, there may be subclinical alterations in cardiac function in some MG patients, possibly related to the autoimmune diathesis and reversible with acetylcholinesterase inhibitors. Focal myocarditis and non-specific myocardial changes have been reported in pathological series, especially in MG associated with thymoma.9

A central cholinergic deficit in MG, commensurate with that at the neuromuscular junction, has been suggested, with resulting impaired memory function (cholinergic deficits are thought to be important in both Alzheimer’s disease and dementia with Lewy bodies). Some studies have suggested cognitive impairments in MG patients, some of which improve with immunotherapy, but others have found no evidence for such impairments in MG patients compared with normal controls and hence no support for the idea of impaired central cholinergic mechanisms.10

Penicillamine-Associated Myasthenia Gravis

Unlike the many drugs that may temporarily worsen MG, D-penicillamine may induce immune-mediated MG. Typically the disease is mild, often ocular, associated with the transient production of low-titre AChR antibodies in patients who are HLA Bw35 DR1 positive, responds to acetylcholinesterases and remits permanently within months of stopping D-penicillamine. However, clinical, genetic and immunological heterogeneity are reported, as in spontaneous MG, with occasional patients developing severe and persistent seropositive or seronegative MG requiring ongoing immunotherapy.11

Diagnostic Investigations: Bedside

The distinctive clinical picture may enable a confident diagnosis of MG to be made, but additional investigations are desirable since there is a differential diagnosis (see below). Diagnostic confusion arises most frequently when MG is mild or when one of the clinical features dominates the presentation. Patients may not volunteer a history of fluctuating weakness and it is useful to ask about this, particularly diurnal variability with sleep benefit, in anyone presenting with tiredness, ptosis, diplopia, dysphagia or hoarseness. Examination should include assessment of muscle power and fatigability with repetitive contraction. Even when symptoms are restricted to one area, it is sometimes possible to demonstrate weakness in the typical pattern described above.

Anticholinesterase (Tensilon) Test

Although this is the least specific of the standard tests for MG, it is frequently used because it is relatively easy to perform at the bedside and provides an immediate result, whereas other tests and their results (blood tests, neurophysiology) may be delayed.

Edrophonium chloride (Tensilon) is a short-acting acetylcholinesterase inhibitor. A test dose of 1–2 mg is given through an intravenous cannula, a further 5–8 mg being given if there is no adverse reaction. The test is positive if muscle strength improves within 1 min. Assessment should be as objective as possible and include VC measurement and forward elevation of the arms, in addition to monitoring of ptosis and diplopia. Increased muscle power lasts for about 5 min. Some patients may develop a severe bradycardia and occasionally ventricular fibrillation. Pretreatment with i.v. atropine (0.6 mg) is probably advisable and the test is best performed with ECG monitoring and definitely with resuscitation equipment discreetly to hand.

Positive responses to the Tensilon test may occur in a wide range of conditions, including LEMS, motor neurone disease, neuropathies, myopathies and even psychogenic weakness and intracranial tumours. This test is probably best reserved for the situation where there is a strong clinical suspicion of MG but the results of antibody tests are negative or not yet available and EMG is awaited.

Ice Pack Test

The ‘ice pack test’ or ‘ice on eyes’ test has been proposed as a useful method of distinguishing ptosis due to MG from other causes. An ice cube is applied to the ptotic eyelid for at least 2 min and the response noted: improvement in ptosis (>2 mm, positive response) is both sensitive and specific for the diagnosis of myasthenia and correlates with the result of the Tensilon test, although false negatives have been described.12 Pooling of results from six studies (n = 76 MG patients, n = 77 patients with non-myasthenic ptosis) gave a test sensitivity of 89%, a specificity of 100% and positive and negative predictive values of 100 and 91%, respectively, for the ice pack test.12 Utility of the ice pack test in the assessment of extraocular muscle weakness remains to be shown.13

Compared with AChR antibody assay and neurophysiological testing, the ice pack test has the advantages of being cheap, quick and not requiring specialist equipment. Moreover, compared with the Tensilon test, no specialist medications are required, it is free of adverse effects and its result, although not unequivocal, is usually easy to interpret.12

Sleep Test

That rest improves myasthenic ptosis is widely observed. A standardized ‘sleep test’ or ‘rest test’ has been advocated for the diagnosis of MG, a positive result being resolution of ptosis or ophthalmoparesis after 30 min of sleep.14

Diagnostic Investigations: Laboratory

Laboratory tests are essential to confirm the diagnosis, as treatment may involve surgery and drug therapy with potentially serious adverse effects.

Acetylcholine Receptor (AChR) Antibodies

The autoimmune nature of MG was first suggested by Simpson in 1960,15 the evidence for which is summarized in Table 66.2. The most specific blood test for MG is the presence of serum AChR IgG antibodies detected by radioimmunoprecipitation assay (RIA). This uses AChRs labelled with an iodinated toxin that binds specifically to these receptors. False positives are rare in the healthy British population, including the elderly, although 7% of a group of patients over the age of 65 years selected for their predisposition to autoimmune disease (assessed by raised antithyroid antibody titres) had raised levels. The assay does not detect AChR antibodies in patients with seronegative MG.

Table 66.2 Evidence that MG is an antibody-mediated autoimmune disease.

Antibody can be demonstrated in the majority of patients with the disease: AChR antibodies are detected in 85% of patients with generalized MG

Passive transfer of the antibody to experimental animals reproduces the disease: IgG from myasthenics injected into mice induces the clinical and electrophysiological features of MG

Antibody interacts with the target antigen: electron microscope immunohistochemistry has shown that AChR antibodies, in addition to complement, localize to postsynaptic structures in a pattern appropriate to affect AChRs in a destructive autoimmune process

Immunization with antigen produces a model of the disease: animals immunized with purified AChR develop myasthenia

Lowering serum antibodies improves the disease: removal of circulating antibodies by plasma exchange results in marked, but transient, improvement in disease in most myasthenics. After treatment, the antibody titre rises and the weakness returns

Anti-MuSK Antibodies

About 10–50% of MG patients without AChR antibodies have antibodies directed to the muscle-specific receptor tyrosine kinase MuSK.16 MuSK mediates the agrin-induced clustering of AChRs during synapse formation and is also expressed at the mature neuromuscular junction. MG with MuSK antibodies is often associated clinically with persistent bulbar involvement, including marked facial weakness involving buccinators, orbicularis oris and orbicularis oculi and tongue muscle wasting and respiratory crises.17

Striated Muscle and Other Antibodies

Antibodies that bind to components of striated muscle cell membrane are found in 30% of all MG patients and in 70–90% of those with a thymoma. Therefore, anti-striated muscle antibodies may be used as a serum marker for this tumour. In addition, subgroups of these antibodies reacting with titin or ryanodine receptors are particularly associated with severe MG and also with thymoma. Antibodies that react with myosin, α-actin, actinin, β-adrenergic receptors and muscarinic AChR have also been demonstrated in MG, but their pathophysiological significance, if any, remains unclear.