Clinical features of myasthenia gravis

• Typically, patients present with extraocular muscle weakness (ptosis or diplopia) and later develop limb and bulbar muscle weakness.

• Patients with MuSK antibodies have predominantly ocular, facial and bulbar muscle involvement.

• Worsening of weakness after prolonged and sustained muscle contraction (fatigability) is the hallmark of myasthenia.

• Patients are often tested before and after a brief amount of muscle exertion to test for fatigability—sustained up-gaze for a few seconds to elicit weakness of the eyelids, limb strength after repeated abduction/adduction at the shoulder, or neck flexion against sustained resistance, if the weakness is not apparent otherwise.

• Tendon reflexes and sensory examination are normal.

Exacerbating factors

Several physiological, pathological and iatrogenic factors exacerbate myasthenia and can occasionally lead to respiratory failure and myasthenic crisis. These are summarised in box 1. In many female myasthenic patients, worsening of symptoms may occur regularly around their menses. However, very often a clear trigger may not be identified. Infection is probably the most common trigger for exacerbation of myasthenic symptoms. It is crucial to obtain a detailed drug history in case any recent new drug introduction could be a potential culprit for a patient’s presentation, or worsening of symptoms.

Myasthenic crisis

• A medical emergency that may progress to respiratory failure requiring ventilation.

• Affects approximately 10–15% of patients, usually within 2–3 years of diagnosis.

• MuSK antibody myasthenia patients are more likely to have myasthenic crises.

• Very occasionally, patients present in myasthenic crisis at the onset of disease.

• Increasing muscle weakness and double vision may be seen prior to the development of crisis.

• Quieter breath sounds, reduced chest expansion, tachycardia and rise in blood pressure indicate imminent deterioration.

• Since the ventilation–perfusion ratio is well maintained, oxygen saturation and arterial blood gases are normal until late in the crisis.

• Measurement of forced vital capacity is a useful predictor for impending respiratory failure.

• Typically forced vital capacity less than 1 l or 15 ml/kg requires intensive care treatment and respiratory support.

• Myasthenic crisis should be differentiated from other conditions causing respiratory failure (table 2).

Treatment

Symptomatic treatment (table 3)

• Pyridostigmine improves neuromuscular transmission by inhibiting acetylcholinesterase and so increasing the availability of acetylcholine at the motor endplate.

• Maximum daily dose of pyridostigmine is 360 mg; higher doses are unlikely to give additional benefit. Most patients require around 180 mg/day.

• Cholinergic adverse effects such as abdominal cramps, diarrhoea, increased salivation and sweating are counteracted by giving oral propantheline (15 mg usually 15–30 min before the pyridostigmine dose is due).

• For fixed deficits such as ptosis and diplopia, ophthalmic surgical intervention may be helpful

Immunosuppression (table 3)

• Corticosteroids are the definitive therapy.

• Prednisolone is usually initiated slowly (eg, starting dose of 10 mg, daily or on alternate days and increasing by 10 mg every week until target dose is achieved or symptoms and signs resolve). This is to minimise the possibility of exacerbation and crisis, especially in patients with bulbar symptoms. Faster titrations (eg, increasing by 10 mg daily, if a daily regimen is prescribed, or when steroid dose is due if alternate day regimen is used) can be achieved if steroids are initiated in hospital.

• The target dose of prednisolone is 1–1.5 mg/kg on alternate days (maximum 100 mg) for generalised myasthenia gravis and 0.75 mg/kg on alternate days (maximum 60 mg) for ocular myasthenia gravis.

• Alternate day steroid regimen is recommended from initiation of treatment since there is some suggestion that there are fewer adverse effects than with daily steroid regimens. However, a few patients feel significantly worse on the non-steroid day, in which case changing over to a daily regimen is sensible. Also, daily regimens are recommended in diabetics to avoid fluctuations in blood glucose levels.

• The dose should be increased until the target dose is achieved or until symptoms and signs resolve if this occurs at a lower dose. Once remission is achieved (which may take several months), the dose should be reduced gradually to the minimum maintenance dose.

• In generalised myasthenia gravis, a second line immunosuppressant (“steroid sparing agent”) is started at the same time as prednisolone; azathioprine takes at least 12 months to become effective. Other immunosuppressants probably act more rapidly.

• Azathioprine is the preferred first line steroid sparing drug; target dose 2.5 mg/kg/day.

• Thiopurine methyltransferase blood levels, if available, can be checked before starting azathioprine, but whatever the result the patient should still be closely monitored for bone marrow suppression and liver dysfunction.

• Macrocytosis and lymphopenia while on azathioprine are to be expected and are possibly desirable responses; the drug should not be withdrawn because of these.

• If remission is not achieved after 18 months of an adequate dose of azathioprine, other immunosuppressants may be considered; methotrexate, ciclosporin and mycophenolate mofetil.

• Once remission is achieved with corticosteroids with or without immunosuppressants, patients should not require pyridostigmine and it should be withdrawn.

• Any increased long term risk of malignancy in patients with myasthenia taking second line immunosuppressant drugs is uncertain, but the possibility should be discussed. Skin lesions (warts and non-melanomatous cancers) are relatively common with azathioprine and advice should be given about sun exposure

Emerging therapies for myasthenia gravis

• Rituximab, an anti-CD20 B cell monoclonal antibody, has been used in several refractory patients, especially MuSK cases. This depletes the antibody producing B cells and is given as an infusion once every 4 weeks.

• Genetic modification of cholinesterase using Monarsen has completed early clinical trials with good results without cholinergic adverse effects.

• Etanercept and infliximab, anti-tumour necrosis factor α monoclonal antibodies have been trialled on a limited basis, with mixed results.

• Complement inhibitors such as eculizimab are currently undergoing clinical trials.

Treatment of exacerbations of myasthenic weakness

• Intravenous immunoglobulin (IVIg) is the most commonly used therapy for acute worsening of myasthenia; 0.4 g/kg/day for 5 days. Improvement occurs within 1–2 weeks and lasts up to 12 weeks.

• Plasma exchange usually involves exchanging a plasma volume of 2–3 l daily for 5 days. Improvement is probably more rapid than with IVIg but they have similar efficacy.

• Respiratory crisis requires ventilatory support in addition to the above.

• It is crucial to recognise significant bulbar weakness even without enough respiratory muscle weakness to require ventilation. The patient should be kept nil by mouth and fed via a nasogastric tube until bulbar function recovers with no risk of aspiration.

Thymectomy in myasthenic syndromes

• 10–15% of myasthenia gravis patients have an associated thymoma.

• Conversely, 50% of patients with thymoma have myasthenia.

• The characteristic pathological change in the thymus of young patients with AChR antibodies is hyperplasia, comprising lymphoid follicles with or without germinal centres extending around perivascular spaces.

• The thymus is usually normal in MuSK myasthenia but screening is recommended to exclude a neoplasm which has been reported, albeit rarely.

• Thymomas can be seen in neuromyotonia but only very rarely in the Lambert–Eaton myasthenic syndrome.

• The role of thymectomy is uncertain and is currently the subject of an international multicentre trial. Currently, younger (less than 45 years) patients with AChR antibodies and generalised, rather than purely ocular, myasthenia gravis are often offered thymectomy

• Myasthenic control should be optimised preoperatively. However, high dose immunosuppression (especially steroids) immediately prior to surgery leads to greater postoperative complications.

• Histologically confirmed thymoma patients need surveillance with CT or MRI of the chest at a minimum of 1, 3 and 7 years to detect recurrence. Depending on the histological diagnosis and extent of spread, some thymoma patients require postoperative radiotherapy and/or chemotherapy.

Lambert–Eaton myasthenic syndrome (LEMS)

This rare autoimmune disorder affects synaptic transmission at both the neuromuscular junction and autonomic ganglia.

• It is caused by antibodies against P/Q type voltage gated calcium channels.

• It is about 20 times less common than myasthenia gravis.

• 50–60% of patients have an underlying neoplasm, usually small cell lung cancer, and rarely adenocarcinomas and lymphoproliferative disorders.

• Non-cancer cases may be associated with other autoimmune diseases, such as insulin dependent diabetes mellitus and thyroid disease.

Clinical features

• Non-paraneoplastic patients can present in any age group.

• Paraneoplastic patients are generally >50 years old and are usually smokers.

• Typically presents with proximal muscle weakness, predominantly affecting the lower limbs.

• In contrast with myasthenia gravis, strength may improve after sustained exercise.

• The tendon reflexes are commonly reduced or absent but strong contraction of the relevant muscle against resistance often allows the reflex to be elicited; this “potentiation” of absent or hypoactive tendon reflexes is virtually diagnostic.

• In addition to the muscle weakness, almost all patients have some autonomic involvement; dry mouth, postural lightheadedness, sphincter disturbance or impotence. In comparison with myasthenia gravis, ocular, facial and bulbar muscle involvement is less common.

Pointers for paraneoplastic Lambert–Eaton myasthenic syndrome

• Rapid progression of symptoms

• Early involvement (within 6 months) of distal muscles

• Dysarthria

• Impotence

Diagnosis

• VGCC antibodies are detected in approximately 90% of cases.

• VGCC antibody is almost always positive in patients with an underlying small cell lung cancer.

• Neurophysiological assessment classically demonstrates reduction in compound muscle action potential amplitude with a subsequent increase in amplitude of >100% following voluntary maximal activation or repetitive nerve stimulation at 40 Hz.

• A comprehensive work-up for an underlying neoplasm should be undertaken. If initially negative, chest imaging should be repeated annually for at least 5 years, especially in a smoker. Positron emission tomography scanning is likely to play an important role to detect occult malignancy in these patients.

Treatment

• Symptomatic treatment with 3,4-diaminopyridine (3,4-DAP), typically 10–20 mg four times daily. This drug blocks potassium channels in the nerve terminal, prolonging the nerve action potential and enhancing calcium ion entry at the presynaptic nerve terminal, which in turn allows more calcium dependent release of acetylcholine.

• Pyridostigmine provides less benefit than in myasthenia gravis although in conjunction with 3,4-DAP it can allow a lower dose of the latter.

• Immunosupression with corticosteroids is used in both forms of the Lambert–Eaton myasthenic syndrome.

• Additional treatment with azathioprine, ciclosporin and mycophenolate mofetil is used in non-paraneoplastic cases although the evidence is limited to case reports/series and is certainly less robust than for myasthenia gravis.

• In severe disease, plasma exchange and IVIg are probably equally effective but the effect of each is short lived (and generally less effective than in myasthenia gravis), lasting up to 8 weeks.

• In paraneoplastic cases, treatment of the small cell lung cancer improves both the prognosis and the neurological outcome.

Disorders of peripheral nerve hyperexcitability

The two main disorders of peripheral nerve hyperexcitability are neuromyotonia and cramp fasciculation syndrome. There is considerable clinical and neurophysiological overlap between them, which also merge with frequent simple cramps without associated features. Some authors lump them all together and use the term “peripheral nerve hyperexcitability syndrome”. A proportion of these patients have antibodies to the voltage gated potassium channels at the presynaptic nerve terminal of the neuromuscular junction.

Peripheral nerve hyperexcitability, however, can occur in other autoimmune processes, such as paraneoplastic syndromes, and is also seen in association with inherited neuropathies. Toxins may produce a similar clinical picture. Relevant conditions to be considered are shown in box 2.

Clinical features

• The clinical features of cramp fasciculation syndrome are muscle cramps, stiffness and fasciculations which often occur following exercise.

• In neuromyotonia there is additional myokymia (undulating rippling of muscles) and pseudomyotonia (excessively slow relaxation of muscles but without percussion myotonia); this may lead to muscle hypertrophy.

• Limb and trunk muscles are commonly affected, extraocular muscles more rarely.

• Hyperhidrosis is common.

• Neuromyotonia may also be seen in the context of Morvan’s syndrome, a limbic encephalitis associated with voltage gated potassium channel antibodies. The patients may present with insomnia, seizures and psychiatric disturbances. However, there may also be peripheral (including neuromyotonia) and autonomic features.

Diagnosis

• Voltage gated potassium channel antibodies are identified in about 50% of neuromyotonia cases, less in cramp fasciculation syndrome.

• Electromyography in neuromyotonia demonstrates spontaneous motor unit discharges (myokymia or neurmyotonia) consisting of doublet, triplet or multiplet discharges in addition to fasciculations and fibrillations.

• In cramp fasciculation syndrome, the electromyographic features are milder—single motor unit discharges and fasciculations.

• CT scan of the chest is usually recommended to exclude an underlying thymoma, especially with positive voltage gated potassium channel antibodies.

Treatment

• Peripheral nerve hyperexcitability is treated symptomatically with carbamazepine, phenytoin, sodium valproate, gabapentin, pregabalin or lamotrigine.

• In severe cases with voltage gated potassium channel antibodies, plasma exchange or IVIg provide short term benefit, typically 6 weeks.

• Further maintenance immunosuppressive therapy with corticosteroids (plus azathioprine or methotrexate) is occasionally given.

Congenital myasthenic syndromes

These are rare, approximately 5 per million in the UK, although the true prevalence is likely to be higher. Two-thirds have identifiable genetic mutations in proteins of the neuromuscular junction. There are several distinct syndromes, with clinical features varying with the nature of the mutation and the gene. Crucially, several of the syndromes deteriorate with pyridostigmine, despite sometimes an initially positive response, and alternatives are required. Immunosuppression is ineffective but frequently given inappropriately because of incorrect initial diagnosis (table 4).