Dr. Rahul Chakor Neurologist
Special Interest in Neuroimmunology, Epilepsy

Myasthenia gravis (MG) is a relatively rare chronic disease characterized by weakness and rapid fatigue of the voluntary muscles. Though the name denotes grave muscular weakness treatment is available for this disease. It is a snowflake disease, with different manifestation in each patient, a different course and different treatment in every single case.

The prevalence of MG is estimated to be about 20/100,000 population. However, MG is probably under diagnosed and the prevalence may be higher. MG affects people of all ages and either sex but is common in young women and elderly men.

Symptoms

The onset of MG can be sudden, with severe and generalized muscle weakness, but more often its symptoms in the early stages are subtle and variable, making it difficult to diagnose correctly. The signs and symptoms neuromuscular junction disorder such as MG result from fluctuating strength of the voluntary muscles. The degree of weakness is partly dependent on the exertion of a muscle group but also varies spontaneously over longer periods without apparent cause. Remissions occur. All types of voluntary muscle may be involved but usually not to the same extent. The following classification of MG is useful 1) purely ocular MG (weakness restricted to the palpebral levator and the extraocular muscles); 2) early-onset generalized MG, (clinical onset before age 40 years); 3) late-onset generalized MG (onset after age 40 years); and 4) patients with a thymoma, with onset at any age.

Ocular:

Ocular symptoms are the most frequent manifestations of MG. Ptosis (drooping of the eyelid, eye appears small) or diplopia (double vision) are the common symptoms. Some patients appreciate fluctuation of the diplopia from onset and are able to analyze the double images themselves. Others only complain of blurred vision, which becomes normal when looking with one eye.

Bulbar:

Among bulbar symptoms, speech difficulties manifesting as nasality of the voice or a difficulty in articulation (dysarthria) are the most common at onset of MG. Sensation that food is sticking in the throat, chewing difficulty at the end of the meal, or when chewing bubble gum or eating peanuts may be seen. Weakness of neck muscles leads to difficulty in balancing the head. Weakness of the facial muscles may occur. The facial expression may be changed. Laughing becomes distorted (“we did not know whether she laughed or cried”). There is change of facial expression and person appears sad. People ask them why they always look sad or angry. Orbicularis oris weakness is first noticed by the inability to whistle or to kiss, sneeze forcefully, or eat soup with a spoon, or by difficulty in pronouncing labials (p, f, s). Swallowing difficulties may be caused by weakness of the lips, the tongue or the pharyngeal muscles. Some MG patients may be seen to support their jaws, underlips, and floor of the mouth, to counteract gravity and to chew with their hands. Severe impairment of swallowing manifests with drooling of saliva, choking, and ventilatory insufficiency.

Limb, Trunk, and Respiratory:

Fifteen to 20% of patients complain first of weakness of the arms, hands, or legs. Inability to maintain arm position or elevate the upper extremity repetitively, e.g., when hanging clothes, hammering a nail, or washing or combing hair, is a common complaint. Leg weakness frequently leads to sudden falls. If the first manifestations are weakness of the limbs or trunk muscles, most patients complain of undue fatigability, difficulty climbing stairs and peculiar feelings of heaviness. Weakness of the respiratory and other trunk muscles is rarely the first, isolated sign of the disease.

Cause

MG is an autoimmune disease. Acetylcholine receptor antibodies (AChR) are seen in the majority of patients (~85%), while in 6% antibodies against the muscle-specific kinase (MuSK) are detected. Antibodies to the muscle-specific tyrosine kinase are detected in approximately 50% of generalized myasthenia gravis patients who are seronegative for anti-acetylcholine receptor antibodies. In around 10% of MG patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG). In 50 % of ocular myasthenia AchR antibodies are detected.

Course of the disease

The initial manifestations of MG have a highly variable pattern and evolution in the individual patient. MG does not have a classical clinical course (Osserman). There is a tendency for weakness to spread to muscle groups beyond those initially affected, and in only 10% to 16%) of the patients is MG clinically confined to the ocular muscles in the first 3 years. However, after 3 years, generalization occurs in only 3–10% of the purely ocular patients.

In most patients the diagnosis is made in the second year after symptom onset, but a much longer delay is not unusual), especially among early onset women. Severe exacerbation of MG leading to myasthenic crisis occurs usually in the first years.

Exacerbating Factors

Infectious diseases, psychological stress, hyper- or hypothyroidism, and certain drugs such as antimalaria drugs (quinine, chloroquine), aminoglycosides, adrenergic receptor blocking drugs and D-penicillamine exacerbate the weakness in MG. The effect of pregnancy on MG is the subject of conflicting reports: either improvement or deterioration or no influence, each one-third in all the series.

Genetics

MG is not considered a hereditary disease with a definite mode of genetic transmission; familial cases are reported in 1–4% of several series.

Differential diagnosis

The diagnosis of ocular MG may be difficult . If the patient has bulbar symptoms, one might have reason to include such neuromuscular diseases as amyotrophic lateral sclerosis, oculopharyngeal dystrophy, bulbar spinal atrophy, or myotonic dystrophy in the differential diagnosis. Isolated dysphagia may be caused by a mechanical impairment or innervation of the esophagus (achalasia). For predominant limb weakness, the possibility of Lambert-Eaton syndrome, other acquired diseases with more or less fluctuating weakness of limb and trunk muscles may be motor neuron disease, polymyositis, endocrine myopathies, and mitochondrial myopathies should be considered.

Diagnosis

The diagnosis of MG can be supported by clinical, laboratory and electrophysiological investigations. Tensilon test - An intravenous bolus of edrophonium (tensilon) may transiently improve the symptoms and signs of myasthenia and is the basis of this test. However, false negatives are common and false positives occur with many other neuromuscular diseases.

Electrophysiological studies looking at repetitive stimulation and single fibre EMG (SFEMG) are abnormal in MG (RNS). Repetitive stimuli at a rate of 3 Hz lead to a decrement in the CMAP amplitude of >15% which should be reproducible.RNS may be negative in ocular myasthenia and mild generalized myasthenia gravis. SFEMG is the most sensitive neurophysiological investigation of neuromuscular transmission.

AChRAb are detected in approximately 75% of patients with generalized myasthenia and 50% with pure ocular myasthenia. AChRAb are the most specific marker for MG but they may be found in association with thymoma, SLE, autoimmune liver disease, inflammatory neuropathies and rheumatoid arthritis (especially when taking penicillamine) without any clinical evidence of myasthenia. Levels of AChRAb fluctuate with disease severity in an individual patient. Anti-MuSK antibodies occur in >50% of seronegative MG cases (AChRAb negative) and are not found in AChRAb positive MG cases.

Management

Patient education is one of the most important factors in allowing patients to adjust to a chronic illness with variable prognosis and treatments with poor side effect profiles. A thorough discussion of the natural history, treatment options, and disease pathogenesis is essential.

There are few randomized controlled trials in MG and treatment is based on expert opinion. Treatment choices must be individualized based on the severity of the disease, the patient’s lifestyle and career, associated medical conditions, and assessment of the risk and benefit of various therapies.

Anticholinesterases – (Pyridostigmine) are the first line of treatment. They are useful in the early symptomatic treatment of MG or later as an adjunct to immunotherapy. The adverse effects are abdominal cramps, diarrhoea, increased bronchial and oral secretions.

Corticosteroids - (Prednisolone) is extremely effective in improving myasthenic weakness and establishing remission. There is considerable variability in dosage, duration of treatment and clinical response to steroids. Treatment is usually commenced in hospital because of the significant risk of deterioration in proximal strength during the first 2 weeks of treatment.

Immunosuppressants - Azathioprine has been shown to reduce the dosage of prednisolone required to maintain remission and to reduce the number of treatment failures. The effects of azathioprine (< 2.5 mg/kg) are extremely slow to develop and a therapeutic dosage may take up to 2 years for the full clinical effect to be seen. Ciclosporin has similar efficacy to azathioprine but works more rapidly.

Plasma exchange - It is valuable in producing short-term improvement of severe myasthenic weakness (Myasthenic crises).

IVIG (Immunoglobulins) - is similar in efficacy to plasma exchange and is valuable in producing short-term improvement in myasthenic crisis and also occasionally as a long term maintenance therapy.

Thymectomy has been used in the treatment of MG for 50 years. Objective evidence of the efficacy and role of thymectomy remains elusive. Thymectomy is indicated for patients with seropositive MG from late childhood up to the age of 60 years.