Myasthenia Gravis

The first descriptions of Myasthenia Gravis (MG) cases occurred more than 300 years ago, yet it was not until a series of discoveries in the mid-1970s that an understanding of and general consensus that MG symptoms are due to an autoimmune response impacting neuromuscular functions developed. The distinctive feature of MG is fluctuating muscle weakness, made worse by use of those muscles and improved at least partially by resting them. The muscles affected are called voluntary muscles … muscles that we use all the time, such as those used to move the eyes or hold the eyelids open. The muscles used for facial expressions, chewing, talking or swallowing can be selectively affected. MG can affect neck muscles holding up the head which can go into spasm because they are weak. Muscles affecting the limbs can prevent a person from accomplishing activities of daily living such as holding up an arm to comb hair, shave, shampoo or put on make-up. Getting out of the bathtub or up from a sofa, climbing stairs or walking distances may be impaired. We take these muscles for granted until they don’t work as expected.

With MG, the body’s immune system mistakenly attacks and destroys its own special proteins (acetylcholine receptors) located on the muscle surface where a nerve meets the muscle. If some acetylcholine receptors are destroyed the muscle response is reduced and weakness occurs.

The seriousness of MG is particularly noticeable when some muscles that we use in breathing are affected. If the ability to breathe becomes insufficient, the patient is said to be in a “Myasthenic crisis” and mechanical breathing assistance in a hospital may be necessary. Different muscle groups are affected from patient to patient and some may only have Ocular Myasthenia involving the eye muscles. Although MG can be fatal if a respiratory crisis is not treated immediately, with proper treatment, normal life expectancy is the rule.

Myasthenia Gravis means “grave weakness”. It can affect people of all racial and ethnic groups and in both sexes, from infancy to old age. It is not uncommon for family members to have the same or different autoimmune diseases and some individuals can have more than one autoimmune condition. The prevalence rate of patients with MG is estimated to be 1 in 5,000, but because MG is often misdiagnosed, the rate may be higher. At present, the cause of MG is unknown and there is no cure.

Similar to other chronic diseases, treatment can be complex, debilitating and expensive. Potent medications and intravenous immune globulin (IVIg) and plasmapheresis, which are dispensed in a drip method through a vein, can cause side effects in themselves. Because the thymus gland is an organ involved in the development of the immune system, removal is often recommended for patients diagnosed with MG. The operation is called a thymectomy and although there may be a lessening of symptoms and reduction of MG-related drugs, there are risks with surgery and relapse is possible. As always, patients must become their own health care advocate in order to deal with insurance companies, pharmacies, physicians and other allied health professionals.

Epidemiology

  • Prevalence has been recorded at 1 in 5,000
  • Mean age at onset for women is 34.9 years and for men it is 48.5 years.
  • Peak incidence is in the third decade for women and the sixth or seventh decade in men.

Aetiology

  • About 10% of patients with MG have a thymoma and around half of patients with thymoma also have MG. Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor.  Once diagnosed, thymomas may be removed surgically. In the rare case of a malignant tumor, chemotherapy may be used.
  • The condition can sometimes be inherited although there is a predisposition for autoimmune diseases to run in families.

Presentation

50% of patients present with problems of the ocular muscles and 90% experience symptoms at some stage.

  • Muscle fatigues more readily after exercise – a feature used in making the diagnosis. Patients with ocular muscle involvement are usually unable to look up for more than a few seconds.
  • Droop of the upper eyelids is typical with weakness of external ocular muscles producing diplopia. Patients may tilt their head upwards to compensate.
  • Weakness is more marked in proximal muscles and isolated weakness of limb muscles is the presenting feature in less than 10%.
  • Weakness of the following muscles may also be seen:
    • Small muscles of the hands (finger extensors).
    • Deltoid and triceps muscles.
    • Bulbar muscles – common, causing a nasal sound to speech that is slurred.
    • Facial muscles – very common, producing an abnormal horizontal smile with a furrowed brow that compensates for ptosis.
    • Muscles involved in chewing – thus eating can become difficult and weak muscles may make the jaw drop so that the patient may sit with his chin on his hand to support it.
    • Flexors and extensors of the head – are often weak.
  • Symmetrical weakness of a number of other muscles may produce difficulty with walking, sitting or even holding the head up.

Progression

  • The most typical pattern is for disease to spread from mild to moderate or severe over the course of weeks or months, although sometimes the disease can remain restricted to the external ocular muscles and eyelids for years.
  • In severe and general weakness it is rare for the ocular muscles to be unaffected.
  • Disease is confined to the ocular muscles in only around 15% of patients.
  • Nearly 90% of patients develop general disease within a year from onset, and onset to maximal weakness is less than 36 years in over 80%.
  • Illness, medications, pregnancy, stress and hypokalaemia can all exacerbate weakness and may swiftly precipitate a myasthenic crisis and respiratory inadequacy.
  • Choking, drooling and difficulty with chewing or swallowing can produce aspiration pneumonia.

Potentially dangerous drugs

There are a number of drugs that can aggravate the condition and they should be used with caution if essential but are best avoided:  DRUGS THAT CAN EXACERBATE MYASTHENIA GRAVIS  CLICK HERE

Commom misdiagnosis

  • Multiple sclerosis – hyperreflexia and extensor plantar response can be seen, which help differentiate it from MG.
  • Motor neurone disease (MND) – usually features of lower motor neurone (LMN) disease with wasting and fasciculation are present.
  • Hyperthyroidism.
  • Myalgic encephalomyelitis (ME) – ‘chronic fatigue syndrome’ – will have vague feelings of exhaustion made worse by any effort and no neurological signs to accompany it unless from disuse. The specific tests for MG will be negative.
  • Other myopathies – may show fasciculation and elevated creatine kinase (CK).
  • Toxins and drugs, e.g. botulin, organophosphate poisoning.
  • Acute Guillain-Barré syndrome – the motor type will have LMN features.
  • Eaton-Lambert syndrome – produces slight benefit from exercise before deterioration and typical autoantibody and electromyographic (EMG) findings and ocular weakness do not occur.9

Investigations

  • Anti-acetylcholine-receptor antibodies are detectable in around 85% of patients with generalized myasthenia but in only about 50% of those with purely ocular myasthenia. False positives may occur with Lambert-Eaton syndrome, thymoma, small cell lung cancer, treatment with penicillamine and between 1 and 3% of all those aged over 70 years.
  • Anti-striated muscle antibody (anti-SM Ab) is positive in 84% of those aged under 40 years with the disease but is less common without a thymoma. If it is positive in a patient aged under 40 it should prompt a search for a thymoma; however, at age over 40 years it more often occurs without one.
  • Anti-MuSK antibodies – may be present in up to a third of patients.
  • Thyroid abnormalities are common enough to justify routine thyroid function tests (TFTs).
  • CXR may show a thymoma as a mediastinal mass but will miss smaller lesions and older smokers may have lung cancer.
  • CT or MRI scanning is used to gain images of the thymus.
  • EMG may also be helpful if there is diagnostic difficulty. Repetitive stimulation may show early fatigue and failure to respond.

Associated diseases

There is an association between MG and other autoimmune diseases in 25%. They include thyroid diseases, rheumatoid arthritis, pernicious anemia and systemic lupus erythematous (SLE) as well as thymoma or hyperplasia of thymus. In terms of thyroid disorders this may include thyroid eye disease.

Management

Reports of vigorously tested trials of management are lacking but it is still regarded as a treatable neurological disorder.

Thymectomy

  • Thymectomy is important if a thymoma is present but may be beneficial even without one.
  • It is often first-line treatment for general disease between the ages of 10 and 55 years.
  • In young patients with a short duration of disease and high antibody titres, they may become asymptomatiac.
  • 7 to 10 years after thymectomy asymptomatic rate has reached 40 to 60% except in those with histologically proven thymoma.
  • Factors associated with a good response are age less than 60 years, symptoms less than 2 years and low doses of pyridostigmine required.
  • Factors associated with poor prognosis are the opposite of these plus use of steroids and either thymoma or thymic atrophy on histology.

Myasthenic versus cholinergic crisis (too much medication)

It can be extremely difficult to distinguish between worsening of myasthenia or excessive anticholinergic medication when a patient with known MG presents with rapidly increasing muscular weakness, with or without respiratory difficulty.

Features suggestive of a cholinergic crisis (too much medication) include muscle fasciculation, pallor, sweating, hypersalivation and small pupils. If in doubt, perform an edrophonium test. Improvement suggests too little medication, i.e. myasthenic crisis, but aggravation suggests too much medication. Be prepared to stop all medication, ventilate and possibly arrange a plasmapheresis. This test should only be performed with the necessary skills and equipment ready for intubation and ventilation.

Complications

  • Aspiration pneumonia due to throat muscle weakness.
  • Acute respiratory failure during an exacerbation.
  • Babies born to mothers with the disease may show transient signs due to antibodies crossing the placenta. Antibodies are present in nearly all babies but only 10 to 20% have symptoms. It may not present until 10 to 14 days after birth. Babies are also more likely to have arthrogryposis multiplex.

Prognosis

  • A typical picture involves exacerbations and asymptomatic periods.
  • Without treatment there is a mortality of 25 to 30% but, with modern management of crisis, this falls to about 4%.
  • Most of the mortality occurs in the first 3 years or so, and it tends not to get any worse after this time.
  • Onset after the age of 40 years, a rapid and progressive disease and thymoma are all bad prognostic signs.
  • Infection and hot weather can aggravate features.

Seronegative Myasthenia Gravis: MuSK

  • There is a subgroup of MG patients who are seronegative to the usual tests but have muscle-specific tyrosine kinase (MuSK) autoantibodies (in up to 40%).
  • They are predominantly female, tend to be aged under 40 years, a third failing to respond to anticholinesterase drugs, but nearly half responding to immunosuppression with steroids.
  • At the end of a period of observation, 6 (35%) patients were asymptomatic, 5 (30%) improved, 4 (24%) were unchanged, and 2 (12%) had died.
  • They concluded that patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients.