Myasthenia Gravis – symptoms, diagnosis and treatment

Myasthenia gravis is an autoimmune neuro muscular disorder characterized by muscular weakness and easy fatiguability. An antibody mediated autoimmunc attack directed against acetyl choline receptors (AchR) situated in the post synaptic muscle and plate membrane is responsible for the disease.

Pathophysiology

There is a decrease in the number of acetylcholine receptors at neuromuscular junctions. Though acetylcholine is released normally but its effect on post synaptic membrane is reduced resulting in weakness in muscle contraction.

The amount of acetyl choline released per impulse declines by repeated activity and in patients of myasthenia, decreased efficiency of neuromuscular transmission and normal decline in release of acetyl choline results in activation of fewer and fewer number of muscle fibres by successive nerve impulses. This results in increasing muscular weakness (myasthenic fatigue).

The neuromuscular abnormality at myoneural junction is associated with the presence of serum IgG antibody and antiacetyl choline receptor antibody. The mechanism by which anti-AchR antibodies cause AchR loss include complement mediated lysis, cross linking down regulation and direct agonist block.

There is accelerated rate of degradation of AchR, blockage of active site by antibodies and damage of post synaptic muscle membrane by the antibody along with complement. Thymus has important role to play in the etiopathogenesis of the disease.

Thymic abnormality in myasthenia appears to be a breakdown in immune tolerance towards self-antigens leading to immunological reaction on acetyl choline receptors. Thymus is abnormal in approximately 75% of patients and in about 65% it is hyperplastic and contains active germinal centers. In 10% of patients there is thymic tumour.

Thymus is the site where I cell repertoire Is generated and CD 4 + T cell act mainly as helper cells in the formation of antibodies. It is likely that muscle like cells within the thymus (Myoid cells) are involved in the pathogenesis of early onset of myasthenia gravis by acting as source of auto antigen and triggering autoimmune response.

Genetic factors also have a role to play. There is strong association with HLA antigens B8 ançl DRW 3 in young patients of myasthenia without a thymoma. Though myasthenia is not transmitted by mendelian inheritance yet family membranes of patients are many times more susceptible to develop the disease.

There is strong association of myasthenia gravis with other autoimmune disorders such as SLE, rheumatoid disease, and thyroid disease.

Myasthenia Gravis

Clinical features

The onset of the disease is either gradual or sudden. It is twice as common in women as compared to men. The peak incidence of the disease is between the ages of 20 and 30 when it affects women more and second peak mainly in men is between 60-70 years of age. Hallmark of the disease is muscular weakness and easy fatiguability. This is worsened by exercise and activity and relieved by rest. Severity of weakness fluctuates during the day and is worse in the afternoon or evening. It is least severe in the morning.

Ocular symptoms in the form of ptosis, dipbopia or blurred vision occur early. Ptosis is often worse towards the end of the day and in some patients (10%) disease may remain localized to eye (ocular myasthenia).

The disease gradually spreads and involves facial muscles leading to difficulty in closure of eyes, inability to whistle and flattened smile with a vertical ‘snarl’. Bulbar muscles involvement leads to S’nasal speech, difficulty in chewing and swallowing, aspiration of liquids or foods. With laryngeal and respiratory muscle involvement, voice becomes low and inaudible if patient goes on speaking.

In 85 per cent of patients, the weakness becomes generalized, the proximal muscles are involved early and distal ones late. Weakness of upper limbs results in difficulty to carry out normal routine activities. Lower limbs which are involved less commonly, but when affected, patient may have difficulty in getting up from squatting position or climbing stairs.

Respiratory muscle weakness is generally not a presenting feature but when it occurs due to bulbar paralysis or involvement of intercostals muscles and diapharagm. It is a serious complication.

Muscle weakness in myasthenia is variable. Muscular weakness is present when patient has exerted himself. Despite muscle weakness, tendon reflexes are intact. Drugs like chloroquine, quinidine, aminoglycosides, tetracyclines, sulfonamides and polymyxin. B worsen the symptoms of myasthenia. Cardiac arrhythmias may occur occasionally and thcse are associated with anticardiac muscle antibodies.

Ocular findings in myasthenia gravis

1. Ptosis that shifts from one eye to the other

2. Cold applied to the eye improves lid ptosis.

3. Weakness of one or more ocular muscle

4. Diplopia

5. No pupillary abnormalities.

Investigations

The clinical picture of myasthenia is quite diagnostic but in doubtful cases certain investigations are required.

1. Tensilon (Edrophonium Chloride) Test

Edrophonium, an anti-cholinesterase is injected I/V in a test dose of 2 mg and response monitored in next 60 seconds. Subsequently 8 mg is injected and improvement in muscle weakness observed. If improvement is seen within 60 seconds and lasts for 2-3 minutes the test is positive.

Sometimes the test may cause bronchial constriction, syncope and respiratory distress.

2. Prostigmine test

Patients who do not respond to edrophonium, prostigmine methyl sulfate (Neostigmine) is administered intramuscularly in a dose of 0.04 mg/kg. If the result is negative or equivocal another dose of 0.04mg/kg. may be administered 4 hours after the first dose. The patient is observed for 20-40 minutes for signs of clinical improvement. If the patient shows muscarine side effects, atropine 0.6mg may be given.

3. Acetylcholine (Ach.) receptor antibodies

Finding ofAch-R binding antibodies in a patient with compatible clinical features of myasthenia confirm the diagnosis. These antibodies are detectable in the serum of approximately 80% of all myasthenic patients and in about 50% of those with ocular involvement.

The measured level of anti-AchR antibody does not correspond with the severity of disease. The concentration of these antibodies may be low at onset of symptoms and rises later. Repeat studies are required. In general their presence suggests the diagnosis but normal concentrations do not exclude the diagnosis of myasthenia.

4. Striational antibodies (Str Abs)

Anti-striated muscle antibody is detectable in more than 90% of patients of myasthenia and thymoma and in about 30% of patients with Thymoma who do not have myasthenia gravis. Levels of striational antibodies are rarely elevated in the absence of AchR antibodies.

4. Repetitive nerve stimulation

In this test three stimulations per second are given to muscles and action patientiales are recorded from surface electrodes over muscles. A rapid reduction in the amplitude of the evoked muscle action potential (decremental response of 159 is considered a positive response. Results may be misleading if a patient is on anticholenesterase medicine, RNS is positive in about 75% of patients with generalized myasthenia gravis.

5. Single fibre electromyography (SF-EMG)

It is a sensitive test and can demonstrate abnormal neuromuscular transmission as increased “jitter” in muscles that are normal. A normal ‘jitter’ in a weak muscle conclusively rules out MG.

Patients with mild or purely ocular muscle weakness may have increased jitter in facial muscles. At least half of the patients with persistent ocular myasthenia have increased jitter in the limb. These observations can be useful in following the course of disease and for monitoring the effects of treatment.

6. Other investigation like skiagram of the chest

CT and MRI will be required to detect any Thymic tumour or its enlaigement. Where there is suspicion of hyperthyroidism being present, thyroid functions should be assessed.

Treatment

It consists of cholinesterase inhibitors, thymectomy, corticosteroids, immuno suppressive drugs. Plasmapharesis and intravenous immunoglobulins.

Anticholinesterase Medications

Anticholinesterase drugs are the first line of treatment. These improve muscle weakness but do not effect underlying disease or modify its natural course. The two most commonly used drugs are Neostigmine and pyridostigmine.

Oral doseof neostigmine is 15-30 mg daily. It is partially hydrolyzed and partially excreted unchanged in urine. Side effects include salivation, sweating, blurring of vision, nausea and breathlessness.

Pyridostigmine is the preferred drug out of the two because of its longer duration of action and fewer gastro intestinal side effects. Its effect begins within 30 minutes, peak action about 2 hours and then gradually declines. Dosage is 30-120mg every 4 hrly.

The dose, frequency and timings of administration should be tailored to the patients needs. Side effects of the drug called cholinergic reactions include excessive salivation, sweating, diarrhoea and abdominal colic. These can be controlled by either Atropine (0.125-0.25 mg) or Probanthine (15 mg).

Over dosage with anti-cholinesterase drugs can produce ‘Cholinergic crisis’ signaled by fasciculations especially around the eyes and an increase in weakness.

Corticosteroids

Prednisolone in a dose of 1 mg/kg body weight given daily produces marked improvement or remission in 70-80% of the patients. Most patients show improvement in the first 6-8 weeks.

Some degree of worsening may occur in 30% of patients. Dosage of 60-100 mg per day is given for atleast 10 days and improvement monitored. Subsequently the drug is shifted from daily to altemate days.

Thymectomy

Thymectomy is employed to induce partial or complete remission. It is helpful in all patients of myasthenia in all age groups and both sexes. The beneficial effects of thymectomy usually occur in the first year but may be sen as late as 5 years from the time of surgery.

With thymoma there is clear role for thymectomy but in all those patients of myasthenia who do not have a thymoma, there is evidence of remission in 60-70% of patients following surgery. Patients with generalized myasthenia (osserman stage 2b or worse) are ideally selected for this operation.

The exact mechanism by which thymectomy produces benefits are not certain but in general acetyl choline receptors antibody levels fall after thymectomy possibly removing the source of antigenic stimulation.

Immunosuppressive drugs

Several immunosuppressive drugs (Azathioprine, cyclosporine, cyclophosphamide) have been employed in patients who have not responded well to corticosteroids or thymectomy. These drugs’may produce marked sustained improvement in some patients.

Azathioprine is the most commonly used drug. Dose 2-3 mg/kg (initial dose is 1mg/kg with gradual increase in dose). Improvement is slow often taking 3-6 months. Symptoms always recur after 2-3 months of discontinuation of the drug or its dose is reduced. Side-effects include hepatotoxicity, rashes and myelosuppression.

Cyclophosphamide is another drug employed. It inhibits cell proliferation by acting on DNA. It is effective in severe forms of myasthenia. Dose 500 mg/m2 given intravenously in monthly dosage. The drug can also be given orally (dose 150-200 mg per day). The drug has side effects like bone marrow depression, alopecia, pulmonary fibrosis and cardiotoxicity.

Cyclosporine (CYA) a potent immunosuppressant is also an important agent in improving myasthenia weakness (dose 5-6 mg/kg given in two divided doses). The drug is nephrotoxic.

Patients on immuno suppressive drugs should have their blood counts regularly as well as liver and kidney function tests.

Plasma pharesis and intravenous immunoglobulins

Patients who have not responded to other forms of therapy, plasma exchange is done as a short term intervention to rapidly improve the worsening condition. A typical protocal consists of exchange done three times a week until improvement occurs.

Usually improvement occurs on the first exchange and may last for weeks or months. Side effects include flu like syndrome, headache, obscured vision, chills and cardiac arrhythmias. Intravenous immunogrobulins is alternative to plasmapharesis (Dose 0.4 G/Kg/day for 5 consecutive days).

Improvement begins in 50-100% of patients beginning within one week and lasts several weeks.

Course and prognosis. It is variable. Improvement is more in ocular myasthenia since the involvement here is mild. About 50% of cases have either partial or complete remission during the first few years.

Prognosis is poor in patients with thymoma, non-responders to anti-cholinesterase, corticosteroids immuno suppressive drugs and thymectomy. Emotional disturbances, inter current infections, pregnancy use of certain drugs like Dpenicillamine, aminoglycosides sulfonamides, colistin and quinidine worsen the disease.

Osserman Classification of Myasthenia Gravis

Grade I: Ocular myasthenia

Grade II: Generalized myasthenia

(a) Mild

(b) Generalised with bulbar involvement

(c) Severe generalized

Grade III: Acute fulminating myasthenia with early involvement of respiratory muscles

Grade IV. Late severe myasthenia developing after atleast 2 years of group I and 2 symptoms.

Myasthenic crisis

It signifies rapid deterioration of myasthenic status characterized by marked generalized weakness and respiratory failure. It is a life threatening complication and occurs in patient with severe bulbar weakness. It generally follows fulminating respiratory infections or after surgical procedures. Patients with poorly controlled symptoms are more likely to go into it.

Treatment consists of maintenance of respiratory functions by maintaining gas exchanges aspiration of secretions and treatment of infection by antibiotics. These patients shall require ventilatory support which should be continued until the condition improves. Plasmapharesis, I/V immuno globulins and corticosteroids are the other limes of treatment.

Myasthenic crisis carries high degree of morbidity and mortality. Early recognition of impending respiratory failure in a case of myasthenia gravis is essential to save these patients. Mortality ranges from 5-7%.

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