Medicine – Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction that produces fluctuating, fatigable weakness of voluntary skeletal muscle. Weakness typically becomes worse with repeated activity and improves after rest.

The disease commonly affects the ocular, bulbar, limb, and respiratory muscles, while sensation and tendon reflexes are usually preserved.

1. Pathophysiology

In most patients, the immune system produces antibodies directed against components of the postsynaptic membrane of the neuromuscular junction.

The commonest antibodies are directed against the nicotinic acetylcholine receptor (AChR).

These antibodies reduce effective neuromuscular transmission by decreasing the number and function of available acetylcholine receptors and damaging the postsynaptic membrane.

2. Neuromuscular Junction Mechanism

Normally, acetylcholine is released from the presynaptic motor nerve terminal and binds to acetylcholine receptors on the muscle membrane.

This generates an end-plate potential and triggers muscle contraction.

In myasthenia gravis:

AChR antibodies → fewer functional postsynaptic acetylcholine receptors → reduced neuromuscular transmission → fatigable muscle weakness.

With repeated activity, neuromuscular transmission becomes progressively less effective, explaining the characteristic fatigability.

3. Other Antibodies

Not all patients have acetylcholine-receptor antibodies.

Some have antibodies against other postsynaptic proteins, particularly:

MuSK – muscle-specific kinase.

LRP4 – low-density lipoprotein receptor-related protein 4.

Therefore, a negative acetylcholine-receptor antibody test does not completely exclude myasthenia gravis.

4. Fatigable Weakness

The hallmark of MG is fluctuating weakness that worsens with repeated activity and improves with rest.

Patients may feel relatively strong in the morning but become weaker later in the day or after repeatedly using the same muscle group.

This contrasts with Lambert–Eaton myasthenic syndrome, in which strength may temporarily improve after brief exercise.

5. Ptosis

Ptosis is one of the most common presenting features.

It may be unilateral or bilateral and often fluctuates.

A characteristic feature is that the ptosis may become more obvious when the patient is asked to maintain prolonged upward gaze.

After resting or closing the eyes, the ptosis may improve.

6. Ophthalmoplegia

Weakness of the extraocular muscles can produce:

Diplopia.

Variable ophthalmoplegia.

The pattern may change during examination because different ocular muscles fatigue at different rates.

Importantly, pupillary function is preserved in myasthenia gravis because the pupil is controlled by autonomic smooth muscle rather than skeletal muscle.

Thus:

Ptosis + ophthalmoplegia + normal pupils → consider myasthenia gravis.

7. Bulbar Weakness

Muscles involved in speech, swallowing, and facial movement may become affected.

Patients may develop:

Dysarthria.

Dysphagia.

Nasal speech.

Difficulty chewing.

Facial weakness.

Speech may become progressively weaker or more nasal after prolonged talking.

8. Limb Weakness

Limb involvement generally produces proximal greater than distal weakness.

Patients may have difficulty:

Climbing stairs.

Getting up from a chair.

Lifting objects above the head.

Combing their hair.

The weakness fluctuates and becomes more pronounced after repeated muscular activity.

9. Sensation and Reflexes

Sensation is normally intact in myasthenia gravis.

Deep tendon reflexes are also generally preserved.

This is useful when distinguishing MG from conditions such as Lambert–Eaton syndrome, where tendon reflexes are commonly reduced.

10. Respiratory Muscle Weakness

Respiratory muscle involvement is potentially life-threatening.

Weakness of the diaphragm and other respiratory muscles can cause ventilatory failure.

Severe respiratory weakness in a patient with myasthenia gravis is known as a myasthenic crisis.

This requires urgent assessment and often intensive respiratory monitoring.

11. Myasthenic Crisis

A myasthenic crisis is severe worsening of MG resulting in respiratory insufficiency and/or severe bulbar weakness.

Common triggers include:

Infection.

Surgery.

Medication changes.

Pregnancy or physiological stress.

Certain drugs that impair neuromuscular transmission.

Patients may require ventilatory support and specialist treatment with intravenous immunoglobulin or plasma exchange.

12. Acetylcholine-Receptor Antibodies

Blood testing for AChR antibodies is an important diagnostic investigation.

The old figure of approximately 90% needs qualification.

AChR antibodies are found in the great majority of patients with generalised MG, but sensitivity is lower in purely ocular disease.

Therefore:

Positive AChR antibodies strongly support the diagnosis, but negative antibodies do not exclude MG.

13. MuSK Antibodies

Patients who are negative for AChR antibodies may be tested for MuSK antibodies.

MuSK-positive MG can particularly involve:

Bulbar muscles.

Facial muscles.

Neck muscles.

Respiratory muscles.

The clinical phenotype and treatment response can differ somewhat from classic AChR-positive disease.

14. Electromyography

Electrophysiological testing assesses the reliability of neuromuscular transmission.

With repetitive nerve stimulation, patients with MG typically show a decremental response in the compound muscle action potential.

In simple terms:

Repeated stimulation → progressively smaller muscle response.

This reflects failure of neuromuscular transmission.

15. Single-Fibre EMG

Single-fibre electromyography is particularly sensitive for detecting impaired neuromuscular transmission.

It demonstrates increased variability in the timing of muscle-fibre activation, called increased jitter.

It is useful when routine investigations are inconclusive but clinical suspicion remains high.

16. Edrophonium – Tensilon Test

Historically, the Tensilon test used intravenous edrophonium, a very short-acting acetylcholinesterase inhibitor.

By inhibiting acetylcholinesterase, edrophonium temporarily increased acetylcholine at the neuromuscular junction.

A patient with MG could therefore show rapid temporary improvement in weakness.

The mechanism was:

Edrophonium → acetylcholinesterase inhibition → ↑ acetylcholine → improved neuromuscular transmission → temporary improvement in weakness.

17. Tensilon Test in Modern Practice

The Tensilon test is now largely historical and is not routinely used in many modern clinical settings because edrophonium can cause significant adverse effects, including bradycardia and other cardiovascular complications.

Modern diagnosis relies more heavily on:

Antibody testing.

Repetitive nerve stimulation.

Single-fibre EMG.

Clinical bedside assessment remains important.

18. Ice-Pack Test

For patients with prominent ptosis, the ice-pack test can provide useful bedside evidence.

An ice pack is placed over the closed eyelid for a few minutes.

Improvement in ptosis after cooling supports a diagnosis of myasthenia gravis because lower temperatures can improve neuromuscular transmission.

It is particularly useful in ocular MG.

19. Thymus Association

Myasthenia gravis has an important relationship with the thymus gland.

Patients may have:

Thymic hyperplasia.

or

Thymoma.

The thymus is believed to play an important role in generating the abnormal autoimmune response in many patients with AChR-positive MG.

20. CT Thorax

Patients with newly diagnosed MG are generally evaluated for a thymoma, commonly using CT imaging of the chest.

Therefore:

Myasthenia gravis → image the mediastinum to exclude thymoma.

This association is particularly important for examinations.

21. Pyridostigmine

Pyridostigmine is a commonly used symptomatic treatment.

It is an acetylcholinesterase inhibitor.

By reducing the breakdown of acetylcholine, it increases the amount of acetylcholine available at the neuromuscular junction.

The mechanism is:

Acetylcholinesterase inhibition → ↑ acetylcholine in synaptic cleft → improved activation of remaining ACh receptors → improved strength.

22. Limitations of Pyridostigmine

Pyridostigmine improves symptoms but does not remove the underlying autoimmune process.

Adverse effects arise mainly from excess cholinergic activity and may include:

Abdominal cramps.

Diarrhoea.

Increased salivation.

Sweating.

Muscle fasciculations in excessive doses.

23. Corticosteroids

Corticosteroids, such as prednisolone, are frequently used when symptomatic therapy alone is insufficient.

They suppress the autoimmune response and can substantially improve muscle strength.

Because steroids can occasionally cause transient worsening when first introduced, initiation and dose escalation may require careful specialist supervision in patients with significant bulbar or respiratory involvement.

24. Other Immunosuppressive Treatments

Additional steroid-sparing immunosuppressive drugs may be used for long-term disease control.

Examples include:

Azathioprine.

Mycophenolate mofetil.

Other immunotherapies, including targeted biologic agents, are increasingly used for selected patients with refractory or severe disease.

25. Thymectomy

Thymectomy is indicated when a thymoma is present, provided the patient is an appropriate surgical candidate.

Thymectomy can also improve outcomes in selected patients with generalised AChR-antibody-positive MG even without thymoma.

Therefore, thymectomy is not simply a treatment for thymoma; in appropriately selected patients it can modify the course of autoimmune MG itself.

26. Plasma Exchange

Plasma exchange removes circulating pathogenic antibodies and can produce relatively rapid improvement.

It is particularly useful in:

Myasthenic crisis.

Severe exacerbations.

Preparation for surgery in selected high-risk patients.

Its effects occur rapidly but are relatively short-lived.

27. Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIG) is another rapid immunomodulatory treatment.

It is commonly used for:

Myasthenic crisis.

Severe exacerbations.

Situations where rapid improvement is required.

Like plasma exchange, it is primarily used for relatively rapid short-term disease control rather than routine symptomatic therapy.

28. Drugs That Can Worsen Myasthenia

Certain medications can impair neuromuscular transmission and worsen MG.

Important examples include some:

Aminoglycoside antibiotics.

Fluoroquinolones.

Macrolides.

Magnesium-containing preparations.

Beta-blockers.

Neuromuscular-blocking drugs used during anaesthesia.

Medication decisions depend on clinical circumstances, but patients with MG should have potentially aggravating drugs reviewed carefully.

29. Myasthenia Gravis versus Lambert–Eaton Syndrome

Myasthenia gravis:

Postsynaptic disorder.

Usually antibodies against ACh receptors.

Weakness worsens with repeated activity.

Ocular symptoms are common.

Reflexes generally preserved.

Autonomic symptoms are uncommon.

Associated with thymic hyperplasia or thymoma.

Lambert–Eaton syndrome:

Presynaptic disorder.

Antibodies against voltage-gated calcium channels.

Weakness may improve temporarily with brief exercise.

Proximal lower-limb weakness is prominent.

Reflexes reduced.

Autonomic symptoms common.

Strongly associated with small-cell lung carcinoma.

30. Myasthenia Gravis – Note Form

Definition: autoimmune neuromuscular-junction disorder causing fluctuating, fatigable skeletal-muscle weakness.

Main antibody: postsynaptic acetylcholine-receptor antibody.

Other antibodies: MuSK and LRP4.

Ptosis: common, fluctuating and worsens with prolonged upward gaze.

Ophthalmoplegia: causes diplopia; pupils remain normal.

Bulbar involvement: dysarthria, dysphagia, nasal speech and chewing fatigue.

Weakness: worsens with repeated activity and improves with rest.

Sensation: normal.

Reflexes: usually normal.

Respiratory involvement: can cause life-threatening myasthenic crisis.

Antibody testing: AChR antibodies are highly useful, particularly in generalised MG.

EMG: decremental response with repetitive nerve stimulation.

Single-fibre EMG: increased jitter and high sensitivity.

Tensilon test: historical edrophonium test; rapid improvement occurred after short-acting acetylcholinesterase inhibition, but it is now rarely used.

Thoracic imaging: performed to look for thymoma.

Symptomatic treatment: pyridostigmine.

Immunotherapy: corticosteroids and other immunosuppressive treatments.

Thymectomy: mandatory consideration with thymoma and beneficial in selected generalised AChR-positive patients without thymoma.

Severe exacerbation/crisis: IVIG or plasma exchange ± ventilatory support.

Key Clinical Pattern

Remember myasthenia gravis as:

Ptosis + diplopia + bulbar weakness + fatigable skeletal-muscle weakness that worsens with repeated activity.

The neurological examination typically shows:

Weak muscles + normal sensation + preserved reflexes + normal pupils.

The core mechanism is:

Postsynaptic ACh-receptor antibodies → impaired neuromuscular transmission.

The key association is:

Myasthenia gravis → thymoma/thymic abnormalities.

And the easiest comparison remains:

MG → weakness worsens with activity.

LEMS → weakness initially improves with activity.

1. Pathophysiology In most patients, the immune system produces antibodies directed against components of the postsynaptic membrane of the neuromuscular junction. The commonest antibodies are directed against the nicotinic acetylcholine receptor (AChR). These antibodies reduce effective neuromuscular transmission by decreasing the number and function of available acetylcholine receptors and damaging the postsynaptic membrane. 

2. Neuromuscular Junction Mechanism Normally, acetylcholine is released from the presynaptic motor nerve terminal and binds to acetylcholine receptors on the muscle membrane. This generates an end-plate potential and triggers muscle contraction. In myasthenia gravis: AChR antibodies → fewer functional postsynaptic acetylcholine receptors → reduced neuromuscular transmission → fatigable muscle weakness. With repeated activity, neuromuscular transmission becomes progressively less effective, explaining the characteristic fatigability. 

3. Other Antibodies Not all patients have acetylcholine-receptor antibodies. Some have antibodies against other postsynaptic proteins, particularly: MuSK – muscle-specific kinase. LRP4 – low-density lipoprotein receptor-related protein 4. Therefore, a negative acetylcholine-receptor antibody test does not completely exclude myasthenia gravis. 

4. Fatigable Weakness The hallmark of MG is fluctuating weakness that worsens with repeated activity and improves with rest. Patients may feel relatively strong in the morning but become weaker later in the day or after repeatedly using the same muscle group. This contrasts with Lambert–Eaton myasthenic syndrome, in which strength may temporarily improve after brief exercise. 

5. Ptosis Ptosis is one of the most common presenting features. It may be unilateral or bilateral and often fluctuates. A characteristic feature is that the ptosis may become more obvious when the patient is asked to maintain prolonged upward gaze. After resting or closing the eyes, the ptosis may improve. 

6. Ophthalmoplegia Weakness of the extraocular muscles can produce: Diplopia. Variable ophthalmoplegia. The pattern may change during examination because different ocular muscles fatigue at different rates. Importantly, pupillary function is preserved in myasthenia gravis because the pupil is controlled by autonomic smooth muscle rather than skeletal muscle. Thus: Ptosis + ophthalmoplegia + normal pupils → consider myasthenia gravis. 

7. Bulbar Weakness Muscles involved in speech, swallowing, and facial movement may become affected. Patients may develop: Dysarthria. Dysphagia. Nasal speech. Difficulty chewing. Facial weakness. Speech may become progressively weaker or more nasal after prolonged talking. 

8. Limb Weakness Limb involvement generally produces proximal greater than distal weakness. Patients may have difficulty: Climbing stairs. Getting up from a chair. Lifting objects above the head. Combing their hair. The weakness fluctuates and becomes more pronounced after repeated muscular activity. 

9. Sensation and Reflexes Sensation is normally intact in myasthenia gravis. Deep tendon reflexes are also generally preserved. This is useful when distinguishing MG from conditions such as Lambert–Eaton syndrome, where tendon reflexes are commonly reduced. 

10. Respiratory Muscle Weakness Respiratory muscle involvement is potentially life-threatening. Weakness of the diaphragm and other respiratory muscles can cause ventilatory failure. Severe respiratory weakness in a patient with myasthenia gravis is known as a myasthenic crisis. This requires urgent assessment and often intensive respiratory monitoring. 

11. Myasthenic Crisis A myasthenic crisis is severe worsening of MG resulting in respiratory insufficiency and/or severe bulbar weakness. Common triggers include: Infection. Surgery. Medication changes. Pregnancy or physiological stress. Certain drugs that impair neuromuscular transmission. Patients may require ventilatory support and specialist treatment with intravenous immunoglobulin or plasma exchange. 

12. Acetylcholine-Receptor Antibodies Blood testing for AChR antibodies is an important diagnostic investigation. The old figure of approximately 90% needs qualification. AChR antibodies are found in the great majority of patients with generalised MG, but sensitivity is lower in purely ocular disease. Therefore: Positive AChR antibodies strongly support the diagnosis, but negative antibodies do not exclude MG. 

13. MuSK Antibodies Patients who are negative for AChR antibodies may be tested for MuSK antibodies. MuSK-positive MG can particularly involve: Bulbar muscles. Facial muscles. Neck muscles. Respiratory muscles. The clinical phenotype and treatment response can differ somewhat from classic AChR-positive disease. 

14. Electromyography Electrophysiological testing assesses the reliability of neuromuscular transmission. With repetitive nerve stimulation, patients with MG typically show a decremental response in the compound muscle action potential. In simple terms: Repeated stimulation → progressively smaller muscle response. This reflects failure of neuromuscular transmission. 

15. Single-Fibre EMG Single-fibre electromyography is particularly sensitive for detecting impaired neuromuscular transmission. It demonstrates increased variability in the timing of muscle-fibre activation, called increased jitter. It is useful when routine investigations are inconclusive but clinical suspicion remains high. 

16. Edrophonium – Tensilon Test Historically, the Tensilon test used intravenous edrophonium, a very short-acting acetylcholinesterase inhibitor. By inhibiting acetylcholinesterase, edrophonium temporarily increased acetylcholine at the neuromuscular junction. A patient with MG could therefore show rapid temporary improvement in weakness. The mechanism was: Edrophonium → acetylcholinesterase inhibition → ↑ acetylcholine → improved neuromuscular transmission → temporary improvement in weakness. 

17. Tensilon Test in Modern Practice The Tensilon test is now largely historical and is not routinely used in many modern clinical settings because edrophonium can cause significant adverse effects, including bradycardia and other cardiovascular complications. Modern diagnosis relies more heavily on: Antibody testing. Repetitive nerve stimulation. Single-fibre EMG. Clinical bedside assessment remains important. 

18. Ice-Pack Test For patients with prominent ptosis, the ice-pack test can provide useful bedside evidence. An ice pack is placed over the closed eyelid for a few minutes. Improvement in ptosis after cooling supports a diagnosis of myasthenia gravis because lower temperatures can improve neuromuscular transmission. It is particularly useful in ocular MG. 

19. Thymus Association Myasthenia gravis has an important relationship with the thymus gland. Patients may have: Thymic hyperplasia. or Thymoma. The thymus is believed to play an important role in generating the abnormal autoimmune response in many patients with AChR-positive MG. 

20. CT Thorax Patients with newly diagnosed MG are generally evaluated for a thymoma, commonly using CT imaging of the chest. Therefore: Myasthenia gravis → image the mediastinum to exclude thymoma. This association is particularly important for examinations. 

21. Pyridostigmine Pyridostigmine is a commonly used symptomatic treatment. It is an acetylcholinesterase inhibitor. By reducing the breakdown of acetylcholine, it increases the amount of acetylcholine available at the neuromuscular junction. The mechanism is: Acetylcholinesterase inhibition → ↑ acetylcholine in synaptic cleft → improved activation of remaining ACh receptors → improved strength. 

22. Limitations of Pyridostigmine Pyridostigmine improves symptoms but does not remove the underlying autoimmune process. Adverse effects arise mainly from excess cholinergic activity and may include: Abdominal cramps. Diarrhoea. Increased salivation. Sweating. Muscle fasciculations in excessive doses. 

23. Corticosteroids Corticosteroids, such as prednisolone, are frequently used when symptomatic therapy alone is insufficient. They suppress the autoimmune response and can substantially improve muscle strength. Because steroids can occasionally cause transient worsening when first introduced, initiation and dose escalation may require careful specialist supervision in patients with significant bulbar or respiratory involvement. 

24. Other Immunosuppressive Treatments Additional steroid-sparing immunosuppressive drugs may be used for long-term disease control. Examples include: Azathioprine. Mycophenolate mofetil. Other immunotherapies, including targeted biologic agents, are increasingly used for selected patients with refractory or severe disease. 

25. Thymectomy Thymectomy is indicated when a thymoma is present, provided the patient is an appropriate surgical candidate. Thymectomy can also improve outcomes in selected patients with generalised AChR-antibody-positive MG even without thymoma. Therefore, thymectomy is not simply a treatment for thymoma; in appropriately selected patients it can modify the course of autoimmune MG itself. 

26. Plasma Exchange Plasma exchange removes circulating pathogenic antibodies and can produce relatively rapid improvement. It is particularly useful in: Myasthenic crisis. Severe exacerbations. Preparation for surgery in selected high-risk patients. Its effects occur rapidly but are relatively short-lived. 

27. Intravenous Immunoglobulin Intravenous immunoglobulin (IVIG) is another rapid immunomodulatory treatment. It is commonly used for: Myasthenic crisis. Severe exacerbations. Situations where rapid improvement is required. Like plasma exchange, it is primarily used for relatively rapid short-term disease control rather than routine symptomatic therapy. 

28. Drugs That Can Worsen Myasthenia Certain medications can impair neuromuscular transmission and worsen MG. Important examples include some: Aminoglycoside antibiotics. Fluoroquinolones. Macrolides. Magnesium-containing preparations. Beta-blockers. Neuromuscular-blocking drugs used during anaesthesia. Medication decisions depend on clinical circumstances, but patients with MG should have potentially aggravating drugs reviewed carefully. 

29. Myasthenia Gravis versus Lambert–Eaton Syndrome Myasthenia gravis: Postsynaptic disorder. Usually antibodies against ACh receptors. Weakness worsens with repeated activity. Ocular symptoms are common. Reflexes generally preserved. Autonomic symptoms are uncommon. Associated with thymic hyperplasia or thymoma. 

Lambert–Eaton syndrome: Presynaptic disorder. Antibodies against voltage-gated calcium channels. Weakness may improve temporarily with brief exercise. Proximal lower-limb weakness is prominent. Reflexes reduced. Autonomic symptoms common. Strongly associated with small-cell lung carcinoma. 

30. Myasthenia Gravis – Note Form Definition: autoimmune neuromuscular-junction disorder causing fluctuating, fatigable skeletal-muscle weakness. 

Main antibody: postsynaptic acetylcholine-receptor antibody. 

Other antibodies: MuSK and LRP4. 

Ptosis: common, fluctuating and worsens with prolonged upward gaze. 

Ophthalmoplegia: causes diplopia; pupils remain normal. 

Bulbar involvement: dysarthria, dysphagia, nasal speech and chewing fatigue. 

Weakness: worsens with repeated activity and improves with rest. 

Sensation: normal. 

Reflexes: usually normal. 

Respiratory involvement: can cause life-threatening myasthenic crisis. 

Antibody testing: AChR antibodies are highly useful, particularly in generalised MG. 

EMG: decremental response with repetitive nerve stimulation. 

Single-fibre EMG: increased jitter and high sensitivity. 

Tensilon test: historical edrophonium test; rapid improvement occurred after short-acting acetylcholinesterase inhibition, but it is now rarely used. 

Thoracic imaging: performed to look for thymoma. 

Symptomatic treatment: pyridostigmine. 

Immunotherapy: corticosteroids and other immunosuppressive treatments. 

Thymectomy: mandatory consideration with thymoma and beneficial in selected generalised AChR-positive patients without thymoma. 

Severe exacerbation/crisis: IVIG or plasma exchange ± ventilatory support. 

Key Clinical Pattern Remember myasthenia gravis as: Ptosis + diplopia + bulbar weakness + fatigable skeletal-muscle weakness that worsens with repeated activity. The neurological examination typically shows: Weak muscles + normal sensation + preserved reflexes + normal pupils. The core mechanism is: Postsynaptic ACh-receptor antibodies → impaired neuromuscular transmission. The key association is: Myasthenia gravis → thymoma/thymic abnormalities. And the easiest comparison remains: MG → weakness worsens with activity. LEMS → weakness initially improves with activity.