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Myasthenia Gravis

High EvidenceUpdated: 2025-12-24

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Red Flags

  • Myasthenic Crisis (Respiratory Failure)
  • Severe Bulbar Palsy (Aspiration Risk)
  • Head Drop (Neck weakness precedes respiratory failure)
  • Paradoxical Breathing
Overview

Myasthenia Gravis

1. Clinical Overview

Summary

Myasthenia Gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by fatiguable muscle weakness. Pathogenic autoantibodies (most commonly against the Acetylcholine Receptor, AChR) block neuromuscular transmission. Weakness typically affects the eyes (ptosis/diplopia), bulbar muscles (chewing/swallowing), and proximal limbs. Symptoms fluctuate, worsening with physical activity and improving with rest. Management involves symptomatic treatment with acetylcholinesterase inhibitors (Pyridostigmine) and long-term immunosuppression. A subset of patients have a Thymoma, necessitating screening. [1,2]

Key Facts

  • Hallmark: "Fatiguability". The patient is strong in the morning but weak by evening.
  • Ocular MG: 15% of patients have symptoms restricted to the eyes (Ptosis/Diplopia).
  • Thymus Connection: ~15% have a Thymoma (tumour). ~65% have Thymic Hyperplasia. All patients need a CT Thorax.
  • The "Ice Pack Test": Cooling the muscle improves neuromuscular transmission. Placing ice on a ptotic eyelid for 2 minutes often resolves the ptosis (sensitivity ~80%).
  • Drugs to AVOID: Gentamicin, Beta-blockers, Magnesium, Penicillamine (Can trigger crisis).

Clinical Pearls

Look at the Neck: Neck FLEXION weakness is a red flag. If the patient's head falls back or they can't lift it off the pillow, respiratory failure is often imminent.

Sternal Split: If you see a median sternotomy scar in a neurology patient, think Thymectomy (MG).

The "Snarl": When asked to smile, facial weakness causes a transverse smile ("Myasthenic Snarl") where the lips don't lift.

Sensory is Normal: MG is a pure motor disorder. If there is sensory loss, look for another diagnosis (e.g., LEMS, neuropathy).

2. Epidemiology

Incidence

  • Prevalence: 15-20 per 100,000.
  • Bimodal Distribution:
    1. Early Onset: Women less than 40 years (HLA-B8/DR3, Thymic hyperplasia).
    2. Late Onset: Men >50 years (Thymoma association).
3. Pathophysiology

The Neuromuscular Junction (NMJ)

  1. Normal: Nerve impulse releases Acetylcholine (ACh). ACh crosses synaptic cleft. binds AChR on muscle. Muscle Depolarises -> Contracts.
  2. Myasthenia: IgG antibodies bind to post-synaptic AChRs.
    • Blockade of binding site.
    • Complement-mediated destruction of receptor folds.
    • Result: Fewer receptors. ACh fails to generate Action Potential. Weakness.
  3. AChE Inhibitors: Stop breakdown of ACh, keeping more in the cleft to compete with antibodies.

Serotypes

  • AChR +ve: 85% of cases.
  • MuSK +ve (Muscle Specific Kinase): 5-10%. Often atypical (bulbar/respiratory predominant, less ocular). Poor response to pyridostigmine.
  • LRP4 +ve.
  • Seronegative: 10%.
4. Clinical Presentation

Symptoms

Myasthenic Crisis

Ocular (60% onset)
Ptosis: Often asymmetrical. Worse late in day. Diplopia: Complex ophthalmoplegia. Not restricted to single nerve distribution.
Bulbar
Dysphagia: Choking on liquids. Dysarthria: Nasal quality voice. Chewing Fatigue: "Jaw gets tired halfway through dinner."
Limb
Proximal weakness (Arms > Legs). Hard to brush hair / climb stairs.
Respiratory
Shortness of breath (Diaphragm weakness).
5. Clinical Examination

Bedside Tests for Fatiguability

  1. Sustained Upgaze: Ask patient to look at ceiling for 1 minute. Watch eyelids slowly droop (Ptosis).
  2. Repeated Shoulder Abduction: Ask patient to lift arms 20 times. Power decreases.
  3. Counting: Ask patient to count to 50. Voice becomes nasal/quiet.
  4. Cogan's Lid Twitch: Ask patient to look down, then suddenly look up. Eyelid overshoots (twitches up) before settling.

General

  • Normal reflexes (usually).
  • No muscle wasting (unless very chronic).
  • Normal sensation.
6. Investigations

Serology

  • Anti-AChR Antibodies: Positive in 85% generalised, 50% ocular. Highly specific.
  • Anti-MuSK: Check if AChR negative.

Neurophysiology

  • Repetitive Nerve Stimulation (RNS): Shows "Decrement" (>10% drop in amplitude) in muscle response with repeated shocks.
  • Single Fibre EMG: Gold standard (Sensitivity >95%). Shows increased "Jitter".

Imaging

  • CT Thorax: Mandatory for all confirmed cases to screen for Thymoma.

Edrophonium (Tensilon) Test

  • Historical. Short acting AChE inhibitor injected. Risk of bradycardia. Rarely done now (Ice pack test safer).

3. Deep Dive: The Thymus Connection

"The Training Ground."

  • Role: The Thymus gland is the school for T-cells. It selects them and trains them to distinguish "Self" from "Non-Self".
  • In MG: The Thymus contains "Myoid Cells" (muscle-like cells) that express AChR.
  • The Theory: In MG, the Thymus becomes hyperplastic (lymphoid follices) or neoplastic (Thymoma). It aberrantly "presents" the AChR to the immune system as a foreign antigen, triggering the antibody production.
  • Thymectomy:
    • Thymoma: Surgery is mandatory (oncological risk).
    • Non-Thymomatous MG: The MGTX Trial (2016) proved that thymectomy improves outcomes in AChR+ generalized MG even without a tumour. It reduces steroid requirement and hospitalisations.

4. Surgical Atlas: Thymectomy

Approaches:

  1. Trans-Sternal (Sternotomy): The gold standard for maximal clearance (removing all fat pads). Invasive. 6-week recovery.
  2. VATS / Robotic (Da Vinci): Minimally invasive. 3 small ports. Less pain. Equal oncological efficacy? (Debated, but widely accepted now).
  3. Key Steps:
    • Identify Phrenic Nerves (must be preserved!).
    • Dissect the Thymus from the Pericardium and Brachiocephalic vein.
    • Remove all mediastinal fat (ectopic thymic tissue).
7. Management

Management Algorithm

         DIAGNOSIS CONFIRMED
                ↓
    ┌───────────┼──────────────┐
 SYMPTOMATIC   IMMUNO-      SURGERY
 CONTROL       SUPPRESSION   
    ↓           ↓              ↓
Pyridostigmine Prednisolone  Thymectomy
(Mestinon)     (Start low)   (if Thymoma
               Azathioprine   or Generalised
                              less than 50y)

1. Deep Dive: Pregnancy and Myasthenia

"The High Risk Obstetric Patient." MG affects young women in their childbearing years.

  • Course: 30% improve, 30% stay same, 30% worsen (especially in 1st trimester and postpartum).
  • Transplacental Transfer: IgG antibodies cross the placenta.
    • Transient Neonatal Myasthenia: 10-20% of babies. Weak cry, suck, hypotonia. Self-resolves in 3 months as maternal antibodies washout.
    • Arthrogryposis: Rare. If mother has antibodies against fetal AChR (gamma subunit), baby can be born with multiple contractures (fetal akinesia).
  • Management in Pregnancy:
    • Safe: Pyridostigmine, Prednisolone, Azathioprine (mostly).
    • Unsafe: Methotrexate, Mycophenolate (Teratogenic).
  • Labour:
    • Uterus is smooth muscle (cholinergic but muscarinic, not nicotinic NMJ), so uterine contractions are NORMAL.
    • Second stage (pushing) involves skeletal muscle and may be weak. Instrumental delivery is more common.
    • Magnesium Sulphate (for Pre-eclampsia) is CONTRAINDICATED (blocks NMJ).

2. Deep Dive: Drug Induced Myasthenia (The Unsafe List)

"Vigilance is Key." Many drugs impair NMJ transmission and can precipitate a crisis.

  • Antibiotics:
    • Aminoglycosides (Gentamicin/Amikacin) - High Risk. Block presynaptic Ca channels.
    • Fluoroquinolones (Ciprofloxacin) - High Risk.
    • Macrolides (Erythromycin/Azithromycin).
  • Cardiovascular:
    • Beta-blockers (Propranolol/Atenolol).
    • Calcium Channel Blockers (Verapamil).
    • Procainamide / Quinidine.
  • Anaesthetic:
    • Neuromuscular Blockers (Rocuronium/Suxamethonium). Note: MG patients are very sensitive to non-depolarisers (Roc) but resistant to depolarisers (Sux).
  • Others:
    • Magnesium (IV).
    • Penicillamine.
    • Lithium.
    • Phenytoin.

3. Comprehensive Pharmacology

Pyridostigmine (Mestinon)

  • Class: Reversible Anticholinesterase (Carbamate).
  • Mechanism: Inhibits Acetylcholinesterase in the synaptic cleft -> Accumulation of ACh -> Increased probability of binding to remaining receptors.
  • Pharmacokinetics:
    • Oral bioavailability: Poor (3-8%).
    • Onset: 30 mins.
    • Peak: 2 hours.
    • Duration: 3-6 hours.
  • Dosing Strategy:
    • Start 30mg TDS. Titrate up.
    • Max dose usually 60-120mg QDS.
    • Mestinon Timespan: Slow release form for night-time symptoms.

Immunosuppression Detail

  • Azathioprine:
    • Mechanism: Purine analogue. Inhibits DNA synthesis in T/B cells.
    • Dose: 2-2.5 mg/kg/day.
    • Onset: Slow (6-12 months to peak effect).
    • Pharmacogenetics: Check TPMT (Thiopurine Methyltransferase) level before starting.
  • Mycophenolate Mofetil (MMF):
    • Mechanism: Inhibits IMPDH (Guanine synthesis).
    • Dose: 1g BD.
    • Onset: Faster than Aza (2-3 months).
  • Rituximab:
    • Mechanism: Anti-CD20 (B-cell depletion).
    • Indication: MuSK-MG (Excellent response), Refractory AChR-MG.

1. Symptomatic (All patients)

  • Pyridostigmine: 30-60mg TDS/QDS.
  • Effect: Starts in 30 mins, lasts 4 hours.
  • Side effects (Cholinergic): Stomach cramps, Diarrhoea (treat with Propantheline), Salivation, Bradycardia.

2. Immunosuppression

  • Corticosteroids (Prednisolone): Indicated if symptoms uncontrolled.
    • Caution: High dose steroids can acutely WORSEN weakness initially (inpatient initiation often required). Start low, go slow.
  • Steroid Sparing Agents: Azathioprine (First line), Mycophenolate, Rituximab (especially for MuSK).

3. Surgical Atlas: Thymectomy

"Removing the Engine of Autoimmunity." The thymus is the training ground for T-cells. In MG, it trains them to attack the NMJ.

  • Anatomy: The thymus sits in the anterior mediastinum, overlying the pericardium and great vessels.
  • Techniques:
    • Trans-sternal (Open): The gold standard for large tumours (>5cm) or invasive disease. Full median sternotomy.
    • VATS (Video-Assisted Thoracoscopic Surgery): Keyhole surgery. Left or right sided approach. Three ports. Equally effective for non-thymomatous MG. Faster recovery.
    • Robotic (Da Vinci): Increasing popularity. Excellent visualisation of phrenic nerves.
  • Post-Op Care:
    • Myasthenic Crisis: Surgery is a major trigger. Monitor FVC hourly. Have ICU standby.
    • Analgesia: Good pain control is vital to prevent respiratory splinting.

4. Deep Dive: Physiology of the NMJ

The Molecular Battlefield.

  1. Presynaptic: Voltage gated calcium channels open -> Calcium influx -> Vesicle fusion -> Release of "Quanta" of Acetylcholine (ACh).
  2. Cleft: ACh diffuses across the 50nm gap. Acetylcholinesterase (AChE) sits here, ready to degrade ACh.
  3. Postsynaptic: ACh binds to Nicotinic ACh Receptors (AChR) on the crests of the junctional folds.
  4. End Plate Potential (EPP): Channel opens -> Sodium influx -> Local depolarisation.
  5. Safety Factor: Normally, the EPP is 3-4x larger than the threshold needed to trigger an Action Potential.
  6. In MG: The number of receptors is reduced. The EPP falls below threshold. No Action Potential = No contraction = Weakness.
    • Why Fatiguability? Presynaptic stores of ACh deplete slightly with repeated firing (normal). In a healthy person, the Safety Factor compensates. In MG, the Safety Factor is gone, so the slight drop causes failure.

5. Deep Dive: Myasthenic Crisis vs Cholinergic Crisis

Why is the patient breathless? In the old days of high dose anticholinesterases, this was a common dilemma.

  • Myasthenic Crisis:
    • Cause: Under-treatment or Infection.
    • Pathology: Not enough signal.
    • Signs: Dilated pupils, Tachycardia, No fasciculations.
    • Edrophonium Test: IMPROVES strength.
  • Cholinergic Crisis:
    • Cause: Overdose of Pyridostigmine.
    • Pathology: "Depolarising Block". Too much ACh keeps the channel open (like Suxamethonium), so it can't reset.
    • Signs: SLUDGE (Salivation, Lacrimation, Urination, Diarrhoea, GI Cramps, Emesis). Constricted pupils. Fasciculations.
    • Edrophonium Test: WORSENS weakness (Dangerous!).
    • Treatment: Stop drug, Give Atropine, Ventilate.

6. Acute Crisis Management (Hospital)

(Renumbered)

4. Acute Crisis Management (Hospital)

  • Monitoring: Forced Vital Capacity (FVC). Usually intubate if FVC less than 20ml/kg or less than 1L.
  • Rescue Therapy:
    • IVIG (Intravenous Immunoglobulin): 2g/kg over 2-5 days.
    • Plasma Exchange (PLEX): Removes antibodies. Faster acting than IVIG.
  • Stop Anticholinesterases: Temporarily (to reduce secretion load in airway).
8. Complications
  • Myasthenic Crisis: Mortality ~4%.
  • Cholinergic Crisis: Weakness caused by overdose of pyridostigmine (Depolarising block). Signs: Pupil constriction, sweating, salivation, fasciculations.
  • Thymoma Malignancy: Spread to pleura/pericardium.
9. Prognosis and Outcomes
  • Generally good. Normal life expectancy with treatment.
  • "Burnt out" stage: Some patients eventually stabilise with fixed weakness but no fluctuation.
  • Ocular MG: 50% progress to generalised within 2 years.
10. Evidence and Guidelines

Key Guidelines

GuidelineOrganisationKey Recommendations
MG ManagementEFNS / AANThymectomy for all AChR+ generalised MG patients aged 18-50.
ThymomaITMIGResect all thymomas.
CrisisIntensive CareUse non-invasive ventilation early. PLEX or IVIG equally effective.

Landmark Studies

1. MGTX Trial (2016)

  • Question: Does Thymectomy help in non-thymomatous MG?
  • Result: Yes. Complete Stable Remission was higher in the Thymectomy + Prednisolone group vs Prednisolone alone.
  • Impact: Confirmed the role of surgery even without a tumour.
11. Patient and Layperson Explanation

What is Myasthenia Gravis?

It is a condition where the connection between the nerves and muscles is blocked. The nerves send the signal "Contract!", but the immune system has destroyed the "letterboxes" (receptors) on the muscle, so the message doesn't get through.

Why does it get worse during the day?

Your nerves rely on a chemical called Acetylcholine to send the signal. When you rest, you build up a supply. When you move, you use it up. In MG, because you have fewer "letterboxes," you run out of signal transmission faster than normal people.

The Ice Test

Cold makes the chemical signal work better. That's why putting an ice pack on a droopy eyelid makes it open up for a few minutes!

Is it curable?

Not exactly, but highly treatable. Most people live normal lives with tablets. Some people have an operation to remove the Thymus gland (in the chest), which can sometimes cure it permanently.

12. References

Primary Sources

  1. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023-1036. PMID: 26376969.
  2. Wolfe GI, et al. Randomized Trial of Thymectomy in Myasthenia Gravis (MGTX). N Engl J Med. 2016;375:511-522. PMID: 27509100.
  3. Sussman J, et al. Myasthenia gravis: Association of British Neurologists management guidelines. Pract Neurol. 2015;15:199-206.
13. Examination Focus

Common Exam Questions

  1. Neurology: "Patient with ptosis. Ice pack improves it. Diagnosis?"
    • Answer: Myasthenia Gravis.
  2. Pharmacology: "Mechanism of Pyridostigmine?"
    • Answer: Acetylcholinesterase Inhibitor (Reversible).
  3. Emergency: "MG Patient gets pneumonia, then stops breathing. Why?"
    • Answer: Myasthenic Crisis (triggered by infection). Treatment: IVIG/PLEX.
  4. Anatomy: "Position of Thymus?"
    • Answer: Anterior Mediastinum.

Viva Points

  • Lambert-Eaton Myasthenic Syndrome (LEMS): How to distinguish? LEMS improves with activity (facilitation), has absent reflexes, and autonomic symptoms. Associated with Small Cell Lung Cancer (VGCC antibodies).
  • Tensilon Test: Why do we need Atropine? To reverse severe bradycardia caused by the Edrophonium.
14. Technical Appendix: Diagnostic Tests Detailed

1. Ice Pack Test

  • Mechanism: AChE enzymatic activity is temperature dependent. Cooling the muscle inhibits the enzyme (just like the drug does).
  • Protocol:
    1. Measure ptosis (mm).
    2. Apply ice pack (in gauze) to eye for 2-5 mins.
    3. Immediatley re-measure.
  • Result: Improvement of >2mm is Positive. Sensitivity ~80%. Specificity ~98%.

2. Edrophonium (Tensilon) Test

  • Drug: Short acting anticholinesterase.
  • Protocol:
    1. Prepare Atropine (0.6mg IV) in case of bradycardia.
    2. Inject 2mg Edrophonium ("Test dose"). Wait 30s.
    3. Inject remaining 8mg.
  • Result: Dramatic improvement in strength within 30-60 seconds. Lasts 5 mins.
  • Side Effects: Fainting, Bradycardia, AV block, Diarrhoea. (Rarely used now).

3. Repetitive Nerve Stimulation (RNS)

  • Concept: Stimulate a motor nerve 6-10 times at low frequency (3Hz).
  • Normal: Amplitude stays constant.
  • MG: Amplitude drops ("Decrement") by >10% between 1st and 4th response.
15. Rehabilitation: Living with the Battery

"The Spoon Theory." Patients have a limited amount of energy per day.

  1. Energy Conservation:
    • Plan heavy tasks (showering, shopping) for the morning (when strength is best).
    • Sit down to chop vegetables / iron.
    • "Pacing": Stop before you are tired.
  2. Speech Therapy:
    • Thickened fluids if dysphagic.
    • Chin tuck manoeuvre.
    • Eat small meals, frequently. (Large meals divert blood to gut -> fatigue).
  3. Home Adaptations:
    • Grab rails.
    • Stair lift (Stairs are the hardest obstacle for proximal weakness).
16. Examination Focus

Common Exam Questions

1. MRCP / PLAB:

  • Q: A 25-year-old woman presents with double vision and difficulty swallowing. Symptoms are worse in the evening. Examination shows fatigable weakness of the arms. Diagnosis?
  • A: Myasthenia Gravis. (Classic Triad: Ocular + Bulbar + Fatigable).

2. Pharmacology:

  • Q: A patient with MG is started on Gentamicin for a UTI and rapidly deteriorates. Why?
  • A: Aminoglycosides inhibit presynaptic calcium channels, reducing ACh release. They can precipitate a Myasthenic Crisis. (Also: Macrolides, Quinolones).

3. Surgical Rotation:

  • Q: Why do we remove the thymus even if there is no tumour?
  • A: To remove the source of autosensitisation (the "Training ground"). It increases the chance of drug-free remission.

Viva Points

  • "Ocular vs Generalised": 15% stay ocular. 85% generalise. Risk is highest in first 2 years.
  • "Seronegative MG": 10-15% of patients. Usually have milder disease, or purely ocular. (Always check MuSK and LRP4 before calling it seronegative).
  • "Neonatal MG": Transient weakness in baby born to MG mother (IgG crosses placenta). Resolves in 3 months.
17. Deep Dive: Thymoma Staging (Masaoka-Koga)

The Critical Determination for Adjuvant Therapy. All thymomas extracted are staged.

  • Stage I: Macroscopically encapsulated. Microscopically no capsular invasion.
    • Tx: Surgery alone.
  • Stage II: Microscopic invasion into capsule (IIA) or macroscopic invasion into fatty tissue (IIB).
    • Tx: Surgery + Radiotherapy?
  • Stage III: Macroscopic invasion into neighbouring organs (Pericardium, Lung, SVC).
    • Tx: Surgery + Radiotherapy.
  • Stage IVa: Pleural or Pericardial dissemination (Droplets).
    • Tx: Debulking + Chemo/Radio.
  • Stage IVb: Lymphogenous or Haematogenous metastasis.

Histology (WHO Classification)

  • Type A: Spindle cell (Medullary). Benign behaviour.
  • Type AB: Mixed.
  • Type B1: Lymphocyte rich / Organoid (Cortical).
  • Type B2: Cortical.
  • Type B3: Epithelial. Atypical. More aggressive.
  • Type C: Thymic Carcinoma. High grade malignancy.
18. Medical History: The Story of Mary Broadfoot Walker

"The Miracle at St Alfege's." In 1934, Dr Mary Broadfoot Walker, a house physician in Greenwich, London, noticed the similarity between MG symptoms and Curare poisoning. Physostigmine (an antidote to Curare) was known. She injected a patient with Physostigmine.

  • Result: The patient, who was bedbound, got up and walked within minutes.
  • Legacy: This established the NMJ as the site of pathology and introduced anticholinesterases as the first effective treatment. Before this, MG was largely fatal (respiratory failure) or untreated.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24
Emergency Protocol

Red Flags

  • Myasthenic Crisis (Respiratory Failure)
  • Severe Bulbar Palsy (Aspiration Risk)
  • Head Drop (Neck weakness precedes respiratory failure)
  • Paradoxical Breathing

Clinical Pearls

  • **Look at the Neck**: Neck FLEXION weakness is a red flag. If the patient's head falls back or they can't lift it off the pillow, respiratory failure is often imminent.
  • **Sternal Split**: If you see a median sternotomy scar in a neurology patient, think Thymectomy (MG).
  • **The "Snarl"**: When asked to smile, facial weakness causes a transverse smile ("Myasthenic Snarl") where the lips don't lift.
  • **Sensory is Normal**: MG is a pure motor disorder. If there is sensory loss, look for another diagnosis (e.g., LEMS, neuropathy).
  • Legs). Hard to brush hair / climb stairs.

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines