Myasthenia gravis

🔬 Pathophysiology

• MG is an autoimmune disorder of the neuromuscular junction, most commonly associated with IgG autoantibodies targeting:
  • Acetylcholine receptors (AChR) on the postsynaptic membrane (~85% of generalised MG cases).
  • Less commonly: MuSK, LRP4, or agrin in AChR-seronegative patients.
• These antibodies impair neuromuscular transmission via:
  • Blockade of ACh binding,
  • Receptor internalisation,
  • Complement-mediated membrane damage.
• The result is fluctuating skeletal muscle weakness that worsens with exertion and improves with rest (fatigability).

Thymic Pathology and Its Role in MG

🔹 Immunopathogenesis:

Thymic Feature	Mechanism in MG
T-cell education failure	The thymus, responsible for establishing central tolerance, fails to eliminate T-cells reactive to AChR.
Thymic hyperplasia	Found in ~65–75% of AChR-positive, early-onset MG. Germinal centres within the thymus produce AChR antibodies.
Thymoma	Present in ~10–15% of MG cases (peak 40–60 yrs). Neoplastic thymic epithelium causes loss of tolerance and persistent autoimmunity.
Autoantigen expression	Thymic myoid cells express AChR, contributing to the generation of autoreactive T and B cells.

🔹 Types of Thymic Pathology :

Type	Frequency	Features
Thymic hyperplasia	65–75% (esp. <40 yrs, women)	Numerous germinal centres; associated with high AChR antibody titres; not malignant.
Thymoma	10–15%	Benign or malignant epithelial tumour; may cause paraneoplastic syndromes (e.g., pure red cell aplasia); often more severe MG.
Involution/Atrophy	Late-onset MG or MuSK-positive MG	Age-related thymic regression; less antibody-driven.

🔹 Clinical Implications :

Scenario	Management Relevance
Thymoma present	Mandatory surgical resection—even in mild MG. Improves survival and reduces relapse risk.
Thymic hyperplasia (no tumour)	Consider thymectomy in generalised AChR-positive MG (especially <60 yrs).
No thymic pathology	Often MuSK-positive or late-onset MG. Thymectomy offers no proven benefit.

Epidemiology

Demographic	Pattern
Age/Gender	Bimodal onset: • Women: 20–30 yrs • Men: 60–75 yrs
Thymoma-associated MG	Peak at 40–60 yrs
Incidence	~8–15 cases/million/year
Prevalence	Rising due to improved survival; >200/million in developed countries

Common Triggers & Precipitants

Category	Examples
Infection	URTI, pneumonia, COVID-19, UTI
Surgery / Trauma	Perioperative stress may precipitate crisis
Metabolic	Electrolyte imbalance (e.g., hypokalaemia), thyroid dysfunction
Medications	High risk: aminoglycosides, fluoroquinolones, macrolides, magnesium, β-blockers, verapamil, penicillamine, phenytoin
Pregnancy & postpartum	May exacerbate symptoms or cause transient neonatal MG

Prognosis

Scenario	Prognostic Outlook
General MG (modern therapy era)	>95% 10-year survival with immunosuppressives (steroids, azathioprine, mycophenolate, rituximab, efgartigimod, eculizumab). Remission/improvement in ~80%.
Thymoma-associated MG	With resection: 5-year survival >90%. Old references quoting 30% reflect unresectable/malignant thymoma cases.
MuSK-MG	Often more severe bulbar symptoms and less responsive to AChE inhibitors, but responds well to rituximab.

Autoimmune Comorbidities

MG is frequently associated with other autoimmune diseases. These include:

• Thyroid disease – Graves’ disease, Hashimoto’s thyroiditis
• Rheumatological – Rheumatoid arthritis, Systemic lupus erythematosus, Polymyositis, Sjögren’s syndrome
• Dermatological – Pemphigus vulgaris
• Haematological – Pernicious anaemia

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Clinical

• external ocular muscles
  • affected in over 90% of cases, and are the muscles first affected in 65% of cases
  • Fluctuating ptosis (asymmetric, “curtain sign” when one lid is lifted), diplopia that varies through the day.
  • ocular myasthenia describes myasthenia confined to the eyes.
  • Ice-pack test over eyelid for 2 min → ptosis improves ≥ 2 mm.
• Limb weakness
  • increased by exercise – easily fatigued
  • may complain of difficulty in raising their arms above their head, or of brushing their hair; arm flexion is often more strong than extension
  • Proximal Muscle Weakness are typically more affected than distal Muscles
  • Distal wrist extensors and foot dorsiflexors are most often involved
  • tone is normal and reflexes are often brisk
  • muscle wasting may occur in chronic disease.
• bulbar – loss of facial expression
  • Nasal speech
  • dysphagia
  • fatigable chewing (need to rest mid-meal)
  • jaw drop
  • unable to smile and may seem to snarl
    • Ask patient to gaze upward for 60 s → eyebrow droop.
  • inability to whistle
  • dysarthria – often, slurring speech
  • Count aloud to 50 → voice becomes hyper-nasal or fades.
  • weakness of the neck muscles may force the patient to sit with their jaw propped by a hand
  • Respiratory (crisis)
    • Rapidly progressive dyspnoea, weak cough, paradoxical diaphragm.
    • FVC < 15 mL/kg or MIP < -20 cmH₂O.

EXAMINATION

• swallow
• functional capacity
• effectiveness of cough
• jaw closure often weak and cannot be maintained against resistance
• airway assessment
• focused RESP and CVS examination
• evidence of proximal myopathy and strength

DIFFERENTIALS

Associated symptoms presented with muscle weakness

Disease	Symptoms
Dermatomyositis	Skin rash, e.g., upper eyelids (heliotrope rash), erythema of the knuckles (Gottron rash), anterior chest (v sign), or back (shawl sign) Weight loss, anorexia, bleeding tendency, abnormal vaginal bleeding, chronic cough (malignancy).
Inclusion body myositis	Frequent falls, dysphagia
Myasthenia gravis	Squint, dysphagia Compression symptoms of thymoma (cough, SOB)
Lambert-Eaton syndrome	Autonomic symptoms, e.g., dry mouth, impotence History of lung cancer
Mixed connective tissue disease and overlap syndrome	Other connective tissue disease’s symptoms; arthritis, skin rash
Rhabdomyolysis	History of trauma, seizure, dark urine

Common signs with specific myopathies

	Head and neck	Hands	Chest and abdomen
Dermatomyositis	–  Upper eyelids (heliotrope ash) –  Lymphadenopathy or any mass (malignancy)	–  Erythema of the knuckles (Gottron rash) –  Clubbing (lung cancer)	–  Erythema of anterior chest (v sign), or back (shawl sign) –  Axillary lymphadenopathy, breast lump or abdominal mass
Overlap syndrome and MCTD	–  Fish mouth, pinched nose (in scleroderma) –  Malar rash, discoid lupus (in SLE)	Sclerodactyly, Raynaud’s (in scleroderma). Arthritis (in SLE)	Signs of lung fibrosis and serositis
Lambert-Eaton syndrome	–  Dry mouth and skin (autonomic neuropathy)	–  Clubbing (lung cancer)	–  Chest finding if there are complications for lung cancer e.g. pleural effusion, lymphadenopathy
Myasthenia gravis	SVC syndrome (thymoma)	–	–

Correlation between findings and suggestive diagnoses of weakness

Findings	Suggestive diagnosis
Acute focal weakness decreased muscle power, hyperreflexia, hypertonia, positive Babinski sign, ± sensory deficit, ± loss of bladder/bowel control	Stroke, or spinal cord injury
Diffuse or localized peripheral weakness, muscle atrophy, fasciculations, hypotonia, loss of reflexes	Lower motor neuron disease
Asymmetrical distal weakness, muscle atrophy, hypotonia, loss of reflexes, sensory deficit “Glove and stocking” distribution	Peripheral neuropathy Diabetic neuropathy
Acute onset of combined weakness (ascending), fasciculations, loss of deep tendon reflexes, sensory deficit	Guillain-Barre syndrome
Facial weakness, fatigability, ptosis	Myasthenia gravis
Symmetrical weakness of proximal muscles, muscle wasting, with some types, muscle tenderness, normal reflexes, no sensory level	Proximal myopathies
Symmetrical distal weakness, with myotonic contractions	Myotonic dystrophy
Cardiomyopathy, and proximal muscle weakness	Inflammatory myopathies, hereditary myopathies
Mental status changes with proximal weakness	Myopathy-inducing electrolyte disorder (calcium or magnesium)

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Investigations

• Acetylcholine receptor antibody
  • Highly specific for MG (rare false positives)
  • Up to 15% of generalised MG and ~50% of ocular MG are AChR-antibody negative.
• Consider
  • CT chest – for thymoma
  • Brain MRI – exclude other intracranial abnormality with a neurological presentation
  • Thyroid function test
  • Electrophysiological studies – helpful if seronegative
  • Lumbar puncture

 Complications

1. Aspiration Pneumonia
2. Cholinergic crisis (excessive Acetylcholinesterase Inhibitor)
3. Myasthenia Crisis (30% of cases)

Treatment

• oral anticholinesterase medication
  • pyridostigmine
  • neostigmine
• thymectomy
  • required if there is a thymoma because of the risk of local infiltration
• immunosuppression with corticosteroids +/- cytotoxic agents
• intravenous immunogobulin (IVIg) or plasmapheresis 
• rituximab

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Advice for Patients

1. Understanding the Disease:
   • Knowledge is Power: Understanding MG helps in managing the disease better and recognizing when to seek medical intervention.
   • Stay Informed: Keep up with new research and treatment options through reputable sources and medical consultations.
2. Energy Conservation:
   • Plan and Prioritize: Organize daily tasks to distribute energy throughout the day.
   • Rest Periods: Incorporate regular rest periods between activities to avoid fatigue.
3. Diet and Nutrition:
   • High-Calorie, Nutritious Foods: Focus on nutrient-dense foods that are easy to swallow.
4. Exercise and Physical Therapy:
   • Moderation is Key: Engage in regular, moderate exercise tailored to your capabilities.
   • Professional Guidance: Work with physical and occupational therapists to develop a safe exercise regimen.
5. Speech and Swallowing:
   • Therapeutic Techniques: Follow prescribed exercises from speech and swallowing therapists to improve function.
   • Safe Eating Practices: Use techniques to reduce aspiration risk, such as eating slowly and ensuring proper food texture.
6. Psychosocial Support:
   • Join Support Groups: Participate in support groups for shared experiences and emotional support.
   • Mental Health Care: Seek counseling or therapy for coping strategies and stress management.
7. Avoiding Triggers:
   • Identify Personal Triggers: Keep a diary to track and identify triggers that exacerbate symptoms.
   • Infection Control: Practice good hygiene and take preventive measures to avoid infections.
8. Lifestyle Adjustments:
   • Adaptive Devices: Use assistive devices to maintain independence and safety.
   • Stress Reduction: Practice relaxation techniques and manage stress proactively.

Myasthenic Crisis

Overview

Myasthenic crisis is a severe complication of myasthenia gravis (MG) characterized by respiratory muscle weakness leading to respiratory failure. It is a medical emergency requiring prompt recognition and intervention.

Pathophysiology

Myasthenic crisis occurs due to exacerbation of the underlying autoimmune process of MG, which targets the neuromuscular junction. In MG, autoantibodies attack acetylcholine receptors (AChRs) or other components involved in neuromuscular transmission, impairing signal transmission from nerves to muscles.

Several factors can precipitate a myasthenic crisis, including:

Category
Intercurrent illness	URTI, pneumonia, gastro-enteritis, COVID-19.
Physiological stress	Surgery (esp. thymectomy), trauma, childbirth, fever, thyroid storm.
Metabolic	Electrolyte disturbance, adrenal crisis.
Medications	• Absolute caution: Aminoglycosides, fluoroquinolones, macrolides, magnesium salts, quinine, chloroquine, d-penicillamine, interferon-α, ipilimumab. • May worsen MG: β-blockers, verapamil, lithium, phenytoin, statins, botulinum toxin.
Pregnancy & postpartum	Fluctuating course; 10–20 % risk of transient neonatal MG (passive antibody transfer).

Clinical Presentation

Patients in myasthenic crisis typically present with:

• Severe Generalized Weakness: Worsening of existing muscle weakness, including bulbar muscles (affecting speech and swallowing).
• Respiratory Distress: Dyspnea, reduced tidal volume, and inability to clear secretions.
• Dysphagia and Dysarthria: Difficulty swallowing and speaking due to bulbar muscle weakness.

Diagnosis

Diagnosis is clinical and supported by:

• Pulmonary Function Tests: Decreased forced vital capacity (FVC) and negative inspiratory force (NIF) indicating respiratory muscle weakness.
• Arterial Blood Gases (ABGs): May show hypoxemia and hypercapnia.
• Electrophysiological Studies: Repetitive nerve stimulation or single-fiber electromyography (EMG) may show characteristic findings of MG.

Treatment

The goals of treatment are to support respiration, reverse the crisis, and address the underlying causes or triggers.

Respiratory Support

• Noninvasive Ventilation (NIV): BiPAP or CPAP may be used initially in less severe cases.
• Intubation and Mechanical Ventilation: Indicated for severe respiratory failure or when NIV is inadequate. Early intubation should be considered to avoid emergency situations.

Pharmacological Treatment

1. Intravenous Immunoglobulin (IVIG) or Plasmapheresis:
   • IVIG: Given at a dose of 2 g/kg over 2-5 days.
   • Plasmapheresis: Typically, 3-5 exchanges over 7-14 days.
   • Both therapies aim to reduce circulating autoantibodies.
2. Corticosteroids:
   • High-dose steroids may be initiated, but care must be taken as they can initially worsen symptoms.
   • Start with a low dose and gradually increase to minimize the risk of steroid-induced exacerbation.
3. Cholinesterase Inhibitors:
   • Pyridostigmine: Typically continued but may be withheld temporarily if there is significant bulbar weakness due to the risk of excessive secretions.

Addressing Precipitating Factors

• Infections: Prompt diagnosis and treatment of underlying infections.
• Medication Review: Discontinue or adjust any offending drugs.
• Electrolyte Imbalances: Correct any underlying electrolyte abnormalities.

Supportive Care

• Nutritional Support: Enteral feeding may be required for patients with significant bulbar weakness.
• Physiotherapy: To prevent complications of immobility.

Monitoring and Follow-up

• Continuous monitoring in an intensive care unit (ICU) setting is often required.
• Regular reassessment of respiratory function and muscle strength.
• Gradual weaning off mechanical ventilation as respiratory function improves.
• Long-term immunosuppressive therapy may be optimized to prevent future crises.