W11 - Myasthenia Gravis (MG) Flashcards
Define the term “Myasthenia Gravis (MG)”.
An autoimmune mediated disease affecting the neuromuscular junction (NMJ), characterized by episodic weakness of striated muscle, which is typically improved by cholinesterase-inhibiting drugs.
Discuss the underlying pathological process in Myasthenia Gravis.
May be 2 underlying pathological processes (AChR & MuSK receptors affected). They may occur individually or in conjunction.
Acetylcholine receptor (AChR)
- More commonly causes MG
1. Individual has genetic predisposition (HLA-DR3, B8, A1 etc)
2. Pathological thymus produces abnormal T-lymphocytes
3. Cascade of events leading to abnormal proliferation of B lymphocytes (plasma cells) that secrete auto antibodies (AutoAb’s) that inhibit function of AChR - three types of AutoAb’s: - Binding Ab’s - Activate complement, causing destruction of AChR –> Type 2 hypersensitivity (inflammatory) reaction (if severe, motor end plate may be damaged)
- Blocking Ab’s - Impair ACh’s ability to attach to the receptor, resulting in poor muscle contraction
- Modulating Ab’s - Cause receptor endocytosis, resulting in loss of AChR’s on membrane - most closely correlated with clinical severity of MG
Muscle-specific Tyrosine Kinase (MuSK) receptor
- In embyronic development, MuSK plays a role in development of NMJ (facilitates aggregation of proteins that form AChR)
- Plays a similar role in adults - replaces lost AChR’s, maintaining normal NMJ structure and function
- Accounts for 35-40% of generalised MG cases negative for anti-AChR Ab’s (these cases have a female predominance)
- Appears to be unrelated to thymus pathology
1. Anti-MuSK Ab’s attach and destroy MuSK receptors on motor endplate
2. Inhibited recruitment of rapsyn and casein kinase 2
3. Impaired AChR clustering, anchoring and maintenance - These cases have a female predominance
- Less frequently causes ocular MG compared to anti-AChR Ab mediated MG.
Discuss the role on the thymus in Myasthenia Gravis.
Antigen presentation and subsequent sensitization is thought to occur in the thymus of MG sufferers.
2 distinct types of thymic enlargement:
Thymic hyperplasia (“thymitis”)
- Seen in ½ to 2/3 of pt’s
- Mainly seen in young females (20-40)
- Many fully developed medullary lymphoid follicles in the thymus
- Increased numbers of B-lymphocytes in the thymus
- Similar changes occasionally seen in SLE, RA etc.
Thymoma
- Tumour containing mixed epithelial cells and lymphocytic cells
- Seen in 10-25% of MG sufferers
- Mainly seen in middle aged men (~40-60)
Discuss the aetiology of Myasthenia Gravis.
Neonatal – Passive movement of anti-AChR Ab’s across the placenta
Adult
– Idiopathic but HLA-DR3 B8 A1 etc have been associated with MG
- Cross reactivity between AChR and glycoprotein D found on the Herpes simplex virus
Congenital – Rare autosomal recessive disorder.
Describe the typical Myasthenia Gravis patient.
2 “typical” patients - disease of young women and old men
- Young female between 20-40 with no thymoma
- Middle aged males between 40-60 years old
List the six (6) most frequently encountered symptoms and signs in Myasthenia Gravis
- Ptosis (very common, early finding) - presenting sign in 40% of pt’s, eventually affects 85% of sufferers
- Diplopia (very common, early finding) - Double vision (CN III & VI affected)
- Muscle fatigue - Abnormal, post-exertional and better after rest, initially affects single muscles but progresses
- Dysarthria - Small muscles associated with with speaking affected
- Dysphagia - Muscles of larynx and pharynx affected
- Proximal limb weakness (later stage finding) - Post-exertional, fluctuating, improves with rest.
List three (3) important negative findings which would allow you to exclude other pathologies.
- Absence of sensory changes (not observed in MND or myopathy either)
- Muscle bulk preserved (ongoing transmission of trophic signals across NMJ)
- Normal DTRs
* Exclude neuropathy or myopathy
Describe the clinical manifestations that could be seen in severe Myasthenia Gravis.
- Generalised quadriparesis (muscle weakness affecting all four limbs)
- Bulbar Ssx (voice alteration, nasal regurgitation, dysphagia and choking)
- Myasthenic crisis (ie respiratory muscle involvement, seen in 10% of cases)
Discuss ocular Myasthenia gravis.
- Mild form of MG that affects the extrinsic ocular muscles, causing progressive ptosis when patient is gazing upward
- After a few minutes of rest, the eyelids return to near normal position
- Presenting sign in 40% of pt’s and eventually affects 85% of cases
- Patient may complain of diplopia, headaches etc
Discuss the clinical course of Myasthenia gravis.
- Usually presents as mild “ocular” form of disease (all Ssx limited to extraocular muscles)
- ~80% of pt’s will progress from ocular MG to more severe generalized form
- Most pt’s experience a chronic, remitting, relapsing course (Ssx fluctuate in intensity but progressively worsen) stretching over many years
- Max severity reached within 1 year (55% of cases) to 5 years (85% of cases)
- Respiratory muscles usually affected within 5-20 years after onset
- 3-4% of pt’s die within 10 years (mainly due to aspiration pneumonia)
- 7% of pt’s die despite treatment
Severe cases: Rapid progression with death occurring within months.
List four (4) events which often trigger relapses of Myasthenia Gravis
- Emotional disturbances
- Pregnancy
- Intense muscular effort
- Infections
Discuss the tests and procedures that are employed in the diagnosis of Myasthenia Gravis.
Diagnosis often takes 1-2 years because:
- Weakness is a common symptom, and many other diseases need to be ruled out (often mild and restricted to only a few muscles initially)
Tests and procedures:
- ANTIcholinesterase administration - Should result in increased ACh –> stronger muscle contraction
- Electrophysiological studies - Repetitive Nerve Stimulation (shows progressive decline in compound muscle action), single fibre EMG (shows increased “jitter”)
- Serological studies - 80-85% seropositive for AChRm Ab’s, 15-20% seronegative
- CT-scan
- Thyroid tests
Which of the above tests are usually used to establish the diagnosis of Myasthenia Gravis?
- Short acting anticholinesterase
- Electrophysiological studies (Repetitive nerve stimulation and single fibre EMG)
- Serum studies (Testing for presence of AChRm Ab’s)
How is Myasthenia Gravis treated?
Anti-acetylcholinesterase drugs Immunosuppression - Corticosteroids (may stimulate increased ACh receptor synthesis) - Azathioprine and cyclosporine Thymectomy Plasmapheresis IV immunoglobulin (antiAb) Rest (minimize physical exertion)
