2. Myasthenia Gravis
Highly Complex Phenotype for inexpirienced
Clarity of Clinical Features
Skill of iliciting Clinical Signs
Myasthenia Mimics & Differential Diagnosis
Excellent Model to learn Clinical Neurology & Neuroimmunology
5. John Simpson - 1922 - 2009
Autoimmune Theory of Myasthenia Gravis in 1960
6. Epidemiology
Incidence 1/10,000 in US, 1/20000 in UK
Females > Males
In US 25000 cases
In India 100,000 cases
Peak age 2 nd & 3 rd decades,
Second Peak 70 plus
Diagnosis is delayed for 2 yrs
7. Drachman D. N Engl J Med 1994;330:1797-1810
Normal (Panel A) and Myasthenic (Panel B) Neuromuscular Junctions
AChR antibodies impair the neuromuscular transmission
by complement-mediated focal muscle
membrane damage, accelerated degradation of
AChR,
8. Clinical Features
Weakness of Limb muscles, Lower & Upper
Weakness of Ocular & Bulbar Muscles
Weakness of Respiratory Muscles
Weakness of Neck & Trunk Muscles
Fatiquability with Diurnal Variation
Pure Motor Syndrome with DTR preserved
9. Class Distribution
I Ocular
II Mild generalized weakness, usually with ocular muscle weakness
III
Predominantly bulbar involvement, usually with mild generalized
weakness
IV Moderate generalized weakness
V Severe generalized weakness
Ann Thorac Surg 2006;82:1863-1869
Modified Osserman Classification
11. 1- primary position, 2- upward gaze for >20 seconds, 3- primary position, 4- forced
lid closure, 5- eyes open in primary position. A short lived lid twitch sign is
encountered after re-opening.
Ptosis in myasthenia gravis: Extended fatigue and recovery bedside test
Klaus V. Toyka,
13. ICE Pack Test
It is performed by keeping Icepacks over eyes for 2-5
minutes & looking at improvement in Ptosis
Cooling improves Neuromuscular Transmission-
15. Large mass in the left Ant Mediastinum, Histology revealed thymoma
CT Scan of Chest Showing Thymoma
16. Lange, D. J. Neurology 1997;48:18S-22S
Repetitive stimulation at 3 Hz in the medianthenar system in a patient with mild generalized
myasthenia gravis. A: Pre-exercise, showing decrement with U-shaped response. B: Immediately
after 10 seconds of maximal exercise, showing postactivation facilitation (note change in
amplitude). C: Three minutes after 1 min of maximal exercise, showing postactivation exhaustion.
A
B
C
Decrement . 10 %
Post activation Facilitation
Post activation Exaustion
17. Neuromuscular Junction and Key Elements for the Pathogenesis of Myasthenia Gravis.
Gilhus NE. N Engl J Med 2016;375:2570-2581
19. Antibodies in Myathenia Gravis
AchR Antibody Positive
Musk Antibody Positive
LRP-4 Antibody Positive
Cortactin Antibody Positive
Striational Antibodies-Titin, RyR and Kv1.4 Positive
Ach R Posititive in 85% of Myasthenia Gravis
Seropositive MG has more severe Disease
MuSK Positive require advanced Treatment, sometimes resistant
21. Disorders Associated with Myasthenia Gravis
Thyroid Disorders
Collagen Vascular Disorders
Autoimmune Disorders
Diabetes Mellitus
More than 100 diseases are Associated with Myasthenia Gravis
27. MuSK Positive MG
Female: Male Ratio, 3:1
Age of Onset, 6-68 yrs, 60% Under 40 Years.
Cranial & Bulbar Muscles severely involved
High frequency of Respiratory Crisis,
Limb Muscle involvement less Severe
Edrophonium test negative in 30 %
Response to Pyridostigmine Unsatisfactory
Thymus Atrophic, No Benefit from Thymectomy
PLEX & Immunosupression Good response
Remission & Exacerbation frequent
Mild Residual Weakness after Treatment
Sometimes Poor Response to all Treatment
AchR Positive MG
Female : Male Ratio, 2:1
Age of Onset, 2 nd & 3rd decade, late
Peak at 70 Plus
Respiratory Crisis Uncommon
Limb Muscle Weakness more severe
Edrophonium Test mostly Positive
Pyridostigmine Good Response
Thymus enlargrd-Thymoma
PLEX & Immunosupresants Good Response
Remission mostly, Less Exacerbation
No Residual Weakness after Treatment
Excellent Response to all Modalities
28. MuSK Ab Positive Myasthenia Gravis
Atrophic Triple furrowed tongue
29. Patient at age 34 years.
Triple Furrowed Tongue in MuSK Positive
Figure 1. Normal (Panel A) and Myasthenic (Panel B) Neuromuscular Junctions. In neuromuscular junctions, vesicles release acetylcholine at specialized release sites of the nerve terminal. Acetylcholine crosses the synaptic space to reach receptors that are concentrated at the peaks of junctional folds. Acetylcholinesterase in the clefts rapidly terminates transmission by hydrolyzing acetylcholine. The myasthenic junction has reduced numbers of acetylcholine receptors, simplified synaptic folds, a widened synaptic space, and a normal nerve terminal.
Figure 1 Neuromuscular Junction and Key Elements for the Pathogenesis of Myasthenia Gravis. Neuromuscular transmission involves release of presynaptic acetylcholine, which binds to acetylcholine receptors in the postsynaptic membrane. The receptors interact with several other proteins in the membrane, including Dok7 and rapsyn. Mutant Dok7 and rapsyn are important in the development of congenital myasthenia. Antibodies against acetylcholine receptors, as well as antibodies against muscle-specific kinase (MuSK) and lipoprotein receptor–related peptide 4 (LRP4), induce myasthenic weakness. Antibodies against the intramuscular proteins titin and ryanodine receptor are relevant biomarkers in some subgroups of myasthenia gravis. Acetylcholine is degraded by local acetylcholinesterase, and acetylcholinesterase inhibition leads to symptomatic improvement in patients with myasthenia gravis.
Figure 2 Subgroups of Myasthenia Gravis and Coexisting Conditions. Panel A shows myasthenia gravis subgroups defined on the basis of clinical, antibody, and thymic features. MuSK denotes muscle-specific kinase, and LRP4 lipoprotein receptor–related protein 4. As shown in Panel B, patients with myasthenia gravis commonly have coexisting conditions that are related to their disease (especially thymoma and other autoimmune conditions), induced by therapy, or unrelated to their disease.
Figure. Anatomy of the thymus. This illustration represents what is now generally accepted as the surgical anatomy of the thymus.41 The frequencies (percent occurrence) of the variations are noted. Black = thymus; gray = fat that may contain islands of thymus and microscopic thymus. A-P window = aorto-pulmonary window. Source: Neurology 1997;48(suppl 5):S52–S63.
Figure 1. Patient at age 34 years. Note facial weakness, thin temporalis and masseter muscles, mild asymmetric ptosis, high-arched palate, and triple-furrowed atrophic tongue.
Table 1 Features of Myasthenia Gravis Subgroups.
Table 2 Drugs Used Most Frequently for the Treatment of Myasthenia Gravis.