MYASTHENIA GRAVIS

M. HIDAYAT
NEURO-OPHTHALMOLOGY SUBDIVISION
OPHTHALMOLOGY DEPARTMENT
FACULTY OF MEDICINE – ANDALAS
UNIVERSITY
DR. M. DJAMIL HOSPITAL PADANG
2021
 INTRODUCTION
 Myasthenia Gravis
 Autoimmune process:
 Acetylcholine receptor (AchR) 80% MG
 Disorder of neuromuscular junction, classical
 Muscle-specific Kinase (MuSK)
symptom: fluctuative or fatiguable muscular
weakness  Low-density lipoprotein receptor related
protein-4 (LRP-4)
 Mimicking other neuro-ophthalmology disorders
(the great masquaerader)
 Chronic disease with varied clinical course of the
Impaired
disease: recurrent, spontaneous remission
neuromuscular
 Muscle involvement: ocular myasthenia, transmission
systemic/generalized myasthenia

muscular weakness
 INTRODUCTION
 Myasthenia Gravis

 Incidence: 0.04-5 cases/100.000

population/year
 Prevalence: 0.5-12.5 cases/100.000
population/year
 Female > male in 2nd-3rd decade
Male > female in 6th-7th decade
 Better prognosis in younger patients
 ANATOMY OF THE NEUROMUSCULAR JUNCTION

Chemical synapse between motor

neuron (synaptic end bulbs) & muscle
fibres (motor end-plate of muscle fibre)

1. Presynaptic
terminal

3. Post-synaptic
2. Synaptic cleft
membrane
 ANATOMY OF THE NEUROMUSCULAR JUNCTION
 Presynaptic terminal

Knob/bulbous
swelling

Key-points & Synaptic vesicles

Important contain
structures: neurotransmitter

Voltage-gated Ca2+
channel
 ANATOMY OF THE NEUROMUSCULAR JUNCTION
 Synaptic cleft

Key-points:
 Space between presynaptic terminal and post-
synaptic membrane; 30 nm width
 Traversed by the neurotransmitters
 Enzymatic process of the neurotransmitters
excess
 ANATOMY OF THE NEUROMUSCULAR JUNCTION
 Post-synaptic membrane

Key-points & important structures

 Membrane of skeletal muscle fibres
(sarcolemma)
 Post-junctional fold: increase
neurotransmitter surface area of action
 Acetylcholine receptors
 ANATOMY OF THE NEUROMUSCULAR JUNCTION
 Acetylcholine receptors

 Key-points:
 Key-points:
 Nicotinic-cholinergic receptor
 Nicotinic-cholinergic receptor
 Ionotropic receptors
 Ionotropic receptors
 Consist of: 2α sub-units, 1β sub-unit, 1δ sub-unit, 1γ
 Consist of: 2α sub-units, 1β sub-unit, 1δ sub-unit, 1γ
sub-unit
sub-unit
 Alfa sub-unit is Ach binding site
 Alfa sub-unit is Ach binding site
 Two α sub-units must be occupied to
 Two α sub-units must be occupied to
open the ion channel
open the ion channel
 PHYSIOLOGY OF THE
NEUROMUSCULAR JUNCTION
 Continuous process from the presynaptic terminal synaptic cleft post-synaptic membrane. Outcome:
 Continuous process from the presynaptic terminal synaptic cleft post-synaptic membrane. Outcome:
muscle contraction
muscle contraction
Nerve impulse reaches The synaptic vesicles & cell Release of acetylcholine to
the presynaptic terminal membrane of neuron fusion the synaptic cleft

Nerve fibre membrane Ca2+ molecules activate Acetylcholine(s) diffuse

depolarization SNARE protein across the synaptic cleft

Voltage-gated Ca2+ ion Ca2+ ion diffusion into Acetylcholine(s) bind to

channels open the presynaptic axon AchReceptor(s)
 PHYSIOLOGY OF THE
NEUROMUSCULAR JUNCTION
Acetylcholine(s) bind to Ca2+ion influx Actin-myosin bridging
AchReceptor(s)

Cation channels open Voltage-gated Ca2+ Muscle

Na+ influx, K+ efflux channels open contraction

Muscle cell membrane

depolarization
Acetylcholine excess:
hydrolysed by
AchEsterase acetate +
Voltage-gated Na+ choline
channels open (re-uptake)
 PATHOPHYSIOLOGY OF
MYASTHENIA GRAVIS (MG)

Neuromuscular
transmission defect Autoantibody

Mechanisms:

Thymus gland Immune

pathology system defect
 AUTOANTIBODY & NEUROMUSCULAR
TRANSMISSION DEFECT
Autoantibody
Mostly anti-AchR (IgG G1 & G3 subclass)
 complement activation  post-
junctional folds damage
 cross-reaction with AchR
competitive inhibitor of Ach)
 AchR binding site blockade
 inhibit ion channel opening

Decrease Ach+AchR binding Neuromuscular transmission defect:

Increase Ach excess in synaptic cleft Ach+AchR binding fluctuation
Increase Ach degradation by Ach-esterase Muscle weakness/fatigability
 AUTOANTIBODY & NEUROMUSCULAR
TRANSMISSION DEFECT

 Autoantibody anti-AchR production,

induced by: D-penicillamin, atorvastatin
 Others: aminoglycosides, nitrofurantoin, beta-blockers,
quinidine  induce MG exacerbation

 In minor cases: autoantibody against MuSK and

LRP-4 molecules

Formation and activation of Agrin-LRP4-MuSK

complex blockade
Decrease AchR clustering on NMJ
Decrease neuromuscular transmission
 THYMUS GLAND PATHOLOGY AND
IMMUNE SYSTEM DEFECT

 Thymoma in 10% cases of MG

 Follicular thymus hyperplasia: early onset MG
 Thymus atrophy: late onset MG

Thymoma

Production and selection of autoreactive T-cell

lymphocytes  activate plasma
cells to produce autoantibody
 CLINICAL MANIFESTATION OF MG
 Symptoms and Signs

 Painless muscle weakness & fatigability

 Resolved by: resting
 Triggered or enhanced by: physical activity, sport, emotional
stress, fever, infection, trauma, operative procedures, etc.
 Ocular muscles mostly affected
 Extremity involvement: proximal parts are more severe than
distal ones

 Ptosis, ophthalmoparesis
 Dysphagia, dysartria
 Limb weakness/paresis
 Respiratory distress
CLINICAL MANIFESTATION OF MG
 Myasthenia Gravis Classification (MGFA, 1997)
 EXAMINATIONS OF MG

1. Sustained upgaze test

 Duration: 60-180 sec
 Induce fatiguable ptosis in one or both eye  Ophthalmology Examination
 Result: more eyelid drooping
 Hallmark of Myasthenia Gravis
EXAMINATIONS OF MG
Ophthalmology Examination

2. Enhanced ptosis test or Curtain’s sign

 In asymmetric ptosis
 Elevation of more ptotic eye

fellow eyelid drooping (curtaining)

 Based on Hering’s Law of equal innervation
 EXAMINATIONS OF MG
3. Orbicularis oculi weakness test
Maintaining eyelid closure

Ophthalmology
Induce orbicularis oculi fatigue
Examination

Palpebral fissure opened slowly

(peek a boo sign)
 EXAMINATIONS OF MG
Ophthalmology Examination

4. Fatiguable diplopia
 By inducing extraocular muscle
weakness(ophthalmoparesis)
 Maintaining lateral gaze for 60 sec

lateral rectus muscle weakness and

horizontal diplopia

5. Pupillary reflex
 normal direct and consensual reflex
 EXAMINATIONS OF MG
Ophthalmology Examination

6. Cogan’s lid –twitch sign test

 Patient with myasthenic ptosis looks downward
for 10-15 sec
 Looks up quickly into primary gaze

the eyelid appears to overshoot upward

then quickly falls
 Positive result: highly suspicious as MG

 A similar upward twitch may occur on glancing quickly

to the side from primary position (eyelid hopping)
 EXAMINATIONS OF MG
Diagnostic Examination

At least one positive diagnostic procedure

1. Autoantibody testing
to confirm the diagnosis
 Anti AchR antibody:
 50%-75% OMG & 80%-90% generalized MG
 Strongly correlated with thymus pathology
(follicular hyperplasia in younger patients &
thymoma in older ones)
 Anti MuSK antibody:
• No thymus pathology found in this MG sub-type
 Anti LRP-4 antibody:
• Correlated with follicular hyperplasia of thymus gland
 Seronegative
 EXAMINATIONS OF MG
Diagnostic Examination
Diagnostic Examination

2. Electromyography (EMG) testing

 Repetitive Nerve Stimulation (RNS)
 Using low frequency electrical current
 Stimulate the nerve and record muscle response (action
potensial)
 Decremental response of muscle’s action potensial 
positive for NMJ disorder
 Low sensitivity for ocular MG (10%-17%) but up to 53%-
100% for generalized MG
 EXAMINATIONS OF MG
Diagnostic Examination
2. Electromyography (EMG) testing
(cont’d)
 Single-Fibre Electromyography (SFEMG)
 The most sensitive examination to evaluate
NMJ transmission
 Using fine needle electrode in clinically
weak muscle (OMG: levator palpebra or
orbicularis oculi)
 Evaluate the time interval/latency from the
given stimulation until action potensial to
occur  jitter
 MG: increased jitter or increased jitter
with blocking
 EXAMINATIONS OF MG
Diagnostic Examination: Acetylcholine-esterase inhibitor test
1. Edrophonium (tensilon) test  High sensitivity but not specific to diagnose
Myasthenia Gravis
 Rapid onset and short duration acetylcholine-
esterase inhibitor
 Administered (iv)ly in 2 mg/0,2 ml increments
separated by 30-60 seconds up to a total of 10 mg
 Done in clinically marked ptotic or
ophthalmoparetic patients
 Dangerous complications: bradycardia and
syncope. Milder complications: lacrimation,
salivation, sweating, nausea/vomitus, and
abdominal cramp
 Must be done with patient’s consent and under
precaution (anti dote: atropine sulfate)
 EXAMINATIONS OF MG
Diagnostic Examination: Acetylcholine-esterase inhibitor test

2. Neostigmine methylsulfate
(prostigmine) test
 Slow onset and longer duration acetylcholine-
esterase inhibitor
 Administered (im)ly. Adults: 1.5 mg
neostigmine+0.6 mg atropine sulfate. Children:
neostigmine
0.04 mg/kg not to exceed a total of 1.5 mg
 Can be done in children or adults whose signs
are subtle
 The effect: usually begins by 15’ and is maximal
by 30’
 Ocular Myasthenia: Tensilon
Test

iv edrophonium
before injection

after
 EXAMINATIONS OF MG
Office-Based Test

1. Ice pack test

 Very useful for patients with current or previous cardiovascular disease
 Procedures: ice pack is placed over the affected lid for 2’
 Result: positive if there is eyelid elevation ≥ 2mm for at least 1’
 EXAMINATIONS OF MG

Office-Based Test
 2. Sleep test  3. Rest test
o Safe and simple o Modification of sleep test
o Procedures: o Procedures:

 measure the degree of ptosis and/or EOM movement
 patient is allowed to sleep for 30’
 re-measure the degree of ptosis and/or EOM
movement
o Result: positive if there is improvement of ptosis and/or
EOM movement
 measure the degree of ptosis and/or EOM
movement
 patient is allowed to close his/her eyes for 2-5’
 re-measure the degree of ptosis and/or EOM
movement
o Result: positive if there is improvement of ptosis
and/or EOM movement
 OTHER ANCILLARY EXAMINATIONS

 Thyroid Function Test : MG with hyperthyroid

 Rheumatoid Factor and Anti Nuclear Antibody
(ANA) : MG with SLE and RA
 Orbital and brain CT-scan/MRI  to exclude
other Differential Diagnosis
 Mediastinal CT-scan/MRI: thymoma or thymus
enlargement
 MANAGEMENT

 Medication:
 Surgery:
 Oral acetylcholine-esterase inhibitor:
pyridostigmine  Thymectomy : ocular myasthenia with
 Steroid : prednisone (first line thymoma
immunosuppressant agent)  Strabismus surgery : diplopia with large
 Steroid-sparing agents : azathioprine, deviation (stable deviation minimal 6-12
mycophenolate mofetil, cyclosporine, months)
cyclophosphamide
 Plasma exchange and intravenous
immunoglobuline (IV Ig) Multidiscipline
o Ophthalmologist
o Neurologist
o Intensivist
o Surgeon
 CONCLUSION

1. Myasthenia Gravis (MG) is a NMJ disorder caused by autoimmune process resulted in neuromuscular
transmission blockade which is characterized by fluctuative skeletal muscle weakness.
2. There are 4 underlying mechanisms of MG; ie: neuromuscular transmission defect, autoantibody,
thymus gland pathology, and immune system defect.
3. Clinical manifestation of MG can involve only ocular muscles with ptosis and diplopia as the main
symptoms (ocular myasthenia) or implicate extremity muscles, muscles for swallowing, and even
respiratory muscles (generalized myasthenia) with any degree of severity.
4. The examinations for establishing MG diagnosis consist of ophthalmology examination to evaluate
muscle weakness and diagnostic procedures such as autoantibody serology, electromyography using
RNS or SFEMG technique, and acetylcholine-esterase inhibitor test. Moreover, there are some office-
based test that can be done if there is limitation or contraindication to diagnostic procedures.
5. Diagnosis of MG is established with suggested symptoms and signs plus at least one confirmatory
result of diagnostic test.
6. Management of Myasthenia Gravis : medication and surgical approach based on its severity
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