2. INTRODUCTION
Myasthenia gravis is a neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal
muscles.
decrease in the number of available acetylcholine receptors (AChRs) at NMJs due to an antibody-mediated autoimmune
attack.
Prevalence is as high as 200 in 100,000.
Affects individuals in all age groups
Peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties.
Women >Men, in a ratio of ~3:2.
3. PATHOPHYSIOLOGY
At the neuromuscular junction, acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in
vesicles.
(When an action potential travels down a motor nerve and reaches the nerve terminal)
ACh from 150 to 200 vesicles is released and combines with AChRs that are densely packed at the peaks of
postsynaptic folds, the AChR consists of five subunits (2α, 1β,1δ, and 1γ or ε) arranged around a central pore.
When ACh combines with the binding sites on the α subunits of the AChR, the channel in the AChR opens,
permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the
muscle fiber.
If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber,
triggering muscle contraction.
This process is rapidly terminated by hydrolysis of Ach by acetylcholinesterase(AChE), which is present within
the synaptic folds, and by diffusion of ACh away from the receptor.
4.
5. In Myasthenia Gravis,
Fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane.
In addition, the postsynaptic folds are flattened, or “simplified.”
These changes result in decreased efficiency of neuromuscular transmission.
Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger
muscle action potentials causing weakness of muscle contraction.
Presynaptic rundown
The decreased efficiency of neuromuscular transmission
Activation of fewer and fewer muscle fibers by successive nerve impulses
Increasing weakness, or myasthenic fatigue.
6. Role of Thymus
Most patient have thymic abnormalities
Response after thymectomy
Thymus contains “myloid “ cells( Striations) that bear surface AChR which may serve as a source of auto-
antigen triggering auto-immune reaction.
The thymus is abnormal in ~75% of patients with AChR antibody–positive MG
In ~65% the thymus is “hyperplastic,” not necessarily enlarged.
An additional 10% of patients have thymic tumors (thymomas).
7. CLINICAL FEATURES
The cardinal features are weakness and fatigability of muscles.
The weakness increases during repeated use (fatigue) or late in the day and may improve following rest or
sleep.
Exacerbations and remissions ( especially in first few years after onset)
The cranial muscles, particularly the lids and extraocular muscles, are typically involved early in the
course
Diplopia and ptosis
Facial weakness produces a “snarling expression” while smiling
Weakness in chewing is most noticeable after prolonged effort
Speech may have a nasal tone or a dysarthric “mushy” quality
Difficulty in swallowing
nasal regurgitation or aspiration of liquids or food.
Bulbar weakness is especially prominent in MuSK antibody–positive MG.
8. Ocular MG.
If weakness remains restricted to the extraocular muscles for 3 years
Myasthenic Crisis
If weakness of respiration becomes so severe as to require respiratory assistance.
OCULAR Signs
Sustained upward gaze for 30 sec- induce or exaggerate ptosis.
Twitching of eyelids after the patient moves the eyes downward to primary position
U/L painless ptosis without ophthalmoplegia (Bright sunlight aggravate ocular signs and cold transiently
relieves it)
In advanced cases, all muscles including diaphragmatic, intercostal and abdominal muscles, external
sphincters of bowel and bladder.
Rarely muscle atrophy
DTR are normal
Trident tongues
9.
10.
11. DIAGNOSIS AND EVALUATION
Weakness and fatigability in the typical distribution
Without loss of reflexes or impairment of sensation or other neurologic function
Bedside tests
Ice pack test
Relieves ptosis
Less depletion of AChR in cold and less activity of AChE
Edrophonium test-
2 mg IV-every 60 seconds-total 10 mg
Contraindicated in elderly, cardiac disease or bronchial asthma
Atropine should be ready
Sensitivity 80-90% but not specific
12. Neostigmine test
Longer duration
1.5 mg IM
IV 0.5 mg can be given but its effect is short
Objective improvement is noticed within 10-15 minutes, peak at 20 min and lasts up to 1 hour
Positive test means improved muscle contractility, fusion of diplopia and resolution of fatigable ptosis
Not confirmatory if positive but if negative then “strong point against diagnosis”
Small risk of ventricular arrhythmia
13.
14. MuSK antibodies
Present in 38-50% of those with generalized MG
Generally not present in those with well-established ocular MG except in few cases
Onset at any age, Female preponderance
An oculobulbar form with diplopia, ptosis and dysarthria; not purely ocular myasthania gravis
A restricted myopathic form with prominent respiratory and/or proximal weakness, esp neck
extension
No thymic pathology ; Uncertain role of thymectomy
Less responsiveness to Acetylcholinesterase inhibitors
Good responsiveness to plasma exchange and immunesuppression
15. Other antibodies
Anti-striated muscle Antibody
Anti-lipoprotein related protein 4 (LRP4) antibody
Anti-striational antibody
Antibody against agrin
16. How does this Antibody act?
Blocks the binding of Ach to AChR
Increases the degradation rate of AChR
Complement mediated destruction of post synaptic folds
19. Repetitive nerve stimulation test
Most frequently used electro diagnostic test
Repetitive nerve stimulation at 3-15/sec provides consistent CMAP(Compound
Muscle Action Potential) in healthy muscle.
CMAP amplitude is noted after electrical stimulation of motor end plate
Decremental response >-10 %(MG)
Most often from the proximal limb muscle followed by facial muscles
Sensitivity is much lower in ocular myasthenia
20. Single-fiber EMG
the most sensitive test for MG
Positive in >90% in generalized
MG
In ocular MG, 80-95 %
Simultaneous recording of the
action potentials of two muscle
fibers innervated by same motor
axon.
Variability = "Jitter
Any disorder, such as MG, that
reduces safety factor of
transmission at the NMJ increases
jitter
Normal
MG
21.
22. Differential Diagnosis
Ocular Myasthenia Generalized Myasthania
Thyroid Ophthalmopathy Generalized fatigue (Tiredness)
Chronic progressive ophthalmolegia or Kearns-
Sayre Syndrome
Motor Neuron Disease
Myotonic Dystrophy and oculopharyngeal
muscular dystrophy
Lambert- Eton myasthenic syndrome
Brainstem and motor cranial nerve pathology Miller Fisher and pharyngeal-cervical-brachial
variants of GBS
Botulism
Penicillamine induced myasthenia
Congenital Myasthenic Syndromes
24. Anticholinesterase
Retards the degradation of Ach; Ach effect prolonged
Partial benefit
Pyridostigmine most widely used
30–60 mg TDS/QID, Max 120 mg q4hrly
60 mg tablets, long acting 180 mg night time
Neostigmine
7.5-45 mg every 2-6 hr
Anti-MuSK MG: less benefit
25. Chronic Immune therapies
Glucocorticoid Therapy
For patient with moderate to severe generalized weakness who is responding inadequately to
anticholinesterase
Prednisolone started with 15-20 mg /day and titrated by 5 mg/d at 2- to 3-day intervals
This dose is maintained for 1–3 months and then is gradually modified to an alternate-day regimen
over the course of an additional 1–3 months
Other Immunosuppressive Drugs
Mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, rituximab, and occasionally
cyclophosphamide
Azathioprine
Adjunct to steroids
50 mg BD and titrated up to 150-200 mg daily
Slow improvements-make take months to year
26. Chronic Immune therapies
Mycophenolate
Sooner response than Azathioprine
1-1.5 mg BD
S/E: Diarrhoea
Calcineurin inhibitors cyclosporine and tacrolimus (FK506)
Sooner response than Azathioprine
Alone or adjunct to steroids
S/E: Hypertension and Nephrotoxicity
Rituximab
particularly effective in MuSK antibody–positive MG
Cyclophosphamide
50mg/kg/d for 4 consecutive days followed by GSF to”reboot” the immune system in refractory cases
27. Plasma Exchange and IV Ig
For rapid improvement/ Myasthenic crisis
Refractory to treatment with cholinesterase and steroids
Prior to surgery.
A course of five exchanges (3–4 L per exchange) is generally administered
over a 10- to 14-day period.
Plasmapheresis produces a short-term reduction in anti-AChR antibodies,
with clinical improvement
IV Ig 2 g/ kg over 3-5 days
Improvement occurs in ~70% of patients, beginning during treatment, or within
a week, and continuing for weeks to months.
28. Thymectomy
Generalized MG between puberty and 55 years
Practically in all patients with CT chest showing thymoma
Antibodies are reduced/ disappear
Up to 85% of patients experience improvement
Remission rate ~35%
Response by 3 years
MuSK antibody–positive MG respond less well to thymectomy than those
with AChR antibody.
29.
30. Prognosis
Given the current treatment, most patients have normal life expectancy
Mortality 3-4% principal risk factors being age >40 years, short h/o
progressive disease, and thymoma
Morbidity from intermittent impairment, aspiration, pneumonia, falls and
respiratory failure
31. Myasthenic Crisis
Rapid and severe deterioration
Respiratory failure and quadriparesis
Precipitated by respiratory infection or sedatives or NM blocking drugs
Tx:
Timely intubation and ventilator
BIPAP
Stop cholinergic drugs
Plasma exchange/ IV Ig for early weaning
33. Inherited Myasthenic Syndromes
Heterogeneous group of disorders of the neuromuscular junction that are not autoimmune but rather are due to
genetic mutations in which virtually any component of the neuromuscular junction may be affected.
Alterations in function of the presynaptic nerve terminal, in the various subunits of the AChR, AChE, or the
other molecules involved in end-plate development or maintenance, have been identified in the different forms.
These disorders share many of the clinical features of autoimmune MG, including weakness and fatigability of
skeletal muscles, in some cases involving extraocular muscles (EOMs), lids, and proximal muscles, similar to the
distribution in autoimmune MG.
Suspected when symptoms of myasthenia have begun in infancy or childhood and AChR antibody tests are
consistently negative.
34.
35. PATIENT ASSESSMENT
Assess patient’s clinical status systematically at baseline and on repeated interval examinations.
Most useful clinical tests include
Forward arm abduction time (up to a full 5 min)
Spirometry with determination of forced vital capacity
Range of eye movements
Time to development of ptosis on upward gaze.
Manual muscle testing or, preferably, quantitative dynamometry of limb muscles, especially
proximal muscles, is also important.
A progressive reduction in the patient’s AChR antibody level also provides clinically valuable
confirmation of the effectiveness of treatment; conversely, a rise in AChR antibody levels during
tapering of immunosuppressive medication may predict clinical exacerbation.
One consistent finding is Ach-R negative and MuSK-Ab positive……..
Diagnostic sensitivity
The test is performed by placing the recording electrode over the endplate region of muscle and stiulating the motor nerve to that muscle. The nerve is electrically stimulated 6-10 times at low rates (2 or 3 hertz). The compound muscle action potential ( CAMP) amplitude is noted, in normal…no change…IN G decremental resonse
Penicillamine :weakness is usually mild, and recovery occurs within weeks or months after discontinuing its use.
LEMS is a presynaptic disorder of the neuromuscular junction that can cause weakness similar to that of MG. The proximal muscles of the
lower limbs are most commonly affected, but other muscles may be involved as well. Cranial nerve findings, including ptosis of the eyelids
and diplopia, occur in up to 70% of patients and resemble features of MG. However, the two conditions are usually readily distinguished,
because patients with LEMS have depressed or absent reflexes and experience autonomic changes such as dry mouth and impotence.
Nerve stimulation produces an initial low-amplitude response and, at low rates of repetitive stimulation (2–3 Hz), decremental responses
like those of MG; however, at high rates (50 Hz), or following exercise, incremental responses occur.
S/E: Abdomenal crmaping and diarrhoea, salivation. Bronchial secretions.
Take pyridosctigmine with food. Glycopyrrolate 1 mg, Propantheline 15 mg, Hyoscyamine 0.125 mg
Loperamide for diarrhoea
2 L of exchange: decrease 80 percent of antibodies
