2. Introduction
Introduction
Most common primary disorder of
neuromuscular transmission
Usually due to acquired immunological
abnormality
Also due to genetic abnormalities at
neuromuscular junction.
3. History
History
In 1862, Willis described a disease with
fluctuating weakness that varied throughout
the day.
Erb described the classic signs of Myasthenia
gravis in 3 patients & recognized that
fluctuating weakness differed from that seen
in other diseases.
In 1893, Goldflam provided a comprehensive
description of the disease
In 1895, Jolly used the term Myasthenia
Gravis Pseudoparalytica
4. Epidemiology
Epidemiology
Most common age of onset :
women : 2nd
& 3rd
decades
men : 5th
& 6th
decades
< 40 yrs , females are affected 2 to 3
times as often as males.
Later in life, incidence is higher in males.
Of pts with thymomas, majority are older
( 50 60 yrs ) & males.
5. Clinical Presentation
Clinical Presentation
c/o specific muscle weakness rather & not
of generalized fatigue.
2/3rd
ocular motor disturbances, ptosis
or diplopia
1/6th
oropharyngeal muscle weakness
difficulty in chewing, swallowing
or talking
10 % - limb weakness
6. Clinical Presentation
Clinical Presentation
Severity of weakness fluctuates during the
day
least severe in the morning & worse as
the day progresses, especially after
prolonged use of affected muscles.
Patient usually gives h/o
Worsening of ocular symptoms while
reading, watching television, driving.
Worsening of jaw muscle weakness on
prolonged chewing meat / chewy candy.
7. Clinical Presentation
Clinical Presentation
Also give h/o :
Frequent purchase of new eyeglasses to
correct blurred vision
Avoidance of foods that became difficult
to chew or swallow
Cessation of activities that require
prolonged use of specific muscles.
8. Clinical Presentation
Clinical Presentation
Course of disease is variable but often
progressive.
Symptoms fluctuate over a short period &
then become more severe for several
years ( Active Stage )
Followed by a period in which fluctuations
in strength still occurred ( Inactive Stage )
After 15-20 yrs, weakness becomes fixed
& most severely involved muscles become
atrophic ( Burnt-out Stage )
9. Ocular manifestations :
Ocular manifestations :
Weakness of levator palpebrae &
extraocular muscles initial manifestation
in 遜 cases.
Ocular palsies, ptosis usually accompanied
by weakness of eye closure always
myopathic & not neuropathic in origin
Diplopia- due to asymmetric weakness of
muscles in both eyes.
11. Ocular manifestations :
Ocular manifestations :
Sustained upgaze for 30 or more seconds
induce / exaggerate ptosis & uncover
myasthenic motor weakness.
Lid-twitch sign : twitching of upper eyelid
appears a moment after the patient moves
the eyes from downward to primary
position
After sustained upward gaze, 1or more
twitches are observed with closure of
eyelids.
13. Ocular manifestations :
Ocular manifestations :
Combined weakness of extraocular muscles,
levators & orbicularis oculi combined with
Normal pupillary response to light
Normal accomodation
is virtually diagnostic of myasthenia.
Bright light aggravates ocular signs
Cold ( application of ice pack ) improves
them.
14. Oropharyngeal manifestations :
Oropharyngeal manifestations :
Voice may be nasal after prolonged
talking
Weakness of laryngeal muscles
hoarseness
Frequent choking due to difficulty in
swallowing & chewing after eating for a
while.
Characteristic facial appearance
15. At rest, b/l lid ptosis,
downward curve of
corners of mouth,
giving pt a sad
appearance
Smiling: myasthenic
snarl resulting from
upward movement of
medial portion of
upper lip & horizontal
contraction of corners
of mouth
16. Oropharyngeal manifestations :
Oropharyngeal manifestations :
Jaw weakness shown by manually
opening the jaw against resistance, which
is not possible in normal people.
Patient holds
jaw closed with thumb under chin,
middle finger curled under nose/lower lip
index finger extended up the cheek
producing studious appearance.
17. Neck flexors are weaker than neck
extensors
Bulbar weakness is prominent in MuSK
antibody positive MG.
Limb weakness is often proximal &
asymmetric
Tendon reflexes are unaffected
Even repeated tapping of tendon does
not tax muscles to the point where
contraction fails.
18. Clinical Presentation
Clinical Presentation
I Ocular myasthenia ( 15-20% )
II A. Mild, generalized myasthenia with
slow progression; no crises;
drug responsive ( 30% )
II B. Moderately severe generalized
myasthenia; severe skeletal & bulbar
involvement but no crises;
drug response less satisfactory(25%)
19. Clinical Presentation
Clinical Presentation
III. Acute fulminant myasthenia;
rapid progression of severe symptoms
with respiratory crises & poor drug
response; high incidence of thymoma;
high mortality ( 15% )
IV. Late severe myasthenia; symptoms
same as III; resulting from
steady progression over 2 years from
class I to class II ( 10% )
20. Congenital Myasthenic Syndromes
Congenital Myasthenic Syndromes
type Clinical
features
genetics treatment
SLOW
CHANNEL
MOST
COMMON
WEAK
FOREARM
EXTENSORS
AUTOSOMAL
DOMINANT
QUINIDINE
LOW AFFINITY
FAST CHANNEL
PTOSIS, EOM
INVOLVEMENT
AUTOSOMAL
RECESSIVE
3,4-DAP,
ANTI AChE
SEVERE AChR
DEFICIENCIES
VARIABLE
SEVERITY
TYPICAL MG
FEATURES
AUTOSOMAL
RECESSIVE
ANTI AChE
? 3,4-DAP
AChE
DEFICIENCY
NORMAL EOM
ABSENT
PUPILLARY
RESPONSE
- WORSE WITH
ANTI AChE
DRUGS
21. Inheritance
Inheritance
Not transmitted by mendelian inheritance
but family members of patients are 1000
times more likely to develop disease.
Increased jitter on SFEMG 33 to 45 %
of asymptomatic first degree relatives
AChR antibodies are elevated in 50 %
22. Pathophysiology
Pathophysiology
Decrease in number of available AChR at
postsynaptic muscle membrane due to
antibody mediated autoimmune attack.
Postsynaptic folds are flattened or
simplified.
So, although ACh is released normally, it
produces small endplate potentials that
may fail to trigger muscle action potential.
Failure of transmission at many NMJs result
in weakness of muscle contraction.
24. Anti AChR antibodies reduce
Anti AChR antibodies reduce
number of available AChRs by :
number of available AChRs by :
Accelerated turnover of AChRs
( cross-linking & rapid endocytosis of
receptors )
Blockade of active site of AChR
( site that normally binds ACh )
Damage to postsynaptic muscle
membrane by antibody in collaboration
with complement.
25. Pathophysiology
Pathophysiology
Decreased efficiency of neuromuscular
transmission combined with presynaptic
rundown results in activation of fewer &
fewer muscle fibres by successive nerve
impulses & hence increasing weakness /
myasthenic fatigue
An immune response to MuSK - result in
MG, by interfering with AChR clustering.
Antibodies are IgG & T cell dependent
27. Thymus in Myasthenia gravis
Thymus in Myasthenia gravis
10 % of pts with MG have Thymic tumour
70 % have hyperplastic changes in thymus
Muscle-like cells within thymus
( myoid cells ) which bear AChR on their
surface serve as source of autoantigen &
trigger autoimmune reaction within thymus.
29. Anticholinesterase Test / Edrophonium
Anticholinesterase Test / Edrophonium
Chloride ( Tensilon ) Test
Chloride ( Tensilon ) Test
Positive in > 90 % of patients with MG
Initially 2mg Edrophonium IV given,
response monitored for 60 sec
- if definite improvement of muscular
weakness occurs, it is + & test is
terminated.
If no change, additional 8mg IV is given in
2 parts ( 3mg & 5 mg ) , if improvement is
seen within 60 sec after any dose, no
further injections are given.
30. Anticholinesterase Test / Edrophonium
Anticholinesterase Test / Edrophonium
Chloride ( Tensilon ) Test
Chloride ( Tensilon ) Test
10 mg of Edrophonium does not weaken
normal muscle & occurrence of weakness
indicates neuromuscular transmission
weakness.
IM Neostigmine can be used ( infants &
children )
False positive in neurologic disorders like
Amyotropic lateral sclerosis
Now reserved for those with clinical
features suggestive of MG but antibody &
electromyographic tests are negative
31. Antibodies to AChR , MuSK :
Antibodies to AChR , MuSK :
Anti-AChR Radioimmunoassay :
85 % positive in generalized MG
50 % positive in ocular MG
Presence of Anti-AChR antibodies is
virtually diagnostic
But negative result does not rule out MG
Antibodies to MuSK 40 % of AChR
antibody negative pts with generalized
MG.
34. Single Fiber Electromyography
Single Fiber Electromyography
Most sensitive clinical test of
neuromuscular transmission & shows
increased jitter in some muscles in almost
all pts with MG.
It is confirmatory but not specific
Pts with mild / purely ocular muscle
weakness may have increased jitter only
in facial muscles.
When jitter increases, EMG should be
done.
35. CT / MRI
CT / MRI
For ocular MG : Do CT / MRI to exclude
intracranial lesions
36. Disorders associated with
Disorders associated with
Myasthenia gravis
Myasthenia gravis
Disorders of thymus : thymoma,
hyperplasia
Other auto-immune disorders :
Hashimotos Thyroiditis
Graves Disease
Rheumatoid Arthritis
SLE
37. Disorders / Circumstances that
Disorders / Circumstances that
worsen Myasthenia gravis
worsen Myasthenia gravis
Emotional upset
Systemic illness ( especially viral
respiratory infection )
Hypothyroidism
Hyperthyroidism
Pregnancy
Drugs
39. Disorders that interfere with
Disorders that interfere with
therapy
therapy
Tuberculosis
Diabetes
Peptic ulcer
GI bleeding
Renal disease
Hypertension
Asthma
Osteoporosis
Obesity
40. Investigations -
Investigations -
CT /MRI of Mediastinum
ANA, Anti ds DNA, RA Factor,
Antithyroid antibodies
Thyroid function tests
Mantoux
Chest X Ray
FBS, HbA1c
Pulmonary Function Tests
Bone densitometry
43. Based on natural history of disease in
each patient & predicted response to
specific form of treatment
Treatment goals are individualized
Successful treatment requires close
medical supervision & long term followup
Return of any weakness after a period of
improvement to be taken as heralding
further progression.
44. Cholinesterase Inhibitors
Cholinesterase Inhibitors
Pyridostigmine Bromide
initial dose 30 60 mg TID / QID
Dose to be tailored according to pts need
Used as diagnostic test
Early symptomatic treatment
May be satisfactory chronic treatment in
some.
Neostigmine, Mestinon,
Ambenonium chloride are also used.
45. Thymectomy
Thymectomy
Recommended for most pts with MG
Maximal favourable response occurs
2 - 5yrs after surgery
Best response is seen in young people
operated early in the course of disease
But improvement can occur even after 30
yrs of symptoms.
Improvement is also seen in seronegative
MG pts.
46. Thymectomy
Thymectomy
Indicated in all pts with generalized MG
who are b/w ages of puberty & 55 yrs.
Thymectomy in children, > 55yrs,
ocular MG Still a ?
Pts with MuSK antibody + MG may not
respond to thymectomy.
47. Corticosteroids
Corticosteroids
Produce rapid improvement in many
Produce total remission / marked
improvement in > 75 % of patients
Used as initial definite therapy
Used as secondary treatment in who do
not respond to thymectomy /
immunosuppressive therapy
Initial dose prednisone 15 25 mg/day
increased until maximal improvement is
seen or upto 50 60 mg/day
48. Immunosuppressants
Immunosuppressants
Produces marked & sustained
improvement in many
Azathioprine initially 50 mg OD, which
is increased in 50 mg/day increments
every 7 days to total of 150-200 mg/day
Cyclosporine initially 5-6 mg/kg/day
Cyclophosphamide IV 200 mg/day-
5days
150-200mg/day oral
49. Plasma exchange / IV Ig
Plasma exchange / IV Ig
Produces rapid improvement
Mainly used as adjunctive treatment
As treatment in those who have not
responded to other forms of treatment
51. Generalized myasthenia
Generalized myasthenia
onset < 60 yrs
onset < 60 yrs
High dose daily prednisone / plasma
exchange preoperatively
Thymectomy in all
Weakness + after surgery / recurs / no
improvement 12 months after surgery
high dose daily prednisone,
cyclosporine / azathioprine
52. Generalized myasthenia
Generalized myasthenia
onset > 60 yrs
onset > 60 yrs
Initially cholinesterase inhibitors
If response is unsatisfactory
add azathioprine
If response is unsatisfactory
add high dose prednisone or
substitute cyclosporine for azathioprine
53. Thymoma
Thymoma
Thymectomy in all cases
Pretreated with high dose prednisone
with / without plasma exchange
Postoperative radiation is used if tumour
resection is incomplete / tumour is
spread beyond thymic capsule
Small tumours managed medically
54. Juvenile myasthenia gravis
Juvenile myasthenia gravis
Onset of immune mediated MG < 20 yrs is
referred to as Juvenile MG
Female : male = 3 : 1
When myasthenic symptoms develop in
childhood determine if pt has acquired
form or genetic form that does not respond
to immunotherapy
Spontaneous remission is high
Cholinesterase inhibitors initially
Later thymectomy can be done.
55. Seronegative myasthenia gravis
Seronegative myasthenia gravis
More likely male
Have milder disease
Ocular myasthenia, fewer thymomas, less
frequent thymic hyperplasia, more
frequent thymic atrophy
Treatment same as seropositive
myasthenia
56. Myasthenic Crisis
Myasthenic Crisis
An exacerbation of weakness sufficient to
endanger life , usually consists of
respiratory failure caused by
diaphragmatic & intercostal muscle
weakness.
Usually have precipitating event such as
infection (most common), surgery, rapid
tapering of immunosuppression
57. Cholinergic crisis
Cholinergic crisis
Respiratory failure from overdose of
cholinesterase inhibitors
It was more common before the
introduction of immunosuppressive
therapy
Possibility that deterioration could be due
to cholinergic crisis is best excluded by
temporarily stopping the
anticholinesterase drugs.
58. Management
Management
Admit in intensive care unit
Discontinue all cholinesterase inhibitors
Ventilate the patient
Cholinesterase inhibitors should be
resumed at low doses & slowly increased
as needed
Treat the intercurrent infection
