MYASTHENIA GRAVIS

Sukma Wicaturatmashudi
INTRODUCTION
 Most common primary disorder of
neuromuscular transmission

 Usually due to acquired immunological

abnormality

 Also due to genetic abnormalities at

neuromuscular junction.
 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”
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.
 CLINICAL PRESENTATION
 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
 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.
 Worsening of ocular symptoms while reading,
watching television, driving.
 Worsening of jaw muscle weakness on
prolonged chewing – meat / chewy candy.
 Clinical Presentation

 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.
 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 )
Ocular manifestations :

 Weakness of levator palpebrae & extraocular

muscles – initial manifestation in ½ 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.
www.nanosweb.org/.../images/mythenia_1.jpg
 Ocular manifestations
 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, more twitches
are observed with closure of eyelids.
Unilateral painless ptosis without ophthalmoplegia or
pupillary abnormality.
 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.
 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
 At rest, 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
 Oropharyngeal manifestations
 Jaw weakness – shown by manually opening
the jaw against resistance, which is not possible
in normal people.
 Neck flexors are weaker than neck extensors
 Bulbar weakness is prominent
 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.
Clinical Presentation
I Ocular myasthenia ( 15-20% )

II A. Mild, generalized myasthenia with slow

progression; no crises; drug responsive (
30% )

IIB. Moderately severe generalized

myasthenia; severe skeletal & bulbar
involvement but no crises; drug response
–less satisfactory(25%)
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% )
 Congenital Myasthenic Syndromes
type Clinical features genetics treatment

SLOW CHANNEL MOST COMMON AUTOSOMAL QUINIDINE

WEAK FOREARM DOMINANT
EXTENSORS

LOW AFFINITY FAST PTOSIS, EOM AUTOSOMAL ANTI AChE

CHANNEL INVOLVEMENT RECESSIVE

SEVERE AChR VARIABLE SEVERITY AUTOSOMAL ANTI AChE

DEFICIENCIES TYPICAL MG RECESSIVE ?
FEATURES

AChE DEFICIENCY NORMAL EOM - WORSE WITH ANTI

ABSENT PUPILLARY AChE DRUGS
RESPONSE
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.
Anti AChR antibodies reduce 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.
 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

 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.
INVESTIGATIONS
Anticholinesterase Test / Edrophonium 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.
Anticholinesterase Test / Edrophonium 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
 Antibodies to AChR :
 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.
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.
 CT / MRI
For ocular MG : Do CT / MRI to
exclude intracranial lesions
 Disorders / Circumstances that
worsen Myasthenia gravis

 Emotional upset
 Systemic illness ( especially viral
respiratory infection )
 Hypothyroidism
 Hyperthyroidism
 Pregnancy
 Drugs
 INVESTIGATIONS
 CT /MRI of Mediastinum
 Antithyroid antibodies
 Thyroid function tests
 Mantoux
 Chest X Ray
 HbA1c
 Pulmonary Function Tests
 Bone densitometry
TREATMENT
 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.
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.
 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.
 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.
 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
 PLASMA EXCHANGE

 Produces rapid improvement

 Mainly used as adjunctive treatment
 As treatment in those who have not
responded to other forms of treatment
OCULAR MYASTHENIA

 Started on Cholinesterase inhibitors

 If unsatisfactory – prednisone is added
 Thymectomy in young
 Generalized myasthenia
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
 Generalized myasthenia
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
 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
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.
 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
 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.
 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