Myasthenia gravis is an autoimmune disorder where antibodies target acetylcholine receptors at the neuromuscular junction, impairing muscle contraction. Symptoms include weakness of eye muscles and facial muscles that worsens with activity. Diagnosis involves tests like edrophonium testing showing improved strength or electrodiagnostic testing showing impaired neuromuscular transmission. Treatment focuses on symptomatic relief with anticholinesterases and immunosuppression with steroids, IVIG, or thymectomy. Lambert-Eaton syndrome is a related disorder where antibodies target calcium channels, impairing acetylcholine release.

1. MYASTHENIA GRAVIS
PRESENTER: DR JITHIN GEORGE

4. immune disease in which circulating
antibodies against components of the motor
postsynaptic membrane and subsequent
structural changes in that membrane
any age from infancy to very old age
women are affected nearly three times more
often than men before age 40
but the incidence is higher in males after age
50 and roughly equal during puberty.

5. PATHOPHYSIOLOGY
• acetylcholine (ACh), releases from the motor nerve
terminal in discrete packages (quanta) that cross the
synaptic cleft and bind to receptors (AChR) on the
folded muscle end-plate membrane.
• Muscle contraction results when ACh-AChR binding
depolarizes the end-plate region and then the muscle
membrane.
• Acetylcholinesterase attached to the postsynaptic
muscle membrane hydrolyzes the released ACh,
terminating its action and preventing prolonged
muscle depolarization.

6. Neuromuscular transmission is impaired in several
ways:
the antibodies
block the binding
of AChto the
AChR
serum IgG from
myasthenic
patients has
been shown to
induce an
increase in the
degradation rate
of AChR. This
may be the
result of the
capacity of
antibodies to
cross-link the
receptors
antibodies
causes
complement-
mediated
destruction of
the postsynaptic
folds

10. CLINICAL FEATURES
specific muscle weakness or dysfunction
typically worsens with activity and improves
with rest
Ptosis or diplopia is the initial
symptom : 2/3rd of patients
Difficulty chewing,
swallowing, or talking is the
initial symptom in 1/6th
limb weakness in 10%.

12. Factors that worsen myasthenic
symptoms
• emotional upset,
• systemic illness (especially viral respiratory
infections),
• hypothyroidism or hyperthyroidism,
• pregnancy, the menstrual cycle,
• drugs affecting NMT
• fever.

13. OCULAR
Asymmetrical weakness of several muscles in both eyes
the medial rectus more frequently and more severely involved.
pupillary responses are normal.
Ptosis is usually asymmetrical
To compensate for ptosis, chronic contraction of the frontalis muscle
produces a worried or surprised look.

14. • Unilateral frontalis contraction is a clue that
the lid elevators are weak on that side
• Fatigue in these muscles may result in slight
involuntary opening of the eyes as the patient
tries to keep the eyes closed; this is called the
peek sign

16. Ptosis that shifts from one eye to the other is virtually
pathognomonic
With limited ocular excursion, saccades are superfast,
producing ocular “quiver”
After downgaze, upgaze produces lid overshoot (“lid
twitch”)
Pseudo-internuclear ophthalmoplegia—limited adduction,
with nystagmoid jerks in abducting eye

17. OROPHARYNGEAL MUSCLES
changes in the voice, difficulty chewing and swallowing,
and inadequate maintenance of the upper airway.
The voice may be nasal, especially after prolonged talking
liquids may escape through the nose when swallowing
because of palatal muscle weakness.
Weakness of laryngeal muscles causes hoarseness

18. • frequent choking or throat clearing or coughing
after eating indicates difficulty in swallowing.
• a characteristic facial appearance. At rest, the
corners of the mouth often droop downward,
giving a depressed appearance.
• Attempts to smile often produce contraction of
the medial portion of the upper lip and a
horizontal contraction of the corners of the
mouth without the natural upward curling, which
gives the appearance of a sneer

20. LIMB MUSCLES
Weakness begins in limb or axial muscles in about 20% of MG
patients
Neck flexors are usually weaker than neck extensors
deltoids, triceps, and extensors of the wrist and fingers and ankle
dorsiflexors are frequently weaker than other limb muscles
“dropped head syndrome” due to severe neck extensor weakness.
the appearance of a chronic myopathy; this is particularly likely in
muscle-specific tyrosine kinase (MuSK) antibody–positive MG

23. Diagnostic Procedures in Myasthenia
Gravis

24. EDROPHONIUM TEST
inhibiting the action of
acetylcholinesterase
thus allows ACh to diffuse more widely
throughout the synaptic cleft
more prolonged interaction with AChR on
the postsynaptic muscle membrane

25. The most important
consideration in performance of
the edrophonium test is the
choice of endpoint.
Only unequivocal improvement
in strength of an affected muscle
is acceptable as a positive result.
resolution of eyelid ptosis,
improvement in strength of a
single paretic extraocular
muscle, or clear improvement of
dysarthria have been proposed
as the only truly valid endpoints

27. edrophonium test :positive in 60% to 95% of patients with
OMG and in 72% to 95% with GMG
Improvement after edrophonium is not unique to MG;
it is also seen in congenital myasthenic syndromes, the
Lambert-Eaton syndrome, intracranial aneurysms, brainstem
lesions, cavernous sinus tumors, end-stage renal disease,
and in muscle diseases affecting the ocular muscles

28. • Inject an initial test dose of 2 mg, and monitor
the response for 60 seconds.
• Subsequent injections of 3 and 5 mg may then
be given
• If clear improvement is seen within 60
seconds after any dose, the test is positive,
and no further injections are necessary

29. • Common side effects of edrophonium are
increased salivation and sweating, nausea,
stomach cramps, and fasciculations.
• Serious complications (bradyarrhythmia or
syncope) have been reported in only 0.16% of
edrophonium tests.
• These symptoms generally resolve with rest in
the supine position.
• Atropine (0.4-2 mg) should be available for
intravenous (IV) injection if bradycardia is
severe.

30. NEOSTIGMINE TEST
0.5 mg
intramuscularly
(IM) or
subcutaneously
(SQ)
Onset of action
after IM
injection is 5 to
15 minutes.
The longer
duration of
action is
particularly
useful in
children.
Monitor BP and
pulse for 1-5
hours
Ptosis improves
better than
diplopia

31. Autoantibodies in Myasthenia Gravis
Ach receptor Abs
Musk Abs
• Ig G4 subclass
• Most females
• Associated muscle atrophy
• Fluctuation of musle strenth is less
• Concentration of Abs proportional to disease severity
LRP4 Ab
• Lipoprotein receptor protein 4
• Milder symptoms
• Mainly ocular symptoms
Anti- striational
• the first autoantibodies discovered in MG.

32. ELECTRODIAGOSTIC TESTING
Repetitive nerve stimulation (RNS) is the most
commonly used electrophysiological test of NMT
RNS depletes the store of readily releasable ACh at
diseased motor end-plates, causing failure of NMT
Decrement of 10% or more between 1st and 5th
CMAP is significant

33. MUSCLES USED FOR RNS
Abductor
digiti
minimi
Facial
muscles
Trapezius
Tibialis
anterior

35. Single fibre EMG
Records extracellular
action potential during
voluntary action
Measures
JITTER
Increase at higher
frequency rates :
myasthenia gravis
Increase at
low
frequency
rates:
LEMS,
Botulism

37. • The presence of serum AChR or anti-MuSK antibodies
virtually ensures the diagnosis of MG, but their
absence does not exclude it.
• RNS confirms impaired NMT but is frequently normal
in mild or purely ocular disease.
• Almost all patients with MG have increased jitter, and
normal jitter in a weak muscle excludes MG as the
cause of the weakness.
• Neither electrodiagnostic test is specific for MG,
because increased jitter, even abnormal RNS, occurs in
other motor unit disorders that impair NMT.

39. MANAGEMENT

40. TREATMENT
• SYMPTOMATIC
– Anticholinesterase : pyridostigmine quarternary
60mg
– neostigmine 7.5 to 15 mg.
– In infants and children, the initial oral dose of
pyridostigmine is 1 mg/kg, and of neostigmine is
0.3 mg/kg
– Action begin in 45 min. Last 3-6 rs
– Max 960 mg

41. MANAGEMENT OF CRISES
• Resp failure needs artificial ventilation
• Crises mostly within 2 yrs
• Stop AChE once pt is on ventilator.
• Respiratory assistance is needed when the NIF(
negative insp force) is less than −20 cm H2O, when
tidal volume is less than 4 to 5 mL/ kg body weight and
maximum breathing capacity is less than three times
the tidal volume, or when the forced vital capacity is
less than 15 mL/kg body weight .
• Specific treatment is plasma exchange or IV Ig

42. Short-Term (Rapid-Onset) Immune
Therapies
• used for short-term treatment of severe
MG, myasthenic crisis, in preparation for
surgery (e.g., thymectomy), or to prevent
corticosteroid-induced exacerbations.
• A typical course of PLEX consists of 5 to 6
exchanges administered on an every-
other-day schedule, during which 2 to 3 L
of plasma are removed
• Musk ab positive cases more benefit
from PE than IVIg
PLASMA
EXCHANGE

43. IVIg
Improvement in MG occurs in 50% to 100% of MG
patients
intravenous immunoglobulin (IVIG), typically given
at a dose of 2 g/kg given over 2 to 5 days.
400mg/kg per day
Improvement usually begins within 1 week and
lasts for several weeks or months
Contadindicated in IgA deficiency

44. Long-Term Immune Therapies
CORTICOSTEROIDS
IMMUNOSUPPRESSANTS
THYMECTOMY
EVOLVING TREATMENTS

45. CORTICOSTEROIDS
0.75 to 1 mg /
kg / day
60-80 MG / DAY
initially.
Much of the
improvement
occurs in the
first 6 to 8
weeks
50 % will
worsen. If
worsen
plasmapheresis.

46. IMMUNOSUPRESSANTS
AZATHIOPRINE
• Affects S phase. T cell apoptosis
• 50mg/kg.
• monitor complete blood cell counts and liver enzymes every week
during the 1st month, every 1 to 3 months for a year, and every 3 to
6 months thereafter.
• Reduce the dose if the peripheral white blood cell (WBC) count falls
below 3500 cells/mm3
• Stop the drug immediately if counts fall below 1000 WBC/mm3.
• discontinue treatment if the serum transaminase concentration
exceeds twice the upper limit of normal,
METHOTREXATE
• 7,5 mg to 20 mg per week

47. MYCOFENOLATE MOFETIL
• Blocks purine synthesis
• Inhibit B and T cell proliferation
• 500mg bd to 2gm / day
• Target is absolute lymphocyte count 1000-12000
CYCLOSPORIN A
• binds to the cytosolic protein, cyclophilin (immunophilin)
• Calcineurin inhibitor
• Monitor blood pressure and serum creatinine monthly, and adjust the dose
to keep the creatinine below 150% of pretreatment values
• Start as 5-6 mg /kg in 2 divided doses 12 hrs apart
• Side eff: nephrotoxicity
TACROLIMUS
• From streptomyces
• 0.1mg/kg/day
CYCLOPHOSPHAMIDE

48. THYMECTOMY
nonthymomatous
autoimmune MG:
as an option to
increase the
probability of
remission or
improvement
The response
to
thymectomy
is
unpredictable
best
responses in
young people,
especially
women, early
in the
disease,

49. preferred surgical approach :
• transthoracic sternal-splitting procedure
Transcervical and endoscopic approaches :
• less postoperative morbidity and shorter recovery times but
not sufficient exposure for total thymic removal
recommend thymectomy:
• In nonthymomatous MG in all early-onset anti-AChR-positive
MG patients.
• And as option for 40-60rs age

50. EVOLVING TREATMENTS
RITUXIMAB ETARNECEPT
COMPLEMENT
INHIBITION
AUTOLOGOUS
STEM CELL
TRANSPLANTATION

52. ASSOCIATED DISEASES
• Thymoma
• Hyperthyroidism
• Rheumatoid arthritis
• Seizures
• Diabetes

53. annual vaccination against
influenza (including H1N1).
Vaccination against
pneumococcus is a
recommendation for at-risk
patients before starting
prednisone or other
immunosuppressive drugs.
Never give live attenuated
vaccines to
immunosuppressed
patients.
Patients with prior
thymectomy should not
receive the yellow fever
vaccine.

54. NEONATAL MG
•ANTI CHE AGENTS, STEROIDS, IVIg are
safe.
JUVENILE MG
•<18 YRS.
•DELAY THYMECTOMY

55. PREGNANCY AND MG
1/3 IMPROVE. 1/3 SAME. 1/3 WORSEN
Oral ChEIs are the first-line treatment during pregnancy.
Intravenous ChEIs may produce uterine contractions and are
contraindicated.
Prednisone is the immunosuppressive agent of choice.
Azathioprine. Cyclosporine tacrolimus, IVIg are safe
Rituximab, methotrexate, cyclophosphamide are contraindicated.

56. LAMBERT
EATON
SYNDROME

57. • immune-mediated attack against the P/Q-type
voltage-gated calcium channels (VGCC) on
presynaptic cholinergic nerve terminals at the
neuromuscular junction and in autonomic
ganglia
• first described in patients with lung cancer(
small cell ca mostly)
• also occurs as an organ-specific autoimmune
disorder

58. • gradual onset of lower-extremity weakness, sometimes
with muscle tenderness.
• Dry mouth is a common symptom of autonomic
dysfunction; other features are erectile dysfunction,
postural hypotension, constipation, and dry eyes.
• Ocular and bulbar symptoms are generally not
prominent
• Symptoms usually begin after age 40, but LES can occur
in children.
• Males and females are equally affected
• Tendon reflexes are almost always absent or
diminished.

59. Diagnostic Procedures
• CMAPs with low amplitude, which increases
during 20- to 50-Hz stimulation and after brief
maximum voluntary muscle activation.
• Low-frequency repetitive nerve stimulation
produces a decrementing response in a hand or
foot muscle in almost all patients, and almost all
have small CMAPs in some distal muscle
• The characteristic increase in CMAP size after
activation is more prominent in distal muscles .
• Immunoprecipitation assays demonstrate VGCC
antibodies in almost all patients with CA-LES and
in more than 90% with NCA-LES

60. TREATMENT
• search for underlying malignancy, especially SCLC
• pyridostigmine, 30 to 60 mg, every 6 hours for several
days.
• Guanidine hydrochloride . Divide the initial oral dose of
5 to 10 mg/kg daily into 3 doses, 4 to 6 hours apart,
and increase as needed to a maximum of 30
mg/kg/day. Bone marrow depression is a major risk
and may occur with doses as low as 500 mg/day.
• Other side effects include renal tubular acidosis,
chronic interstitial nephritis, cardiac arrhythmia,
hepatic toxicity, pancreatic dysfunction, paresthesias,
ataxia, confusion, and alterations of mood.
• Administering 3,4-DAP facilitates release of ACh from
motor nerve terminals and produces clinically
significant improvement of strength and autonomic
symptoms in most LES patients

61. BOTULISM
Clostridium botulinum
eight types of botulinum toxins (A, B, Cα, Cβ, D, E, F, and G)
types A and B are the cause of most cases of botulism
block ACh release from the presynaptic motor nerve terminal and the
parasympathetic and sympathetic nerve ganglia.
The intracellular target is the SNARE proteins of the presynaptic
membrane.

62. • five forms: classic or food-borne, infantile, wound,
hidden, and iatrogenic.
• The EMG findings in botulism include:
• ■ Reduced CMAP amplitude in at least two muscles.
• ■ At least 20% facilitation of CMAP amplitude during
tetanic stimulation.
• ■ Persistence of facilitation for at least 2 minutes after
activation.
• ■ No postactivation exhaustion.
• ■ Short-duration motor unit potentials resembling
myopathic motor units in affected muscles on EMG

63. • Treatment consists of administration of bivalent
(type A and B) or trivalent (A, B, and E) antitoxin.
• Antibiotic therapy is not effective, since the cause
of symptoms (in all but infantile botulism) is the
ingestion of toxin rather than organisms.
• In infantile botulism, IV human botulism immune
globulin (BIG-IV) neutralizes the toxin for several
days after illness onset, shortens the length and
cost of the hospital stay, and reduces the severity
of illness

64. THANK
YOU