This document provides information on Myasthenia Gravis (MG), an autoimmune neuromuscular disease caused by antibodies against postsynaptic muscle membranes. It discusses the prevalence and classification of MG, clinical features including weakness and fatigability, diagnostic testing such as repetitive nerve stimulation and edrophonium testing, treatment including acetylcholinesterase inhibitors and immunotherapies, and management of symptoms. Key points covered include the fluctuating muscle weakness that worsens with exertion seen in MG, different classifications based on symptoms and severity, and first line treatment involving pyridostigmine and corticosteroids.

1. Dr.SUMIT KAMBLE
SR NEUROLOGY
GMC,KOTA

2. Myasthenia gravis is autoimmune neuromuscular disease
caused by antibodies against postsynaptic muscle
membrane ,characterized by weakness and fatigability of
skeletal muscles
•Prevalence- 140 per million
•Annual incidence- 10-30 per million

3. – Postsynaptic nicotinic
acetylcholine receptor:
reduce the number of
functional receptors
• loss of structural integrity
of receptors: by Ab and
complement
– Morphologic changes of
simplification of the
pattern of postsynaptic
membrane folding;
– An increased gap
between the nerve
terminal and the post
synaptic muscle
membrane
• Blockade
• Turnover of AchRs:
Accelerated
degradation of
acetylcholine receptors

5.  MG occurs at any age, involves either sex and begins
insidiously.
 Bimodal peak of incidence
 Women < 40 years, men >50 years
 Hallmark is fluctuating muscle weakness that worsens
with exertion.

6.  Ptosis and/or diplopia – initial symptoms in 85% of
patients
 Oropharyngeal muscle weakness – difficulty in
swallowing and talking initial symptoms in 15 % of
patients
 Limb or neck weakness with proximal muscle
involvement- presenting symptom in only 10% of cases.
 Isolated respiratory failure in 1%.
 Rarely, distal weakness can occur.
 Symptoms are exacerbated by heat, stress, infection,
drugs and rarely vaccines.

7.  Within 2 years 80% of patients with ocular symptoms
progress to GMG.
 10% will remain purely ocular.
 Disease usually most severe during first 1 or 2 years.
 10% will go in clinically stable remission.
 15-20% of AChR+ patients will develop myasthenic
crisis.
 Frequency of crisis is higher in MuSK+ patients(30%).
 Mortality 5-14%
 After 15 to 20 years, weakness becomes fixed. Burnt-
Out-Stage + muscle atrophy.

9.  Cogan's lid twitch sign- patient first looks down for a short
period and then makes a saccade back to primary position.
Upper eyelid elevates excessively during this upward
saccade, sometimes causing a transient lid retraction, and
then twitches in nystagmoid fashion or slowly droops back to
a ptotic position.
 Peek sign- manifestation of orbicularis fatigue
 Lid hopping
 Sleep Test
 Curtain sign- Patient looks straight ahead and refrains from
blinking. Examiner holds one eye open , which results in the
other lid starting to droop more (like a curtain falling).

11. I. Ocular alone
IIa. Mild generalized
IIb. Moderately severe generalized plus
usually some bulbar involvement
III. Acute severe over weeks-months with
severe bulbar involvement
IV. Late severe with marked bulbar
involvement

12. Early onset MG-
 AChR antibody positive, non-thymoma, generalized MG
with onset before 40 yr.
 Thymus hyperplasia
 65% of all MG.
 Females (male/female ratio: 1:4)
 AChR antibodies high, titin and ryanodine receptor
(RyR) muscle antibodies only very rarely
 High frequency of autoimmune diseases.
 HLA A1, B8, DQB1, DR3, DR52a; in Japanese HLA
DPB1, DQB1, DR9

13. Late-onset MG –
 AChR antibody positive, non-thymoma, generalized MG
with onset at 50 yrs or later.
 Thymus atrophy is predominant
 Equal in men and women
 Peak between 70 and 80 yrs
 AChR antibodies is usually lower.
 One half have titin and RyR antibodies
 HLA-A3, B7, DR2, HLA-DR4, and in titin antibody
positive patients HLA-DR7

14. Ocular MG-
 AChR antibody positive (50%), non-thymoma MG with
purely ocular (non-generalized) symptoms.
 More common in children and in late-onset males.
 10-15% of all MG.
 More common in Asia (58%)
 HLA-DQ6 , BW46

15. Thymoma MG –
 MG patients with thymoma regardless of the extent of
muscular involvement.
 Usually have AChR antibodies.
 15% of MG patients.
 Peak of onset around 50 years
 In addition to AChR antibodies, frequent occurrence of
titin and RyR antibodies.
 Thymoma and non-thymoma MG patients have similar
MG long-term prognosis.
 HLA DR2 mostly in women.

16. MuSK- Antibody Myasthenia Gravis
 Seen in 50% of patients with GMG who lacks AChR
antibodies.
 Predominantly affects female.
 Begins from childhood through middle age.
 Thymic changes are absent or minimal.
 Many patients do not improve with cholinesterase
inhibitors, some may become worse, may have profuse
fasciculations with this medications.
 Disease severity tends to be worse but most improve
dramatically with PLEX or corticosteroids.

17. Seronegative MG –
 Double seronegative (AChR antibody and Anti-MuSK)
no evidence of thymoma.
 Low affinity anti-AChR antibodies can be detected using
specialized assays.
 Frequency is low..
 Seronegative MG patients lacking MuSK antibodies
appear to have less severe MG than seropositive MG
patients.

18. Ocular alone 34%
Bulbar alone 8%
Extremities alone 15%
Ocular and bulbar 7%
Ocular and extremities 7%
Bulbar and extremities 6%
Ocular, bulbar and extremities 21%

19.  Co-existing autoimmune diseases
◦ Hyperthyroidism
 Occurs in 10-15% MG patients
 Exopthalamos and tachycardia point to
hyperthyroidism
 Weakness may not improve with treatment of MG
alone in patients with co-existing hyperthyroidism
◦ Rheumatoid arthritis (<2%)
◦ Diabetes mellitus 7%
◦ Scleroderma
◦ Lupus
◦ 3% have extrathymic neoplasm

20.  Edrophonium (Tensilon test)
◦ Acetylcholinesterase inhibitor with rapid onset (30 to 45
seconds) and short duration of action (5 to 10 minutes).
◦ Evaluate weakness (i.e. ptosis and opthalmoplegia) before
and after administration)
◦ Steps
 0.1ml(1-2mg) of a 10 mg/ml iv edrophonium solution is
administered . Subsequent injections of 3 and 5 mg may
be then given. (maximum total dose 10 mg)
 If clear improvement is seen within 60 sec of any dose ,
test is positive.
 Keep atropine ready.

21.  Sensitivity- 60-95% of patients with OMG and in 72-95%
with GMG.
 Specificity: not clear but can be positive in many other
condition
◦ False positive= ALS, poliomyelitis, and some
peripheral neuropathies, congenital myasthenic
syndrome, Lambert-Eaton syndrome, intracranial
aneurysms, brainstem lesions, cavernous sinus
tumours, end stage renal disease, and in muscle
disease affecting ocular muscles.

22. Side effects of endrophonium-
 Increased salivation, sweating, nausea, muscle
creamps, and fasciculations.
 Serious complications (Bradycardia or Syncope) occurs
in 0.16% only.
 Cardiac disease and bronchial asthma- Relative
contraindications.

23.  Neostigmine test
Longer acting
1.5 mg im or 0.5 mg iv
Action begins in 15-20 mins

24.  Apply ice pack to ptotic lid for 2 mins
 in whom the Tensilon test is considered too risky
 Sensitivity
◦ 80%

25. AChR antibodies-
 85% with generalized MG, 70% with ocular MG
 Positive in nearly all thymomatous MG.
 May be normal at symptom onset.
 Level fall in most patients after treatment.
 Main immunogenic region (MIR) for the AChR antibodies
is located on the a-subunit.
 MOA- complement-mediated focal muscle membrane
damage, accelerated degradation of AChR, and also
direct blockade of AChR ligand binding.
 Polyclonal, mainly IgG, IgG1 and IgG3 subclasses

26. False positive AChR-Ab tests-
 Autoimmune liver disease
 SLE
 Inflammatory neuropathies
 Amyotrophic lateral sclerosis
 Penicillamine treated RA
 Patients with Thymoma but without MG
 First degree relatives

27. Antistriational muscle antibodies-
 StrAbs react with contractile elements of skeletal
muscles.
 Recognise muscle cytoplasmic proteins (titin, myosin,
actin, and ryanodine receptors).
 Found in 75- 85% of patients with thymomatous MG.
 Not pathogenic, also found in one-third of patients with
thymoma without MG.
 Frequent in older MG patients and in more severe
disease.
 Rarely elevated in MG in absence of AChR-Ab.
 Clinical use- predicting thymoma- 60% of patients with
MG with onset before 50 years who have elevated
StrAbs have thymoma.

28. Anti MuSK Antobodies-
 50 % of AChR antibody negative patients with
generalized MG have autoantibodies against MuSK, and
5-7% of all MG patients.
 Are IGG4 isotype.
 MuSK antibodies may correlate with MG severity in
AChR antibody negative MG

29. LRP4 Antibodies
 2-50% in seronegative patients
Agrin Antibodies
 Seen infequentely in seronegative MG
Cortactin antibodies
 Seen in 20% seronegative MG and 4.8% of seropositive
MG
 Thymoma MG patients have higher titers of anti-myosin
and anti-actomyosin antibodies than MG patients
without thymoma

30.  Lab studies
◦ Interleukin-2 receptors
 Increased in generalized and bulbar forms of MG
 Increase seems to correlate to progression of
disease

31.  Imaging studies
◦ Chest x-ray
 Plain anteroposterior and lateral views may identify a
thymoma as an anterior mediastinal mass
◦ Chest CT scan is mandatory to identify thymoma
◦ MRI of the brain and orbits may help to rule out other
causes of cranial nerve deficits.

32.  Electrodiagnostic studies
◦ Repetitive nerve stimulation
◦ Single fiber electromyography (SFEMG)
◦ SFEMG is more sensitive than RNS in MG

33. • Performed by stimulating the nerve supramaximally at 2- 3
Hz.
• 10% decrement between the first and the fifth evoked muscle
action potential is diagnostic for MG.
• In the absence of the decrement, exercise can be used to
induce exhaustion of muscles and document decrement.
• Test is abnormal in approximately 75% of patients with GMG
and 50% of patients with OMG
• Should not test clinically normal muscle
• Proximal muscles are better tested than unaffected distal
muscles
• AChE inhibitors should be avoided for atleast 1 day prior to
testing.

34. Exercise protocol-
 Patient is asked to exercise muscle maximally for 30 to
60 seconds.
 Train of stimuli is performed immediately after exercise.
 A repair of the CMAP decremental response is
commonly seen, reflecting post-exercise or post-
activation facilitation.
 Additional train of stimuli is delivered at one, three, and
five minutes after exercise.
 This may result in a larger decrement than seen at rest,
termed post-exercise or post-activation exhaustion.
 This exercise protocol may increase the sensitivity of
RNS by an additional 5 to 10 percent.

36.  Concentric or monopolar needle
electrodes that record single
motor unit potentials
 Increased jitter and normal
fiber density

37. ◦ Generalized MG
 Abnormal extensor digiti minimi found in 87%
 Examination of a second abnormal muscle will
increase sensitivity to 99%
◦ Occular MG
 Frontalis muscle is abnormal in almost 100%
 Sensitive(60%)

39.  AChE inhibitors
 Immunomodulating therapies
 Immunoglobulins
 Plasmapheresis
 Thymectomy

40. ◦ Patients should be advised to be as active as possible
but should rest frequently and avoid sustained activity
◦ Educate patients
◦ Speech therapy
◦ Speech assistive/communicative devices
 If dysphagia develops, liquids should be thickened
 Thickened liquids decrease risk for aspiration

41. AChE inhibitor
◦ Pyridostigmine bromide
 Starts working in 30-60 minutes and lasts 3-6 hours.
 Individualize dose
 Adult dose:
 30-60 mg every 4 hrly.
 2mg IV/IM q2-3h
 Pediatric=7mg/kg/day
 MuSk positive MG respond poorly
 Mestinon- 180 mg timed release

42. Neostigmine- shorter acting
Adult dose-15mg every 3-4 hrly
0.5-2.5mg iv/im/sc every 1-3 hrs
Pediatric dose-2mg/kg/day
 Side effects-
 Muscarinic (nausea, vomiting, salivation, bronchospasm,
abdominal cramps, diarrohea)
 Nicotinic- cholinergic crisis

43. 1)Prednisone
 Most commonly used
 High starting dose-60-80mg/day
 Early remission
 Worsens weakness in half
 Given for 3-6 months then tapered 5 mg per week to
less than 20 mg every other day.
 Low starting dose-15-20mg/day
 Increased by 5mg every 3 day till remission (60-
80mg)
 Trial showed that steroid decrease incidence of
disease generalisation.

44. 2) Azathioprine
 inhibits T and B cell proliferation by interaction with
purine metabolism
 First choice of steroid sparing agent
 Effect may take 6-12 months
 Dose-1mg/kg/day increased to 2-3mg/kg/day
 Effect monitored by MCV = >100 fl or >16fl increase over
baseline

45.  Monitor CBC, LFT every week for first 3-4 months
 3 fold elevation requires dose reduction
 Pregnancy cat D drug
 Side effects-hepatotoxicity, Bone marrow suppression,
pancreatitis, Rare risk of lymphoreticular malignancy,
Flu-like reactions.

46. 3) Cyclosporine
 Calcineurin inhibitor ,Inhibits T helper cell mediated
synthesis of cytokines.
 Third line immunosupressant choice
 Indicated in severe steroid and thymectomy resistant
MG
 Response seen in <7 months
 Dose- 4-10mg/kg/day divided in 2-3 doses
 Side effects- nephrotoxicity, hypertension, infection, BM
depression, neoplasm

47. 4) Mycophenolate mofetil
 IMPDH inhibitor
 Add on drug in generalised MG
 Dose- 500 mg twice day for 4wks f/b increase till 1gm
twice a day
 C/I in Lesch-Nyhan and kelley seegmiller syndrome
 Not co-administered with azathioprine

48. 5) Tacrolimus-
• Second line choice for moderate to severe MG
• Dose 0.1mg/kg/day
• Less nephrotoxic than cyclosporine
6)Cyclophosphamide- 500mg/m2 monthly pulse
Third line choice
7) Rituximab (anti CD20)-
More effective in MuAK+ MG than AChR+ MG
Response rate of > 80%

49.  Elliminates autoantibodies
 Treatment of choice for myasthenic crisis, preparation
for thymectomy, other surgery
 Short lived effect (2-3wks)
 5-6 exchanges alternate day with 2-4 litre per exchange
 Replacement with 5% albumin

50. Side effects
 Platelet depletion
 Citrate toxicity
 Electrolyte disturbances
 Infection
 Hypotension
 Thrombotic complications

51.  MOA-modulation of autoantibody response, inhibition of
complement activation, decrease membrane attack
complex formation, decrease cytokine response,
interference with antigen recognition
 More effective QMG score >11
 73% favourable response within 4-5 days
 Dose- 2g/kg over 2 to 5 days

52.  C/I in IgA defeciency (use IgA depleted
immunoglobulins)
 Side effects-flu like, transient HTN, renal failure,
thrombotic events, serum sickness
 High cost
 Cockrane review- similar efficacy of PE vs IvIg

53.  Indicated in non thymomatous patients with generalized
autoimmune MG of age group 10-55yrs
 All pts with thymoma
Techniques
1. Transcervical
2. Transternal extended thymectomy- standard
procedure used
3. Videoendoscopic including robotic assisted

54.  Remission rate-40-60% maximum with transternal
 Young pt. with short duration of disease with no
thymoma but with hyperplasia do best
Complication
 Perioperative
 Myasthenic crisis(6%)
 Infection(11%)
 Recurrent laryngeal or phrenic nerve injury(0-2%)

55.  Etanercept-TNF alpha receptor antibody
Concerns abt worsening MG
 Methotextrate-17.5 mg/week
 Terbutaline-beta 2 agonist
2.5 mg 3 times a day
 Complement inhibitors

56.  Respiratory failure from myasthenic weakness
 Respiratory assistance is needed if
- Negative inspiratory force of less than -20 cmH2O
- Tidal volume of less than 4mL/kg
- Force vital capacity < 15 mL/kg (normal 50-60 in female, 70 in male)
 Neurologic emergency
 Causes: concurrent infection, medications, drug withdrawal , aspiration,
surgery
 DDx from cholinergic crisis
 Management
 -Stop every medications
 -Assisted ventilation
 -IVIg or plasmapheresis

57. Myasthenic Crisis
Under medication
 Increased HR/BP/RR
 Bowel and bladder
incontinence
 Decreased urine output
 Absent cough and swallow
reflex
 May need mechanical
ventilation
 Temporary improvement
of symptoms with
administration of Tensilon
Cholinergic Crisis
Overmedication
 Decreased BP
 Abd cramps
 N/V, Diarrhea
 Blurred vision
 Pallor
 Facial muscle twitching,
fasciculations
 Constriction of pupils
 Tensilon has no effect
 Symptoms improve with
administration of
anticholinergics (Atropine)

60. Drugs that unmask or exacerbate MG

62.  Myasthenia gravis: clinical, immunological, and therapeutic
advances; Acta Neurol Scand 2005: 111: 134–141 DOI:
10.1111
 Seminars in neurology vol 35 August 2015;Neuromuscular
Diorders
 Current treatment options in neurology vol 35 may 2010:
myasthenia gravis
 Current and emerging therapies for the treatment of
myasthenia gravis Neuropsychiatric Disease and Treatment
2011:7 151–160
 Guidelines for treatment of autoimmune neuromuscular
transmission disorders EFNS GUIDELINES
 UPTODATE. COM

63. THANK YOU