Myasthenia gravis is a disease of skeletal muscle acetylcholine receptors caused by antibodies that prevent acetylcholine from binding to receptors, inhibiting nerve impulse transmission and muscle contraction. Symptoms vary in severity and commonly involve the eyes, face, throat, or limbs. Diagnosis involves the Tensilon test and repetitive nerve stimulation or single-fiber electromyography to confirm impaired neuromuscular transmission. Treatment includes acetylcholinesterase inhibitors, immunosuppression with corticosteroids and other drugs, immunomodulation therapies like plasmapheresis, and thymectomy in some cases.

1. Dr Parag Moon
SR1, Neurology

2. •Myasthenia gravis is a disease of skeletal
muscle acetylcholine receptors.
•Acetylcholine (ACh) is unable to bind to the
receptors (AChR) on the postsynaptic
membrane
•Transmit the nerve impulse to muscle fibers
to produce a muscle contraction

3.  MG occurs at any age, involves either sex
and begins insidiously
 Second and third decades commonest age
of onset in women. Seventh and eighth
decades in men
 Patients complain of specific muscle
weakness

4.  Ptosis or diplopia – initial symptoms in
65% of patients
 Oropharyngeal muscle weakness –
difficulty in swallowing and talking initial
symptoms in 17% of patients
 Limb weakness presenting symptom in
only 10% of cases

5.  Ocular myasthenia – if progressing to
generalized MG usually does so within the
first two years after onset
 After 15 to 20 years, weakness becomes
fixed. The Burnt-Out-Stage + muscle
atrophy

6. 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

7.  Early onset MG- AChR antibody positive, non-thymoma,
generalized MG with onset before 50 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

8.  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

9.  Ocular MG- AChR antibody positive, non-thymoma
MG with purely ocular (non-generalized)
symptoms.
 More common in children and in late-onset males.
 HLA-DQ6

10.  Thymoma MG –MG patients with thymoma
regardless of the extent of muscular involvement.
 Usually have AChR antibodies.
 15% of MG patients, is of cortical type.
 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

11.  Seronegative MG - AChR antibody negative, no
evidence of thymoma
 Occurrence of muscle specific kinase (MuSK)
antibodies in 10–40% of AChR antibody negative
MG patient.
 Seronegative MG patients lacking MuSK antibodies
appear to have less severe MG than seropositive
MG patients

12.  AChR antibodies –85% with generalized
MG,70% with ocular MG
 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.
 C3 and C4 is low
 Polyclonal, mainly IgG, IgG1 and IgG3
subclasses

13.  Ab against titin and rynodin receptor
 MIR of titin is called myasthenia gravis titin-30
(MGT-30) and situated near the A/I band
junction
 Two forms of RyR, skeletal (RyR1) and cardiac
(RyR2).
 RyR antibodies from MG patients react with both
 Titin and RyR antibodies occur more often in
severe MG
 Antibodies against rapsyn (a 43-kDa
postsynaptic protein essential for anchoring and
clustering AChR) .

14.  Anti MuSK-41% of AChR antibody negative
patients with generalized MG have
autoantibodies against MuSK
 MuSK antibodies may correlate with MG
severity in AChR antibody negative MG
 Thymoma MG patients have higher titers of
anti-myosin and anti-actomyosin antibodies
than MG patients without thymoma

15. 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%

16.  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
◦ Scleroderma
◦ Lupus

18. 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
 Constriction of pupils
 Tensilon has no effect
 Symptoms improve with
administration of
anticholinergics (Atropine)

19.  Lab studies
◦ Anti-acetylcholine receptor antibody
 Positive in 74%
 80% in generalized myasthenia
 50% of patients with pure ocular myasthenia
◦ Anti-striated muscle
 Present in 84% of patients with thymoma who
are younger than 40 years

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

21.  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

22.  Edrophonium (Tensilon test)
◦ Edrophonium is a short acting Acetylcholine
Esterase Inhibitor.
◦ Onset within 30secs
◦ Evaluate weakness (i.e. ptosis and
opthalmoplegia) before and after administration

23.  Edrophonium (Tensilon test)
◦ Steps
 0.1ml(1-2mg) of a 10 mg/ml edrophonium
solution is administered as a test
 If no unwanted effects are noted (i.e. sinus
bradychardia), the remainder of the drug is
injected
 Keep atropine ready

24.  Sensitivity 71.5- 95%
 Specificity: not clear but can be positive in
many other condition
 False positive= ALS, poliomyelitis, and some
peripheral neuropathies

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

26.  Apply ice pack to ptotic lid
 Sensitivity
◦ 89%
 Specificity
◦ 100% (!?)

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

28. During RNS EPSP’s may not reach threshold and
no action potential is generated
 Results in a decremental decrease in the
compound muscle action potential
 Any decrement over 10% is considered
abnormal
 Should not test clincally normal muscle
 Proximal muscles are better tested than
unaffected distal muscles

30.  Most common employed stimulation rate is 3Hz
◦ Lower temperature increases the amplitude of the
compound muscle action potential
 Many patients report clinically significant
improvement in cold temperatures
◦ AChE inhibitors prior to testing may mask the
abnormalities and should be avoided for atleast 1
day prior to testing

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

32. ◦ 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%)

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

34. ◦ 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

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

36.  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

37. 1)Prednisone
 Most commonly used
 High starting dose-60-80mg/day
 Early remission
 Worsens weakness in half
 Given for 3-6 months then tapered 5mg per
week
 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.

38. 2) Azathioprine
 inhibits T and B cell proliferation by interaction
with purine metabolism
 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

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

40. 3) Cyclosporine
 Inhibits T helper cell mediated synthesis of
cytokines
 Indicated in severe steroid and thymectomy
resistant MG
 Response seen in <7 months
 Dose- 4-10mg/kg/day divided in 2-3 doses
 Trough levels= 100-200mcg/ml
 Side effects-nephrotoxicity, hypertension,
infection, BM depression, neoplasm

41. 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

42. 5) Tacrolimus- indicated in steroid and cyclosporine
resistant MG in dose 0.1mg/kg/day
Less nephrotoxic than cyclosporine
6)Cyclophosphamide- 500mg/m2 monthly pulse
Not indicated
7) Rituximab (anti CD20)

43.  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

44. Techniques
 Plasma filtration
 Plasma seperation
 Antigen specific immuno-adsorption
Side effects
 Platelet depletion
 Citrate toxicity
 Electrolyte disturbances
 Line related S/E

45.  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-0.4 mg/kg /day for 3-4 days
 Maintainance- 1gm/kg/ day for 1- 2 days

46.  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

47.  Indicated in non thymomatous pts with generalised
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

48.  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%)

49.  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

51. Drugs that unmask or exacerbate MG

54.  Myasthenia gravis: clinical, immunological,
and therapeutic advances; Acta Neurol Scand
2005: 111: 134–141 DOI: 10.1111
 Seminars in neurology vol 32 july
2011;Neuromuscular therapy
 Current treatment options in neurology vol
35 may 2010: myasthenia gravis

55. Thank you!