Small Presentation about the treatment

1. DR. DHILEEBAN MAHARAJAN P
SENIOR RESIDENT
DEPARTMENT OF NEUROLOGY
NEIGRIHMS
Myasthenia Gravis

2. Introduction
 Autoimmune disorder of NMJ
 AChR antibody mediated destruction of AChR
 Impaired transmission of nerve impulse across NMJ
 Lead to muscle weakness
 Effective treatments are available

3. Epidemiology
 MG begin at any age
 Incidence - 0.3 to 2.8 per 100,000
 Worldwide Prevalence- >700,000
 Women : Men – 3:1 (<40 years)
 After 50 years M > F

4. Clinical Presentation
 Ptosis or diplopia - Initial symptom (2/3)
 Difficulty chewing, swallowing, or talking (1/6)
 Limb weakness (10%)
 Fluctuating Weakness
 Maximum weakness within one year in 2/3 of patients
 Remission, Relapse, Active stage, Burn-out stage
weakness or dysfunction that typically worsens with activity
and improves with rest

5. Factors worsen MG
 Emotional upset
 Systemic illness (especially viral respiratory infections)
 Hypothyroidism or Hyperthyroidism
 Pregnancy
 Menstrual cycle
 Drugs affecting NMT
 Fever

6. Physical Findings
 Ocular muscles
 Medial Rectus - more frequently
and severely involved
 Ptosis - Asymmetrical and varies
during sustained activity
 Eyelid closure usually weak
 Peek sign

7.  Oropharyngeal muscle
 Characteristic facial appearance
 Manually opening the jaw against
resistance shows jaw weakness
 Limb Muscles
 Weakness begins in Limb or Axial
muscles
 Neck flexors weaker than neck
extensors
 Dropped head syndrome
Physical Findings

8. Immunopathology

10.  80%–85% Generalised MG patients have anti-AChR antibodies
 Complement-mediated destruction of the folds
 Accelerated internalization
 Degradation of AChR
 T lymphocytes play a pivotal role
 10% - Antibodies to muscle specific tyrosine kinase (MuSK)
 predominantly IgG4
 Double seronegative - Agrin, LRP4
Immunopathology

11. Thymus in Myasthenia Gravis
 Abnormal in most MG patients
 70% - Lymphoid follicular hyperplasia
 10% - Thymoma
 Thymic-derived AChR subunits may serve as an antigen for the
auto-sensitization against the AChR

12. Myasthenia Gravis Subtypes

13. Ocular MG (OMG)
 10%–15% of all MG
 Weakness remains limited to the ocular muscles after 2 years
 Ptosis and/or diplopia - Initial symptoms of MG (85%)
 Both symptoms within 2 years of disease onset
 More common in Asian populations
 RNS studies and anti-AChR antibodies are often negative
 Single-fiber EMG (SFEMG) testing may be required.

14. Generalized Myasthenia Gravis
 Two types
 Early onset MG (EOMG)
 Late onset MG (LOMG)

15. Early onset MG
 Generalized MG < 40 years
 Common in females
 AChR AB + and High
 Thymus hyperplasia +
 65% of all MG
 HLA -DR3 B8 DR9
• GMG > 40 years
• Common in males
• AChR ab usually lower
• Thymus normal or atrophied
• ≈ 50% have Titin and RyR AB
• HLA-A3, B7, DR2, HLA-DR4
Late onset MG

16. Thymomatous Myasthenia Gravis
 In 10%–15% of MG patients
 Thymic epithelial tumor or thymoma
 M = F
 Occur at any age (peak onset at 50)

17. MuSK-Antibody Myasthenia Gravis
 MuSK ab - 50% in GMG with AchR ab –
 Mostly affects females
 Begin from childhood through middle age
 Predominant weakness in cranial and bulbar muscles
 Marked atrophy of muscles
 Prominent neck, shoulder, and respiratory weakness, with little or
no involvement of ocular or bulbar muscles

18.  Electrodiagnostic abnormalities are not conclusive
 Do not improve with ChEIs (some actually become worse)
 Improve dramatically with therapeutic plasma exchange (PLEX)
or corticosteroids
 Long-term outcome is generally good
 Thymic changes are absent or minimal
 Thymectomy in MuSK-MG is not yet clear
MuSK-Antibody Myasthenia Gravis

19. MuSK-Antibody Myasthenia Gravis

20. Seronegative Myasthenia Gravis
 Lack both anti-AChR and anti-MuSK antibodies
 No evidence of thymoma
 Low affinity anti-AChR antibodies can be detected using
specialized assays
 Less severe MG than seropositive MG patients

21. Osserman Classification

22. MGFA Clinical Classification

23. Diagnostic Procedures
Diagnostic
testing
Repetitive nerve
stimulation
Anti cholinesterase
test
Assay for acetyl
cholinesterase
Receptor antibody
Single fiber
electromyography
EDROPHONIUM
Unequivocal
improvement in
objectively weak
muscle is
positive
Decrementel
response of 15%
Is considered
positive
Human AchR
labeled with alpha
bungarotoxin
Delayed or failed
NMT in pairs of
muscle fibres
supplied by br of

24. Edrophonium Chloride Test
 Facilitates repeated interaction of ACh with the reduced AChRs
 Only unequivocal improvement in strength of an affected muscle
 Also seen in
 congenital myasthenic syndromes (CMS)
 Lambert–Eaton syndrome (LES)
 intracranial aneurysms
 brainstem lesions
 cavernous sinus tumors
 Maximum - 10 mg IV (2mg, 3mg, 5mg)
 Neostigmine methylsulfate, 0.5 mg IM or SC

25. Auto-Antibodies
1. Acetylcholine Receptor Antibodies
2. Anti-striational Muscle Antibodies
3. Anti-MuSK Antibodies

26.  Acetylcholine Receptor Antibodies
 AChR-ab binding assay
 Specific serologic markers for MG
 Sensitivity - 85% for GMG
 Normal antibody measurements do not exclude
Auto-Antibodies

27.  Anti-striational Muscle Antibodies
 First autoantibodies discovered in MG.
 Muscle cytoplasmic proteins (titin, myosin, actin, and ryanodine receptors)
 60% of patients with MG with onset before age 50, who have elevated StrAbs
have thymoma
 Anti-MuSK Antibodies
 Antibodies to MuSK are present in up to 50% of GMG patients who are
seronegative for AChR abs and in some patients with OMG
Auto-Antibodies

28. Electrodiagnostic Testing
 Repetitive nerve stimulation (RNS) – Commonly used
 Decrementing response of at least 10% to trains of 2–3 Hz
stimulation
 Sensitivity - 53% to 100% in GMG and 10% to 48% in OMG
 SFEMG
 Most sensitive
 Shows increased jitter

29. EMG in Myasthenia Gravis

30. Ocular Cooling (Ice pack Test)
 Myasthenic weakness typically improves with muscle cooling
 Cooling of a ptotic lid improves lid elevation
 Useful in patients with lid ptosis, particularly if the edrophonium
test is negative or contraindicated

32. Treatment of Myasthenia Gravis

35. 1. Symptomatic and immunosuppressive (IS) treatments
2. IV immunoglobulin (IVIg) and plasma exchange (PLEX)
3. Impending and manifest myasthenic crisis
4. Thymectomy
5. Juvenile MG (JMG)
6. MG with antibodies to muscle-specific tyrosine kinase
(MuSK-MG)
7. MG in pregnancy
Guidance statements were developed for :

36. Preliminary definitions
 Minimal Manifestation Status (MMS)
 The patient has no symptoms or functional limitations from MG
but has some weakness on examination of some muscles
 Remission
 The patient has no symptoms or signs of MG. Weakness of eyelid
closure is accepted, but there is no weakness of any other muscle
on careful examination

37.  Ocular MG
 Any ocular muscle weakness. May have weakness of eye closure.
Strength in all other facial, bulbar, and limb muscles is normal.
 Impending myasthenic crisis
 Rapid clinical worsening of MG that, in the opinion of the treating
physician, could lead to crisis in the short term (days to weeks)
Preliminary definitions

38.  Manifest myasthenic crisis
 Worsening of myasthenic weakness requiring intubation or non-
invasive ventilation to avoid intubation, except when these
measures are employed during routine postoperative management
 Refractory MG
 PIS is unchanged or worse after corticosteroids and at least 2 other
IS agents, used in adequate doses for an adequate duration, with
persistent symptoms or side effects that limit functioning, as
defined by patient and physician
Preliminary definitions

39. Symptomatic And Immunosuppressive (IS)
Treatment Of Mg
 Pyridostigmine - Initial treatment in most cases
 Dose adjusted based on symptoms
 Ability to discontinue pyridostigmine - Patient met treatment goals
 Corticosteroids or IS therapy - not met Rx goals after an adequate trial
 A non-steroidal IS agent should be used alone when corticosteroids are
contraindicated or refused
 A non-steroidal IS agent used initially with corticosteroids when the risk of
steroid side effects is high

40.  A non-steroidal IS agent should be added to corticosteroids when:
 Significant side effects
 Inadequate response to an adequate trial of corticosteroids
 Corticosteroid dose cannot be reduced d/t symptom relapse
 Following IS agents may also be used in refractory MG
 Chronic IVIg and chronic PLEX
 Cyclophosphamide
 Rituximab
Symptomatic And Immunosuppressive (IS)
Treatment Of Mg

41. IS Agent Dosage And
Duration Of Treatment
 Once patients achieve treatment goals, the corticosteroid dose
should be gradually tapered
 In many patients, continuing a low dose of corticosteroids long-
term can help to maintain the treatment goal
 For non-steroidal IS agents, once treatment goals have been
achieved and maintained for 6 months to 2 years, the IS dose
should be tapered slowly to the minimal effective amount

42.  Dosage adjustments should be made no more frequently than every
3–6 months
 Tapering of IS drugs is associated with risk of relapse
 Risk of relapse is higher in symptomatic, or after rapid taper
 Usually maintenance immunosuppression is needed for many years
 Monitored for potential adverse effects and complications from IS
drugs
 Changing to an alternative IS agent should be considered if adverse
effects and complications occurs
IS Agent Dosage And
Duration Of Treatment

43. INDICATIONS FOR IVIG AND PLEX
 Short-term treatment in patients with MG with life-threatening
signs such as respiratory insufficiency or dysphagia
 In preparation for surgery in patients with significant bulbar
dysfunction
 When a rapid response to treatment is needed
 When other treatments are insufficiently effective
 Prior to beginning corticosteroids if deemed necessary to prevent
or minimize exacerbations

44.  Depends on individual patient factors and the availability
 Equally effective in the treatment of severe GMG
 Efficacy of IVIg is less certain in milder MG or in ocular MG.
 PLEX may be more effective than IVIg in MuSK-MG
 The use of IVIg as maintenance therapy can be considered for
patients with refractory MG or for those in whom IS agents are
relatively contraindicated
INDICATIONS FOR IVIG AND PLEX

45. Impending and Manifest
Myasthenic Crisis
 Emergent situations - Aggressive management and supportive
care.
 Although cholinergic crises are rare, excessive ChEI cannot be
completely excluded as a cause of clinical worsening.
 ChEIs increase airway secretions, which may exacerbate
breathing difficulties.

47. Myasthenic Crisis
 PLEX and IVIg are the mainstay of management
 Impending crisis requires hospital admission and close
observation of respiratory and bulbar function, with the ability to
transfer to an ICU if it progresses to manifest crisis
 PLEX and IVIg are used as short-term treatment for impending
and manifest myasthenic crisis and in patients with significant
respiratory or bulbar dysfunction

48.  Corticosteroids or other IS agents are often started at the same
time to achieve a sustained clinical response.
 Clinical trials - IVIg= PLEX
 Expert consensus - PLEX> IVIg
 A greater risk of hemodynamic and venous access complications
with PLEX may be minimized by using peripheral rather than
central venous access.
Myasthenic Crisis

49. Thymectomy in MG
 Non-thymomatous MG - Thymectomy is an option to
potentially avoid or minimize the dose or duration of
immunotherapy
 Thymectomy for MG is an elective procedure
 Should be performed when the patient is stable
 Value of thymectomy in the treatment of pre-pubertal patients
with MG is unclear.

50.  Considered in children with generalized AChR ab positive MG-
 If the response to pyridostigmine and IS therapy is unsatisfactory
 In order to avoid potential complications of IS therapy
 For Seronegative generalized MG, the possibility of a
congenital myasthenic syndrome or other neuromuscular
condition should be entertained
 Current evidence does not support an indication for
thymectomy in patients with MuSK, LRP4, or agrin antibodies
Thymectomy in MG

51.  All patients with MG with thymoma should undergo surgery
to remove the tumor
 All thymus tissue should be removed along with the tumor
 Further treatment of thymoma will be dictated by histologic
classification and degree of surgical excision
 Incompletely resected thymoma - Surgery with an interdisciplinary
treatment approach (radiotherapy, chemotherapy)
Thymectomy in MG

52. Juvenile MG
 Children with ocular MG are more to go into spontaneous remission
 Initial therapy - pyridostigmine.
 Immunotherapy - if goals of therapy are not met
 Children are at particular risk of steroid side effects-
 Eg. - Growth failure, poor bone mineralization, and susceptibility to
infection
 Corticosteroids should use the lowest effective dose to minimize side effects
 Maintenance PLEX or IVIg are alternatives to IS drugs

53. MG WITH MuSK ANTIBODIES
 Respond poorly to ChEIs
 Respond well to corticosteroids and steroid-sparing IS agents
 Dependent on prednisone despite concomitant treatment with steroid-
sparing agents
 MuSK-MG responds well to PLEX, while IVIg seems to be less effective
 Rituximab should be considered as an early therapeutic option in
patients with MuSK-MG who have an unsatisfactory response to initial
immunotherapy

54. MG IN PREGNANCY
 Planning for pregnancy should be instituted well in advance
 Majority of women can be reassured that they will remain stable throughout
pregnancy.
 If worsening occurs, it may be more likely during the first few months after
delivery
 Oral pyridostigmine is the first-line treatment
 IV ChEIs may produce uterine contractions
 Thymectomy should be postponed until after pregnancy, as benefit is unlikely to
occur during pregnancy
 Prednisone is the IS agent of choice during pregnancy

55.  Azathioprine and cyclosporine are relatively safe
 Mycophenolate mofetil and methotrexate - teratogenic
 PLEX or IVIg are useful during pregnancy.
 Spontaneous vaginal delivery should be the objective
 Magnesium sulfate is not recommended
 Barbiturates or phenytoin usually provide adequate treatment
 All babies born to myasthenic mothers should be examined for
evidence of transient myasthenic weakness
MG IN PREGNANCY

56. Evolving Treatments
 Etanercept - Recombinant human TNF receptor:Fc
 Eculizumab - Complement inhibitor
 Belimumab - Monoclonal antibody against BAFF
 Autologous stem-cell transplantation

57. Differential diagnosis
CONDITIONS
SYMPTOMS AND
CHARECTERISTICS
COMMENT
Congenital myasthenia
syndromes
Rare, early onset non
autoimmune disorder
Specialized EP &
immunocytochemical test
Drug induced Myasthenia
Penicillamine,procainamide,
aminoglycosides
Triggers autoimmune
Myasthenia
Recovery within weeks of drug
withdrawal
Lambert Eaton syndrome
Weakness, fatigue, areflexia
60% A/W oat cell
carcinoma
Incremental response to RNS,
Abs to calcium channel present
Hyperthyroidism Exacerbation of Myasthenia Thyroid function abnormal
Graves disease Diplopia,opthalmoplegia Thyroid stimulating Ig present
Botulism
Generalized weakness,
opthalmoplegia
Incremental response , pupils
are dilated
Intracranial mass
compressing CN
Opthalmoplegia , CN
palsies
Abnormalities on CT or MRI

58. Disorders Associated with Myasthenia
Associated disorders
Recommended lab
test and procedure
Disorder of Thymus Thymoma , hyperplasia MRI or CT of Mediastinum
Autoimmune Disorders
Thyroiditis, Graves disease,
Rheumatoid arthritis, SLE, skin
disorders and F/H/O autoimmune
disorders
Test for Rh-factor, Thyroid function
test, ANA
Disorders That May
Exacerbate Myasthenia
Hypo or hyperthyroidism, Occult
infection and Drugs
Disorders That May Interfere
With Therapy
Tuberculosis, diabetes, peptic ulcer,
renal disease, hypertension ,asthma,
Osteoporosis
Tuberculin test, Chest X-Ray, FBG,
Pulmonary function test, Bone
densitometry

59. Drugs that may Exacerbate MG
Drugs with important
interactions in MG
Antibiotics
Amino glycosides eg. SM, Tobra, Kana
Quinolones eg. Cipro, Levo, O, Gati
Macrolides eg. Erythro, azithro
Cyclosporine
Broad Range of drug interactions which may
raise or lower cyclosporine levels
Non Depolarizing Muscle Relaxants
Curare, Pancuronium, Ve, Atracurium
Azathioprine
Avoid Allopurinol- combination leads to
myelosuppression
Beta Blockers
Propranolol, Atenolol, Metoprolol
LA and related agents
Procaine, Xylocaine (Large amts)
Procainamide (anti arrhythmic)
Botulinum Toxin
Quinine derivatives
Quinine, quinidine, Chloro, Meflo
Magnesium (Decrease Ach Release)

60. Myasthenic Crisis
 Respiratory failure from myasthenic weakness
 Precipitating Factors – Infection, Surgery, Aspiration, Medication
 Cholinergic crisis is respiratory failure from overdose of ChEIs
 Admit the patient to an Intensive Care Unit
 Serial measurements of Negative Inspiratory Force (NIF)
 NIF less than –20 cm H2O
 When tidal volume less than 4 to 5 cc/kg body weight and maximum
breathing capacity less than three times the tidal volume
 Forced vital capacity less than 15 cc/kg body weight.

61.  Many case series report short-term benefit from PLEX and IVIg in
myasthenic crisis
 Retrospective studies suggest that both are equally effective in
disease stabilization
 Once ventilated, discontinuing ChEIs is safe and recommended
 Extubation
 when the patient has a NIF greater than –20 cm H2O and an
expiratory pressure greater than 35 to 40 cm H2O
Myasthenic Crisis

62. CONGENITAL MYASTHENIC SYNDROMES
 AChR Deficiency
 Choline Acetyl Transferase (ChAT) Deficiency
 Congenital Acetylcholinesterase (AChE) Deficiency
 Slow-Channel Congenital Myasthenic Syndrome (SCCMS)
 Fast Channel Syndrome
 Rapsyn Mutations
 DOK-7 Mutations
 GFPT1 and DPAGT1 Mutations

64. LAMBERT–EATON SYNDROME (LES)
 Immune-mediated attack against the P/Q type voltage-gated calcium channels (VGCC)
 Neuromuscular junction and Autonomic ganglia
 Gradual onset lower extremity weakness, autonomic dysfunction
 Usually after 40 years
 60% patients have an underlying malignancy (80% - small-cell lung cancer)
 Tendon reflexes absent
 Compound muscle action potentials (CMAPs) with low amplitude, which increases
during 20 to 50 Hz stimulation and after brief maximum voluntary muscle activation

65. Thank you