Myasthenia Gravis

1. Myasthenia Gravis Dr.Chaitanya Vemuri

2. Introduction Most common primary disorder of neuromuscular transmission Usually due to acquired immunological abnormality Also due to genetic abnormalities at neuromuscular junction.

3. 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�

4. 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.

5. Clinical Presentation c/o 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

6. 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. Patient usually gives h/o Worsening of ocular symptoms while reading, watching television, driving. Worsening of jaw muscle weakness on prolonged chewing � meat / chewy candy.

7. Clinical Presentation Also give h/o : 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.

8. 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 )

9. Ocular manifestations : Weakness of levator palpebrae & extraocular muscles � initial manifestation in � 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.

11. Ocular manifestations : Sustained upgaze for 30 or more seconds � induce / 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, 1or more twitches are observed with closure of eyelids.

12. Unilateral painless ptosis without ophthalmoplegia or pupillary abnormality.

13. 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.

14. 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

15. At rest, b/l 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

16. Oropharyngeal manifestations : Jaw weakness � shown by manually opening the jaw against resistance, which is not possible in normal people. Patient holds jaw closed with thumb under chin, middle finger curled under nose/lower lip index finger extended up the cheek producing studious appearance.

17. Neck flexors are weaker than neck extensors Bulbar weakness is prominent in MuSK antibody positive MG. 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.

18. Clinical Presentation I Ocular myasthenia ( 15-20% ) II A. Mild, generalized myasthenia with slow progression; no crises; drug responsive ( 30% ) II B. Moderately severe generalized myasthenia; severe skeletal & bulbar involvement but no crises; drug response �less satisfactory(25%)

19. 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% )

20. Congenital Myasthenic Syndromes

21. Inheritance Not transmitted by mendelian inheritance but family members of patients are 1000 times more likely to develop disease. Increased jitter on SFEMG � 33 to 45 % of asymptomatic first degree relatives AChR antibodies are elevated in 50 %

22. 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.

24. 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.

25. Pathophysiology 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

27. 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.

28. investigations

29. 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.

30. 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

31. Antibodies to AChR , MuSK : 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.

32. electromyography

33. Repetitive Nerve Stimulation Decrement > 15 % at 3Hz is highly probable.

34. 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.

35. CT / MRI For ocular MG : Do CT / MRI to exclude intracranial lesions

36. Disorders associated with Myasthenia gravis Disorders of thymus : thymoma, hyperplasia Other auto-immune disorders : Hashimoto�s Thyroiditis Graves� Disease Rheumatoid Arthritis SLE

37. Disorders / Circumstances that worsen Myasthenia gravis Emotional upset Systemic illness ( especially viral respiratory infection ) Hypothyroidism Hyperthyroidism Pregnancy Drugs

38. Drugs D-pencillamine ( never use ) Succinylcholine, D-tubocurarine, other neuromuscular blocking agents Quinine, Quinidine, Procainamide Aminoglycosides � Gentamycin, Kanamycin, Neomycin, Streptomycin Beta blockers Calcium channel blockers Magnesium salts Iodinated contrast agents

39. Disorders that interfere with therapy Tuberculosis Diabetes Peptic ulcer GI bleeding Renal disease Hypertension Asthma Osteoporosis Obesity

40. Investigations - CT /MRI of Mediastinum ANA, Anti ds DNA, RA Factor, Antithyroid antibodies Thyroid function tests Mantoux Chest X Ray FBS, HbA1c Pulmonary Function Tests Bone densitometry

41. Differential Diagnosis Lambert Eaton Myasthenic Syndrome Botulism Neurasthenia

42. treatment

43. 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.

44. 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.

45. 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.

46. 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.

47. 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

48. Immunosuppressants Produces marked & sustained improvement in many Azathioprine � initially 50 mg OD, which is increased in 50 mg/day increments every 7 days to total of 150-200 mg/day Cyclosporine � initially 5-6 mg/kg/day Cyclophosphamide � IV 200 mg/day-5days 150-200mg/day oral

49. Plasma exchange / IV Ig Produces rapid improvement Mainly used as adjunctive treatment As treatment in those who have not responded to other forms of treatment

50. Ocular myasthenia Started on Cholinesterase inhibitors If unsatisfactory � prednisone is added Thymectomy in young

51. Generalized myastheniaonset < 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

52. Generalized myastheniaonset > 60 yrs Initially cholinesterase inhibitors If response is unsatisfactory � add azathioprine If response is unsatisfactory � add high dose prednisone or substitute cyclosporine for azathioprine

53. 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

54. 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.

55. Seronegative myasthenia gravis More likely male Have milder disease Ocular myasthenia, fewer thymomas, less frequent thymic hyperplasia, more frequent thymic atrophy Treatment same as seropositive myasthenia

56. 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

57. 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.

58. 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

59. Thank you