Myasthenia gravis

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) L imb 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 D ropped head syndrome Physical Findings

8. Immunopathology

9. 80%–85% Generalised MG patients have anti-AChR antibodies C omplement-mediated destruc tion 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

10. 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

11. Myasthenia Gravis Subtypes

12. 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%) B oth 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.

13. Generalized Myasthenia Gravis Two types Early onset MG (EOMG) Late onset MG (LOMG)

14. 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

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

16. 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

17. 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

18. MuSK-Antibody Myasthenia Gravis

19. 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

20. Osserman Classification

21. MGFA Clinical Classification

22. 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 single nv . fibre

23. Edrophonium Chloride Test F acilitates 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 M aximum - 10 mg IV (2mg, 3mg, 5mg) N eostigmine methylsulfate , 0.5 mg IM or SC

24. Auto-Antibodies Acetylcholine Receptor Antibodies Anti- striational Muscle Antibodies Anti-MuSK Antibodies

25. Acetylcholine Receptor Antibodies AChR- ab binding assay Specific serologic markers for MG S ensitivity - 85% for GMG N ormal antibody measurements do not exclude Auto-Antibodies

26. 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

27. Electrodiagnostic Testing Repetitive nerve stimulation (RNS ) – Commonly used D ecrementing 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 M ost sensitive S hows increased jitter

28. EMG in Myasthenia Gravis

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

30. Treatment of Myasthenia Gravis

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

32. 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

33. 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

34. 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

35. Symptomatic And Immunosuppressive (IS) Treatment Of Mg Pyridostigmine - Initial treatment in most cases Dose adjusted based on symptoms A bility 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

36. 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

37. 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

38. Dosage adjustments should be made no more frequently than every 3–6 months Tapering of IS drugs is associated with risk of relapse R isk 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

39. 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

40. 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

41. 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.

42. 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

43. 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

44. 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 .

45. 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

46. 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

47. Juvenile MG Children with ocular MG are more to go into spontaneous remission I nitial 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

48. 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

49. MG IN PREGNANCY Planning for pregnancy should be instituted well in advance M ajority 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

50. 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

51. Evolving Treatments E tanercept - Recombinant human TNF receptor:Fc Eculizumab - Complement inhibitor Belimumab - Monoclonal antibody against BAFF Autologous stem-cell transplantation

52. 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

53. 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

54. 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) Penicillamine

55. Myasthenic Crisis Respiratory failure from myasthenic weakness Precipitating Factors – Infection, Surgery, Aspiration, Medication Cholinergic crisis is respiratory failure from overdose of ChEIs A dmit the patient to an Intensive C are U nit Serial measurements of Negative I nspiratory F orce (NIF) NIF less than – 20 cm H2O W hen tidal volume less than 4 to 5 cc/kg body weight and maximum breathing capacity less than three times the tidal volume F orced vital capacity less than 15 cc/kg body weight.

56. 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 E xtubation when the patient has a NIF greater than –20 cm H2O and an expiratory pressure greater than 35 to 40 cm H2O Myasthenic Crisis

57. 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

58. LAMBERT–EATON SYNDROME (LES) I mmune-mediated attack against the P/Q type voltage-gated calcium channels (VGCC ) N euromuscular junction and A utonomic ganglia G radual onset lower extremity weakness, autonomic dysfunction U sually after 40 years 6 0% 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

59. Thank you