Advances in myasthenia gravis

1. Advances in myasthenia gravis Dr Parag Moon SR1, Neurology

2. Myasthenia Gravis 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 Presentation

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 Presentation

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 Presentation

6. Myasthenia Gravis Clinical Classification Ocular alone IIa . Mild generalized IIb . Moderately severe generalized plus usually some bulbar involvement Acute severe over weeks-months with severe bulbar involvement 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 Subgroups

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 Immunological

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. Muscle groups involved at onset 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

17. Physical examination

18. Myasthenic Crisis VS. Cholinergic Crisis 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 Work-up

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

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 Work-up

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 Workup Pharmacological testing

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 Workup Pharmacological testing

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. Ice pack test Apply ice pack to ptotic lid Sensitivity 89% Specificity 100% (!?)

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

28. Electrodiagnostic studies: Repetitive Nerve Stimulation 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

29. Repetitive nerve stimulation 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

30. Electrodiagnostic studies: Single-fiber electromyography Concentric or monopolar needle electrodes that record single motor unit potentials Increased jitter and normal fiber density

31. Electrodiagnostic studies: Single-fiber electromyography 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 %)

32. Treatment AChE inhibitors Immunomodulating therapies Immunoglobulins Plasmapheresis Thymectomy

33. 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 Treatment Behavioral modifications

34. Treatment 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

35. 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

36. Immunomodulating therapies 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 .

37. 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

38. 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

39. 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

40. 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

41. 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)

42. 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 Plasma exchange

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

44. 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 Immunoglobulins

45. 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

46. Indicated in non thymomatous pts with generalised autoimmune MG of age group 10-55yrs All pts with thymoma Techniques Transcervical Transternal extended thymectomy - standard procedure used Videoendoscopic including robotic assisted Thymectomy

47. 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%)

48. 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 Other drugs

49. Drugs that unmask or exacerbate MG

50. 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 References

51. Thank you!