Myasthenia Gravis

1. Myasthenia Gravis Erin O’Ferrall Colin Chalk March 11, 2009

2. Objectives • To identify key features of the history & physical exam of a patient with Myasthenia Gravis (MG) • To learn how to elicit a history of fatigable weakness • Learn what investigations to order if you suspect a diagnosis of MG • Describe what are MUSK antibodies and their significance • Discuss the potential therapies and evidence for each • To describe the approach and management to refractory MG • To describe the role of thymectomy

3. Outline • Case • History & Physical exam • Investigations • Treatment • Case

4. Neuromuscular Junction (NMJ)

5. Case 1 • 57yr old female with 3 month history of fatigue, ptosis, dysphagia

6. Clinical Course of MG Current estimates of prevalence? ~20 in 100 000

7. Bimodal Distribution

8. History • What are the presenting symptoms of MG? • Ocular (ptosis, diplopia) 45-50% • Bulbar (dysarthria, dysphagia) 20% • Extremity weakness (usually proximal) 30-35% • Distal extremity -rare • Respiratory -rare

9. History: General • Key: • Elicit a history of fatigable weakness • Differentiate from generalized weakness or fatigue: affects the specific muscle group being used • Ask about repetitive activities: talking on the phone, chewing • Recovery with rest... • How to you feel first thing in the morning? • Does your weakness ever get better after a nap or a rest?

10. Diplopia: • Worse with prolonged reading, watching TV, driving Ptosis: • Droopy eyelids • Do you ever have to hold (or tape) your eye open? • Compensatory frontalis contraction can give you a headache • Worse with bright lights • May wear sunglasses (also to hide droopy eyes) Dysarthria: • Nasal quality; breathy, hoarse • With long conversations or presentations or singing • Do you avoid talking on the phone? Or only make calls in the morning? Facial weakness: sleepy or sad appearance Dysphagia: • “food gets stuck” SOB: • Worse supine

11. History: for follow-ups... • Exacerbations • Triggers • medications • Infections • Heat/ fever, stress, menstrual cycle/ pregnancy, Hyperthyroidism • For known MG patients • Medication effects & side effects • Pyridostigmine: onset, offset or missed dose effects • Can have fixed weakness with atrophy (late or MUSK)

12. Physical Exam: fatigability Can also use to assess SOB Rowin, Julie CONTINUUM: Lifelong Learning in Neurology Volume 15(1) Myasthenic Disorders and ALS February 2009 pp 13-34

13. Physical Exam • Ptosis • Describe (%complete, mm below upper pupil margin) • Compensation: head tilt, frontalis contraction • Worse with upgaze; better with rest/ cooling • Curtain sign aka enhanced ptosis or paradoxical ptosis • Lid twitch sign

14. Physical Exam: what do you see here? (the patient was asked to smile)

15. Questions • Can the weakness be focal? • One-sided ptosis • Foot drop • Even single digit weakness for finger extn • Isolated head drop • Can the weakness be limited to dysphagia or respiratory muscles only? • How many remain restricted to EOM? • When will you know?

16. Investigations • What tests would you order? • Antibodies • Tensilon & Ice Pack test • EMG/ NCS: what should you ask for? • Repetitive stimulation • Single fiber EMG (SFEMG) • CT chest

17. AchR Abs in MG? • Anti-AChR antibody is positive in what percentage of generalized & ocular MG? • 85-90% of generalized adult MG patients • 50% of childhood MG • 50-70% of Ocular MG • MUSK • In >40% of patients with no Ach Abs • “Seronegative”

18. Are Ach Abs pathogenic? • Give three mechanisms: • Block AchR • Complement mediated lysis of endplate • Accelerated degradation of cross-linked AchRs

19. MuSK • receptor tyrosine kinase in muscle; IgG • In general MG: 30-70% of AChR negative MG patients (Pestronk); 40-50% (Bradley 5th Ed) • Compared to AChR Ab patients, Patients with Musk antibodies are: • Slightly younger on average but can occur at any age • More females • Similar clinical presentation to MG with AChR OR have atypical presentations • atrophy (ex: tongue) • Respiratory weakness • May be more difficult to treat and have permanent weakness • Less response to AchEI • Very rare to have thymoma; effect of thymectomy =uncertain • Usually NOT seen with pure ocular MG (1 case report) • Usually NOT seen in patients with AChR positivity (1 case report)

21. Agrin, released by motor neurons, induces clustering of AChR’s, by interacting with MuSK on myotube membranes.

22. Seronegative MG • Is there such thing as seronegative MG? • In one study, 66% of “seronegative” MG patients were found to have antibodies to AChR • Leite MI et al Brain (2008); 131:1940

23. Tensilon Test • Edrophonium chloride • Inhibits acetylcholinesterase • Onset 30 seconds; duration 5-10 min • NEED A CLEAR OBJECTIVE ENDPOINT • Works best with complete ptosis • Compare to placebo (saline) • Prepare atropine • Give test dose 1-2 mg then up to 10 mg total • SFX: • salivation, sweating, nausea, abdo cramping, fasciculations; hypotension & bradycardia are rare (may be as low as 0.16%) • Sensitivity 71.5- 95% • Specificity: not clear but can be positive in many other conditions (even ALS or normal controls) • Not availible

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

25. EMG: repetitive stimulation • Decremental response of CMAP amplitude or area with 2-5 Hz stimulation • Sensitivity 53-100% for generalize; 10-17% for ocular If safe: stop mestinon 12 hr before EMG!

26. Single Fiber EMG

27. Treatment

28. Treatment: the basics • What should you tell your MG patients? • Always tell physicians (especially surgeons/ anesthetists). Why? • What to do if you can’t swallow or get short of breath. Why? • Don’t take medications / OTC / vitamins/ herbals without consulting an MD or pharmacist • Check B12, TSH. Why? • “Should I get the flu shot?” • Prednisone: bone protections & monitor for side effects (BP, glucose, cataracts, etc)

29. Drugs that unmask or exacerbate MG

30. Medications that can cause autoimmune MG • D-Penicillamine, chloroquine, alpha-interferon, IL-2, wasp stings or coral snake bite, trimethadione • Implicated in isolated instances or MG exacerbation: • Cimetidine, citrate, chloroquine, diazepam, lithium carbonate, quinine, beta blockers, trihexylphenidyl hydrochloride, radiocontrast material, gemfibrozil, ?statins

31. Treatment: what are the options? • Mestinon: symptomatic therapy Immune Modulators: • Prednisone • Azathioprine • Mycophenylate mofetil • Cyclosporine • IVIG • PLEX

32. Treatment IVIG -Class I -First line therapy for short term use in worsening of moderate to severe MG. See Zinman et al Neurology 2007; 68: 837

33. Thymectomy • How many MG patients have a thymic tumour? • 10% of MG patients have a thymic tumour • 20% of patients with MG whose symptoms began between 30 and 60 yrs had thymoma • lower incidence of thymoma if symptoms began after age 60 • And the rest? • 70% of MG patients have hyperplastic changes (germinal centers) …indicate as active immune response • thymic tumours are usually benign, well-differentiated, encapsulated and can be completely removed

34. Thymectomy • Mandatory if you have a thymoma but if not... • AAN practice parameter (2000) • For patients with nonthymomatous autoimmune MG, thymectomy is recommended as an option to increase the probability of remission or improvement (Class II). • Often done in generalized MG patients <50 yrs within 1-2 yr of disease onset (expert opinion) • Trial underway: Dr Chalk... • Multicenter, single blind RCT (thymectomy or not) • Ab positive, < 60 yr

35. Refractory MG • Is this really refractory MG or is this under treated MG? • Adequate doses & duration of medications • Did you try all the options we already discussed? • Compliance • Is the thymoma gone or did you miss one? • Is this really MG? • Comorbidities? Check thyroid • Could this be a congenital form of MG? • Is the risk worth the potential benefit if you want to resort to experimental therapies: • Rituximab (Ab to Cd20): case series • Tacrolimus (suppresses T cell activation) • Stem cell transplant???

36. Case 1: HPI • 57 yr F with 3 month history of fatigue, ptosis, dysphagia • 3 months: • Fatigue & “weak all over” • Ptosis: • right side, better in am (for first 5-10 minutes); needed to tape her eye open; did not note recovery with rest; progressively worse • Blurred vision • 1 mo: progressive dysphagia

37. Case1: PMHx • Graves disease • Coincidence? • Headaches • All: sulfa • Med: synthroid, prn ibuprofen, sudafed

38. Case 1 On exam... • Ptosis • Proximal weakness of the limbs • What to do?

39. Case 1: Investigations • Tensilon test • EMG • sfEMG • CT chest: thymic mass • What now?

40. Case 1: Mngmt • Thymectomy: thymoma • IVIG • Prednisone • Mestinon • D/c home 10 postop

41. Conclusion • Signs & symptoms of MG can be elicited by the history and physical exam--> clinical diagnosis • The diagnosis of MG can be confirmed by electrophysiological & serological tests • Anti-Musk patients are probably different • Treatment consists of symptomatic & immune modulatory therapies • Thymectomy is mandatory for thymoma and should be considered for non-thymomatous patients (consider enrolling in a trial)

42. References • Continuum Feb 2009; 15(1): 13-82 • See Ethics chapter by K Brownell & Phil! • Bradley 4th & 5th Ed • www.utdol.com: comprehensive list of drugs to avoid in MG • Good reviews: • Muscle & Nerve Apr 2004 • Lancet June 30, 2001 • AAN guideline on thymectomy 2000 • Evidence for treatments & good review of pathophysiology: • Nat Clin Prac Neurol Jun 2008 • Important papers: • L Zinman Neurol Mar 13, 2007 (IVIG RCT) • ‘Seroneg MG’ Brain May 31, 2008