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

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

Outline Case History & Physical exam Investigations Treatment Case

Neuromuscular Junction (NMJ)

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

Clinical Course of MG Current estimates of prevalence?~20 in

Bimodal Distribution

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

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?

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

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)

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

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

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

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?

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

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”

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

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)

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

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

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 % Specificity: not clear but can be positive in many other conditions (even ALS or normal controls) Not availible

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

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

Single Fiber EMG

Treatment

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)

Drugs that unmask or exacerbate MG

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

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

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 Treatment

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

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

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???

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

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

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

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

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

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)

References Continuum Feb 2009; 15(1): See Ethics chapter by K Brownell & Phil! Bradley 4th & 5th Ed 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