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 100 000

Bimodal Distribution

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

History: General

Key:

Elicit a history of fatigable weaknessDifferentiate 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 eyelidsDo you ever have to hold (or tape) your eye open?Compensatory frontalis contraction can give you a headacheWorse with bright lightsMay wear sunglasses (also to hide droopy eyes)

Dysarthria:Nasal quality; breathy, hoarseWith long conversations or presentations or singingDo you avoid talking on the phone? Or only make calls in the morning?

Facial weakness: sleepy or sad appearanceDysphagia:

“food gets stuck”

SOB:Worse supine

History: for follow-ups...

ExacerbationsTriggers

medicationsInfectionsHeat/ fever, stress, menstrual cycle/ pregnancy, Hyperthyroidism

For known MG patientsMedication effects & side effectsPyridostigmine: 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 13-34

Can also use to assess SOB

Physical Exam

PtosisDescribe (%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?AntibodiesTensilon & Ice Pack testEMG/ NCS: what should you ask for?

Repetitive stimulationSingle 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

MUSKIn >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

MuSKreceptor tyrosine kinase in muscle; IgGIn 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 ageMore femalesSimilar clinical presentation to MG with AChR OR have atypical presentations

atrophy (ex: tongue)Respiratory weakness

May be more difficult to treat and have permanent weaknessLess response to AchEI

Very rare to have thymoma; effect of thymectomy =uncertainUsually 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 TestEdrophonium chloride

Inhibits acetylcholinesterase

Onset 30 seconds; duration 5-10 minNEED A CLEAR OBJECTIVE ENDPOINT

Works best with complete ptosis

Compare to placebo (saline)Prepare atropineGive test dose 1-2 mg then up to 10 mg totalSFX:

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

Ice pack test

Apply ice pack to ptotic lid

Sensitivity89%

Specificity100% (!?)

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!

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 MGD-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 therapyImmune Modulators:

PrednisoneAzathioprineMycophenylate mofetilCyclosporineIVIGPLEX

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 medicationsDid you try all the options we already discussed?ComplianceIs 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 seriesTacrolimus (suppresses T cell activation)Stem cell transplant???

Case 1: HPI

57 yr F with 3 month history of fatigue, ptosis, dysphagia3 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 vision1 mo: progressive dysphagia

Case1: PMHx

Graves diseaseCoincidence?

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

EMGsfEMG

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 diagnosisThe diagnosis of MG can be confirmed by electrophysiological & serological testsAnti-Musk patients are probably differentTreatment consists of symptomatic & immune modulatory therapiesThymectomy is mandatory for thymoma and should be considered for non-thymomatous patients (consider enrolling in a trial)

ReferencesContinuum Feb 2009; 15(1): 13-82

See Ethics chapter by K Brownell & Phil!

Bradley 4th & 5th Edwww.utdol.com: comprehensive list of drugs to avoid in MGGood reviews:

Muscle & Nerve Apr 2004Lancet June 30, 2001

AAN guideline on thymectomy 2000Evidence 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