Transcript Myasthenia Gravis - McGill University

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) 3035%
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
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
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 crosslinked 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 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
Sensitivity
89%
Specificity
100% (!?)
EMG: repetitive stimulation
Decremental response of CMAP amplitude or area
with 2-5 Hz stimulation
Sensitivity 53-100% for generalize; 10-17% for
If safe: stop mestinon 12 hr before EMG!
ocular
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, IL2, 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
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
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, welldifferentiated, 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): 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