Neuro muscular disorders Myasthenia Gravis. and nppt

Diagnosis , investigation and management of myasthenia gravis.

1. Myasthenia Gravis
Dr Hafiz Rauf
Assistant Professor Medicine
MBBS,FCPS,MRCP

2. Anatomy
Neuromuscular Junction (NMJ)
Components:
Presynaptic membrane
Postsynaptic membrane
Synaptic cleft
Presynaptic membrane contains vesicles with
Acetylcholine (ACh) which are released into
synaptic cleft in a calcium dependent manner
ACh attaches to ACh receptors (AChR) on
postsynaptic membrane
2

3. Neuromuscular Junction
Nrets, Wikimedia Commons
3

4. Anatomy
Neuromuscular Junction (NMJ)
The Acetylcholine receptor (AChR) is a
sodium channel that opens when bound by
ACh
There is a partial depolarization of the
postsynaptic membrane and this causes an
excitatory postsynaptic potential (EPSP)
If enough sodium channels open and a threshold
potential is reached, a muscle action potential is
generated in the postsynaptic membrane
4

5. Pathophysiology
In MG, antibodies are directed toward the
acetylcholine receptor at the
neuromuscular junction of skeletal muscles
Results in:
Decreased number of nicotinic acetylcholine
receptors at the motor end-plate
Reduced postsynaptic membrane folds
Widened synaptic cleft
5

6. Pathophysiology
Anti-AChR antibody is found in 80-
90% of patients with MG
MG may be considered a B cell-
mediated disease
Antibodies
6

7. Pathophysiology
T-cell mediated immunity has some influence
Thymic hyperplasia and thymomas are
recognized in myasthenic patients*
Source Undetermined
Source Undetermined
7

8. Bimodal Distribution

9. 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

10. 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?

11. 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

12. 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)

13. 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

14. 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

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

16. 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?

17. Myasthenia Gravis
Clinical Classification
I. Ocular alone
IIa.Mild generalized
IIb.Moderately severe generalized plus
usually some bulbar involvement
III. Acute severe over weeks-months with
severe bulbar involvement
IV. Late severe with marked bulbar
involvement

18. 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

19. 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”

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

21. MuSK
receptor tyrosine kinase in muscle; IgG
In general MG: 30-70% of AChR negative MG patients
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)

22. 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

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

24. 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)

25. Drugs that unmask or exacerbate MG

26. 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

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

28. 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

29. 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

30. 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

31. 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???

32. 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)