1. Myasthenia Gravis 2015 Update
Florida Osteopathic Medical Association
16th Annual Cardiovascular & Medicine Symposium
April 30, 2015
Myasthenia Gravis Update
Kenneth Hentschel, DO, PhD, FAANEM
St. Vincent’s Spine & Brain Institute

2. Disclosures
I have no financial relationships that impact on this activity

3. Learning Objectives
To recognize the signs & symptoms of myasthenia gravis (MG)
To understand the options for diagnosis of MG
To identify treatment options for MG

4. Relevance
Myasthenia gravis is a treatable disorder which should have no mortality
Undiagnosed/untreated MG may be complicated by respiratory failure
The prevalence of MG is 1:10,000
Diagnosis may be delayed 2y in 30% of MG patients
Primary physicians are first line, well-positioned to make this diagnosis

5. Overview Normal neuromuscular transmission Pathophysiology
Clinical signs & symptoms
Classification
Epidemiology
Etiology & Provocation
Diagnosis
Evaluation
Prognosis
Management 5

6. Neuromuscular Transmission
An action potential travels down the motor nerve axon to the presynaptic terminal causing a series of events leading to release of acetylcholine into the synapse
ACh diffuses across the synapse where it may activate densely clustered postsynaptic nAChR on the muscle membrane

7. Neuromuscular Transmission
Ach bound to the nAChR creates an mini- endplate potential, which depolarizes the muscle cell if the threshold is reached
Acetylcholinesterase inactivates/hydrolyzes ACh from the synaptic area

8. Definition
Myasthenia gravis is an autoimmune disorder of neuromuscular transmission which involves antibodies directed at the nicotinic acetylcholine receptor of skeletal muscles, leading to weakness

9. Pathophysiology
In MG, Antibodies interact with the postsynaptic nAChR which leads to increased turnover of receptors, and damage to the postsynaptic membrane
As a result, there are fewer functional receptors and simplified postsynaptic membrane
Once the number of AChR is reduced to 30%, there is failure of neuromuscular transmission and symptomatic weakness
Failure of NM transmission leads to a variety of clinical symptoms

10. Clinical Symptoms & Signs
The hallmark of MG is fluctuating weakness
Presenting symptoms:
Ocular presentation in 50%
Ptosis 25%
Blurred vision/diplopia 25%
Generalized weakness in 10%
Extremity weakness in 10%
Dysarthria, dysphagia in 10%
Respiratory failure in 1%

11. Clinical Symptoms & Signs
Typical
Atypical
Ocular
Involved
Spared
Distribution
Proximal > Distal
Segmental
Pain
Painless
Painful
Sensation
Normal
Abnormal

12. Clinical Symptoms & Signs
Modifying Factors/Timing:
Worse with exercise, repetitive use…more prominent later in the day
Palliated by rest…fewer symptoms in the morning
Temporal Course:
80-90% have ocular symptoms by 1 month
General progression: ocular => bulbar => axial => extremities
87% have generalized MG by 1 year after onset; 13% of ocular MG will never progress

13. Classification Myasthenia Gravis Foundation of America
Class 1 = ocular
Class 2 = ocular and mild systemic weakness
Class 3 = ocular and moderate systemic weakness
Class 4 = ocular and severe systemic weakness
Class 5 = MG crisis, respiratory failure
Subtypes:
A, appendicular
B, bulbar
Does not apply to class 1

14. Epidemiology Gender ratio: female predominance 2:1 or 3:2
Means: female 28y & males 42y
Occurs at any age:
Young: 20-30y
Older: 60-70y
Prevalence: 1 in 10,000

15. Etiology Idiopathic autoimmune in most patients Genetic predisposition
90% of MGFA Class 2 or greater show antibodies
Genetic predisposition
HLA-B8
HLA-DRw3
HLA-DQw2
Autoimmune comorbidities RA
SLE
Pernicious anemia
Thyroid

16. Etiology Iatrogenic D-penicillamine (Wilson’s, RA) Alpha interferon
Bone marrow transplant (chronic graft v host dz)

17. Provocation Antibiotics Beta-blockers Lithium Aminoglycosides
Telithromycin*
Polymyxins
Ciprofloxacin
Erythromycin
Ampicillin
Beta-blockers
Lithium
Magnesium
Verapamil
Quinadine
Chloroquine
Prednisone
Statins
Phenytoin
Neuromuscular blocking agents

18. Provocation Infection Thyroid dysfunction Surgery Immunization
Uncontrolled diabetes
Stress: physical or emotional
Overheating

19. Diagnosis Appropriate clinical history
PE showing probable ptosis, ocular mobility impairment and possibly fluctuating proximal weakness
Differential diagnosis
Brainstem disease (stroke, neoplasm)
Myopathy (channelopathies)
Lambert Eaton Myasthenic Syndrome
Botulism
Motor neuropathies

20. Diagnosis Acetylcholine receptor antibodies***
Binding, blocking, & modulating
Highly specific (~100%)
Class 2 MGFA or higher, 80-90% Ab+
Class 1 MGFA, 40-50% are Ab+
False positives
Thymoma, LEMS, SCLC
Penicillamine therapy

21. Diagnosis “Seronegative” if no AChR Ab detected Other antibodies:
Anti-muscle specific kinase (MuSK*) 25%
Anti-striated muscle
Anti-striational
MuSK phenotype
Young females
Bulbar predominant symptoms
More difficult to treat; less responsive

22. Diagnosis Electrodiagnostic testing Repetitive nerve stimulation
Highly variable among centers, MGFA class, n/m protocol used
Ocular/Class 1: sensitivity 50%
Nonspecific. False+ in motor neuron dz, myopathy, neuropathy
Single fiber EMG
Sensitivity 90%
Few centers provide service

23. Diagnosis “Tensilon”/edrophonium test Acetylcholinesterase inhibitor
Monitor patient weakness, ptosis or ocular motility in response to IV medication
Subjective, non-specific
Complications
Respiratory failure
Syncope
Bradycardia
Hypotension

24. Evaluation
If ocular & seronegative, check MRI brain & orbits to exclude structural lesion
CXR/CT chest to evaluate for thymoma
Thymectomy has resulted in delayed improvements, even remission in some
General consensus
Perform Thymectomy if thymoma present
Consider Thymectomy if 10-55y, class 3-5 MGFA, and not well controlled medically
Transsternal approach for total gland removal

25. Prognosis/Clinical Course
By 1 month after onset 80% with Class1 will progress to systemic symptoms
If Class 1 does not progress in the first year, it is unlikely to ever progress
Maximal weakness usually occurs by year 3
Spontaneous remission occurs in 15-20%

26. Management Symptomatic: Acetylcholinesterase inhibition
Decreases breakdown of ACh, leaving more active neurotransmitter to act in the synapse
Indicated for MGFA classes 1-4
Side effects through muscarinic AChR
Diarrhea, cramps
Salivation, diaphoresis
Bradycardia?

27. Management Acetylcholinesterase inhibition Pyridostigmine (Mestinon)
Start dose: 30mg po q4-6h
Onset: 30 min, peak 1-2h
Forms: Tablet, elixor
Goal dose: 60mg po q4-6h
Sustained release (Timespan180mg) for qhs use if needed
Caution: overuse may provoke cholinergic crisis
Depolarized blockade of nAChRs
NTE 1500mg/d

28. Management Immunomodulatory For Class 3-5 myasthenia gravis
Reduces the immune-mediated neutralization of AChR and simplification of postsynaptic membrane
Steroids
Steroid-sparing medications
Thymectomy
Plasmaphersis & IVIG

29. Management Prednisone Very inexpensive & pretty fast
For MGFA classes 2-5
Dose: mg/d, po, divide dose
Hospitalize: beware 50% worsen ~day3, for a few days, before improving
10% can be severe, respiratory failure
80% will response to steroids (50% marked)
Onset range: 12h-2 mo., usually by 2 wks

30. Management Prednisone Max improvement by 9 months
After improvement, wean to lowest effective dose
Decrease by 10mg every 1-2 months
Many complications:
Cushingoid changes, hypertension
Weight gain, diabetes
Edema, osteoporosis, Cataracts
Prednisone bridge to steroid sparing agents

31. Management Mycophenolate mofetil (Cellcept)
Steroid sparing immunosuppressant
Purine inhibitor of B & T cell proliferation
75% MG patients respond
Onset: 3 months
Start dose: 250mg po BID
Goal dose: 1000mg PO BID
Well tolerated, monitor for GI & heme toxicity

32. Management Azathioprine (Imuran) Steroid sparing immunosuppressant
Cytotoxic purine inhibitor of T lymphocytes
50% MG patients respond
Onset: 4-8 months
Start dose: 50mg PO QD
Goal dose: 150mg PO QD
Monitor for liver & hematologic toxicity

33. Management Cyclosporine Steroid sparing immunosuppressant
50% MG patients respond
Onset: 2 months
Start dose: 3-5mg/kg/d, divided BID
Monitor for renal toxicity, hypertension and med-med interactions

34. Management Emergent/acute therapy
For rapidly progressive disease, MG crisis, impending respiratory failure
Plasmaphersis: removes AChR antibodies
IVIG: possible immunoneutralization

35. Management Plasmapheresis
2-3L plasma/exchange, QOD, until improvement, usually 3-5 exchanges
Often improving by 2nd exchange
Max improvement at 2-3wks later
Moderate-marked efficacy
Duration: 1-2 months
Requires dialysis grade catheter (Quinton)
Complications: HoTn, bradycardia, lytes, pneumothorax, infection, hemolysis

36. Management IVIG 0.4g/kg/d x 5 days Often improving by 3rd infusion
Max improvement at 2-3wks later
Moderate efficacy
Duration: 1-2 months
Complications: fever, chills, malaise, aseptic meningitis, renal failure, stroke
Pretreat with Tylenol & diphenhydramine

37. Summary
Clinical signs & symptoms involve fluctuating fatigable weakness, usually involving the eyes, and frequently progressing to other body areas
Diagnosis of MG may be confirmed by serologic antibody testing*, electrodiagnostic tests, or sometimes pharmacologic challenge

38. Summary
MG treatment is tailored for the individual, usually involving symptomatic acetylcholinesterase inhibition (Class 1-4 MG), and frequently immunomodulatory therapies.
Emergent treatment of MG crisis may utilize plasmapheresis or IVIG, in the ICU setting

39. References
Medscape: Myasthenia gravis. Aashit Shah. Updated 5/2/14. Editor: N Lorenzo. Accessed 3/28/15.
Practical Neurology, by Jose Biller. 4th Edition. Lippincott, Williams & Wilkins, Philadelphia PA Chapter 48: Disorders of the Neuromuscular Junction, by R Pascuzzi & CL Bodkin, pp 39

40. Thank You Kenneth Hentschel, DO, PhD, FAANEM
St Vincent’s Spine & Brain Institute
Office phone:
General neurology or subspecialty referrals: