1. March 3, 2016
C. Ulane, MD, PhD
Myasthenia gravis

2. Case#1
30yo woman presents with several months of shortness of breath on exertion, diplopia at the end of the day and after reading for a significant period of time, and her parents note that her speech is slurred by the end of the day or after she is talking for awhile. She also reports generalized fatigue and weakness. She has never had these symptoms in the past.

3. Clinical symptoms of myasthenia gravis
Hallmark: fluctuating weakness brought on by exertion, improves with rest
Ocular 40% initial, 85% eventual
Bulbar (dysarthria, dysphagia, difficulty chewing) prominent in 20%
Generalized

4. Case continued
PMH: extensive psychiatric history (bulimia, PTSD, ADD, possible personality disorder and substance abuse), no prior surgeries
MEDS: Adderall, dilaudid, NKDA
SH: lives with a friend on the UES, denies t/e/d, was working until 1 month ago when developed shortness of breath

5. Epidemiology Prevalence: 14 per 100,000
Familial cases rare; first degree relatives with increased incidences of other autoimmune diseases (SLE, RA, thyroid), HLA
Thymoma 10%, thymic hyperplasia 60%

6. Case#1 continued EXAM: general physical exam-unremarkable MSE-intact
CNs-no ptosis, no fatigueable upgaze, diplopia on lateral gaze in both directions with subtle incomplete abduction of each eye, no dysarthria

7. Case#1 continued
Motor-very mild proximal arm and leg weakness, with a component of give-way weakness
DTRs-2+symmetrical, toes downgoing
Sensory exam, coordination and gait are all normal

8. Exam findings in MG Pattern of weakness: Ocular: 17%
If restricted to ocular for 2-3 years, unlikely to generalize
Ocular and generalized: 50%
Ocular and bulbar: 13%
Ocular and limb: 20%

9. Case#2
88yo man with no significant PMH presents with 4-5 months of dysarthria and dysphagia. He notes that the symptoms are worse at the end of the day, and he also has blurry vision when reading at night. Dysarthria worsens after he has been talking for awhile, and improves if he rests. He denies limb weakness and walks several miles every day. He has lost ~10lbs due to difficulty eating, but has a good appetite.

10. Case#2 continued EXAM General physical exam: thin man in NAD
MSE-normal
CNs-no ptosis, normal EOMs but diplopia on endgaze, +significant dysarthria, nasal speech, increased salivation, mild tongue weakness
Motor-full strength throughout
DTRs-2+symmetric, toes downgoing, negative Hoffmann’s, Babinski
Sensory-normal
Coordination/gait-normal

11. Exam findings in MG Pattern of weakness: Ocular: 17%
If restricted to ocular for 2-3 years, unlikely to generalize
Ocular and generalized: 50%
Ocular and bulbar: 13%
Ocular and limb: 20%

12. Diagnostic Work-up for MG
AchR antibodies
Found in 75-80% of patients with generalized symptoms, 50% of patients with ocular
88% sensitive, 97-98% specific
MuSK antibodies
7-10% of all patients, prominent oropharyngeal symptoms
Poor response to cholinesterase inhibitors
“Seronegative”: 10%
Lrp4 (low-density lipoprotein receptor related protein)

13. Table 89-2: Diagnostic testing for myasthenia gravis
Laboratory Test
Comments
Acetylcholine receptor (AchR) antibodies
AchR binding
AchR blocking
AchR modulating
80-85% of all MG
50% of ocular MG
Binding most common
Blocking positive in ~10% of MG with negative binding
Modulating positive in <1% of MG with negative binding
MusK antibodies
10% of all MG
50% of AchR-negative MG
Other antibodies
Striational
(titin, RyR, myosin, actin)
LPR4, agrin
Present in 75-85% of thymomatous MG
May be associated with more severe disease (titin, RyR)
Found in other disorders
Electrodiagnostic Test
Nerve Conduction Studies
Repetitive nerve stimulation reveals decrement (> 10%)
Sensitivity % in generalized MG
Sensitivity 10-48% in ocular MG
Not specific
Single-fiber EMG
Most sensitive test for MG (>95%) but not specific (~70%)
Radiology
Computed tomography of the chest
10% thymoma

14. Electrophysiological testing in MG
Nerve conduction studies with repetitive stimulation: 60% sensitive
Single fiber EMG: 90-99% sensitive, less specific

15. Meriggioli, Matthew N. CONTINUUM: Lifelong Learning in Neurology Volume 15(1) Myasthenic Disorders and ALS February 2009 pp 35-62

16. Results-Case#1 (30F)
AchR binding, blocking, modulating antibodies are negative
MuSK antibody negative
EMG/NCS with repetitive stimulation were performed

17. Neuromuscular Junction
Neuroscience:  Genomics reaches the synapse
Cori Bargmann
Nature 436, (28 July 2005)
doi: /436473a

18. NMJ Transmission
At rest, small number of quanta released (dependent on EC calcium and temperature)
Nerve action potential opens VGCC (P/Q type) leading to calcium influx at presynaptic terminal
Ach vesicles fuse, release Ach which diffuses across synaptic cleft and binds AchR
Threshold EPPinflux of calcium and muscle fiber contraction

19. Quantal Content: Low Frequency -Normal -Myasthenia -LEMS

20. Normal RNS: Pre and Post Exercise

21. 3 Hz RNS in Myasthenia Gravis
A: Baseline
B: After 10 sec exercise (postex facilitation)
C/D: 2 and 3 min after 60 sec exercise (postex exhaustion)
E: after 10 sec exercise again (postex facilitation/repair of decrement)

22. Results continued
EMG/NCS: repetitive stimulation of the distal median-APB system is negative (4% decrement at rest, 6% after exercise), repetitive stimulation of the proximal spinal accessory-trapezius system is consistent with post-synaptic NMJ dysfunction (9% decrement at rest, 17% decrement at 3minutes post-exercise)
Distal: decrement of 10%, proximal: 15%

23. Single-Fiber EMG (SFEMG)

24. Normal Jitter Increased Jitter Jitter + Blocking

25. Case#2 continued 88yo man with fluctuating dysarthria
AchR binding, blocking, modulating antibodies, MuSK antibodies all negative
NCS-rep stim negative
EMG-scattered fasciculations but no active denervation or chronic neurogenic changes; tongue EMG normal
Trial of pyridostigmine-no improvement

26. Treatment *highly individualized*
Pyridostigmine (acetylcholinesterase inhibitor)
60mg, titrate to effect
Extended release
Side effects: diarrhea, increased salivation, nausea, diaphoresis

27. Treatment-steroids Steroids (in 1960s-1970s ACTH was used)
No RCTs for steroids, but multiple case series, anecdotal evidence
Steroids compared to other immunosuppressives in RCTs

28. Treatment-steroids
Alternate day or daily dosing , when achieve remission maintain for ~1month, followed by long, slow taper over months
May have initial worsening in first 2 weeks (50%)
Titrate up (start 20mg) goal of 60-80mg

29. Steroid-Sparing Agents
Mycophenolate mofetil (blocks purine synthesis)
Case reports, open label studies show benefit (reduction in symptoms, medication doses)
Maximal improvement ~6wks
Recent RCT showed no benefit
High cost, risk for late malignancies
Azathioprine (purine analog)
Benefit is at 1-2yrs
Monitor CBC, LFTs

30. Steroid-Sparing Agents
Cyclosporine (calcineurin inhibitor)
Benefit within~1mo, limited by renal toxicity
Rituximab (anti-CD20)
Case series, esp in MuSK
Methotrexate (inhibits DNA synthesis)
Case reports
Cyclophosphamide (DNA cross-linker)

31. Significant bulbar dysfunction Dysarthria, dysphagia
Table 89-3: Signs of Impending Respiratory Failure in MG
VC=vital capacity, NIF=negative inspiratory force, MEP=maximal expiratory pressure
Clinical Features
Significant bulbar dysfunction
Dysarthria, dysphagia
Impaired gag reflex
Tachypnea, dyspnea
Use of accessory muscles
Paradoxical breathing
Single breath count < 15
Poor cough
Impaired secretion clearance
Laboratory Signs
Pulmonary function tests:
VC < 15-20ml/kg (or VC < 1L)
NIF > -20cm H20
MEP < 40cm H20
tidal volume < 4-5ml/kg
Laboratory:
pCO2 > 50mm Hg
*hypoxia is a late finding

32. Treatment IVIg Plasma exchange
RCT evidence for benefit when rapid improvement needed
Plasma exchange
Similar effectiveness when compared to IVIg
Can be used on monthly basis if MG is severe or not tolerating other agents

33. Treatment Thymectomy Thymomasurgery
Non-thymomatous, autoimmune: controversial
Improves outcome (medication-free remission, asymptomatic w/ or w/o meds)
Control population, severity of MG, age/sex
Currently ongoing trial of thymectomy plus prednisone vs prednisone alone

34. Case#3
67yo woman with DM, HTN, CAD (s/p CABG and DES), CHF, interstitial lung disase (on home O2/bipap), pulmonary HTN, and myasthenia gravis (Ach binding antibody positive, rep stim negative x2, SFEMG with increased jitter)
Diplopia, ptosis, proximal weakness, SOB

35. Case#3 continued No response to mestinon
Admitted for IVIg, steroids (renal insufficiency and volume overload with IVIg)
Did not tolerate mycophenolate mofetil
Multiple exacerbations requiring intubation, plasma exchange, IVIg
On steroids, continued to worsen, significant weight gain, difficult to control DM

36. Medications which may worsen MG
Calcium channel blockers (long-term use)
Beta blockers
Quinolones
Penicillamine
Aminoglycosides
Macrolides
H2 antagonists
GBP, PHT