Ocular myasthenia gravis

pearls on ocular myasthenia gravis

1. Ocular Myasthenia Gravis
Devin D. Mackay, M.D.
Director of Neuro-Ophthalmology
Associate Professor of Neurology, Ophthalmology, and Neurological Surgery
Indiana University

2. Objectives
•Become familiar with typical history,
examination, and testing findings
associated with ocular myasthenia gravis
(OMG)
•Describe antibodies associated with
OMG
•Be familiar with special examination
techniques to elicit evidence of OMG
•Apply basic principles to the
management of patients with OMG

3. Introduction
•Myasthenia gravis is an autoimmune disorder
caused by antibody-mediated blockade of
neuromuscular transmission that causes skeletal
muscle fatigability and weakness
•The autoimmune attack impairs the function of
nicotinic post-synaptic acetylcholine receptors on
the muscle cell (motor end plate)
Image courtesy of Wikimedia Commons

4. Pathophysiology

5. Gilhus, NE. Myasthenia Gravis. N EnglJ Med 2016;375:2570-2581.

6. Antibody Types
•Acetylcholine receptor antibodies
–Binding (the most sensitive, very
rare false +)
–Blocking
–Modulating
•Anti-LRP4(1-3% of MG)
–Tend to have only mild to moderate
symptoms, younger
•Anti-MuSK(~ 8 % of MG, not isolated
ocular MG)
–Marked facial and bulbar
weakness, limb and ocular
weakness less common
•Seronegative
–About 6% of generalized MG
patients, up to 50% of OMG
–Serologic testing should be
repeated after 6-12 months

7. Question
•Which of the following muscles or muscle
groups is most likely to show weakness related
to myasthenia gravis?
a)Urinary bladder
b)Frontalis
c)Iris
d)Superior tarsal muscle

8. Epidemiology
–Higher prevalence in
women ages 20-40
–Higher prevalence in
men over age 60
Vincent A, et al. Myasthenia Gravis. Lancet 2001;357(9274):2122-2128.
•There is a bimodal age distribution in MG
patients with acetylcholine receptor
antibodies

9. History
•Fluctuating ptosis and diplopia are the cardinal
symptoms of ocular MG
–More than 50% of all MG patients first present with
ptosis and/or diplopia
•Other common symptoms include
–Weakness of bulbar muscles
•Fatigable chewing, dysarthria, dysphagia
•Speech may sound nasal with palatal muscle
weakness or hypophonic
–Facial muscle weakness
•Difficulty smiling, “myasthenic sneer” where
middle of lip rises but not corners of mouth,
orbicularis weakness
–Neck muscles
•Difficulty holding head up

10. Statistics
•In 15 –25% of patients with MG, symptoms are
confined to the extraocular muscles
•90% of patients with purely ocular MG 2 years after
symptom onset will never generalize
•50-60% of patients with initially isolated ocular
involvement go on to generalized weakness, typically
within 3 years
•The majority of patients have ocular symptoms at
onset (even if they also have generalized weakness)

11. Measurements of Lid Position
•MRD1–distance from corneal light reflex to upper lid margin
•MRD2–distance from corneal light reflex to lower lid margin
•Palpebral fissure height –distance from lower to upper lid margin
MRD1
MRD2
Palpebral
fissure
height

12. Measuring LevatorFunction
•Useful as measure of levatormuscle strength
•May help distinguish ptosis related to muscle weakness from
mechanical ptosis
Place ruler at upper lid margin
with patient looking down
Have patient look up and
measure the distance the upper
lid travelled between downgaze
and upgaze(16 mm in this case)

13. Fatigable Ptosis
with Sustained
Upgaze
•Have patient look up for 2 minutes
•Compare MRD1 and/or palpebral fissure height before and
after
•Does not exclude nonmyasthenic causes of ptosis
Figure from Walsh and Hoyt’s Clinical Neuro-Ophthalmology, The Essentials, 3
rd
Edition, p. 374

14. Enhancement
of Ptosis
•Manually elevating one eyelid causes the contralateral eyelid to
become more ptotic
•Explained by Heringlaw of equal innervation
•Manual eyelid elevation decreases effort needed to keep eyelid open
ipsilaterally, results in relaxation of contralateral levator
•Can also be see in congenital ptosis and other non-MG causes of ptosis

15. Cogan’s Lid
Twitch
•Elicit by having the patient look down for about 10-15 seconds,
then a vertical saccade to primary position
•The ptotic lid “overshoots”, followed by settling in the ptotic
position
•Caused by easy fatiguability and rapid recovery of myasthenic
muscle

16. Pseudo INO
•Common pattern of eye movement abnormality in MG
•Can be distinguished from INO by convergence testing
–Adduction improves with convergence in true INO
–Adduction does NOT improve with convergence in pseudo INO from MG
•Note slowing of the end of the adducting saccade in left eye,
characteristic of MG

17. “Peek” sign
•Orbicularis weakness in MG causes
eyelid closure weakness
•On gentle voluntary eyelid closure,
the lids initially appose without sclera
visible (B)
•Within two seconds, the palpebral
fissure widens, exposing sclera (C)
•Seen in 3/25 myasthenia patients and
only 1/50 patients with other
neuromuscular disorders with facial
weakness
•Can be the only sign of MG in some
patients
OsherRH, Griggs RC. Arch Ophthalmol1979;97:677-679.
A
B
C

18. Ice Pack Test
•Reduced muscle temperature is thought to inhibit acetylcholinesterase activity
•Place ice pack on patient’s eyelids for two minutes
–Significant improvement of ptosis is suggestive of MG
–Ocular misalignment usually does not change, but may with longer ice duration
–May be uncomfortable for the patient
•For MG-related ptosis, sensitivity 92% and specificity 79%
•High negative predictive value of 94% makes ice pack test useful in helping rule out
MG-related ptosis
Liu and Chen. N EnglJ Med 2016;375:e39.

19. Question
•Do you have access to edrophonium (Tensilon)
or neostigmine (Prostigmin) in your practice
location?
a)I have access to both
b)I have access to edrophonium (Tensilon), but not
neostigmine (Prostigmin)
c)I have access to neostigmine (Prostigmin), but
not edrophonium (Tensilon)
d)I do not have access to either

20. Edrophonium (Tensilon) Test
No longer available in the United States
•Rapid onset (< 30 seconds)
•Short duration (about 5 minutes)
Reversible acetylcholinesterase inhibitor injected intravenously
•Verify lid position and ocular alignment
•10 mg (1 cc) of edrophonium in syringe
•Test dose of 2 mg given IV
•Look for improvement in ptosis, ocular misalignment, and/or range of eye movements
•If improvement, test is positive
•If no improvement after 30 sec, administer 2 mg every 60 seconds until response of 10 mg total administered
Test procedure
•Have atropine available at the time of the test
Major side effects in 0.1% include bradycardia, asystole, syncope, seizures
•False positive tests also occur (botulism, ALS, Guillain-Barre syndrome, and others)
Sensitivity is 60-95% in ocular MG, so negative test does not definitively rule out MG

21. Neostigmine (Prostigmin) Test
•Longer duration of action than
edrophonium
–Especially helpful in patients
with diplopia without ptosis,
and children
–Allows time to measure
ocular alignment changes
•Procedure for administration
–Mix 0.6 mg atropine sulfate
and 1.5 mg neostigmine
(0.04 mg/kg for children, up
to 1.5 mg max) in a 3-cc
syringe and inject into
deltoid or gluteus muscle
–Change in lid position and/or
ocular alignment noted after
30-45 minutes
–Monitor with pulse oximetry
and cardiac monitoring for
two hours afterwards
•Sensitivity of 70-94%
Figure from Walsh and Hoyt’s Clinical Neuro-Ophthalmology, The Essentials, 3
rd
Edition, p. 380

22. Rest Test
•Baseline lid position and ocular
deviations were examined and/or
photographed
•Patient told to rest with their eyes
closed for 30 minutes
•Lid position and ocular deviations
again examined/photographed
immediately after
•Photographs and measurements
taken repeatedly over next 5-10
minutes
•42/42 patients with Tensilon-positive
MG had a positive rest test
•26 patients with other causes of
ptosis/ophthalmoparesisshowed no
improvement after rest
OdelJG, et al. J Clin Neuro-ophthalmol1991;11(4):288-292.

23. Diplopia
•First verify the diplopia is
binocular
•Useful to measure the
misalignment to document
variability
•Any pattern of misalignment is
possible
–Pseudo-INO is a common
pattern
•MG-related diplopia is typically
not well-treated with prisms or
strabismus surgery due to
variability

24. Diagnosis
•Made clinically with history
and exam
•Positive antibody testing
confirms the diagnosis, but
many cases are seronegative
–Only about 50% of patients with
OMG have detectable antibodies
•Pharmacologic testing no
longer used as commonly as
in past
•Confirmatory testing with
electrophysiology is helpful in
seronegative cases

25. What about
seronegative cases?
•Diagnosis typically secured
with characteristic clinical
findings, EMG, and expected
response to therapy
•If possible, advisable to seek
EMG confirmation prior to
using immunosuppressants
•Consider repeating antibody
testing in 6-12 months (about
15% later have positive
antibodies)

26. Electromyography
(EMG)
•Repetitive nerve stimulation (2-3
Hz) can screen for MG
•Not as sensitive in ocular MG
(10-50%) as in generalized MG
(75%), but 90% specific
•Measures Compound muscle
action potential (CMAP)
•Decrement of ≥ 10% in CMAP
amplitude is a sign of MG

27. Question
•Are you able to refer a patient for single fiber
electromyography (SFEMG) in your practice
location?
a)Yes
b)No

28. Single Fiber
Electromyography (EMG)
•More technically difficult than standard EMG
–Performed at specialized centers
•Often performed in frontalis muscle for
patients with possible ocular MG
•Electrode is positioned to record action
potentials (APs) from two muscle fibers
innervated by the same motor neuron
•The difference in latency between stimulus
and muscle APs in two muscle fibers is the
“jitter”
•Jitter increases with defects in transmission
at the neuromuscular junction
Figures from https://emedicine.medscape.com/article/1832855-overview#a1
Motor unit = muscle fibers innervated by one motor neuron

29. Mediastinal Imaging
•10% of patients with
MG have a thymoma
–Prevalence
increases with
advancing age
•CT chest or similar
imaging should be
performed in all
patients with MG
Image courtesy of Wikimedia Commons

30. Thymectomy
•Thymus plays key role in inducing
AChRantibody production in MG
•All patients with MG and thymoma
should undergo thymectomy
•Early thymectomy recommended
for patients with early onset
generalized MG (age < 50)
–MG at age < 50 usually
associated with thymic
hyperplasia
•If no thymoma, thymectomy not
recommended in anti-MuSKand
anti-LRP4 MG cases, or purely
ocular cases
Image courtesy of Medscape.com

31. Question
•In which of the following patients with
myasthenia gravis would thymectomy be most
strongly recommended?
a)60 year-old man with purely ocular myasthenia
gravis
b)45 year-old woman with generalized myasthenia
gravis and + anti-MuSKantibodies
c)30 year-old woman with generalized myasthenia
gravis
d)70 year-old man with generalized myasthenia
and no thymoma

32. Symptomatic
Therapy
•Pyridostigmine is the preferred
drug for treatment of symptoms
–Dose is decided based on
effects on symptoms and
dose-dependent side effects
–Side effects include
diarrhea, abdominal
cramps, increased flatus,
nausea, urinary urgency,
increased sweating, and
increased salivation
–If symptoms are mild and in
near-remission, no other
drug therapy is necessary

33. Medications to Avoid in MG
Medications that may unmask of worsen MG
Anesthetic agents
Neuromuscular blocking agents
Aminoglycosides (e.g., gentamicin, neomycin,
tobramycin)
Fluoroquinolones (e.g., cipro, levofloxacin)
Ketolides (e.g., telithromycin)
Macrolides (e.g., azithromycin, erythromycin)
Beta blockers (e.g., atenolol, labetolol, metoprolol)
Procainamide
Quinidine
Botulinum toxin
Chloroquine
Hydroxychloroquine
Magnesium
Pencillamine
Quinine
Ophthalmic drugs
Betazolol
Echothiophate
Proparacaine
Timolol
Tropicamide
•Drugs that interfere with
neuromuscular
transmission can
exacerbate MG
•Even ophthalmic drops
have some systemic
absorption and may
exacerbate MG
•The effects are not enough
to cause symptoms in
most normal patients, but
affect patients with MG

34. Immunosuppressive
Therapy
•Most patients need immunosuppressive
therapy
•First line treatment includes a combination
of prednisone/prednisolone and
azathioprine (2-3 mg/kg)
–There is weak evidence that alternate
day dosing can reduce side effects, and
usually does not cause disease
fluctuation
–Prednisone usually increased up to 60 to
80 mg on alternate days
–After stable control of symptoms,
prednisone can be slowly tapered to a
baseline of usually 10 –40 mg on
alternate days
–Prednisolone monotherapy appears to
reduce the risk of generalization of
ocular MG
Image courtesy of healthline.com

35. Immunosuppressive
Therapy
•Mycophenolate mofetil can also be
considered
•Alternatives include methotrexate,
cyclosporine, and tacrolimus
•Rituximab may be recommended for severe
symptoms
Image courtesy of healthline.com

36. Treatment of Severe
Exacerbations
•Need to be hospitalized
•May require intensive care
•IVIG or plasma exchange
•Supportive care with treatment
of precipitating event (e.g.,
infection, etc.)
•Long-term immunosuppression
should be intensified after
patient improves

37. References
•Gilhus, NE. Myasthenia Gravis. N EnglJ Med 2016;375:2570-2581.
•OsherRH, Griggs RC. Orbicularis Fatigue. The ‘Peek’ Sign of Myasthenia
Gravis. Arch Ophthalmol1979;97:677-679.
•OdelJG, Winterkorn JMS, Behrens MM. The Sleep Test for Myasthenia
Gravis. A Safe Alternative to Tensilon. J Clin Neuro-ophthalmol
1991;11(4):288-292.
•Walsh & Hoyt’s Clinical Neuro-Ophthalmology: The Essentials. Miller NR,
Subramanian PS, Patel VR, editors, 3
rd
edition. Published by Lippincott
Williams & Wilkins, 2015.