1. Brett Mueller, D.O., Ph.D. December 15, 2017
Grand Rounds
Brett Mueller, D.O., Ph.D.
December 15, 2017

2. Patient Presentation CC HPI Droopy left eyelid
28 year-old African American female with no significant PMH presents with a droopy left eyelid for 5 months. States that the eyelid becomes more droopy throughout the day. Mentions having intermittent double vision.
Denies trouble with breathing, swallowing, no hx of trauma or infection

3. History (Hx)
Past Medical Hx: none Past Surgical Hx: none Meds: none Allergies: NKDA Social Hx: none

4. External Exam OD OS VA 20/20 Refraction plano Pupils 4→3mm No rAPD IOP
15 mmHg
17 mmHg
EOM
Full
CVF

5. Will assess in future slides
Anterior Segment Exam
SLE OD OS
External/Lids
Will assess in future slides
Conj/Sclera
WNL
Cornea
Ant Chamber
Iris
Lens

6. Posterior Segment Exam
Fundus OD OS
Optic Nerve
Pink and sharp
Macula
Sharp foveal reflex 
Sharp foveal reflex
Vessels
WNL
Periphery

7. Start of Levator Exhaustion Test 2 minutes of Levator Exhaustion Test
External Exam
Looking Straight
Start of Levator Exhaustion Test
2 minutes of Levator Exhaustion Test

8. 5 min Ice Pack Test

9. Assessment
28 year-old African American female with unilateral ptosis and diplopia that worsens with ocular motility
Diagnosis
Ocular myasthenia gravis

10. Plan Obtain Therapy Anti-Acetylcholine receptor antibody
CT of the chest to rule out thymoma
Therapy
Pyridostigmine

11. Start of Levator Exhaustion Test 2 minutes of Levator Exhaustion Test
1 month later
Start of Levator Exhaustion Test
2 minutes of Levator Exhaustion Test

12. Myasthenia Gravis (MG)
First described in 1672 by Thomas Willis, and the term “Myasthenia Gravis pseudo-paralytica” was coined 1895
First treatment was performed in 1934 by Mary Walker, MD
Felt the disease was similar to curare toxicity and treated with physostigmine
Curare is a nicotinic receptor blocker

13. Myasthenia Gravis
Autoimmune disease resulting in muscle fatigability and weakness
Symptoms improve with rest
Main ophthalmic complaints are: ptosis, diplopia, and extra-ocular muscle palsies
Ocular MG affect only the ocular mms

14. Ocular Myasthenia Gravis (OMG)
85% of patients presenting with only ocular signs and symptoms of myasthenia graves (MG) will develop systemic MG within 2 years of presentation
However, after 2 years 90% of people who have OMG will not develop systemic MG
E. Kerty, A. Elsais, Z. Argov, et al.EFNS/ENS guidelines for the treatment of ocular myasthenia gravis
Eur. J. Neurol., 21 (2014), pp. 

15. Epidemiology Affect any age group and show no geographic predilection
Incidence: /100,000 per year
Prevalence: /100,000 per year

16. Demographics
OMG and MG differ with respect to the demographics of the affected population
MG is a 3:2 female to male ratio
OMG affects males more
Females that are affected typically have a mean age of 28 while men have a mean age of 42.

17. Clinical Presentation
Vary depending on which muscles are affected and can have variable muscular weakness and fatigability
Most common signs are ocular (50% of the time) which include:
Ptosis
Incomitant strabismus
External ophthalmoplegia
Incomitant strabismus affect the MR more than any other mm. External ophthalmoplegia: mimicking motor CN palsies.
EOMs are 80% single innervated twitch fibers with a high firing frequency. This increases their sensitivity to fatigue. 

18. Clinical Presentation
Cogan Lid twitch
Hering’s law of equal innervation is typical of myasthenic ptosis
he Cogan lid twitch is elicited by having the patient look in downgaze, followed with upgaze. As the affected eye saccades up, the upper lid overshoots. Hering's law of equal innervation states that the reciprocal eye muscle of each eye are innervated equally. As such, manual elevation of the more ptotic eyelid decreases the muscle strength required to keep the lid elevated, and so the contralateral levator palpebrae superioris relaxes and causes worsening ptosis. 

19. Clinical Presentation
Variable muscle weakness
Fatigability of the muscles of
Mastication
Facial Expression
Speech
Neck Extensors
Proximal Limb muscles
Respiratory muscles

20. Diagnosis Edrophonium (Tensilon)Test: Need to have atropine on hand
Repetitive Nerve Stimulation: 95% specificity
+ in 75% of patients with MG
+ in 50% of patients with OMG
Single Fiber EMG: 88-99% sensitivity for ocular myasthenia
One should have a high suspicion for MG when a patient's history and main signs and symptoms are variable muscle weakness and fatigability that worsens in the evening or with prolonged use, and improves with rest. The definitive diagnosis is made through various clinical, pharmacological and serologic tests.
This is the most frequently used electrodiagnostic test for MG, with specificity of 95%. The nerve to be studied is electrically stimulated six to ten times at 2 to 3 Hertz. Compound muscle action potential (CMAP) is recorded via surface electrodes placed on the muscle in question. A positive test is the progressive decline in CMAP amplitudes within the first 4-5 stimuli. RNS testing is positive in approximately 75% of patients with generalized MG, but is positive in only 50% of patients with ocular MG. False positive are seen in LEMS, ALS and polyomyositis.

21. Diagnosis Ice Test Serum anti-acetylcholine receptor antibody titer
Present in 85-90% of MG
Present in 50% of OMG
Serum anti-muscle-specific kinase antibody titer

22. Differential Diagnosis
Lambert-Eaton Myasthenic Syndrome
Anything that can cause ptosis:
Intracranial lesion
Aneurysm
Thyroid eye disease can occur in conjunction with MG in up to 5% of patients

23. Pathogenesis
Antibodies against the acetylcholine receptor sites at the post-synaptic neuromuscular junction
Muscle becomes weak due to impaired transmission
Decreases the receptors by 66%

24. Treatment Medical Therapy Acetylcholinesterase inhibitors
Oral Steroids
Immunomodulators
Medical therapy includes acetylcholinesterase inhibitors, pyridostigmine (Mestinon), oral steroids, and immunomodulators. These drugs have no effect on the underlying disease process, they are purely to help manage symptoms.
Acetylcholinesterase inhibitors reduce the hydrolysis of ACh by the enzyme acetylcholinesterase at the synaptic cleft. By inhibiting the hydrolysis of ACh, the ACh released from the presynaptic cleft remains at the NMJ longer, giving the muscle a longer period of activation. Pysidostigmine is a long acting cholinesterase inhibitor used to treat ocular MG. Oral steroids are used adjunctly. Immunomodulators are reserved for refractory cases.
Surgery[edit source]
Mycophenolate
Surgical removal of the thymus gland is recommended for the treatment of symptomatic MG. Approximately 66% of MG patients have thymic hyperplasia (thymomas) with germinal center formation, and 10% of patients have a thymic tumor. Within this lymphoid tissue, B-cells interact with helper T-cells to produce the anti-ACh receptor antibodies.  As such, symptoms of MG generally improve after thymectomy.The role of thymectomy in purely ocular myasthenia is debatable, but it may play a small role in the management of symptoms

25. Treatment Surgery Surgical removal of the thymus gland
66% of patients have thymic hyperplasia (thymomas)
10% of patients have thymic tumors
Surgical removal of the thymus gland is recommended for the treatment of symptomatic MG. Approximately 66% of MG patients have thymic hyperplasia (thymomas) with germinal center formation, and 10% of patients have a thymic tumor. Within this lymphoid tissue, B-cells interact with helper T-cells to produce the anti-ACh receptor antibodies.  As such, symptoms of MG generally improve after thymectomy.The role of thymectomy in purely ocular myasthenia is debatable, but it may play a small role in the management of symptoms

26. Complications Occur when larger muscle groups become involved
Dysphagia and dyspnea can lead to respiratory compromise and death
Myasthenic crises
Surgical removal of the thymus gland is recommended for the treatment of symptomatic MG. Approximately 66% of MG patients have thymic hyperplasia (thymomas) with germinal center formation, and 10% of patients have a thymic tumor. Within this lymphoid tissue, B-cells interact with helper T-cells to produce the anti-ACh receptor antibodies.  As such, symptoms of MG generally improve after thymectomy.The role of thymectomy in purely ocular myasthenia is debatable, but it may play a small role in the management of symptoms

27. Prognosis Fair as long as symptoms are well controlled
Poor if larger muscle groups involved with respiration or swallowing become involved
85% of patients who develop OMG will develop MG within 2 year

28. Conclusions
Ocular manifestations can be the presenting complaint in 50% of patients
Patients with OMG have an 85% chance to progress to MG within 2 year. But if a patient has OMG for more than 2 years, they only have a 10% chance of progressing to MG
Lethal when patients develop dyspnea or dysphagia

29. References
Kanski’s Clinical Ophthalmology A systemic Approach, Eighth Edition. Brad Bowling
Neuro-ophthalmology, BSCS
Oculoplastics, BSCS
E. Kerty, A. Elsais, Z. Argov, et al.EFNS/ENS guidelines for the treatment of ocular myasthenia gravis Eur. J. Neurol., 21 (2014), pp. 
Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: Past, present, and future. J Clin Invest. 2006;116:2843–54.
O’Brien MD. The miracle at St Alfege's: Seventy years on. J R Soc Med. 2007;100:257.
López-Cano M, Ponseti-Bosch JM, Espin-Basany E, Sánchez-García JL, Armengol-Carrasco M. Clinical and pathologic predictors of outcome in thymoma-associated myasthenia gravis. Ann Thorac Surg. 2003;76:1643–9. 
Singhal BS, Bhatia NS, Umesh T, Menon S. Myasthenia gravis: A study from India. Neurol India. 2008;56:352–5. 
Grigg J. Extraocular muscles: Relationship of structure and function to disease. Aust N Z J Ophthalmol. 1999;27:369–70.
Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects. Doc Ophthalmol. 1993;84:309–33.
Neuro-Ophthalmology, Section 5. Basic and Clinical Science Course, AAO,
Miller NR & Newman MJ. The Essentials: Walsh & Hoyt's Clinical Neuro-Ophthalmology. 5th edition. Lippincott:1999.
Burkat, CN., et al., Myasthenia Gravis. Eyewiki. Ed. Burkat, CN. 2017