1. Pupillary deception Sarah Dougherty Wood, OD, MS, FAAO Heart of America February 2011

2. Presentation at the Boston VAMC  79 year old caucasian male  CC: left eye lid closed x 2 weeks, when the lid is lifted he sees double vision, sudden onset  No complaint of blurred vision  No h/o ocular trauma or associated pain  Ocular history: pc iol os (4 years prior), mild dry amd ou, cataract od  No ocular meds

3. DDX  Thyroid orbitopathy  Trauma  Myasthenia Gravis  Restriction of EOM due to a intraorbital mass  Horner’s syndrome  CPEO  Dorsal Midbrain syndrome  CN 3 palsy  Multiple cranial nerve palsies

4. Medical history  Systemic conditions: DM, atrial fibrillation, high cholesterol, allergic rhinitis, cardiomyopathy, asthma, HOH, HTN  Systemic medications: coumadin, simvastatin, furosemide, isosorbide, lisinopril, loratadine, metformin, metoprolol  Last hba1c 6.7 (6-08)  History of moderately heavy EtOh use

5. Examination findings  VA cc: od 20/25, os 20/25  Complete ptosis os  CT: left hypotropia (9prism diopters)  Eoms: left eye superior restriction  Diplopia reported in primary gaze but was worst when attempting superior/abduction and on left head tilt  Confrontations full od, os (lid lifted)  IOP TA: 16/15

6. Other testing  CN 4,5,6,7,11 were all wnl  Also important to note: pt had good articulation of words and reported no trouble with swallowing  Pupils: reactive ou, no anisocoria, no apd ou  No other neuro signs found  No new findings on slit lamp examination or fundus examination  No diabetic retinopathy

7. At this point,  This condition seems to be affecting…… Levator or Muller muscle? Which one will cause a complete ptosis when denervated? Levator  Which EOMS? Which cause elevation? Superior rectus and inferior oblique Between these two, which one would be affected if the diplopia gets worse the AB-duction? Superior rectus

8. So,  We suspected the superior rectus and levator were involved…….

9. Let’s go back to our DDX list  Thyroid orbitopathy- certainly can cause restriction and diplopia, but doesn’t cause complete ptosis- actually lid retraction  Trauma- could be inferior floor entrapment but no h/o trauma per pt, cataract surgery can sometimes cause a mild ptosis due to levator dehiscence  MG-would be unusual to affect only the superior rectus and levator muscles on one side, possible

10. Differentials…………  Intraorbital mass- possible  Horner’s syndrome- can cause a ptosis due to affect on Muller’s muscle but would likely not be so dramatic, can have Horner’s with CN palsies (esp. CN6) if there is a cavernous sinus lesion, no miotic pupil  CPEO- usually slowly progressive and bilateral and external ophthalmoplegia in all directions of gaze

11.  Dorsal midbrain syndrome-signs: supranuclear paresis of upgaze, light-near dissociation, pt had normal pupillary light reflex  Multiple CN palsies- no other neuro abnormalities found  CN3 palsy- If complete, eye would be down and out with a ptosis- Is this our patient?

12. Review of CN3 pathway  CN3 Nucleus is located in the midbrain  Runs through the red nucleus  Exits ventrally  Passes parallel to the posterior communicating artery  Runs through the cavernous sinus laterally  Then divides into two divisions

13. Two divisions of CN3  Splits within the cavernous sinus and superior orbital fissure  Inferior division: carries fibers which innervate the MR, IO, and IR  Superior division: carries fibers which innervate the SR and levator palpebrae  Therefore, we deduced we had a superior division (incomplete) CN3 palsy

15. What is your biggest concern with a CN3 palsy?  Aneurysm!  Which is the most common artery to have an aneurysm which would involve CN3? Posterior communicating artery or the junction of the PCA and ICA  Why is an aneurysm bad? Rupture, increased morbidity and mortality  Timely diagnosis is critical: From time of CN3 palsy (due to aneurysm) to rupture of PCA= avg. 29 days Lee, et al

16.  What exam findings could give us information about the presence of an aneurysm?  Why will an aneurysm potentially affect the pupil? Pupillary fibers are located superficially (dorsal/medial location)  What will the pupil look like if it is in fact involved? Fixed and dilated

18. Our patient  Pupils: reactive ou, no anisocoria, no apd ou  So, can we rule-out an aneurysm? Why or why not?  I intentionally left out a critical piece of information about the inferior division of CN3: it also carries the pupillary fibers to the sphincter muscle

20.  So, no pupil involvement in an incomplete CN 3 palsy (superior division) gives you a false sense of security “Partial external dysfunction (EOM involvement and/or lid) without pupil involvement is not the same thing as true sparing with complete external dysfunction”, Lee et al YOU COULD STILL HAVE A LIFE-THREATENING ANEURYSM IN YOUR CHAIR! Send for a stat MRI/MRA

21. Review of Acquired Complete CN3 palsy management- most commonly ischemic but how do you know?  Steps: 1) Is it truly isolated? (HA, hemiparesis, other CN palsies, eye pain?)  If not, send out ASAP for imaging 2) Pupil involvement? (normal pupil function defined as anisocoria less than or equal to 1mm and light reaction bilaterally, Lee et al)  If yes, send out ASAP for imaging 3) Aberrant regeneration? (example: lid retraction on down gaze, miosis during AD- duction or downgaze)  If yes, likely a compressive lesion, send for imaging

22. Review of CN3 palsy management in general  Steps continued: 4) Less than 40 years of age?  If yes, send ASAP for imaging 5) HTN, DM or vascular disease?  If no, send ASAP for imaging 6) Resolution in 3 months? (100% of ischemic isolated CN3 palsies resolved by 3 months, Capo et al)  If no, send for imaging

23. Summary of CN3 management  Do not have to send for further testing if: All EOMS are involved (SR, IR, IO, MR) +ptosis Pupil spared >40 y.o.a. Isolated AND Have systemic vascular disease (DM, HTN, atherosclerosis) These cases likely have a microvascular cause- Follow closely for the 1 st few days…..

24.  If pupil becomes involved, send them for a STAT MRI/MRA or CT angiography  If not, follow at 6 weeks and then 3 months

25. Potential causes of superior division CN3 palsies from the literature  Microvascular  Post viral  Aneurysm (posterior cerebral, basilar apex, superior cerebellar arteries)  Cavernous sinus or intraorbital mass  Midbrain infarction  Meningitis  Sphenoid sinusitis  Trauma  MG  Giant cell arteritis

26. How did we manage this patient?  We sent for a STAT sed rate and CRP, MRI/MRA and then to neuro-ophthalmology  Sed rate was 22 and CRP was 2.77  MRI/MRA result: paranasal sinusitis but no mass or aneurysm or infarction  Our diagnosis: microvascular but MG is still a possibility  Neuro-ophthalmology agreed with our diagnosis of microvascular- dismissed pt back to optometry  I informed PCP about paranasal sinusitis

27.  Patient returned to optometry 3 weeks later (now roughly 6 weeks in duration) and ptosis was the same but diplopia was only present on attempted upgaze  RTC 6 weeks (now roughly 3 months in duration)- would we expect a microvascular palsy to be resolved by this point?

28. Follow-up  Findings: 18 prism diopter left hypotropia in primary gaze!, ptosis still the same  Should we change our diagnosis?  We sent him back to neuro-ophthalmology who ran a CT scan of the orbit to r/o orbital mass  CT scan: no mass found  Ran lab to detect Ach receptor anti- bodies- what are they looking for?

29. Let’s review normal neuromuscular transmission  Acetylcholine, a neurotransmitter, is stored in the presynaptic vesicles in nerve endings. An action potential causes calcium to enter the cell and the vesicles move to the surface and release the Ach.  The Ach travels across the synaptic cleft and attaches to a receptor on the post- synaptic muscle cell

30. Normal NMJ  This causes increased permeability of Na+ and K+ and depolarization, if the threshold is met, the action potential propagates down the cell.  This will lead to muscle contraction  Acetylcholinesterase removes the Ach from the receptor

32. Myasthenia Gravis  A chronic auto-immune neuromuscular disease  Antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction which prevents the muscle contraction from occurring  Causes weakness and fatigability of the skeletal muscles of the body

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34.  www.mda.org/publications/images/mg_NMJ.jpg

35. Myasthenia Gravis  Occurs in all ethnic groups. It most commonly affects young adult women (under 40) and older men (over 60), but it can occur at any age.  Prevalence: 4-5/100,000

36. Ocular Myasthenia  90% of MG patients will have ocular signs, in 60% it is the initial sign but rare to have only eye signs during the entire course of the disease  Involvement of levator, orbicularis oculi, one or all of the EOMS  Signs: ptosis, diplopia  usually variable- worse at the end of the day or with fatigue  Normal pupils

37. Ocular Myasthenia- Tests you can do  Have the patient to look straight up for a minute. Measure the palpebral fissure before and after. MG=decreased PF  Cogan’s lid twitch- Have patient look down for 10-20 seconds and then have them look back to primary gaze. The upper lid, on the ptotic side, will raise and then slowly begin to droop or twitch as it settles back down Miller, et al

38.  Ice Test- The strength of muscles improve when they are cooled. Therefore, the ptosis can be reduced in a rapid, safe, inexpensive test. Measure the palpebral fissure before and after putting ice on the ptotic lid for 2 minutes.  95% sensitive and 100% specific for MG Miller, et al

39. Our patient  Lab results: high levels of Ach receptor antibodies (1.77, where normal is <0.3), TSH normal- why is this relevant?  Their cover test was 2 prism diopter left hypotropia  They sent him to neurology for another test for MG- what is it?  Tensilon test- how does this work?

40.  Tensilon (Edrophonium) inhibits AchE which potentiates the action of Ach and will cause the ptosis to improve quickly if the patient has MG

41. 2-12-09 appointment  Neuro ran repetitive nerve conduction studies. The right axillary nerve should decreased amplitude of response after exercise- which is consistent with a neuromuscular transmission disorder  Started him on Mestinon (pyridostigmine) PO 30mg bid- what does this do?  Pyridostigmine also is an anti- acetylcholinesterase drug, it allows Ach to remain longer on the nerve receptor

42. 2-26-09 f/u appointment  Pt noted ptosis os got better after first dose of Mestinon but did not last  Neurologist observed a ptosis now od and restricted AB-duction OU  Increased Mestinon to 60mg bid

43. 3-13-09 f/u with neuro-ophtho  CC: lid droop is better- worse towards the end of the day, does still have some diplopia- worse on upgaze  Pupils, CT, and EOMS all wnl  Lid findings: OD OS Marginal reflex distance-1 4 0 to -5 (distance from upper lid margin to pupillary reflex) Palpebral fissure 13 7 (distance between upper and lower eyelids)

44.  Assessment: MG with h/o incomplete CN 3 palsy, may have an element of levator dehiscence from cat ext.  What other systemic test should be run?  Chest CT to r/o thymoma (anterior mediastinum)

45.  Thymoma- tumor of the thymus gland- about 10% of those with MG have a thymoma- need to test for it- the thymus gland is involved in development our of immune system= the connection to MG is not completely understood

47. Patient had chest CT on 4-2-09  Results: No thymoma

48. Other possible systemic involvement in MG  Generalized skeletal muscle weakness  Difficulty with the muscles used in articulation, swallowing*, chewing, breathing*, expression, and phonation  Head ptosis due to weakness of neck extensors  Auto-immune disorders such as thyroid  Overall, MG has a good prognosis- easily managed with medications *potentially the most serious

49. Take Home message from this patient  Pupil findings are not helpful in an incomplete CN 3 palsy!  Also, if your initial diagnosis no longer makes sense, do more investigating!  Consider MG as possible diagnosis for any diplopia patient

50. Second patient, 3-26-09  Had known MG for 20 years and was being treated, also had DM  Came in complaining of worsening of ptosis OS x 2-3 weeks  Upon examination, the ptosis was worse than previous exams and there was a left hypotropia, no horizontal component  Pupils normal

51.  Could this be a superior division CN3 palsy on top of MG (Perhaps a diabetic CN3 palsy) or is it just the MG?  The clinician did a very savvy thing- the ice test and the ptosis completely resolved  One more piece of the patient history: he had recently been taken off one of his MG medications  A CT scan was run and was wnl

52. f/u with neurology  Ach antibody test was wnl  They believe it is an ischemic CN 3 palsy  Kept the MG medications at the same level

53. References  Bhatti, et al, Superior Divisional Third Cranial Nerve Paresis, Arch Neurol/Vol. 63, May 2006, p. 771-776.  Blake, et al, MR of Oculomotor Nerve Palsy, AJNR Am J Neuroradiol 16:1665-1672, September 1995.  Capo, et al, Evolution of oculomotor nerve palsies. J Clin Neuroophthalmol 12:21-5,1992.  Celebisoy, et al, Superior Division Paresis of the Oculomotor Nerve: Report of Four Cases, Eur Neurol 2006;56:50-53.  Friedman, Pineda, Kaiser, The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology, 1998, W.B.Saunders Company.  Lee, et al, The Evaluation of Isolated Third Nerve Palsy Revisited: An Update on the Evolving Role of Magnetic Resonance, Computed Tomography, and Catheter Angiography, Survey of Ophthalmology, Vol. 47, Number 2, March-April 2002, P. 137-157.  Miller, Newman, Biousse, Kerrison, Walsh and Hoyt’s Clinical Neuro- opthalmology: The Essentials, Second edition, Lippincott, Williams, and Wilkins, 2008  http://www.ninds.nih.gov/disorders/myasthenia_gravis