1. Case 74 year old male, recent carotid doppler following episode of dizziness 74 year old male, recent carotid doppler following episode of dizziness 50-79% right carotid stenosis 50-79% right carotid stenosis PMH- coronary artery disease, hypertension, hyperlipidemia PMH- coronary artery disease, hypertension, hyperlipidemia Spell consisting of “fuzzy vision”, uncertain if monocular, lasting minutes up to 15 minutes, with associated “tingling left side of face” Spell consisting of “fuzzy vision”, uncertain if monocular, lasting minutes up to 15 minutes, with associated “tingling left side of face”

2. Questions Is this amaurosis fugax? Is this amaurosis fugax? What is this patient’s risk for stroke? What is this patient’s risk for stroke? Is carotid endarterectomy indicated in this case? Is carotid endarterectomy indicated in this case?

3. Amaurosis Fugax …and the role of Carotid Endarterectomy COL Beverly Rice Scott MD Neurology and Neuro-ophthalmology Madigan Army Medical Center

4. Outline Definition and etiologies of transient visual loss Definition and etiologies of transient visual loss Clinical features & pathophysiology Clinical features & pathophysiology Evaluation of transient monocular blindness Evaluation of transient monocular blindness Amaurosis Fugax and Stroke Risk Amaurosis Fugax and Stroke Risk North American Symptomatic Carotid Endarterectomy Trial (NASCET) North American Symptomatic Carotid Endarterectomy Trial (NASCET) Spectrum of ocular ischemic syndromes and stroke risk Spectrum of ocular ischemic syndromes and stroke risk

5. Definition Painless unilateral transient loss of vision, partial or complete, related to retinal arterial microembolization or hypoperfusion Painless unilateral transient loss of vision, partial or complete, related to retinal arterial microembolization or hypoperfusion “fleeting darkness or blindness” Retinal transient ischemic attack (RTIA) transient monocular blindness (TMB) Accounts for 25% of anterior circulation transient ischemic attacks (TIAs).

6. Transient visual loss Amaurosis Fugax Transient Visual Obscuration Binocular Monocular (TMB) Retinal Migraine Cortical Migraine Heart disease Arteritis

7. Etiologies: Transient visual loss Occlusive retinal artery disease Occlusive retinal artery disease Atheroembolic, cardioembolic, arteritic, hematological disorders, congenital, orbital tumor Atheroembolic, cardioembolic, arteritic, hematological disorders, congenital, orbital tumor Low retinal artery pressure Low retinal artery pressure Ocular ischemia syndrome, arteriovenous fistula, congestive heart failure, anemia Ocular ischemia syndrome, arteriovenous fistula, congestive heart failure, anemia Optic disc disease and anomalies Optic disc disease and anomalies Papilledema, Glaucoma, Drusen Papilledema, Glaucoma, Drusen Vasospasm ( ophthalmic migraine ) Vasospasm ( ophthalmic migraine ) Miscellaneous Miscellaneous Uhthoff’s phenomenon, classic migraine Uhthoff’s phenomenon, classic migraine

8. Clinical Features: Symptoms Abrupt or gradual monocular* visual loss, progressing from peripheral toward center of field Abrupt or gradual monocular* visual loss, progressing from peripheral toward center of field +/- descending/ ascending shade, partial or complete +/- descending/ ascending shade, partial or complete ‘looking through fog’ ‘looking through fog’ Visual disturbance: Dark, foggy, gray, white Visual disturbance: Dark, foggy, gray, white Minutes (1-5 minutes, occasionally longer); full resolution takes 10-20 minutes Minutes (1-5 minutes, occasionally longer); full resolution takes 10-20 minutes Painless Painless Stereotyped Stereotyped Usually occurs in isolation Usually occurs in isolation * may be difficult to distinguish monocular from binocular visual loss

9. Clinical Features: Retinal findings Transient retinal ischemia Often normal Often normal “boxcar-ing” (segmentation of blood columns resulting from stasis) “boxcar-ing” (segmentation of blood columns resulting from stasis) Engorgement of veins Engorgement of veins Swelling of retina Swelling of retina Retinal embolus Retinal embolus

10. Clinical features: Retinal findings Acute infarction Opaque and gray (early) Opaque and gray (early) “bright plaques” of cholesterol or other microemboli; may persist weeks to years “bright plaques” of cholesterol or other microemboli; may persist weeks to years Cotton-wool spot Cotton-wool spot Segmental arteriolar mural opacification Segmental arteriolar mural opacification Optic disc pallor, arteriolar narrowing (late) Optic disc pallor, arteriolar narrowing (late)

11. Hollenhorst Plaque Retina and Vitreous, Basic and Clinical Science Course, AAO 1996

12. Cotton-wool Spot Retina and Vitreous, Basic and Clinical Science Course, AAO 1996

13. Pathophysiology Atheromatous degeneration and stenosis of the cervical carotid arteries Atheromatous degeneration and stenosis of the cervical carotid arteries Estimated 27% - 67% w/ amaurosis or retinal strokes Estimated 27% - 67% w/ amaurosis or retinal strokes Retinal emboli Retinal emboli Cholesterol crystals Cholesterol crystals Platelet aggregates Platelet aggregates Fibrin and blood cells Fibrin and blood cells Neutral fat Neutral fat Vasospasm Vasospasm Primary thrombosis of retinal arteries does not occur

14. Pathophysiology Microemboli occludes retinal vessels, then fragment and pass into retinal periphery Microemboli occludes retinal vessels, then fragment and pass into retinal periphery If disaggregation with reconstitution of blood flow does not occur, ischemic damage to the inner retinal layers may be irreversible If disaggregation with reconstitution of blood flow does not occur, ischemic damage to the inner retinal layers may be irreversible

15. Branch Retinal Artery Occlusion Retina and Vitreous, Basic and Clinical Science Course, AAO 1996

16. Evaluation: Transient Monocular Blindness Consider disorders with greatest morbidity and most common disorders Consider disorders with greatest morbidity and most common disorders Consider age, stereotypy of events Consider age, stereotypy of events Physical exam (blood pressure, carotid/cardiac exam) Physical exam (blood pressure, carotid/cardiac exam) Ophthalmologic Exam Ophthalmologic Exam Visual acuity, visual fields, relative afferent pupil defect Visual acuity, visual fields, relative afferent pupil defect dilated fundus exam (emboli, anomalous discs) dilated fundus exam (emboli, anomalous discs) Visual fields Visual fields Electroretinogram – diminished B-wave amplitude Electroretinogram – diminished B-wave amplitude

17. Evaluation: Transient Monocular Blindness Under age 40 Migraine history, family Migraine history, family Echocardiogram w/ bubble Echocardiogram w/ bubble CBC, ESR, ANA, antiphospholipid antibodies CBC, ESR, ANA, antiphospholipid antibodies stop birth control pill stop birth control pill stop smoking stop smoking Over age 40 History for giant cell arteritis, polymyalgia, coronary artery disease, stroke & risk factors History for giant cell arteritis, polymyalgia, coronary artery disease, stroke & risk factors ESR, Creactive Protein if older than 50) ESR, Creactive Protein if older than 50) Carotid Doppler Carotid Doppler Echocardiogram w/ bubble Echocardiogram w/ bubble MRA, CT angiography MRA, CT angiography Fluorescein angiogram Fluorescein angiogram Carotid angiography Carotid angiography

18. Cerebrovascular disease A spectrum of signs, symptoms, and stroke risks Asymptomatic Asymptomatic w/ signs of atherosclerotic Cerebrovascular disease Symptomatic Atherosclerotic Cerebrovascular disease Low risk High risk

19. Amaurosis Fugax and Stroke Risk Isn’t if funny that I went blind in the wrong eye” CM Fisher. Transient monocular blindness associated with hemiplegia. Archives Ophthalmology, 1952. What is the relationship of AF and the other ocular ischemic syndromes to the carotid arteries?

20. Amaurosis Fugax (AF) & Stroke Risk Early studies and reports uncontrolled Early studies and reports uncontrolled Different populations Different populations Causes aggregated Causes aggregated Best studied ocular ischemic syndrome Best studied ocular ischemic syndrome Prognosis following AF considered more favorable than TIA, unless severe stenosis Prognosis following AF considered more favorable than TIA, unless severe stenosis Prognosis altered by carotid endarterectomy? Prognosis altered by carotid endarterectomy? Stroke risk estimated 2-4% prior to NASCET Stroke risk estimated 2-4% prior to NASCET

21. Carotid Endarterectomy (CEA): Historical Perspective 1954: CEA introduced 1959-70: Joint Study of Extracranial Arterial Occlusion surgery: 32% stroke risk surgery: 32% stroke risk medical: 39% stroke risk medical: 39% stroke risk operative M&M of 11.4% operative M&M of 11.4% CEA benefit if 3% morbidity CEA benefit if 3% morbidity 1970: 15,000 operations/yr 1980s: 100,000 operations/yr Practical Neurology, Vol 4, 2005.

22. NASCET 1987-1996 North American Symptomatic Carotid Endarterectomy Trial (NASCET) 2885 patients enrolled ; TIA/stroke 120 days 2885 patients enrolled ; TIA/stroke 120 days 1583 patients(54.9%) -- TIA 1583 patients(54.9%) -- TIA 1302 patients (45%) – nondisabling stroke 1302 patients (45%) – nondisabling stroke carotid stenosis; angio confirmed carotid stenosis; angio confirmed moderate (30-69%) ; severe (70-99%) moderate (30-69%) ; severe (70-99%) Established CEA over medical RX in patients with high grade stenosis (>70%) Established CEA over medical RX in patients with high grade stenosis (>70%)

23. NASCET MedicalSurgicalAbsoluteDifference Rel Risk Reduction NNT 70-99% 70-99%26.0%9.0%17% 65% 8 50-70% 50-70%22%16% 6% 6% 39% 15 Cumulative risk for ipsilateral stroke in symptomatic Carotid Endarterectomy trials at 2 years < 50%, CEA not better than ASA (aspirin)

24. NASCET: Amaurosis & Stroke Risk The Risk of Stroke in Patients With First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology. 1995. The Risk of Stroke in Patients With First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology. 1995. Prognosis after Transient Monocular Blindness Associated with Carotid-Artery Stenosis. NEJM. 2001 Prognosis after Transient Monocular Blindness Associated with Carotid-Artery Stenosis. NEJM. 2001

25. NASCET Medical Subgroup : High grade stenosis 129 patients with first TIA 129 patients with first TIA 59 retinal TIAs (RTIAs) 59 retinal TIAs (RTIAs) 70 with hemispheric TIAs (HTIAs) 70 with hemispheric TIAs (HTIAs) Characterize the features and course of subgroups with high grade stenosis Characterize the features and course of subgroups with high grade stenosis Compare outcomes with RTIAs to HTIAs Compare outcomes with RTIAs to HTIAs Average follow-up: 19months Average follow-up: 19months Arch Neurol. 1995; 52

26. NASCET Medical Subgroup : High Grade Stenosis HTIAs: older, higher risk factors HTIAs: older, higher risk factors RTIAs: higher risk for smoking RTIAs: higher risk for smoking Longer delay for medical treatment for RTIAs (48 days vs 15.2 days ) Longer delay for medical treatment for RTIAs (48 days vs 15.2 days ) Estimates for stroke risk at 2 years Estimates for stroke risk at 2 years RTIAs 16.6% +/- 5.5% RTIAs 16.6% +/- 5.5% HTIAs 43.5% +/- 6.7% HTIAs 43.5% +/- 6.7% Arch Neurol. 1995; 52

27. NASCET Medical Subgroup: Risk Factors w/ High Grade Stenosis RTIA (n=59) RTIA (n=59) HTIA (n=70) HTIA (n=70) Mean age 61.5 61.5 66.9 66.9 Male gender 59% 59% 70% 70% hypertension 59.3% 59.3% 64.3% 64.3% diabetes 17% 17% 21% 21% heart attack 6.8% 6.8% 18.6% 18.6% Angina 27.1% 27.1% 40% 40% Claudication 13.6% 13.6% 15.7% 15.7% Hyperlipidemia 30.5% 30.5% 40.0% 40.0% Smoking (5yrs) 61% 61% 51.4% 51.4% Antiplatelet Rx 20.3% (delayed, 48d) 25.7% (15 d) 25.7% (15 d)

28. NASCET Medical Subgroup: Outcomes w/ High Grade Stenosis RTIA (n=59) HTIA (n=70) Ipsilateral stroke, minor 7 17 17 major major 0 8 retinal retinal 1 2 Contralateral stroke 0 0 retinal stroke retinal stroke 0 1 Vascular death 0 2 MI 1 2 Arch Neurol. 1995; 52

29. NASCET Surgical Subgroup: Outcomes 328 surgically treated patients 328 surgically treated patients 5.8% perioperative stroke 5.8% perioperative stroke 9% 2 year stroke rate 9% 2 year stroke rate 54 surgical treated patients with RTIA 54 surgical treated patients with RTIA 2 minor perioperative strokes (4%) 2 minor perioperative strokes (4%) One stroke (2%) 17 months post-op One stroke (2%) 17 months post-op 6.8% stroke risk at 2 years 6.8% stroke risk at 2 years

30. NASCET: Amaurosis & Stroke Risk The Risk of Stroke in Patients With First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology. 1995. The Risk of Stroke in Patients With First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology. 1995. Prognosis after Transient Monocular Blindness Associated with Carotid-Artery Stenosis. NEJM. 2001 Prognosis after Transient Monocular Blindness Associated with Carotid-Artery Stenosis. NEJM. 2001

31. NASCET Subgroups: Prognosis of TMB (transient monocular blindness) Compared 397 patients with isolated TMB (medical and surgical subgroups) to 829 patients with hemispheric TIAs Compared 397 patients with isolated TMB (medical and surgical subgroups) to 829 patients with hemispheric TIAs Compared stroke risk for TMB and HTIAs in patients with high grade stenosis with and without collaterals Compared stroke risk for TMB and HTIAs in patients with high grade stenosis with and without collaterals Identified risk factors for ipsilateral stroke in patients with carotid stenosis > 50% Identified risk factors for ipsilateral stroke in patients with carotid stenosis > 50%

32. NASCET Subgroups: Prognosis of TMB HTIAs: older, higher risk factors HTIAs: older, higher risk factors TMB: higher risk for smoking, increased high grade stenosis, higher incidence of collaterals TMB: higher risk for smoking, increased high grade stenosis, higher incidence of collaterals Medically treated TMB had 3 year ipsilateral stroke risk approx ½ HTIA Medically treated TMB had 3 year ipsilateral stroke risk approx ½ HTIA Surgically treated TMB showed 30-day stroke rate ½ of HTIA (3.6% vs 7.4%) Surgically treated TMB showed 30-day stroke rate ½ of HTIA (3.6% vs 7.4%) Stroke risk increased with degree of carotid stenosis and specific stroke risk factors Stroke risk increased with degree of carotid stenosis and specific stroke risk factors

33. NASCET Med/Surg Subgroups : Isolated TMB vs TIA ICA stenosis ICA stenosis TMB TMB (N=397) (N=397) Hemispheric TIA (N=829) (N=829) < 50% < 50% 28.5% 28.5% 50% 50% 50-69% 50-69% 30.5% 30.5% 29.8% 29.8% 70-94% 70-94% 31.7% 31.7% 16% 16% Near occlusion Near occlusion 9.3% 9.3% 3.7% 3.7% NEJM. Vol 345,2001

34. NASCET Med/Surg Subgroups : Isolated TMB vs TIA TMB TMB (N=397) (N=397) Hemispheric TIA (N=829) Collateral Circulation * 24.2% 24.2% 6.9% 6.9% *Collateral circulation = filling of the ACA, PComA, or ophthalmic artery NEJM. Vol 345,2001

35. NASCET Med/Surg Subgroups : Three year stroke risk

36. NASCET Medical Subgroups : Collaterals & 3 year stroke risk TMB w/ collaterals (N=25) 2.9% TMB w/ collaterals (N=25) 2.9% HTIAs w/ collaterals (N=30) 16.7% HTIAs w/ collaterals (N=30) 16.7% TMB w/o collaterals (N=44) 16.0% TMB w/o collaterals (N=44) 16.0% HTIAs w/o collaterals (N=69) 44.4% HTIAs w/o collaterals (N=69) 44.4% NEJM. Vol 345,2001

37. NASCET Med/surg Subgroup : Isolated TMB (N=397) Median # of TMB episodes: 3 (1-7) Median # of TMB episodes: 3 (1-7) 5% had >45 episodes 5% had >45 episodes Median duration : 4 minutes (1-10min) Median duration : 4 minutes (1-10min) 5% had episode > 60min 5% had episode > 60min No correlation to carotid stenosis No correlation to carotid stenosis 3 year stroke risk (N= 198, medical) 3 year stroke risk (N= 198, medical) 1 episode -- 10.4 % 1 episode -- 10.4 % >2 episodes-- 8.2 % >2 episodes-- 8.2 % NEJM. Vol 345,2001

38. NASCET Medical Subgroup : Stroke Risk Factors TMB with > 50% stenosis TMB with > 50% stenosis Age > 75 Age > 75 Male sex Male sex h/o hemispheric TIA or stroke h/o hemispheric TIA or stroke h/o intermittent claudication h/o intermittent claudication Ipsilateral stenosis 80-94% Ipsilateral stenosis 80-94% No collaterals on angiography No collaterals on angiography NEJM. Vol 345,2001

39. Amaurosis Fugax & Stroke Risk: NASCET findings TMB has high stroke risk if high grade carotid stenosis, though less than HTIAs TMB has high stroke risk if high grade carotid stenosis, though less than HTIAs Higher collaterals improve prognosis Higher collaterals improve prognosis Age, gender, h/o stroke/TIA,& claudication may alter stroke risk Age, gender, h/o stroke/TIA,& claudication may alter stroke risk CEA reduces stroke risk if surgeon has low complication rate CEA reduces stroke risk if surgeon has low complication rate Perioperative risk for stroke and death was lower in patients with TMB Perioperative risk for stroke and death was lower in patients with TMB

40. Spectrum of clinical stroke risk Amaurosis Fugax (2% -?6%) TIA (3.7%) Minor Stroke (6.1%) Major Stroke (9%) Low risk High risk Estimated Annual Stroke Rates Asymptomatic Stenosis (2%) Asymptomatic Bruit (2%) AION BRAO Asymptomatic retinal emboli Acute & Chronic Ocular Ischemic Syndrome

41. Conclusions Amaurosis Fugax is caused by ischemia to the retina, often associated with carotid stenosis, and is a risk factor for stroke Amaurosis Fugax is caused by ischemia to the retina, often associated with carotid stenosis, and is a risk factor for stroke Prognosis is better for patients with amaurosis fugax treated both medically and surgically compared to patients with hemispheric TIAs. Prognosis is better for patients with amaurosis fugax treated both medically and surgically compared to patients with hemispheric TIAs. Amaurosis Fugax should be recognized, with strong consideration for carotid endarterectomy with high grade carotid stenosis, vascular risk factors present, and low complication rate of procedure in your center Amaurosis Fugax should be recognized, with strong consideration for carotid endarterectomy with high grade carotid stenosis, vascular risk factors present, and low complication rate of procedure in your center

42. References Benavente, et al. Prognosis after Transient Monocular Blindness Associated with Carotid Artery Stenosis. NEJM, Vol 345(15), 2001. Benavente, et al. Prognosis after Transient Monocular Blindness Associated with Carotid Artery Stenosis. NEJM, Vol 345(15), 2001. Easton and Wilterdink. Carotid Endarterectomy: Trials and Tribulations. Ann Neurology. Vol 35.1994. Easton and Wilterdink. Carotid Endarterectomy: Trials and Tribulations. Ann Neurology. Vol 35.1994. Glaser. Neuro-ophthalmology. 3 rd ed. 1999 Glaser. Neuro-ophthalmology. 3 rd ed. 1999 Mizener, et al. Ocular Ischemic Syndrome. Ophthalmology, Vol 104, 1997. Mizener, et al. Ocular Ischemic Syndrome. Ophthalmology, Vol 104, 1997. Rizzo. Neuroophthalmologic Disease of the Retina. Neuro-ophthalmology. Rizzo. Neuroophthalmologic Disease of the Retina. Neuro-ophthalmology.

43. References Sacco et al. Guidelines for Prevention of Stroke in patients with ischemic stroke or transient ischemic attack. Stroke. Feb 2006. Sacco et al. Guidelines for Prevention of Stroke in patients with ischemic stroke or transient ischemic attack. Stroke. Feb 2006. Streifler, et al. The Risk of Stroke in Patients with First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology, Vol 52(3), 1995. Streifler, et al. The Risk of Stroke in Patients with First-Ever Retinal vs Hemispheric Transient Ischemic Attacks and High-grade Carotid Stenosis. Archives of Neurology, Vol 52(3), 1995. Wilterdink and Easton. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurology. Vol 49. 1992 Wilterdink and Easton. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurology. Vol 49. 1992