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Stroke of the Eye Central Retinal Artery Occlusion To Give or Not to Give” IV tPA Difficult stroke presentations: Case Based Discussion Ayumi Ludwig, M.D. Neurohospitalist McKay-Dee Hospital Stroke Medical Director

Stroke of the Eye - IntermountainPhysician€¦ · Retinal artery occlusion (“Stroke of the eye”) ... Retinal survival time: Animal studies 2 studies with rhesus monkeys: •

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Page 1: Stroke of the Eye - IntermountainPhysician€¦ · Retinal artery occlusion (“Stroke of the eye”) ... Retinal survival time: Animal studies 2 studies with rhesus monkeys: •

Stroke of the EyeCentral Retinal Artery Occlusion

“To Give or Not to Give” IV tPADifficult stroke presentations: Case Based Discussion

Ayumi Ludwig, M.D.

NeurohospitalistMcKay-Dee Hospital Stroke Medical Director

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Financial Disclosure

• (Sadly) None

Page 3: Stroke of the Eye - IntermountainPhysician€¦ · Retinal artery occlusion (“Stroke of the eye”) ... Retinal survival time: Animal studies 2 studies with rhesus monkeys: •

Learning Objectives

• Learn the possible causes of acute monocular blindness

• Learn the causes of retinal artery occlusion

• Learn the studies on Intravenous (IV) tPA therapy on central retinal artery occlusion

• Learn the studies on Intra-arterial (IA) tPA therapy on central retinal artery occlusion

• Think about what you would do for patients presented with acute monocular blindness

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Stroke Alert Case: Sudden onset of monocular Blindness

• 80 yo RH woman with PMHx of HTN and HLD presented with sudden onset of blindness in the right eye. She could make out of shadows but couldn’t count fingers.

• Last seen normal: 16:30

• Stroke alert activated: 17:01

• NIHSS 2? (but not hemianopsia)

• Eye exam: limited fundus exam, normal pupillary reflex, no RAPD (relative afferent pupillary defects)

• CT brain – unremarkable

• CTA head and neck – mild atherosclerosis, no flow limiting stenosis, patent right ophthalmic artery

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Is this a stroke for sure?Am I supposed to give IV tPA?

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Causes of Acute Monocular Vision Loss without Eye Pain1

Amaurosis fugax

Retinal artery occlusion (“Stroke of the eye”)

Retinal vein occlusion

Retinal detachment

Arteritic ischemic optic neuropathy (AION)/Giant cell arteritis

Nonarteritic ischemic optic neuropathy (NION)

Macular hemorrhage

Vitreous hemorrhage

Ocular migraine

Psychogenic/Conversion disorder

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Causes of Acute Vision Loss WITH Eye Pain1:

Acute angle-closure glaucoma

Corneal ulcer

Optic neuritis (usually with pain)

Endopthalmitis

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Causes of Acute Monocular Vision Loss without Eye Pain1

Causes Suggestive Findings

Amaurosis fugax Monocular blindness lasting minutes to hours (typically < 5 min when due to CVA) – DDx: ischemia, retinal vein occlusion, optic nerve compression, papilledema, other ocular causes.

Retinal Artery Occlusion

Nearly instantaneous onset, pale retina, cherry-red fovea, risk factors for vascular disease

Arteritic AION (anteriorischemic optic neuropathy)/Giant cell arteritis

Headache, jaw or tongue claudication, temporal artery tenderness or swelling, pale and swollen disk with surrounding hemorrhages, occlusion of retinal artery or its branches, proximal myalgia with stiffness (polymyalgia rheumatica)

Nonarteritic AION

Optic disk edema and hemorrhages, sometimes loss of inferior and central visual fields, Risk factors: DM, HTN, hypotensive episode

Macular hemorrhage

Blood within or deep to retina in and around the macula

Retinal artery occlusion

AION

Macular Hemorrhage

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Causes of Acute Monocular Vision Loss without Eye Pain1

Causes Suggestive Findings

Retinal Detachment Recent increase in floaters, photopsias(flashing lights), or both visual field defect, retinal folds

Retinal Vein Occlusion

Frequent, multiple, widely distributed retinal hemorrhagesRisk factors (eg, diabetes, hypertension, hyperviscosity syndrome, sickle cell anemia)

Vitreous hemorrhage

Previous floaters or spider web in visionRisk factors (eg, diabetes, retinal tear, sickle cell anemia, trauma)

Ocular Migraine Scintillating scotomata, mosaic patterns, or complete loss of vision lasting usually 10–60 min and often followed by headache. Often in young patients.

Retinal detachment

Retinal vein occlusion

Vitreous hemorrhage

Can any of these be a contraindication for IV tPA?

Can you differentiate these based on your exam??

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Retinal Artery OcclusionCentral Retinal Artery Occlusion (CRAO)Branch Retinal Artery Occlusion (BRAO)

CRAO Incidence: 1 in 100,0002

Present with acute, painless loss of monocular vision

Central retinal artery supplies the inner retina and the surface of optic nerve

15-30% of people have cilioretinal artery also supplying the inner retina

May spare central vision11

80% of patients will have visual acuity < 20/400 8

BRAO

CRAO

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Causes of Retinal Artery Occlusion

Carotid artery atherosclerosis (10-30%) – most common

Cardiogenic embolism – second most common

Small artery disease – older patients, DM, HTN

Vascular disease (carotid artery dissection, fibromuscular dysplasia, radiation injury, Moyamoya, Fabry’s)

Hematologic (sickle cell, hypercoagulable state)

Inflammatory (Giant cell arteritis – 5%, Susac syndrome, SLE, polyarthritis nodosa, Wegener’s granulomatosis

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Conservative Treatments of CRAO

Ocular massage

Anterior chamber paracentesis (sudden drop in ocular pressure may dislodge the embolus)

IV acetazolamide, IV mannitol (reduction of ocular pressure)

Vasodilator medications (Penoxifilline, nitroglycerin, isosorbide mononitrate)

Hyperbaric oxygen therapy

• ***None of these therapies are proven to be effective9, 14

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Acute Treatments of CRAO

Currently no proven treatment/guidelines exists

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So What would you do???

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Funduscopic exam by ophthalmologist on my patient:

No blood flow to the central retinal artery. Normal optic nerve cup. Normal retina.

It confirmed the diagnosis of retinal artery occlusion (and more importantly, it ruled out other eye pathology).

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Now What???

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Would you give IV tPA?

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I DID

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Stroke Timeline

• LSN: 16:30

• Stroke alert activated: 17:01

• CT head read: 17:15

• CTA head and neck read: 17:22

• Ophthalmology consult requested: 17:25

• Was instructed to dilate the pupils

• Total time for ophthalmology consult: ~30 mins

• IV tPA ordered: 18:08

• IV tPA administerd: 18:20 (110 minutes from LSN)

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That feeling when you gave tPA and you are not sure if you did the right thing…

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Did it work???

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MRI brain next day

Right cerebellar infarction

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What do we know about acute treatment for CRAO

“Stroke of the eye”?

All the major studies have been done by ophthalmologists

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Retinal survival time: Animal studies

2 studies with rhesus monkeys:• CRAO was produced in 63 eyes of rhesus monkeys. Monkey retina

can recovered well after ischemia of 97 minutes. After 105 minutes, the retinal damage was irreversible (1980)1.

• CRAO was produced in 38 rhesus monkeys. Eyes with CRAO for 97 minutes showed practically no damage. The degree of permanent damage was associated with the duration of CRAO. CRAO lasting for 240 minutes resulted in massive irreversible damage (2004)2.

1. Hayreh SS, Kolder HE, Weingeist TA. Central retinal artery occlusion and retinal tolerance time. Ophthalmology. 1980 Jan. 87(1):75-8.

2. Hayreh SS, Zimmerman MB, Kimura A, Sanon A. Central retinal artery occlusion. Retinal survival time Exp.EyeRes. 2004; 78:723.

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CRAO and IV tPA #1 (2002, US)

Intravenous Recombinant Tissue-Type Plasminogen Activator Thrombolysis in Treatment of Central Retinal Artery Occlusion7

Method: Prospective study IV tPA (0.9mg/kg, max 90mg) + Anticoagulation with Coumadin and

heparin drip bridge + anterior-chamber paracentesis if intraocular pressure > 12 mmHg.

Inclusion: onset < 24 hours confirmed CRAO diagnosis by ophthalmologist

Results: 12 patients enrolled Mean time to receive tPA 5.75 h (range 2 h to 18 h). 10 patients within

< 6 h. 9 patients received anterior-chamber paracentesis 4 (33%) had >8 Snellen VA lines of improvement 6 (50%) had 2-4 Snellen VA lines of improvement

Complications: 4 developed neovascular glaucoma within 3 to 4 weeks

Conclusion: IV tPA is beneficial. Paracentesis may be beneficial if it’s done in conjunction with IV tPA.

Kattah JC, Wang DZ, Reddy C. Intravenous recombinant tissue-type plasminogen activator thrombolysis in treatment of central

retinal artery occlusion. Arch ophthalmol. 2002;120:1235-1236.

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CRAO and IV tPA #2 (2008, Germany)

Intravenous Thrombolysis With Low-dose Recombinant Tissue Plasminogen Activator in Central Retinal Artery Occlusion6

Method: Prospective study low dose (50mg) IV tPA + IV heparin x 5 days, ASA 100mg QD

Inclusion: onset < 12 hours, VA < 20/100 confirmed CRAO diagnosis by funduscopic exam

Exclusion: Retinal/vitreous hemorrhage Other ocular disease (diabetic retinopathy, macular degeneration)

Results: 28 patients enrolled 32% improved vision (> 3 lines in Snellen visual acuity test) When tPA was given within < 6.5 h, 41% of patients achieved VA

20/50 or better, and 53% achieved > 3 lines VA improvement.

Conclusion: Negative study, BUT IV t-PA can improve vision for patients with CRAO if given < 6.5 hours after the onset of symptoms.

Hattenbach LO, et al. Intravenous thrombolysis with low-dose recombinant tissue plasminogen activator in central retinal artery occlusion. Am J Opthalmol. 2008;146:700-706

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CRAO and IV tPA #3 (2011, Australia)

Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion: Report from a randomized, controlled trial 5

METHODS: A placebo-controlled, double-blinded, randomized trial

Inclusion: CRAO confirmed with funduscopic exam by ophthalmologist < 24 h within onset of symptoms

Exclusion: Temporal arteritis by clinical assessment of ESR

Demographics:

Chen CS et al. The efficacy of intravenous tissue plasminogen activator in central retinal artery occlusion: Report from a randomized, controlled trial. Stroke. 2011;42:2229-2234

tPA(n=8)

Placebo(n=8)

p value

Mean age 73±8 67±9 0.18

Time to presentation (h) 9.1±6.1 3.9±2.7 0.04

Time to treatment (h) 14.4±6.5 7.3±3.0 0.01

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CRAO and IV tPA #3 (2011, Australia) Cont’d

Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion: Report from a randomized, controlled trial 5

Results:

16 patients enrolled

2 out of 8 (25%) of the tPA group had transient improvement in VA at 1 wk. These patients received IV tPA at 4.5 h and 6 h from the onset.

The improvement was not sustained at 6 months

Adverse reaction of tPA: 1 patient had ICH, 1 patient developed retinal revisualization and vitreous hemorrhage

Early termination of the study due to 1 patient with significant ICH s/p tPA.

Conclusion:

Time window for intervention is likely < 6h.

Reocclusion is a potential problem and it may require adjuvant anticoagulation.

Chen CS et al. The efficacy of intravenous tissue plasminogen activator in central retinal artery occlusion: Report from a randomized, controlled trial. Stroke. 2011;42:2229-2234

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CRAO and IV tPA #4 (2016, China)

Observation on therapeutic efficacy of rt-PA intravenous thrombolysis combined with compound anisodine injection on central retinal artery occlusion

Method: Randomized trial 4 treatment groups and 3 “control” groups with different combinations

of IV tPA, sublingual nitroglycerin, retrobulbar atropine injection, IV vitamin, oclular massage, methazolamide, mecobalamine, ozagrel, etc.. It’s a mess.

48 CRAO patients, onset < 72 h.

Results: VF defect 74±13% in the control group, 35±16% in the treatment group (p<0.01)

Wu XJ, Gao F, Liu X, Zhao Q. Observation on therapeutic efficacy of rt-PA

intravenous thrombolysis combined with compound anisodine injection on

central retinal artery occlusion. Experimental and therapeutic medicine.

2016; 12:2617-2621.

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What about IA tPA?Is that effective??

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CRAO and IA Finbrinolysis #1(2002, Germany)

Prognosis of Central Retinal Artery Occlusion: Local Intraarterial Fibrinolysis vs. Conservative Treatment15

Method: Retrospective study Conservative treatment (n=116) IA urokinase/rtPA + heparin gtt x 2 d + ocular massage (n=62) Primary outcome: VA improvement with > 1 line on the Snellen chart

Inclusion: Confirmed CRAO by ophthalmologists < 13 days from the onset of symptoms

Time to Treatment: Conservative – median 9 h (mean 24.2±40.4 h) IA tPA – median 9 h (mean 10.8±9.5 h)

Results: Conservative group – 29% patients improved. No differences based

on the onset to treatment time. IA tPA group – 52% patients improved, Better results if treated <6h

(76% patient improved). 2 thrombotic stroke complications due to catheter manipulation.

SchmLocal intraarterial fibrinolysis versus conservative treatment. Am J Neuroradiol. 2002;23:1301-1307.idt DP, Schulte-Monting J, Schumascher M, Prognosis of central retinal artery occlusion:

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CRAO and IA tPA #2 (EAGLE, 2009)

Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion17, 20

Method: Randomized, controlled, prospective, multi-center study Control group – conservative treatments, heparin BID x 5d Treatment – IA rtPA + heparin BID 5 days

Inclusion: CRAO with < 20 h from onset, VA < 0.32

Exclusion: BRAO, cilioretinal arteries supplying retina, proliferative diabetic retinopathy, intraocular pressure > 30mmHg, ESR > 30, etc.

Results: 84 patients enrolled (conservative n=40, IA tPA n=44) Time to treatment: conservative 10.99±5.49 h, IA tPA 12.78±5.77 h No significant difference between IA tPA vs. conservative therapy (60% vs.

57.1%). Higher adverse effects in the IA tPA vs. conservative therapy (37% vs.

4.3%). Severe complications in the treatment group: 2 symptomatic ICH cases. Early termination of the study due to similar efficacy and higher adverse

effects in the IA tPA group.

Feltgen N, Neubauer A, Jurklies B, et al. Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion: design issues and implications. EAGLE Study report no.1. Graefe’s Arch Clin Exp Ophthalmol. 2006; 244:950-956.

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CRAO and IA tPA #3 (2008, Johns Hopkins)

Local intraarterial fibrinolysis administered in Aliquots for the treatment of central retinal artery occlusion: The Johns Hopkins Hospital16

Methods: nonrandomized interventional study, IA tPA vs. conservative tx

IA tPA stopped when patency of the central retinal artery is clinically established, or max tPA 20mg

Inclusion: CRAO confirmed by ophthalmologist using ophthalmoscopy < 15 h from the onset

Results: 42 patients enrolled Time to IA tPA: 9.3±2.9 h Conservative: n=21, 33% had improvement in VA > 1 line IA tPA: n=31, 76% had improvement in VA > 1 line Multivariate logistic regression analysis: The IA tPA group was 36 times

more likely to have improvement in VA (p=0.0001). Post hoc analysis showed the IA tPA group was 13 times more likely to

have improvement in VA of > 3 lines, and 4.9 times more likely to have final VA of 20/200 or better.

Complications: 2 groin hematomas Conclusions: Local intraarterial fibrinolysis is associated with an

improvement in visual acuity and has few side effects.

Aldrich EM, et al. Local intraarterial fibrinolysis administered in Aliquots for the treatment of central retinal artery occlusion: The Johns Hopkins Hospital Experience. Stroke. 2008;399:1746-1750.

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CRAO and IA tPA #4 (2013, Korea)

Efficacy and Safety of Intra-Arterial Thrombolysis in Central Retinal Artery Occlusion18

Methods: retrospective study

Inclusion: symptom duration ≤ 24h (or ≤7d for incomplete CRAO)

Results:

101 enrolled, conservative group (n=44), IA tPA group (n=57)

Time to treatment: conservative 35.9±27.6h, IA tPA 22.7±30.6h

For incomplete CRAO, the IA tPA group had greater VA improvement after 1 month

No significant difference in total or subtotal CRAO.

Complications: 8% insignificant cerebral infarcts

Ahn SJ, Kim JM, Hong JH, Woo SJ, Ahn J, Park KH, Han MK, Jung C. Efficacy and safety of intra-arterial thrombolysis in central retinal artery occlusion. Invest Ophthalmol Vis Sci. 2013:54:7746-7755.

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In Summary

There is no consensus treatment guidelines for acute CRAO exists currently.

Conservative treatments have not shown to be effective.

Observational studies suggest efficacy of early intervention with both IV and IA tPA for acute treatment of CRAO.

Randomized studies for IV tPA (Australian study) and IA tPA (EAGLE, European study) failed to demonstrate a significant improvement in visual acuity and terminated early due to adverse effects.

But they also had some study design flaws.

ie; the inclusion criteria (time of onset < 24h and < 20h).

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“BE FAST” -- stroke alerts on CRAO/BRAO patients

What do we need to rule out before we give IV tPA? –Challenges of funduscopic exam in ED by neurologists

Is STAT ophthalmology consult worth the time?

All the studies have been done by ophthalmologists and thorough funduscopic exam was done prior to intervention.

Would you give IV tPA to a patient with CRAO? BRAO?

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References:1. Some causes of acute vision loss.

http://www.merckmanuals.com/professional/eye-disorders/symptoms-of-ophthalmologic-disorders/acute-vision-loss#v951406

2. Varma DD, Cugati S, Lee AW, Chen CS. A review of central retinal artery occlusion: clinical presentation and management. Eye. 2013;27(6):688-697.

3. Hayreh SS, Kolder HE, Weingeist TA. Central retinal artery occlusion and retinal tolerance time. Ophthalmology. 1980 Jan. 87(1):75-8.

4. Hayreh SS, Zimmerman MB, Kimura A, Sanon A. Central retinal artery occlusion. Retinal survival time Exp.Eye Res. 2004;78:723.

5. Chen CS, Lee AW, Campbell B, Lee T, Pain M, et al. The efficacy of intravenous tissue plasminogen activator in central retinal artery occlusion: Report from a randomized, controlled trial. Stroke. 2011;42:2229-2234

6. Hattenbach LO, et al. Intravenous thrombolysis with low-dose recombinant tissue plasminogen activator in central retinal artery occlusion. Am J Opthalmol. 2008;146:700-706

7. Kattah JC, Wang DZ, Reddy C. Intravenous recombinant tissue-type plasminogen activator thrombolysis in treatment of central retinal artery occlusion. Arch ophthalmol. 2002;120:1235-1236.

8. Hayreh SS, ,Zimmerman MB. Central retinal artery occlusion: Visual outcome. Am J Opthalmol. 2005;140(3):376-391

9. Fraser SG, Adams W. Interventions for acute non-arteritic central retinal artery occlusion. Cochrane Database Syst Rev. 2009;1:CD001989

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References:10. Schrag M, Youn T, Schindler J, Krishner H, Dgreer D, Intravenous fibrinolytic

therapy in central retinal artery occlusion: A patient-level meta-analysis. JAMA Neurol. 2015;72(10):1148-1154.

11. Cugati et al., Treatment options for central retinal artery occlusion. Current treatment options in neurol. 2013;15:63-77.

12. Biosse V, Clavetti O, Bruce BB, Newman NJ. Thrombolysis for central retinal artery occlusion. J Neuro Ophthalmol. 2007;27:215-30.

13. Paolini SL, Kenmuir CL, Thrombolytic treatment of central retinal artery occlusion (CRAO). J Neuro and neuroscience. 2015;6:1-3.

14. Mueller AJ, Neubauer AS, Shaller U, Kampik A. Evaluation of minimally invasive therapies and rationale for a prospective randomized trial to evaluate selective intraarterial lysis for clinically complete central retinal artery occlusion. Arch Ophthalmol. 121:1377-1381.

15. Schmidt DP, Schulte-Monting J, Schumascher M, Prognosis of central retinal artery occlusion: Local intraarterial fibrinolysis versus conservative treatment. Am J Neuroradiol. 2002;23:1301-1307.

16. Aldrich EM, et al. Local intraarterial fibrinolysis administered in Aliquots for the treatment of central retinal artery occlusion: The Johns Hopkins Hospital Experience. Stroke. 2008;399:1746-1750.

17. Feltgen N, Neubauer A, Jurklies B, et al. Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion: design issues and implications. EAGLE Study report no.1. Graefe’s Arch Clin Exp Ophthalmol. 2006; 244:950-956.

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References:18. Ahn SJ, Kim JM, Hong JH, Woo SJ, Ahn J, Park KH, Han MK, Jung C. Efficacy

and safety of intra-arterial thrombolysis in central retinal artery occlusion. Invest Ophthalmol Vis Sci. 2013:54:7746-7755.

19. Wu XJ, Gao F, Liu X, Zhao Q. Observation on therapeutic efficacy of rt-PA intravenous thrombolysis combined with compound anisodine injection on central retinal artery occlusion. Experimental and therapeutic medicine. 2016; 12:2617-2621.

20. Feltgen N, Neubauer A, Jurklies B, et al. Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE). Treatment of the central retinal artery occlusion: Thrombolysis versus conservative treatment. GEPRIS. 2009.

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