glaucoma risk factors new considerations

Glaucoma Risk Factors: New Considerations

M. Chaglasian, OD 1

Glaucoma Risk Factors:New Considerations

Michael Chaglasian, O.D.Illinois Eye Institute

Illinois College of Optometry

[email protected]

Disclosure Statement

Honorarium, Speaker, Consultant, Research Grant:– Aerie, Alcon, Allergan, B+L, Carl Zeiss, Glaukos,

Heidelberg, Novartis, Reichert, Topcon,

Outline

Risk Factors for Glaucoma Overview– Age, Race, Family History, Systemic Disease,

IOP, Optic Nerve Head

Key Elements for Today’s Practice– Central Corneal Thickness

– Corneal Hysteresis

– Ocular Perfusion Pressure

Why Does Glaucomatous Optic Neuropathy Develop?

Risk Factors

Age and Aging Family History IOP CSF CCT, CH Disc Hemorrhage Low Ocular Perfusion

Pressure

Stressors

Metabolic Dysfunction

Immune Compromise

Oxidative Stress Genetic Biomechanical Ischemic

What effect do Risk Factors have?

Stressors

Metabolic Dysfunction Immune Compromise Oxidative Stress Genetic Biomechanical Ischemic

Effects

Glial Activation

Myofibroblast Activation

Cytokine Production

Stress Response Enzymes

RGC Death by Apoptosis

ECM Remodeling

John G. Flanagan PhD, MCOptom, FAAO

Risk Assessment in Clinical Practice


M. Chaglasian, OD 2

Glaucoma Risk FactorsEvidence Based

Age: – Most commonly occurs after age 60 (risk increases with age)

– Earlier in those with a Family History

Race: – African, Hispanic, Asian

Family history– First degree relatives (OR 2.9; Tielsch et al)

Elevated Intraocular pressure

Other ocular factors:– Thin central corneal thickness, Corneal Hysteresis

– Secondary Mechanisms

Systemic factors:– Diabetes, Hypertension, Low Perfusion Pressure,

LALES

The overall prevalence of open-angle glaucoma among Latinos in this study was nearly 5 percent.– 8% for those 60-70 years old

– 15% for those 70=+

» Nearly four percent of Latinos had ocular hypertension, a risk factor for glaucoma.

Los Angeles Latino Eye Study 2006

Age-Specific Prevalence of OAGAmong Blacks, Whites, and Hispanics

0

2

4

6

8

10

12

40-49 50-59 60-69 70-79 80-89

BlackHispanicWhite

Quigley HA, et al. Arch Ophthalmol. 2001;119:1819-1826.

%

Age Group

RF’s for Glaucoma: Diabetes

Older Data:

No, not a Risk Factor:– Baltimore Eye Survey

– Barbados Eye Study

– European Glaucoma Prevention Study

– Rotterdam Study

– Visual Impairment Project

Yes, a Risk Factor:– Beaver Dam Eye Study

– Blue Mountains Eye Study

– Nurses’ Health Study

– Los Angeles Latino Eye Study

Progression Risk:– EMGT and AGIS

Progression NOT a Risk:– Barbados Eye Study

Lifestyle Factors

Smoking– No definitive evidence as a RF for

glaucoma

Exercise– Can transiently lower IOP

– No definitive evidence as a RF for glaucoma

Diet– No supporting evidence

Obstructive Sleep Apnea and Glaucoma


M. Chaglasian, OD 3

Sleep Apnea: What Relation to Glaucoma??

(AmJOphthalmol2011;xx:xxx.©2011byElsevierInc.Allrightsreserved.)

Snoring

PLoS One. 2014 Feb 13;9(2):e88949.

Risk Factors for ProgressionFactors OHT Glaucoma Glaucoma Progression

Higher age OHTS, Olmsted AGIS, CIGTS, EMGT

CCT OHTS

C:D ratio OHTS

Diabetes mellitus OHTS (protective) AGIS, CIGTS

Disc hemorrhage CNTGS, EMGT

Female CNTGS

IOP (higher) OHTS EMGT

IOP (follow-up) OHTS CNTGS, EMGT

Male OHTS (univariate) AGIS

PXF EMGT

Race (nonwhite) OHTS CIGTS, CNTGS

Visual field OHTS AGIS (found opposite), EMGT

AGIS = Advanced Glaucoma Intervention Study; CIGTS = Collaborative Initial Glaucoma Treatment Study; CNTGS = Collaborative Normal Tension Glaucoma Study.AGIS = Advanced Glaucoma Intervention Study; CIGTS = Collaborative Initial Glaucoma Treatment Study; CNTGS = Collaborative Normal Tension Glaucoma Study.

IOP Is the Most Prominent and Consistent Glaucoma Risk Factor

• Ocular Hypertension Treatment Study (OHTS)• CCT of less than 555 μ has higher risk• IOP: every 1mmHg higher (>22) increased risk by 10%

• Early Manifest Glaucoma Trial (EMGT)• Every 1mmHg of IOP reduction lowers risk of progression by 10%

• Advanced Glaucoma Intervention Study (AGIS)• IOP always under 18mmHg or a mean of 12mmHg has a

lower risk of progression

• Collaborative Normal-Tension Glaucoma Study • 30% reduction of IOP reduces risk of progression

Are We Just Measuring IOP Incorrectly or is it More Than That?

Ocular Hypertension Study


M. Chaglasian, OD 4

J ne

Primary POAG Endpoints*Log Rank P-value <0.001, Hazard Ratio 0.40, 95% CI (0.27, 0.59)

*through

Prop

ortio

n PO

AG

Medication Observation

Months

Medication reduced incidence of POAG in OHT participants by more than 50% at 5 years from 9.5% in the Observation Group to 4.4% in the Medication Group.

Baseline Predictive Factors for the Development of POAG

Age

IOP

Vertical C/D Ratio

PSD

CCT

OHTS/EG

PachymetryPOAG Endpoints by Central Corneal Thickness and

Baseline IOP (mmHg) in Observation Group* OHTS Data

Baseline IOP (mmHg)

Central Corneal Thickness (microns)

* through 8 Nov 2001

< 23.75

>23.75 to < 25.75

>25.75

< 555 >555 to < 588 >588

17% 9% 2%

12% 10% 7%

36% 13% 6%

Pachymetry: 3 Outcomes

Thin: <555 µ High Risk

Average: 555-588 µ No change in Risk

Thick: >588 µ Low Risk

Applied to patients with ocular hypertension

Do Not Adjust IOP Based on CCT


M. Chaglasian, OD 5

The problem with CCT-basedIOP adjustment

Correction Values

Corneal Thickness (µm) Correction Value

405 7

425 6

445 5

465 4

485 3

505 2

525 1

545 0

565 -1

585 -2

605 -3

625 -4

645 -5

665 -6

685 -7

705 -8

Correction values according to corneal thickness of 545 µm

NOT VALID!

Conversion Charts: don’t really work

Taking Glaucoma risk assessment to the next level:

THE ROLE OF CORNEAL HYSTERESIS

Taking Glaucoma risk assessment to the next level:

THE ROLE OF CORNEAL HYSTERESIS

Michael Chaglasian, ODIllinois Eye Institute Illinois College of [email protected]

CASE LP43 year old male

Referred for Open Angle Glaucoma

Without Elevated IOP

Positive Family History

Clinical Background:• IOP

• First Visit:• 21 OD and 21 OS

• Second Visit (AM appt)• 22 OD and 22 OS

• CCT / Pachymetry• 481 OD and 487 OS

• Corneal Hysteresis:


M. Chaglasian, OD 6

Low CH: 7.9 / 8.6 Photos

Discussion

• Young African American with strong family history of OAG

• Could earlier and routine Hysteresis findings helped earlier detection and treatment?

• Low CH and VF findings certainly support very aggressive management.

• Treatment Options:• IOP in normal range can be more difficult to reduce

• What are the treatment goals? What evidence supports this?

• New Medications?


M. Chaglasian, OD 7

1. Glass DH et al. Invest Ophthalmol Vis Sci. 2008;49:3919-3926.2. Wells AP et al. Invest Ophthalmol Vis Sci. 2008;49:3262-32683. Taylor DA et al. Corneal Biomechanics. In: Copeland RA Jr., Afshari NA, eds.: Copeland and Afshari’s Principles and Practice of

Cornea. Two Volume Cornea Textbook. Jaypee Brothers. 2012:148-157.

Section 1: Introduction to Corneal HysteresisBioengineering of the Eye: Emerging Concepts

Viscoelastic tissue with complex, interconnected microstructure1

Geometrical attributes are not a surrogate for biomechanical properties1

• eg: CCT does not describe viscoelasticity

The eye appears to be a mechanical structural continuum2

• Tissue properties may provide additional diagnostic information3

37

©2002 Park et al. Invest Ophthalmol Vis Sci.

Visco-Elastic System

An Automotive “Strut” Assembly

- Coil Spring: Static Resistance (Elasticity) - Shock Absorber: Viscous Resistance (Damping)

The Cornea is a Visco-Elastic System

39

Measure IOP at two different applanation points. The difference = Hysteresis.

Section 4: Ocular Response Analyzer TechnologyHow does it work?

1. Vincent J. Basic elasticity and viscoelasticity. In: Vincent J, ed. Structural Biomaterials. 3rd ed. Princeton, NJ: Princeton University Press; 2012:1-28.

2. PubMed Search for “hysteresis” on October 3, 2014 returned 7696 results. 3. Hjortdal JO1. On the biomechanical properties of the cornea with particular reference to refractive surgery. Acta Ophthalmol Scand Suppl.

1998;(225):1-23.

Section 1: Introduction to Corneal HysteresisHysteresis: Not a New Concept

A measurement that characterizes response to application and removal of force (load/unload)1

• Found in materials or systems that do not instantly follow forces applied to them but react slowly, or dissipate a portion of the applied energy 1

More than 7500 papers published on hysteresis in a variety of medical fields2

• Various tissues and structures (tendon, lung, arteries, etc)

• The importance of Corneal visco‐elasticity had been discussed and explored (EX‐VIVO)prior to the ORA3

40

Classic “Hysteresis Loop”Sir James Alfred Ewing Identified the phenomenonof hysteresis and coined theterm in 1890

Hysteresis Property:“More like a Shock Absorberand NOT just a Coil Spring”

1. Luce DA. J Cataract Refract Surg. 2005;31:156-162.2. Dupps WJ Jr. J Cataract Refract Surg. 2007;33:1499-1501.3. Glass DH et al. Invest Ophthalmol Vis Sci. 2008;49:3919-3926.

Section 1: Introduction to Corneal Hysteresis What is Corneal Hysteresis (CH)

The only in‐vivo measurement of corneal/ocular biomechanics• CH specifically refers to the output

of the measurement process performed by the Ocular Response Analyzer (ORA)1,2

Corneal Hysteresis reflects the ability of the corneal tissue to dissipate energy 1

• Function of viscoelastic damping2

• Not a characterization of stiffness3

Provides insight into ocular properties that were not previously understood or conceived of

41

Ocular Response Analyzer measurement signal

David Luce, PhDInvented the concept of Corneal Hysteresis

1. Pubmed search on terms “corneal biomechanics” and Corneal Hysteresis”, the ORA peer reviewed bibliography provided by Reichert, and a review of the sample size (N) in each of these publications

Section 1: Introduction to Corneal Hysteresis Corneal Hysteresis: No Longer “Novel”

Technology is at a “tipping point”

12 years of clinical studies support CH as an in vivo indicator of corneal biomechanics

Clinical evidence for the utility of CH in glaucoma comes from >400 publications with data from >52,000 patients1

42

Publications about Corneal Biomechanics 1990‐2014

Introduction of ORA


M. Chaglasian, OD 8

Section 1: Introduction to Corneal Hysteresis CH: Average Values in Normal Subjects

1. Fontes BM J Refract Surg. 2008 Nov;24(9):941-5. 2. Carbonaro. The Heritability of Corneal Hysteresis and Ocular Pulse Amplitude A Twin Study doi:10.1016/j.ophtha.2008.02.0113. Lam A. Et Al. Optom Vis Sci. 2007 Sep;84(9):909-144. Kamiya Et Al. J Refract Surg. 2009 Oct;25(10):888-935. Ortiz Et Al. J Cataract Refract Surg. 2007 Aug;33(8):1371-56. John Et. Al. 2007 Spring;39(1):9-14

CH Values in Normals around the worldN CH*

Brazil1 105 10.1 ± 1.8

UK2272 pairs 10.2 ± 1.2

China3125 10.9 ± 1.5

Japan4204 10.2 ± 1.3

Spain5 88 10.8 ± 1.5

USA6 44 10.5 ± 1.2

*CH units are mmHg

Data courtesy New England College of Optometry and Mitsugu Shimmyo, MD

Glaucoma subjects have lower CH than normals, especially those who are still progressing in the disease.

CH distribution - Normals & Glaucoma

Classifying Corneal Pathologies CCT vs. CH - 184 normal eyes

Thin Cornea with Keratoconus

Thin Cornea with no ectasia

CCT 455CH 11.2

CCT 500CH 8.1

Data courtesy Renato Ambrosio, MD - ASCRS 2006

Classifying Corneal Pathologies

Eye & Contact Lens Volume 41, Number 6, November 2015; Cornea 2010; 29:628–631;Eye (Lond) 2011;25:1005–1009.

CH and Systemic Disease

Lower CH in Rheumatoid Arthritis Lower CH in SLE (Lupus)Higher CH in Scleroderma

Aging has some contribution to lowering CH but there are other unknown contributors.

48


M. Chaglasian, OD 9

Section 2: Clinical EvidenceWhy is CH relevant in Glaucoma?

49

(Low) CH has been consistently shown to be independently and strongly associated with or

predictive of glaucoma progression

Corneal Hysteresis

1. Medeiros FA et al. Ophthalmology. 2013;120:1533-1540.

Section 2: Clinical Evidence – Study 5 CH as a Predictor of Progression in the DIGS Cohort

Study Overview and Design

Results from numerous retrospective studies suggested CH is associated with increased risk of glaucoma progression1

Investigated the relationship between baseline CH and rates of glaucoma progression in an observational study cohort to determine whether low CH is reflective of the disease process1

68 glaucoma patients (114 eyes) were evaluated at 6‐month intervals for 4 years2

• CH (ORA)

• IOP (GAT)

• CCT (ultrasound pachymetry)

• VF (VFI)

51

DIGS=Diagnostic Innovations in Glaucoma Study; VFI=visual field index.

Medeiros FA et al. Ophthalmology. 2013;120:1533-1540. 52

Univariate model: each 1 mmHg decrease in CH was associated with a 0.25%/year increase in rate of VFI decline (P<0.001)• By comparison, each 1 mmHg higher

baseline GAT IOP was associated with a 0.11%/year faster rate of VFI loss (P<0.001)

In the multivariate model, CH was >3X more associated with rate of VF progression than CCT (17.4% vs 5.2%)

The relationship between CH and IOP is complex:• For eyes with lower CH, the impact of IOP

was significantly larger than in eyes with higher CH levels.

CH <10 mmHG CH ≥10 mmHG

Time (years)

Section 2: Clinical Evidence – Study 5 CH as a Predictor of Progression in the DIGS Cohort

The prospective longitudinal design of this study supports the role of CH as an important factor to be considered in the assessment of risk for glaucoma progression

Note – NO rapid progressors in CH ≥10 mmHG group!

WHY CORNEAL HYSTERESIS IS A BIOMARKER FOR GLAUCOMA: EVIDENCE

Section 3: Corneal Hysteresis and The Structural Continuum

Section 3: CH and the structural continuum Evidence that CH is a biomarker for glaucoma risk

54

The Evidence suggests that CH is reflective of pressure‐independent mechanisms involved in glaucoma

pathogenesis and associated changes to the optic nerve


M. Chaglasian, OD 10

CH, but not CCT or other anterior segment parameters, is associated with increased deformation of the optic nerve during transient IOP

elevations in glaucoma patients but NOT in normal controls.1

1. Wells AP et al. Invest Ophthalmol Vis Sci. 2008;49:3262-3268.

Section 3: CH and the structural continuum CH is Associated with ONH Deformation in Glaucoma

Prospective experimental study of 100 subjects (38 with glaucoma, 62 without glaucoma)

Data collected included SE, optic disc diameter, CCT, axial length, cylinder, GAT, Pascal IOP, OPA and CH.

Elevation of IOP (approx 64 mm, 30 seconds) was induced OD on each subject with a modified LASIK suction ring.

HRT‐II was used to map the optic nerve surface before and during IOP elevation. Mean cup depth was calculated using built‐in HRT data analysis software.

Change in optic disc depth during IOP elevation was calculated for all right eyes, and tests for correlation with the parameters listed were performed.

55

ONH=optic nerve head. SE Spherical Equivalent; CCT Central Corneal Thickness; GAT Goldmann Applanation Tonometry; OPA Ocular Pulse Amplitude; CH Corneal Hysteresis

Section 3: CH and the structural continuum Conclusion based on evidence in the literature

56

The eye is a mechanical structural continuum

The Evidence suggests that CH is reflective of overall ocular tissue properties

CH appears is related to pressure‐independent mechanisms involved in glaucoma pathogenesis and

associated changes to the optic nerve

2002: Clinical research with ORA commences

2005: The 1st generation ORA was made commercially available

2012: Generation II ORA was launched

3rd Generation “ORA G3” introduced September 2015

Measures:

• Corneal Hysteresis (CH)

• Goldmann‐correlated IOP (IOPg)

• Corneal compensated IOP (IOPCC)

Section 4: Ocular Response Analyzer TechnologyThe instrument

57

Patient positioning Measurement Screen

Section 4: Ocular Response Analyzer TechnologyThe instrument

Corneal Compensated IOP: An IOP measurement that is less influenced by corneal properties than Goldmann or other tonometers. This value is closer to the “true pressure” and has been shown to be a better indicator of glaucoma than Goldmann. Matches GAT on average, so numerical “Scale” is the same

Corneal Hysteresis: An indication of corneal biomechanical properties that has been show to be independently predictive of future glaucoma progression. Reimbursable under CPT 92145.Typical average value is 10.5. Typical Range is 8‐14. Low is bad

IOPg: A Goldmann‐correlated IOP measurement for reference purposes so that clinicians can appreciate what a Goldmann would read simultaneously with the IOPcc value above.

Waveform Score: A signal analysis algorithm that rates the “quality” of the measurement signal on a scale of 0‐10. The higher the value, the more reliable the IOP and CH values are. 6‐10 is excellent. 4‐5 is not so good. 3 or below is poor.

Section 4: Ocular Response Analyzer TechnologyInterpretation of measurement values CASE Example

60



New Risk Factors to Consider in Glaucoma:

Ocular Perfusion Pressure- definitions- clinical studies- impact of topical medications

Ocular Perfusion Pressure

The differential between arterial BP and IOP

– Ocular perfusion is regulated to maintain constant blood flow to the optic nerve despite fluctuating blood pressure and IOP

– The major cause of reduced blood flow is thought to be secondary to vascular dysregulation in susceptible patients, resulting from abnormal/insufficient auto-regulation.

Ocular Perfusion Pressure (OPP): Terminology

• OPP – Ocular Perfusion Pressure

• SPP – Systolic Perfusion Pressure

• DPP – Diastolic Perfusion Pressure

• MPP – Mean Perfusion Pressure

Perfusion Pressure:How it’s Measured

• SPP = SBP – IOP

• DPP = D. Blood Pressure – IOP

• easiest to use

OPP and Glaucoma: Impact of IOP and BP

Leske MC, et al. Ophthalmology 2007; 114,: 1965-72.Leske MC, et al. Ophthalmology 2008;115, 65-93. Reproduced with Permission from “Anatomy and Physiology of the Optic Nerve Head”. Hayreh SS. Trans Am Acad Ophthalmol. 1974;78:240-254.

Perfusion PressureIs a Result ofA Delicate BalanceBetween IOPand Blood Pressure


Leske MC, et al. Ophthalmology 2007; 114,: 1965-72.Leske MC, et al. Ophthalmology 2008;115, 65-93. Reproduced with Permission from “Anatomy and Physiology of the Optic Nerve Head”. Hayreh SS. Trans Am Acad Ophthalmol. 1974;78:240-254..



HigherIOPNegatively ImpactsPerfusion Pressure



Lower Diastolic,Systolic, or Mean PressureReduces PerfusionPressure



LowerPerfusion PressureIs Associated withIncreased Risk forOpen Angle Glaucoma


Leske MC, et al. Ophthalmology 2007; 114,: 1965-72.Leske MC, et al. Ophthalmology 2008;115, 65-93. Reproduced with Permission from “Anatomy and Physiology of the Optic NervHead”. Hayreh SS. Trans Am Acad Ophthalmol. 1974;78:240-254.

OPP and Glaucoma:Population Studies

Study Population

Baltimore Eye Survey AA, Caucasian

Egna-Numarkt Caucasian

Barbados Eye African-Caribbean

Proyecto Ver Hispanic

Los Angeles Latino Eye Study (LALES)

Hispanic

Proyecto Ver

• Cross-sectional study of Hispanics in Nogales and Tucson, AZ.

• Found lower DPP associated with increased risk of POAG.

• Subjects with DPP.

Quigley HA, et al. Arch Ophthalmol. 2001;119:1819-26. Copyright © 2001. American Medical Association. All Rights Reserved.

Los Angeles Latino Eye Study

• Cross-sectional study of 6,357 Latinos, >40 years in Los Angeles, CA.

• Persons with low diastolic and systolic perfusion pressures had a higher risk of POAG.

• DOPP <50 mmHg, the prevalence of glaucoma rapidly increases linearly.

Varma R, et al. Ophthalmology. 2004;111:1439-1448.



Barbados Eye Study: 9-Year Follow-Up

HighestRisk

Reprinted from Ophthalmol, 115, Leske MC, et al. Risk Factors for Incident Open Angle Glaucoma. 85‐93, 2008, with Permission from Elsevier.

Clinical Control of OPP

• Lower IOP improves OPP• Remains number 1 goal !!

• Measure blood pressure on your patients

• Higher systemic BP improves OPP, but you do not necessarily want to raise BP:• Stroke #3 cause of death in US behind CVD & CA!

• Avoid drugs that lower systemic BP beyond patient’s desired systemic control.

• Avoid nocturnal hypotension.

• Communicate with PCP

Nocturnal Hypotension and OPP

• Low blood pressure (BP) at night, coupled with high IOP in supine position, compromise OPP.• ? Up to 50% of patients with HTN

• Using systemic BP meds in the AM to minimize nocturnal hypotension makes sense.

• Using IOP lowering drugs that lower IOP while sleeping makes sense.• Avoiding IOP meds that LOWER systemic BP at night

(beta blockers, alpha agonists) makes sense.Graham SL, Drance S. Surv Ophthalmol. 1999;43(suppl 1):S10-16.Hayreh SS, et al. Am J Ophthalmol. 1994;117:603-624.Colligan JC, et al. Int Ophthalmol 1998;22:19-25. PCON October 1, 2005

Supine

Sitting BloodPressure

Summary: OPP and Glaucoma Progression

Low ocular perfusion pressure (OPP) is an important risk factor for glaucoma

OPP is amenable to modification by lowering IOP and improving perfusion pressure

New strategies are needed to take advantage of this modifiable risk factor

Quigley HA, West SK, Rodriguez J, et al. Arch Ophthalmol. 2001;119:1819-26

Quaranta L, Gandolfo F, Turano R, et al. Invest Ophthalmol Vis Sci 2006; 47: 2917-23.

Questions / Discussion

[email protected]

glaucoma risk factors new considerations

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