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
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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
Glaucoma Risk Factors: New Considerations
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
Glaucoma Risk Factors: New Considerations
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:
Glaucoma Risk Factors: New Considerations
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?
Glaucoma Risk Factors: New Considerations
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
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
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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
Glaucoma Risk Factors: New Considerations
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.
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Glaucoma Risk Factors: New Considerations
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
Glaucoma Risk Factors: New Considerations
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
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
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Glaucoma Risk Factors: New Considerations
M. Chaglasian, OD 11
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
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..
Glaucoma Risk Factors: New Considerations
M. Chaglasian, OD 12
HigherIOPNegatively ImpactsPerfusion Pressure
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.
Lower Diastolic,Systolic, or Mean PressureReduces PerfusionPressure
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.
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.
• 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.
Glaucoma Risk Factors: New Considerations
M. Chaglasian, OD 13
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.