risk factors for glaucoma...primary open angle glaucoma angle closure glaucoma acute or chronic...
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4/1/2017
1
“Decision Making in Glaucoma: When to pull the trigger”
COPE #41665-GL
Robert E. Prouty, O.D., FAAOSpecialty Eye CareParker, Colorado
RProuty@DrMyii.com
Disclosures
� Financial disclosures:
• Speakers Bureaus/Consultant:�Alcon/Novartis�Allergan
�Optovue�Zeiss-Meditec�VSP
�B&L
• I have no personal financial interests in any of these companies
Glaucoma is an Optometric Problem
� ~ 2.5 million Americans are diagnosed with Glaucoma ◦ 1% – 2 % of those > 40 years
◦ 1.6% > 40 (Framingham Eye Study)
� As many as 95,000 Americans lose some degree of sight to Glaucoma each year ◦ 12,000 become blind
It is estimated that 1 million Americans with glaucoma
are undiagnosed!
Risk Factors for Glaucoma
� In general, patients are at risk for glaucoma if they have the following:◦ High IOP
◦ Family history of glaucoma
◦ African ancestry
◦ High myopia
◦ Cardiovascular risk
◦ Age
◦ Other: Chronic steroid use/previous eye surgery
European Glaucoma Society: Terminology and Guidelines for Gaucoma, 1998:63
Glaucoma
� The most common types:◦ Primary Open Angle Glaucoma
◦ Angle Closure Glaucoma� Acute or Chronic
◦ Secondary Glaucomas� Pseudoexfoliation
� Pigment Dispersion
� Uveitic
� Traumatic/Angle Recession
Primary Open Angle Glaucoma
� ~2.5 million Americans have POAG◦ About 1/3 of the POAG is undiagnosed
◦ ~ 25% of all cases of POAG are African Americans
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2
0
5
10
15
20
25
30
35
40-49 50-59 60-69 70-79 80+Age Groups (yrs)
Pre
va
len
ce
(%
)
LALES
Whites
Blacks
Risk Factors
� Race: African Americans ~5X > whites• Comparison of prevalence of Glaucoma in LALES
Latinos and African-Americans and Whites in the Baltimore Eye Study
Varma R, Prevalence and Risk Indicators of Visual Impairment and Blindness in Latinos –The Los Angeles Latino Eye Study, Ophth. 2004;111:1132–1140
21.09
13.8
2.6
21.09
13.8
2.6
Secondary Glaucomas
� Pseudoexfoliation Syndrome (PEX):
◦ 1.6%-2.3% of population > 50 yo in US◦ Pseudoexfoliative Glaucoma (PEG) most
commonly occurs between 60-80 yo◦ PEX is 2-3X more common in women◦ PEX is reported unilateral in 50%-70% of cases on
initial diagnosis
� Pigment Dispersion Syndrome (PDS):� ~2.5% of whites in the US
◦ 20%-60% of PDS OHTN◦ 25%-50% of PDS PDG
Secondary Glaucomas
� Uveitic
◦ Estimated to be 7.6% to 23% among patients with uveitis
◦ Surgery is required in children > adults* � 59% of children and in 35% of adults
� Traumatic/Angle Recession
◦ Of those eyes with angle recession, very few (~ 0-20%) develop glaucoma
◦ In those that do develop glaucoma, the onset is extremely variable
* * Ocular Immunology & Inflammation, Vol 17, Issue 4 August 2009 , pgs 243 - 248
When to pull the trigger
� It is my observation that many ODs question themselves as to “when to pull the trigger”◦ To soon = mistake and meds cost $$$
◦ To late = increases professional liability (malpractice) exposure
� How many ODs have been sued for starting a patient on meds too soon?
None, Nada, Zero, Zilch, The big Goose Egg!
How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
• Poor sensitivity & specificity - Sensitivity 79% - Specificity 64%
* Review by Doughty, M.J., and Zaman, M.L. Surv of Ophthalmol 2000; 44: 367* Liu, J.H.K., Zhang, X., Kripke, D.F., and Weinreb, R.N. IOVS 2003; 44:1586
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Peak IOP Outside Office Hours for 2/3 of Eyes (10:00p-7:00a)
Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204
Times of maximum IOP Over a 24-hr period:
Nu
mb
er
of
eye
s
30
20
10
0
3am-
6am
9am-
12pm
3pm-
6pm
9pm-
12am
20
1012
23
Time of maximum IOP
Liu JH et al. Invest Ophthalmol Vis Sci. Dec 1998; Vol 39 #13
IOP is Higher at Night
Habitual IOP of untreated glaucomatous eyes
Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590
Clock Time
1:3
0 P
M
11:3
0A
M
9:3
0 A
M
7:3
0A
M
5:3
0 A
M
3:3
0 A
M
1:3
0 A
M
11:3
0 P
M
9:3
0 P
M
7:3
0PM
5:3
0 P
M
3:3
0 P
M
22
26
252423
2120
19181716
14
15
n=24
IOP
(m
m H
g)
DIURNAL/WAKE NOCTURNAL/SLEEP DIURNAL/WAKE
12
1086
4
2
0
Med Effects on Diurnal/Nocturnal IOP
• Diurnal period – sitting
• Nocturnal period – supine
1) Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133
2) Liu JH et al. Ophthalmology, 2010 Nov;117(11):2075-9
Baseline
Travoprost 0.004%1
NOCTURNAL/SLEEP DIURNAL/WAKEDIURNAL/WAKE
28
26
24
22
20
18
16
14
IOP
(m
mH
g)
3:3
0 P
M
5:3
0 P
M
7:3
0 P
M
9:3
0 P
M
11
:30
PM
1:3
0 A
M
3:3
0 A
M
5:3
0 A
M
7:3
0 A
M
9:3
0 A
M
11
:30
AM
1:3
0 P
M
0
2
4
6
8
10
12
Brimonidine 0.2%2
How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics� Vascular dysregulation
� The more complex the regulative system, the more susceptible it
is for dysregulation and the more dramatic the potential damage
• Grieshaber M, Mozaffarich M, Flammer J, What is the Link Between Vascular Dysregulation and Glaucoma, Survey Ophth #52, Supp #2, Nov 2007
How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics� Vascular dysregulation
� Primary (PVD) & Secondary (SVD)
� PVD = inborn tendency to inefficiently OBF respond
� Primarily Endothelin modulated (ET-1 dysregulation)
� Variable up & down regulation/perfusion
� SVD = systemic disease related tendency to respond
� More consistent down regulation/perfusion
How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics� Vascular dysregulation
� Primary (PVD) & Secondary (SVD)
� PVD = inborn tendency to inefficiently OBF respond
� Women > men
� Academics > blue collar
� Low BP – Cold hands – low thirst – longer sleep onset
(need feet to warm before they can sleep)
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How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics� Vascular dysregulation
� Primary (PVD) & Secondary (SVD)
� SVD = systemic disease related tendency to respond
� MS – Giant cell arteritis – Lupus – RA – Anorexia – liver cirrhosis - etc
� Basically all chronic inflammatory autoimmune
� Essentially no interference with autoregulation
yet down regulated
How do ODs become more accurate in diagnosis?
�Refined MHx assessment◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics� Vascular dysregulation
� Primary (PVD) & Secondary (SVD)
� PVD is a major risk but SVD is a minor risk in POAG!
• Grieshaber M, Flammer J, Blood Flow in Glaucoma, Curr Opin Ophth 2005 16:79-83 (data from
Satilmis M, OrgÜlS, Doubler B, Flammer J, Rate of progression of glaucoma correlates
with retrobulbar circulation and intraocular pressure, AJO, May 2003 Vol. 135, Issue 5,
Pages 664-669)
How do ODs become more accurate in diagnosis?
�Refined MHx assessment
�Refined Ocular assessment o Gonioscopy� Is Gonioscopy required on all glaucoma patients?
� Does it need to be done more than once?� I only get paid once in their lifetime!
Glaucoma Clinical Workup
� AAO Preferred Practice Pattern Guidelines:◦ Perform gonioscopy periodically (e.g., 1-5
years).
� AOA Clinical Practice Guidelines:◦ To rule out the development of an angle closure
component in the glaucoma, gonioscopy should
be repeated periodically.
~ A Video Atlas ~
Wallace L.M. AlwardFrederick C. Blodi Chair in Ophthalmology
Director, Glaucoma Service
University of Iowa Carver College of Medicine
http://gonioscopy.org/
How do ODs become more accurate in diagnosis?�Refined MHx assessment
�Refined Ocular assessment
�Refined ONH assessment
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1. Observe the scleral Ring to identify the limits of the optic disc and its size
Five Rules for Assessment of the Optic Disc in Glaucoma
Measurement of optic disc size with direct ophthalmoscope
Small aperture (5 degree) of Welch-Allen direct ophthalmoscope
Optic Disc Size
Size of light spot ~ size of average optic disc
Identify small and large optic discs
Small discs: avg vertical diameter <1.5 mm
(1.1 X 1.3 = 1.43)
Large discs: avg vertical diameter >2.2 mm
(1.7 X 1.3 = 2.21)
Size of cup varies with size of disc Large discs have large cups in healthy eyes
Small
1.4
Average
1.9
Large
2.2
Optic Disc Size
1. Observe the scleral Ring
2. Identify the size of the Rim
Five Rules for Assessment of the Optic Disc in Glaucoma
Rim widthDistance between border of disc and position of blood vessel bending
S
NT
ISNT ruleInferior >Superior > Nasal >Temporal
“ISNT” Rule
I
“ISNT” Rule
� Original “ISNT” research: ◦ Jonas J, Gusek G, et al, IOVS, July 1988, Vol.
29: 1151-1158� “It was broadest in the inferior optic disc region
(P< 0.001), followed by the superior, nasal and temporal (P < 0.001) regions.”
◦ Harizman N, Olivera C, et al, Arch Oph. Nov2006; Vol 124:1579-1583 � “The ISNT rule is useful in differentiating normal
from glaucomatous optic nerves and is unaffected by race.”
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“ISNT” Rule
� Original “ISNT” research: ◦ Sihota R, Srinivasan G, et al, Is the ISNT rule
violated in early primary open-angle glaucoma?,
Eye (2008) Vol 22: 819–824 � “The ISNT rule was applicable in 71% of normal eyes
and 68% of early glaucoma eyes.”
“ISNT” Rule
� More recent “ISNT” research: ◦ Pogrebniak A, Wehrung B, et al, “Violation of the
ISNT Rule in Nonglaucomatous Pediatric Optic Disc Cupping”, IOVS, Feb 2010, Vol 51:890-895 � “Violation of the ISNT rule occurs with greater
frequency in the pediatric population with large optic disc cups of nonglaucomatous origin, compared with the pediatric population with normal optic discs”
“ISNT” Rule
� More recent “ISNT” research: ◦ Morgan J, Bourtsoukli I, et al, “The Accuracy of
the Inferior>Superior>Nasal>Temporal Neuroretinal Rim Area Rule for Diagnosing Glaucomatous Optic Disc Damage”, Ophthalmology, April 2012, Vol 119:723-730 � “The ISNT rule has limited utility in the diagnosis of
open-angle glaucoma.”
“ISNT” Rule
� More recent “ISNT” research: ◦ Law SK, Kornmann HL, et al, Evaluation of the
"IS" Rule to Differentiate Glaucomatous Eyes From Normal, J Glaucoma. May ’14 � “…we agree with the conclusion of Morgan ,et al, that
the ISNT rule has only limited utility in the diagnosis of glaucomatous optic neuropathy…”
� “We demonstrated that a diagnostic test that combines the different features of the optic disc (increase of CDR and ISNT or IS rule) may improve the diagnostic accuracy of glaucoma based on optic disc evaluation.”
1. Observe the scleral Ring
2. Identify the size of the Rim
3. Examine the Retinal nerve fiber layer
Five Rules for Assessment of the Optic Disc in Glaucoma
1. Observe the scleral Ring
2. Identify the size of theRim
3. Examine the Retinal nerve fiber layer
4. Examine the Region of parapapillary atrophy
Five Rules for Assessment of the Optic Disc in Glaucoma
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1. Observe the scleral Ring
2. Identify the size of theRim
3. Examine the Retinal nerve fiber layer
4. Examine the Region of parapapillary atrophy
5. Look for Retinal and optic disc hemorrhages
Five Rules for Assessment of the Optic Disc in Glaucoma
How do ODs become more accurate in diagnosis?�Refined MHx assessment
�Refined Ocular assessment
�Refined ONH assessment
�Refined VF interpretation
� As many as 50% optic nerve fibers can be lost prior to a standard perimetric defect 1,2
� By the time there is a 5 dB loss, there is a corresponding 25% loss of RGCs2
1Quigley HA, Addicks EM, Green WR. Arch Ophthalmol. 1982; 100:135
2Quigley HA, Dunkelberger GR, Green WR. Am J Ophthalmol. 1989; 107:453
� A large number of RGCs often are lost prior to detectable visual field abnormalities
Visual Fields: Poor Sensitivity
OHTS
• 86% of visual field abnormalities not replicated on retesting*
*VF defect defined as GHT outside normal limits, CPSD < .05%, or both1 Keltner JL, Johnson CA et al. Arch Ophthalmol. 2000; 118:1187-1194
Visual Fields: Highly Variable
1st VF abnormal(GHT Outside Normal Limits)
2nd VF normal(GHT Within Normal Limits)
3rd VF abnormal(GHT Outside Normal Limits)
Visual Field Progression
Visual
Function
(MD)
Birth Death
Slow progression
Early intervention
Fast progression
Level of visual disability
Later
intervention
Rate of Progression
Caprioli J, The Importance of Rates in Glaucoma, AJO 2008 Vol 145, No. 2 , Pg 192
0
15
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Baseline Follow-up
Multiple exams
Rate-of-progression plot
Glaucoma Progression Analysis (GPA)
11/27/97 4/18/0112/15/98
4/18/02 11/20/02Likely Progression
Possible Progression
Glaucoma Progression Analysis (GPA)� GPA has been found to have high specificity
in determining glaucoma progression � A recent study suggests:
� “GPA criterion of ‘likely progression’ has high specificity on average, but some patients are more prone to false-positive alerts than others
� This report may help to avoid false-positive decisions on progression in patients with uncharacteristically large variability and frequent response errors."
Artes P, Leary N, et al, Visual Field Progression in Glaucoma. What Is the Specificity of the Guided Progression Analysis?, Ophthalmology. 2014 May 28. [Epub ahead of print]
Change Analysis Visual Field Index
� The VFI is less sensitive to a worsening cataract or removal of a cataract than is mean deviation index (MDI).
� The predictive value of VFI depends on the validity of the assumption that “past performance predicts future performance”.
Bengtsson B, Heijl A; A Visual Filed Index for Calculation of Glaucoma Rate of Progression, AJO 2008 Vol 145, No. 2,
Pg 343-353
� Central points weighted more heavily than on periphery
� Reduces cataract effect to the measurement of VF loss
“B”has more damaged central points and lower VFI than “A”
Visual Field Index
A B
VFI = 90% VFI = 81%
Visual Field Index Bar•Shows vision loss in terms of %
•Enhanced visual presentation
100%
% loss to date
% loss in next 5 years
Visual Field Index
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VF Index plotted against age:
• Characterizes trend significance over next 5 years
• Aids in interpretation & patient education
• Helps formulate individualized treatment decisions
Current age at testing
Visual Field IndexSummary of Functional Tests
SITA SAP SITA SWAP FDT Matrix
Advantages “Gold Standard” As fast as SITA SAP
Possibly more sensitive
More portable
Tolerates blur
Possibly more sensitive
Variability does not increase with severity
Disadvantages Not sensitive enough to detect early glaucoma
Limited clinical evaluation
Variability
Cataract effects
Limited clinical evaluation
Best use Baseline VF and following progression in advanced disease
Early diagnosis
Younger patients
Early diagnosis
The “5Rs” of Progression
1. Record baseline structure and function.
2. Risk evaluation.
Developing a Risk Profile
� Each patient must be assessed individually
� Establish baseline risk and reassess from exam to exam
� Criteria- Stage of disease
- Life expectancy � How old is the patient?
� How long did the patient’s parents live?
� How is the patient’s overall health?
Developing a Risk Profile
� Each patient must be assessed individually
� Establish baseline risk and reassess fromexam to exam
� Criteria◦ Stage of disease
◦ Life expectancy
◦ Other risk factors
Independent Risk Factors for Progression
Central corneal thickness (thinner)
Pseudoexfoliation
Disc hemorrhage
Elevated IOP
XXCup-to-disc ratio (greater)
XXX
XXVisual field (higher PSD)
XVisual field (greater MD)
X
XRace (nonwhite)
XAbnormal baseline HRT/OCT/GDx
XLow ocular perfusion pressure
XXX
XXXX
XXXXXAge
OHTSEGPSEMGTCNTGSCIGTSAGIS
Central corneal thickness (thinner)
Pseudoexfoliation/pigment
Disc hemorrhage
Elevated IOP
• Elevated IOP– 24 to 32 mm Hg
– > 32 mm Hg (2 points)
• CCT below 500 µm
• Disc hemorrhage (2 points)
• Pseudoexfoliation/Pigment
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Independent Risk Factors for Progression
Number of Points Level of Risk
0-1 Low
2 Medium
> 2 High
• Elevated IOP– 24 to 32 mm Hg
– > 32 mm Hg (2 points)
• CCT below 500 µm
• Disc hemorrhage (2 points)
• Pseudoexfoliation/Pigment
1. Record baseline structure and function.
2. Risk evaluation.
3. Repeat fields and imaging/photos.
4. Rate of progression.
dB Loss per Year Rate of Progression
< 0.5 Low
0.5-1.5 Moderate
> 1.5 High
The “5Rs” of Progression
1. Record baseline structure and function
2. Risk evaluation
3. Repeat fields and imaging/photos
4. Rate of progression
5. Reassess and revise management plan and re-establish baseline
The “5Rs” of ProgressionHow do ODs become more accurate in diagnosis?�Refined MHx assessment
�Refined Ocular assessment
�Refined ONH assessment
�Refined VF interpretation
�Refined NFL assessment
3 Imaging technologies have been shown to be effective in detecting and managing ocular pathologies
� Scanning Laser Polarimetry (SLP)◦ Measures birefringence
� Confocal Scanning Laser Ophthalmoscopy (CSLO)
� Optical Coherence Tomography (OCT)
Retardation
Light Polarizer
Two polarized components
Birefringent structure
(RNFL)
Fast Optic Disc (Monocular) -Utilizes a 6 line starburst scan (4mm) through the ONH at each 12 clock hours. Each individual scan can be reviewed.
Scans & AnalysisFast RNFL (Bilateral) - Three circular scans with a 3.4mm diameter are used to image the peripapillary region of the ONH to create a TSNITimage.
Fast Macula (Bilateral) - The Stratus uses a 6 line radial pattern to image the macula (6 mm).
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TD Stratus OCT Deficiencies
� Acquisition times are slow so movement artifact affects accuracy
� Database is VERY limited in patients >80 yo� Database is VERY limited in patients outside
-12.00 or +8.00 � Highly myopic eyes have a wide range of “normal”
RNFL thickness � Moderately myopic individuals may have thinner
peri-papillary RNFL at the superior and inferior poles when measured by OCT.
� Interpreting a myopic glaucoma suspect’s RNFL status needs to take into account these limitations.
Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88
RNFL Thickness Average Analysis
Black line is patient’s
RNFL thickness
Fourier Domain OCT Advantage
� Faster speed also allows for greater density of sampling points and reduces artifacts from eye-movements ◦ RTVue FD OCT has 26,000 A scans/sec vs Stratus
TD OCT with 400 A scans/sec
Fourier Domain OCT Advantage
� FD OCT has twice the depth resolution as TD OCT ◦ 5 microns vs 10 microns
� Allows imaging and segmentation of: ◦ Anterior segment
◦ Macula
� Anterior segment OCT scanning has always been possible but improved resolution has made the new generation OCTs far superior. ◦ Angle structures:
OCT Advantages
� Anterior segment OCT scanning has always been possible but improved resolution has made the new generation OCTs far superior. ◦ Angle structures
◦ Cornea:
OCT Advantages
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� Anterior segment OCT scanning has always been possible but improved resolution has made the new generation OCTs far superior. ◦ Cornea:
◦ Angle structures:
◦ Macular Ganglion Cell layers (GCC)
OCT Advantages Ganglion Cell Loss in the Macula
� Histologic studies have shown ganglion cell loss in the macula
� Desatnik et al, found macular ganglion cells are lost in early glaucoma
� Yucel et al, showed loss of cells in the parvocellular layers of the LGN implicating central ganglion cell loss
• Desatnik H, Quigley HA, Glovisnky Y. J Glaucoma 1996; 5: 46-53 • Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N, Prog Retin Eye Res 2003; 22:465-481
Macular Ganglion cell density
• 50% of ganglion cells located in central 4.5mm (16º)• Peak ganglion cell density is 15,000 cells/mm2 in macula (white region left)• Area represents only 7.3% of total retinal area• RTVue Ganglion cell complex map covers central 6mm area
foveaDisc
Diagnostic Accuracy with TD OCT: Macula vs RNFL
� Medeiros et al, found the diagnostic accuracy of peripapillary RNFL thickness was significantly more accurate than macula thickness
� Wollstein et al, found similar results where RNFLthickness was significantly more accurate for detecting glaucoma than macula thickness
• Medeiros FA, Zangwill M, Bowd C et al. Am J Ophthalmol. 2005; 139:44-55• Wollstein G, Ishikawa H, et al. Am J Ophthalmol 2005; 139: 39-43
Progression: Macula vs RNFL
� Using TD OCT, Medeiros et al, compared the accuracy for detecting progression using RNFLversus macula thickness and found the RNFL was significantly more sensitive and specific than macula thickness
RNFL curve
Macula curve
• Medeiros FA, et al. Invest. Ophthalmol Vis Sci2009; 50:5741-5748
TD OCT Study Limitations
� Major disadvantage in these studies is that TD OCT typically measures full retinal thickness only (does not isolate ganglion cells)
� TD OCT does not have enough depth resolution to image and segment the ganglion cells accurately and reliably
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Normal
Glaucoma with thinner GCC
GCC
GCC
GCC Thinning in Glaucoma Overlay of the RNFL and GCC
pRNFL
GCC
GCC Report: Normal
Patient Information
Exam Date and Quality
GCC Thickness Map
Deviation Map
Significance Map
Parameter Table
Fovea Mask
color coded map shows regions where the change from normal reaches statistical significance
◦ Green = values within normal range (p-value 5% to 95%)
◦ Yellow = borderline results (p-value < 5%)
◦ Red = outside normal limits (p-value <1%)
David Huang, MD, PhD www.AIGStudy.net
GCC Deviation Map
GCC Change Analysis
Thickness Maps
Deviation Maps
GCC parameter change analysis
Significance Maps
Trend Analysis
GCC Change Analysis
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Revisiting the Macula
� Can imaging the ganglion cells in macula with FD OCT improve glaucoma detection?
Diagnostic Accuracy: GCC vs FD OCT RNFL
� Rao et al, found GCC had similar accuracy levels as FD RNFL
� Seong et al, found similar results
� Kim et al, found values were higher for RNFL vs GCC in a group of advanced glaucoma patients, but GCC values were higher than RNFL in a group of early glaucoma patients
• Rao HL, Zangwill LM, Weinreb RN et al. Ophthalmology 2010; in press.• Seong M, Sung KR, Choi EH, et al. Invest Ophthalmol Vis Sci 2010; 51:1446-1452.• Kim NR, Lee ES, Sung GJ, et al. Invest Ophthalmol Vis Sci 2010
VF& OCT results show poor correlation in advanced RNFL loss
� A retrospective study of patients with early to advanced glaucoma showed a wide variation in mean deviation in patients with advanced RNFL loss when comparing visual field sensitivity with retinal nerve fiber layer thickness.
� Jessica Neuville, OD, presented at AAOpt 2010, a study that suggests the OCT◦ is moderately correlated to visual function in early loss,
◦ is a poor predictor of visual function at advancedlevels of RNFL loss
GCC Summary
� GCC thickness correlates well with VF
� More reproducible and more accurate for detecting glaucoma than macula thickness with TD OCT
� Similar accuracy for detecting glaucoma as FD OCT RNFL thickness
� Best in early glaucoma
What value is digital technology?
They offer an expert opinion but the new generation OCTs are far superior
How do ODs become more accurate in diagnosis?
�Refined MHx assessment
�Refined Ocular assessment
�Refined ONH assessment
�Refined VF interpretation
�Refined NFL assessment
�Refined Management selection
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Medicinal Management
� Prostaglandin Derivatives
� Topical CAI’s
� Adrenergics
� Beta-Blockers
� Combos
� Cholinergics/Anticholinesterases
� Oral CAI’s
Prostaglandin analogues
� Zioptan™ (was Merck but now is Akorn) ◦ Tafluprost 0.0015%
� The only preservative free PGa!!
◦ ~30% - 35% IOP decr◦ QHs use � Vials often hold > 4 drops
Combinations
� Cosopt® (was Merck but now is Akorn) ◦ Timolol 1/2% & dorzolamide
� As effective as separate dosing (?)
◦ Better convenience & compliance � Still stings!!
◦ 32%-38% IOP decr◦ BID use
� Cosopt PF® (was Merck but now is Akorn) ◦ Preservative Free!!◦ BID use
Combinations
� Simbrinza™ (Alcon/Novartis) ◦ Brinzolamide 1% & Brimonidine 0.2%
◦ As effective as separate dosing
◦ Better convenience & compliance � Less sting!!
◦ 21%-35% IOP decr◦ TID use
� Used BID in Europe
CAI’s
� Sulfonamide sensitivity◦ Topical CAI cross-sensitivity is being re-thought
◦ So the use of topical CAIs may be safely used with sulfonamide allergy depending on severity of allergic response� Hives, swelling of throat, etc. is probably NOT safe!
◦ General atopy is probably LESS safe
Current Medication Paradigm
AAs, BBs, CAIs
Fluid Inflow/Production:Ciliary Processes
Decreases Fluid
Production Rhopressa™
Roclatan™
PGAs & AAs
Fluid Outflow:Secondary Drain
(Uveoscleral)
Increase Fluid
Outflow via
Uveoscleral Pathway
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Glaucoma Medications in the Pipeline
New MOAs
AR-13324 (Aerie) ROCK/NET Inhibitor (qday) Phase 3
K-115 (Kowa) ROCK Inhibitor (bid) Phase 3 (Japan)
AMA0076 (Amakem) ROCK Inhibitor (bid) Phase 2a
INO-8875 (Inotek) Adenosine-A1 agonist (bid) Phase 2
OPA-6566 (Acucela) Adenosine-A2a agonist (bid) Phase 1/2
SYL040012 (Sylentis) RNAi beta blocker (bid) Phase 2
New PGAs
BOL-303259 (B&L) NO donating latanoprost (qday) Phase 3
NCX 470 (Pfizer) NO donating bimatoprost (qday) Phase 1
DE-117 (Santen) EP2 agonist (qday) Phase 2a
ONO-9054 (Ono) FP/EP3 agoniist (qday) Phase 1
All new MOA’s work at the TM
Prostaglandins
� Current commercial PGA’s all bind to the PGFP2α receptor◦ Bimatoprost may also bind to PGEP1
� Newest research is in PGEP2-4
◦ Early studies suggest a decrease in IOP that was long-lasting and greater than PGFP2α
� PGEP2 was less stable in aqueous solution
◦ Allergan’s Butaprost binds to PGEP2
◦ ONO Pharmaceuticals’ ONO-0476� Prodrug of prostanoid EP2
Nitric Oxide Donation
� In the past, nitric oxide (NO) was considered “toxic” as one of several environmental pollutants (i.e. cigarette smoke & smog) ◦ ≠ nitrous oxide (N20) “Laughing Gas”
� By late ’90s, it was determined that NO is a fundamental player in general body physiology as a messenger molecule ◦ Essential to daily functions ranging from BP
regulation & digestion to antimicrobial defense
NO-Prostaglandins
� Nitric Oxide-Donating PGF2α PGA’s:◦ Latanoprostene bunod (Allergan NCX 116)
� Dual Mechanism:◦ PGF2α : enhanced uveoscleral outflow
◦ NO: affects outflow through TM � ?? Analogous to ROCK I’s
NO-Prostaglandins
� Nitric Oxide-Donating PGF2α PGA’s:◦ Pfizer/Nicox Research are investigating
NO-Donating Bimatoprost 0.004% (NCX 470)
Rho Kinase Inhibitors
� Mechanism:◦ Rhokinase is a serine/threonine kinase that serves as
an important downstream effector of Rho GTPase
◦ It plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium-independent manner
◦ ROCK inhibitors reduce IOP by enhancing aqueous humor drainage through the trabecular meshwork� ROCK inhibitors also appear to lower the episcleral venous
pressure, which contributes approximately half of IOP in healthy subjects
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Rho Kinase Inhibitors
� Several companies with phase I to III trials
� Likely not to be packaged with BAK
� Amenable to alternative delivery modes: ◦ Punctal plugs, gel vehicle etc.
Rho-kinase inhibitors (RKIs) appear to lower IOP by inducing cellular relaxation and disrupting focal adhesions in the trabecular meshwork (TM) and the inner wall endothelial lining of Schlemm’s canal. Confocal microscopic analysis demonstrates the penetration of an RKI in an animal study. In a control eye (left), the tracer dye concentrated in only a small segment of the TM. In an eye treated with RKI (right), the drug was distributed more uniformly throughout the TM.
Copied from Scott PA, Lu Z, Liu Y, Gong H. Relationships between increased aqueous outflow facility during washout with the changes in hydrodynamic pattern and morphology in bovine aqueous outflow pathways. Exp Eye Res. 2009 Dec;89(6):942-9
Rho Kinase Inhibitors
Projected Medication Paradigm
AAs, BBs, CAIs
Fluid Inflow/Production:Ciliary Processes
Decreases Fluid
Production Rhopressa™
(netarsudil 0.02%)
Roclatan™
PGAs & AAs
Fluid Outflow:Secondary Drain
(Uveoscleral)
Increase Fluid
Outflow via
Uveoscleral Pathway
Increase Fluid
Outflow via
Trabecular Meshwork
EVP Decrease
• Fluid Outflow: Primary Drain (TM)
• Lower EVP (Episcleral Venous Pressure)
• NET = reduced aqueous production
Triple-Action Rhopressa™
Mechanism of Action:
1. ROCK inhibition relaxes TM, increases outflow
2. NET inhibition reduces fluid production
3. ROCK Inhibition lowers EVPTrabecular Meshwork
Schlemm’sCanal
EpiscleralVeins
Ciliary Processes
Rho Kinase Inhibitors
� Status:◦ April 2014: Rhopressa Phase 3 Trial (Rocket 1)
Misses Primary Endpoint � All end points of subjects <26 were met but not about
above
� FDA allowed modification of study endpoints
� Phase 2 as met and Phase 3 is underway
◦ AMA0076 (Amakem) goes forward
Rho Kinase Inhibitors
� Current status:◦ Roclatan:� Essentially, Rhopressa + Xalatan
� Netarsudil 0.02% + Latanoprost 0.005%
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Projected Medication Paradigm
AAs, BBs, CAIs
Fluid Inflow/Production:Ciliary Processes
Decreases Fluid
Production
Roclatan™
(netarsudil 0.02%/latanoprsot 0.005%)
PGAs & AAs
Fluid Outflow:Secondary Drain
(Uveoscleral)
Increase Fluid
Outflow via
Uveoscleral Pathway
Increase Fluid
Outflow via
Trabecular Meshwork
EVP Decrease
• Fluid Outflow: Primary Drain (TM)
• Lower EVP (Episcleral Venous Pressure)
• NET = reduced aqueous production
• Enhanced uveoscleral outflow
Rhopressa™
(netarsudil 0.02%)
Quadruple action Roclatan™
Mechanism of Action:
1. ROCK inhibition relaxes TM, increase outflow
2. NET inhibition reduces fluid production
3. ROCK Inhibition lowers EVP
4. PGA receptor activationincreases uveoscleraloutflow
Trabecular Meshwork
Schlemm’sCanal
EpiscleralVeins
Ciliary Processes
Uveoscleral Outflow
Latanoprost
Rho Kinase Inhibitors
� Status:◦ Roclatan™:� June 2014: Phase 2b results:
� All clinical endpoints met
� Efficacy >Latanoprost by 1.6-3.2 mm Hg. at all time points
� Hyperemia remains the #1 adverse reaction reported
� Sept 2016: Phase 3 “Mercury 1”� Achieved primary endpoints at IOP’s > 20 but < 36
� Demonstrated statistical superiority over both latanoprost and RhopressaTM
� “If Mercury 1 and 2 are successful, we expect to file the NDA for RoclatanTM near year-end 2017…”
Drug Class Product (Company)
Prostaglandins
PF-4217329 (EP2-agonist, Pfizer) d/c’edEP2-agonist, (Allergan’s Butaprost)NCX 116 (B&L’s Vesneo)NCX 470 (Nicox & Pfizer)Latanoprost & AR-13324 combo (Aerie’s Roclatan)
ROCK Inhibitors
AR-13324 (Aerie’s Rhopressa) AR-12286 & AR-13165 (Aerie) d/c’edAMA0076 AmakemK-115 (Kowa’s Ripasudil (Glanatec) in Europe)H-1337 (Isoquinoline Sulf ROCK by D.WesternTherpeutics)Y39983/SNJ1656/RKI-983 (Senji-Novartis) d/c’edDE-104 (Santen-Ube) d/c’edATS907 (Altheos) d/c’ed
Sustained Delivery
DDS subtenon implant (Allergan)Punctal plugs Latanoprost (Mati) Punctal plugsTravoprost (Ocular Therapeutix)
OtherAC-262271 Muscarinic selective compounds (Acadia-Allergan)SAD 448 (cannabinoid CV 1/2 agonist, Novartis) d/c’edINO-8875 (adenosine-1 agonist, Inotek’s Trabodenoson)
Clinical Ophthalmology 2014:8
Surgical Management
� Is ALT/SLT a better option than primary Txthan medication?
� Early decisions were based on the Glaucoma Laser Trial (GLT) of 1995
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Interpreting the GLT Results
� Initial treatment with ALT is at least as effective as initial treatment topical medication in patients with POAG in terms of control of IOP, optic disc and visual field
� Ultimately, ALT will need to be supplemented with other modes of intervention
� What about SLT????
SLT as an alternative to PGAs� SLT vs. latanoprost for IOP control in OHT
and POAG
� 12-month study
� 90°, 180°, 360° SLT
� Success criterion◦ 20% - 30% IOP reduction from baseline
Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417
SLT as an alternative to PGAs� Results◦ More 360° SLTs (60%) achieved success
criterion ( > 30% IOP reduction) than did 90° or 180°
◦ Latanoprost-treated eyes achieved success criterion in more cases than 90° or 180° and did as well as 360° in maintaining diurnal IOP reduction
Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417
Controversies in Treatment
� Dude….Can you prescribe medical marijuana for my glaucoma?
MJ Use in the USA
� There has been a significant change in the attitude of acceptance of use of marijuana in the U.S. ◦ Over 50% of the states now approve the use of
MJ for either medical or recreational (or both) use.
MJ Use in the USA
� There has been a significant change in the attitude of acceptance of use of marijuana in the U.S. ◦ Over 50% of the states now approve the use of
MJ for either medical or recreational (or both) use.
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Cannabinoid Consequences
� To date, only one large-scale study has sought to determine the frequency with which MJ smokers develop cancer ◦ No association was found between MJ use and any
other type of cancer, including cancers normally linked to tobacco smoking � The study was limited by how many of its participants
were younger than the average ages when many cancers appear as well as by the short duration of their MJ use
Cannabinoid Consequences
� Taken as a whole, these findings indicate that smoking MJ could have dangerous consequences for patients with compromised immune systems (including people with AIDS & cancer) particularly those who are receiving immunosuppressive chemotherapy as well as organ transplant recipients
Cannabinoid Consequences
� Exposure to cannabinoids can also affect the cardiovascular system ◦ Both smoked MJ and synthetic THC have been
shown to raise heart rate � from 20%-100% above normal in some cases
◦ THC can also exaggerate the drop in BP that occurs when a person rises to standing after lying down causing syncope◦ People at risk for cardiovascular disease would be
wise to avoid MJ and THC
Cannabinoid Consequences
� Fertility research on MJ users has yielded conflicting results ◦ The few studies that have been conducted to
assess THC's effects on human reproduction have produced results that are consistent with those of the animal studies
� In a study of Jamaican women (they prepared it as a tea to relieve morning sickness), no neurobiological or behavioral differences were detected between newborn babies of those who used MJ and those who did not
Cannabinoid Consequences
� Fertility: ◦ Decreased sperm count
◦ Size & Shape of sperm
◦ Chromosome breakage/damage
◦ Testosterone levels
Cannabinoid Consequences
� Memory◦ One study involving over a 1,000 individuals
found that chronic cannabis use is associated with cognitive decline � greater deterioration being observed in those individuals
presenting a more persistent use
◦ Among the various cognitive domains studied, memory is one of the most frequently identified as being negatively affected by cannabis
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Chronic use & RGC’s
� Association Between Regular Cannabis Use
and Ganglion Cell Dysfunction
◦ Schwitzer T, Schwan R, et al, JAMA Ophth, 2017;135(1):54-60
◦ 52 participants (18-35 yo)� 28 regular cannabis users (24 male/4 female)
� At least 7 consumptions per week over the last 30 days with (+) THC on urine analysis
� Also + tobacco users
� 24 controls (20 male/4 female)� No history of THC, (-) THC on urine analysis and (–) tobacco user
Chronic use & RGC’s
� Association Between Regular Cannabis Use
and Ganglion Cell Dysfunction
◦ Findings: � There was a significant increase in the N95 implicit time
(latency) of the pattern ERG (pERG) in cannabis users with a median of 8.4 milliseconds difference between controls and users
� It is unclear if this increase in latency (delay in processing) is permanent or disappears after withdrawal from use
Chronic use & RGC’s
� Association Between Regular Cannabis Use
and Ganglion Cell Dysfunction
◦ Conclusion: Our results demonstrate a delay in transmission of action potentials by the ganglion cells in regular cannabis users, which could support alterations in vision. Our findings may be important from a public health perspective since they could highlight the neurotoxic effects of cannabis use on the CNS as a result of how it affects retinal processing.
Chronic use & RGC’s
� Association Between Regular Cannabis Use
and Ganglion Cell Dysfunction
◦ Commentary: However, the conclusion that cannabis causes retinal ganglion cell dysfunction cannot be made with any degree of certainty based on the evidence provided in the current study. This question should be reexamined with some urgency, using a degree of scientific rigor, which may be challenging in jurisdictions where cannabis consumption is illegal.
Cannabinoid Consequences
� In summary, there are many reasons to worry that for people who might choose to use MJ as medicine (and especially those who smoke it) the drug could actually add to their health problems
Societal Trends
� May 7, 2015: “Texas could be on board with legalized cannabidiol before the end of this session, as the Texas Senate voted 26-5 to approve SB 339…. Epilepsy patients in Texas would have access to medicinal oils containing a therapeutic component found in marijuana …”
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Societal Trends
� April 16, 2015: “Georgia Governor Signs
"Haleigh's Hope Act" on CBD Oil for
Kids.”
◦ The bill takes effect immediately, and allows the possession of up to 20 ounces of cannabis oil if a doctor signs off on the treatment
Societal Trends
� Wide Variability In Potency Plagues
Medical Marijuana Edibles, JAMA Study
(Forbes 6/23/2015 )
◦ According to a paper published this morning in JAMA…shows that the active chemicals in edible cannabis products can vary from 1% to 155% the amount listed on the product label
Societal Trends
� Massachusetts
� Nevada
� California
� New York
� Vermont
� Minnesota
� Connecticut
� Maryland
� Rhode Island
� Maine
� Delaware
• Doug McIntyre of 24/7 Wall Street: “The next 11 states to legalize marijuana (in Nov ‘16)…”
Societal Trends
� Massachusetts
� Nevada
� California
� New York
� Vermont
� Minnesota
� Connecticut
� Maryland
� Rhode Island
� Maine
� Delaware
• Doug McIntyre of 24/7 Wall Street: The next 11 states to legalize marijuana (in Nov ‘16)…”
Societal Trends
� Massachusetts
� Nevada
� California
� New York
� Vermont
� Minnesota
� Connecticut
� Maryland
� Rhode Island
� Maine
� Delaware
• Doug McIntyre of 24/7 Wall Street: The next 11 states to legalize marijuana (in Nov ‘16)…”
Societal Trends
� Healthy Kids Colorado Survey
◦ Approximately 17,000 randomly selected youth from 157 middle and high schools throughout the state participated in the 2015 survey
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Societal Trends
� Healthy Kids Colorado Survey
Societal Concerns
� Full legalization of marijuana….
� I will leave THAT to your personal politics!
Things we already know…
� Third party insurers have greatly changed the medical care environment
� Nationwide, nearly 65% of the average ODs gross income is coming from a third party insurer
� Older adults make up >1:6 patients and >1:7 practice revenue dollars
� Glaucoma can be “owned” by Optometry!
Thank You!
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