Download “Decision Making in Glaucoma: When to pull the trigger” COPE

7/15/2015
Disclosures
“Decision Making in Glaucoma:
When to pull the trigger”
COPE #41665-GL
Financial disclosures:
• Speakers Bureaus/Consultant:
Alcon
Allergan
Optovue
Zeiss-Meditec
VSP
B&L
Ivantis
Robert E. Prouty, O.D., FAAO
Specialty Eye Care
Parker, Colorado
[email protected]
• I have no personal financial interests in
any of these companies
Glaucoma is an Optometric Problem
~ 2.5 million Americans are
diagnosed with Glaucoma
Risk Factors for 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!
Glaucoma
The most common types:
◦ Primary Open Angle Glaucoma
◦ Angle Closure Glaucoma
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
Primary Open Angle Glaucoma
In general, patients are at risk for glaucoma
if they have the following:
~2.5 million Americans have POAG
◦ About 1/3 of the POAG is undiagnosed
◦ ~ 25% of all cases of POAG are African
Americans
Acute or Chronic
◦ Secondary Glaucomas
Pseudoexfoliation
Pigment Dispersion
Uveitic
Angle Recession
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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
35
Prevalen ce (%)
30
25
21.09
21.09
20
13.8
13.8
15
LALES
Whites
Blacks
10
5
2.6
2.6
0
40-49
50-59
60-69
70-79
Age Groups (yrs)
80+
Varma R, Prevalence and Risk Indicators of Visual Impairment and Blindness in Latinos –
The Los Angeles Latino Eye Study, Ophth. 2004;111:1132–1140
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
◦ 25%-50% of PDS
OHTN
PDG
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?
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
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
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
None, Nada, Zero, Zilch, The big Goose Egg!
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Time of maximum IOP
1:30 PM
9pm12am
11:30 AM
3pm6pm
7:30 AM
9am12pm
9:30 AM
3am6am
5:30 AM
0
3:30 AM
12
10
Habitual IOP of
untreated
glaucomatous eyes
1:30 AM
23
20
n=24
9:30 PM
10
DIURNAL/WAKE
NOCTURNAL/SLEEP
11:30 PM
20
DIURNAL/WAKE
7:30 PM
Number of eyes
30
26
25
24
23
22
21
20
19
18
17
16
15
14
12
10
8
6
4
2
0
3:30 PM
IOP (mm Hg)
Times of maximum IOP
Over a 24-hr period:
IOP is Higher at Night
5:30 PM
Peak IOP Outside Office Hours
for 2/3 of Eyes
Clock Time
Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204
Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590
Liu JH et al. Invest Ophthalmol Vis Sci. Dec 1998; Vol 39 #13
Med Effects on Diurnal/Nocturnal IOP
DIURNAL/WAKE
NOCTURNAL/SLEEP
DIURNAL/WAKE
28
26
Refined
24
22
20
IOP (mmHg)
How do ODs become more accurate
in diagnosis?
Baseline
18
Travoprost 0.004%1
Brimonidine 0.2%2
16
14
12
10
• Diurnal period – sitting
8
• Nocturnal period – supine
6
1:30 PM
9:30 AM
11:30 AM
7:30 AM
5:30 AM
3:30 AM
1:30 AM
9:30 PM
11:30 PM
7:30 PM
5:30 PM
3:30 PM
4
2
0
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
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
How do ODs become more accurate
in diagnosis?
How do ODs become more accurate
in diagnosis?
Refined
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
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?
How do ODs become more accurate
in diagnosis?
Refined
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
Refined
MHx assessment
Ocular assessment
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)
Glaucoma Clinical Workup
I only get paid once in their lifetime!
AAO Preferred Practice Pattern Guidelines:
◦ Perform gonioscopy periodically (e.g., 1-5
years).
o Gonioscopy
Is Gonioscopy required on all glaucoma patients?
Does it need to be done more than once?
MHx assessment
◦ Remember that IOP alone does not determine
glaucoma!
◦ Compromised ocular hemodynamics
AOA Clinical Practice Guidelines:
◦ To rule out the development of an angle closure
component in the glaucoma, gonioscopy should
be repeated periodically.
How do ODs become more accurate
in diagnosis?
Refined
MHx assessment
Ocular assessment
Refined ONH assessment
Refined
~ A Video Atlas ~
http://gonioscopy.org/
Wallace L.M. Alward
Frederick C. Blodi Chair in Ophthalmology
Director, Glaucoma Service
University of Iowa Carver College of Medicine
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Five Rules for Assessment of the
Optic Disc in Glaucoma
1.
Observe the scleral
Ring to identify the
limits of the optic
disc and its size
Optic Disc Size
Measurement of optic disc size with direct ophthalmoscope
Small aperture (5 degree) of
Welch-Allen direct
ophthalmoscope
Size of light spot ~ size of average optic disc
Optic Disc Size
Five Rules for Assessment of the
Optic Disc in Glaucoma
Size of cup varies with size of disc
Large discs have large cups in healthy eyes
1.4
2.2
1.9
Small
Average
Observe the scleral
Ring
2.
Identify the size of
the Rim
Large
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)
“ISNT” Rule
Rim width
Distance
between
border of disc
and position
of blood
vessel
bending
ISNT rule
Inferior >
Superior >
Nasal >
Temporal
1.
“ISNT” Rule
S
N
T
I
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.”
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Five Rules for Assessment of the
Optic Disc in Glaucoma
Five Rules for Assessment of the
Optic Disc in Glaucoma
1.
Observe the scleral
Ring
1.
Observe the scleral
Ring
2.
Identify the size of
the Rim
2.
Identify the size of the
Rim
3.
Examine the Retinal
nerve fiber layer
3.
Examine the Retinal
nerve fiber layer
4.
Examine the Region of
parapapillary atrophy
Five Rules for Assessment of the
Optic Disc in Glaucoma
1.
Observe the scleral
Ring
2.
Identify the size of the
Rim
3.
Examine the Retinal
nerve fiber layer
4.
Examine the Region of
parapapillary atrophy
5.
Look for Retinal and
optic disc hemorrhages
How do ODs become more accurate
in diagnosis?
Refined
MHx assessment
Ocular assessment
Refined ONH assessment
Refined VF interpretation
Refined
Visual Fields: Poor Sensitivity
A large number of RGCs often are lost prior
to detectable visual field abnormalities
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
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Visual Fields: Highly Variable
OHTS
Visual Field Progression
• 86% of visual field abnormalities not replicated on
retesting*
Slow progression
0
Visual
Function
(MD)
1st VF abnormal
(GHT Outside Normal Limits)
2nd VF normal
(GHT Within Normal Limits)
Early intervention
15
Fast progression
Later
intervention
Level of visual disability
3rd VF abnormal
(GHT Outside Normal Limits)
Birth
Change Analysis
Death
Event Analysis
Baseline
Glaucoma Progression Analysis
(GPA)
Baseline
Rate of Progression
Caprioli J, The Importance of Rates in Glaucoma, AJO 2008 Vol 145, No. 2 , Pg 192
*VF defect defined as GHT outside normal limits, CPSD < .05%, or both
1 Keltner JL, Johnson CA et al. Arch Ophthalmol. 2000; 118:1187-1194
Different from baseline?
Glaucoma Progression Analysis
(GPA)
Follow-up
Multiple exams
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."
11/27/97
12/15/98
4/18/01
Possible Progression
Likely Progression
4/18/02
11/20/02
Rate-of-progression plot
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]
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Visual Field Index
Visual Field Index
Central points weighted more heavily than on
periphery
Reduces cataract effect to the measurement of
VF loss
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”.
B
A
VFI = 90%
Bengtsson B, Heijl A; A Visual Filed Index for Calculation of Glaucoma Rate of Progression, AJO 2008 Vol 145, No. 2,
Pg 343-353
VFI = 81%
B”has more damaged central points and lower VFI than “A”
“
Visual Field Index
Visual Field Index
Current age at testing
% loss to date
% loss in next 5 years
100%
VF Index plotted against age:
• Characterizes trend significance over next 5 years
Visual Field Index Bar
• Aids in interpretation & patient education
• Helps formulate individualized treatment decisions
•Shows vision loss in terms of %
•Enhanced visual presentation
Summary of Functional Tests
SITA SAP
Advantages
“Gold Standard”
SITA SWAP
As fast as SITA
SAP
Possibly more
sensitive
The “5Rs” of Progression
FDT Matrix
More portable
Tolerates blur
Possibly more sensitive
1.
2.
Record baseline structure and function.
Risk evaluation.
Variability does not
increase with severity
Disadvantages
Not sensitive
enough to detect
early glaucoma
Limited clinical
evaluation
Limited clinical evaluation
Variability
Cataract effects
Best use
Baseline VF and
following
progression in
advanced disease
Early diagnosis
Early diagnosis
Younger patients
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Developing a Risk Profile
Developing a Risk Profile
Each patient must be assessed individually
Establish baseline risk and reassess from
exam to exam
Criteria
Each patient must be assessed individually
Establish baseline risk and reassess from
exam to exam
Criteria
- Stage of disease
- Life expectancy
◦ Stage of disease
◦ Life expectancy
◦ Other risk factors
How old is the patient?
How long did the patient’s parents live?
How is the patient’s overall health?
Independent Risk Factors for
Progression
AGIS
CIGTS
• Elevated IOP
Elevated IOP
CNTGS
EMGT
EGPS
OHTS
X
X
X
X
X
X
X
X
X
X Hg X
24 to 32 mm
> 32 mm HgX (2 points)
–
–
Age
• CCT below 500 µm
Central corneal thickness (thinner)
Disc hemorrhage
Independent Risk Factors for
Progression
X
X
• Disc hemorrhage (2 points)
Visual field (higher PSD)
Cup-to-disc ratio (greater)
• Pseudoexfoliation/Pigment
Visual field (greater MD)
X
Pseudoexfoliation
Pseudoexfoliation/pigment
X
Low ocular perfusion pressure
X
–
–
X
X
X
X
24 to 32 mm Hg
> 32 mm Hg (2 points)
• CCT below 500 µm
X
Abnormal baseline HRT/OCT/GDx
Race (nonwhite)
• Elevated IOP
•
•
X
X
Disc hemorrhage (2 points)
Pseudoexfoliation/Pigment
Number of Points
Level of Risk
0-1
2
Low
Medium
>2
High
The “5Rs” of Progression
The “5Rs” of Progression
1.
Record baseline structure and function.
Risk evaluation.
3. Repeat fields and imaging/photos.
4. Rate of progression.
1.
2.
2.
dB Loss per Year
Rate of Progression
< 0.5
0.5-1.5
Low
Moderate
> 1.5
High
Record baseline structure and function
Risk evaluation
3. Repeat fields and imaging/photos
4. Rate of progression
5. Reassess and revise management plan and
re-establish baseline
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How 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
Light
Polarizer
Two polarized components
Birefringent structure
(RNFL)
Retardation
Scanning Laser Polarimetry (SLP)
Confocal Scanning Laser
Ophthalmoscopy (CSLO)
Optical Coherence Tomography (OCT)
Glaucoma Clinical Workup
Tomography - CSLO
Digital Tomography Deficiencies
2D measurement are stacked to achieve a 3D
assessment
An inferred estimate of the RNFL height is based on a
depth of 50 microns
All estimates of glaucoma status are based on a
multivariate analysis
This regression analysis (Moorfields regression analysis) also
compensates for age and identifies glaucomatous eyes with a
relatively high level of sensitivity and specificity
Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma
diagnosis, Curr Opin Ophthalmol 2012, 23:79–88
GDx Basic Principles
GDx Basic Shortcomings
Light
Polarizer
The crystalline lens and cornea have significant
birefringence which is highly variable.1 As such,
the macula was used as a reference to variably
compensate in the interpretation of the reflected
RNFL birefringence (GDx VCC).
It measures NFL thickness but only inferentially
measures loss based on normative database.
Two polarized components
Birefringent structure
(RNFL)
Retardation
The amount of retardation from the RNFL is directly
proportional to the RNFL thickness1
1 Weinreb et al. Arch Ophthalmol 1990; 108: 557-560
540 healthy eyes with 271 glaucomatous eyes
18-82 yo in healthy with 25-89 yo glaucomas
Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma
diagnosis, Curr Opin Ophthalmol 2012, 23:79–88
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GDx Basic Shortcomings
Ocular movement such as nystagmus can render
GDx measurements meaningless.
Older patients, high myopia, or lightly pigmented
fundus eyes, are subject to increased birefringence
with an abnormal s/n ratio which can provide
erroneous readings.
Correlation of the Deviation Map
with Visual Fields
PPA can be a confounding factor if it falls within the
measurement circle.
The circle can be enlarged to avoid scanning the PPA region
and increase the reliability of measurements yet that adds
variability
From Normal to Advanced Glaucoma
Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma
diagnosis, Curr Opin Ophthalmol 2012, 23:79–88
Correlation of the Deviation Map
with Visual Fields
But GDx does NOT assist in differentiating in
congenital NFL decreases or myopic ONH
decreases
Basically it measures but does NOT interpret
Scans & Analysis
Fast RNFL (Bilateral) - Three
circular scans with a 3.4mm
diameter are used to image
the peripapillary region of the
ONH to create a TSNIT
image.
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.
Fast Macula (Bilateral) - The
Stratus uses a 6 line radial
pattern to image the macula
(6 mm).
Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma
diagnosis, Curr Opin Ophthalmol 2012, 23:79–88
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
RNFL Thickness Average Analysis
Black line is patient’s
RNFL thickness
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
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Fourier Domain OCT Advantage
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
FD OCT has twice the depth resolution as
TD OCT
◦ 5 microns vs 10 microns
Allows imaging and segmentation of:
◦ Cornea
◦ Angular structures
◦ Macular Ganglion cell layers
Ganglion Cell Loss in the Macula
Macular Ganglion cell density
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
Disc
fovea
• 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
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
•
•
Diagnostic Accuracy with TD OCT:
Macula vs RNFL
Progression: 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 RNFL
thickness was significantly more accurate for
detecting glaucoma than macula thickness
Using TD OCT, Medeiros et al, compared the
accuracy for detecting progression using RNFL
versus 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 Sci
2009; 50:5741-5748
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
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TD OCT Study Limitations
GCC Thinning in Glaucoma
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
Overlay of the RNFL and GCC
GCC
Normal
GCC
Glaucoma with thinner GCC
GCC Report: Normal
Patient Information
Exam Date and Quality
GCC Thickness Map
pRNFL
Deviation Map
GCC
Fovea Mask
Significance Map
Parameter Table
GCC Deviation Map
GCC Deviation Map
% loss =
actual scan value – normal value
normal value
color coded map
Percent loss value at each pixel location relative to normals (based
on age-adjusted normative database) of over 300 healthy eyes
color coded map shows regions where the change from normal
reaches statistical significance
◦ Green = values within normal range (p-value 5% to 95%)
◦ Blue = thinning 20%-30% relative to normal
◦ Yellow = borderline results (p-value < 5%)
◦ Black = 50% loss or greater
◦ Red = outside normal limits (p-value <1%)
David Huang, MD, PhD www.AIGStudy.net
David Huang, MD, PhD www.AIGStudy.net
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GCC Change Analysis
Revisiting the Macula
Thickness Maps
Can imaging the ganglion cells in macula
with FD OCT improve glaucoma detection?
Deviation Maps
Significance Maps
Trend Analysis
GCC parameter
change analysis
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
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
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What value is digital technology?
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
They offer an expert opinion but the new
generation OCTs are far superior
Medicinal Management
Prostaglandin Derivatives
Topical CAI’s
Adrenergics
Beta-Blockers
Combos
Cholinergics/Anticholinesterases
Oral CAI’s
The “Prosta-somethings”
Travoprost (Travatan™)
Latanoprost (Xalatan®)
Tafluprost (Zioptan™)
Bimatoprost (Lumigan™)
The “Prosta-somethings”
The most common 1st line Tx in nearly all glaucoma
types!!
Increased uveoscleral outflow
Topical CAI’s
IOP decr about 9%-20%
◦ Depending on the iris color
◦ tid use
◦ ~30%-40% mean IOP decr
◦ qhs use
Often used bid
Brinzolomide is equivalent
to Dorzolamide (Trusopt®)
◦ More physiologic pH
less burning on use
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Adrenergics
Alpha2 agonist (Brimonidine 0.15% & 0.2%)
◦ 16% allergy rate (10% for Alphagan P!!)
Decreased aqueous production & increased
uveoslceral outflow
Minimal tachyphylaxis reported
Beta-Blockers
Non-selectives
20%-30% IOP reduction
Available as a generic
Qday use (best in am!)
◦ Timolol maleate
◦ Timolol Gel (Timolol-XE®)
◦ 21% IOP decr
◦ tid use
Gel formulation increase contact time-penetrance
◦ Timolol Hemihydrate (Betimol®)
bid as effective & best compliance
A levoisomer of Timolol
Beta-Blockers
Beta-Blockers
Non-selectives
20%-30% IOP reduction
Available as a generic
Qday use (best in am!)
◦ Levobunolol (Betagan®)
◦ Metipranolol (Optipranolol®)
◦ Carteolol (Ocupress®)
Combinations
Cosopt® (was Merck but now is Akorn)
◦ Timolol 1/2% & dorzolamide
As effective as separate dosing (?)
◦ Better convenience & compliance
Still stings!!
B1 Selective
◦ Selectivity = less efficacy
15%-25% IOP reduction
Available as a generic
bid use
◦ Betaxolol (Betoptic®-S)
“S” = styrene molecule that increases contact time and
penetrance
Combinations
Simbrinza™ (Alcon)
◦ Brinzolamide 1% & Brimonidine 0.2%
◦ As effective as separate dosing
◦ Better convenience & compliance
Less sting!!
◦ 32%-38% IOP decr
◦ 21%-35% IOP decr
◦ bid use
◦ tid use
Cosopt PF® (was Merck but now is Akorn)
Used bid in Europe
◦ Preservative Free!!
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7/15/2015
Cholinergics Anticholinesterases
Pilocarpines
Oral CAI’s
Acetazolamide (Diamox)
◦ 1/2%, 1%, 2%, 4%, 6% concentrations
◦ Generic available
◦ NOT to be used with iritis!
◦ Significant side-effects
◦ Decreases secretion of aqueous
◦ Sulfonamide derivative
◦ Significant side-effects
◦ Doseages:
start lower % and increase to max effect
◦ qid use
Diamox: 250mg bid –qid
Sequels: 500mg bid
Oral CAI’s
Methazolamide (Neptazane)
Oral CAI’s
◦ Topical CAI cross-sensitivity is being re-thought
◦ Sulfonamide derivative
◦ Doseages:
◦ 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
50mg-100mg bid to tid
Back to the Future!
Sulfonamide sensitivity
◦ Decreases secretion of aqueous
Nutritional Treatments:
◦ Blood flow enhancers
Mirtrogenol® (120 mg b.i.d.)
commercial composition of Bilberry extract (Mirtoselect®) and
French maritime pine bark (Pycnogenol®)
Gingko biloba (80 mg b.i.d.)
also works as an antioxidant
Back to the Future!
Nutritional Treatments:
◦ Blood flow enhancers
Mirtrogenol® (120 mg b.i.d.)
Gingko biloba (80 mg b.i.d.)
◦ Calcium channel blockage (i.e. Nifedipine)
Increase blood flow therefore poss neuroprotection
Significant SE’s noted in studies (1/3 dropout from SE’s)
HA’s, flushing, dizziness, swelling, low BP, nausea
Lomerizine HCl (Santen’s DE-090)
Only CA++ antagonist being developed as oral glaucoma
treatment
Excellent safety and minimal SEs to date
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7/15/2015
Back to the Future!
Back to the Future!
Vitamin Treatments:
◦ Magnesium: (<350 mg qday is well tolerated)
◦
◦
◦
◦
Considered “Nature’s calcium channel blocker”
Usually 125 mg bid (d/c with oral antibiotic use)
◦ Vitamin B-complex (water soluble)
In combination with E and Omega 3 (DHA), shown to
stabilize VF
Early ‘14 study supported association of Vit. D
deficiency with presence of glaucoma
No supplementation needed but may want to test
for deficiency in NTG
Prostaglandins
New MOAs
AR-13324 (Aerie)
ROCK/NET Inhibitor (qday)
Phase 3
K-115 (Kowa)
ROCK Inhibitor (bid)
Phase 3 (Japan)
AMA0076 (Amaken)
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
Magnesium: (<350 mg qday is well tolerated)
Vitamin B-complex (water soluble)
Vitamin D
Vitamin E (fat-soluble):
Diet alone is sufficient
Not > 400 IU daily
◦ Vitamin D
Glaucoma Medications in the Pipeline
Vitamin Treatments:
Current commercial PGAs 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
New PGAs
BOL-303259 (B&L)
NO donating latanoprost (qday)
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
Phase 3
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”
◦ Allergan’s Butaprost binds to PGEP2
◦ ONO Pharmaceuticals’ ONO-0476
Prodrug of prostanoid EP2
NO-Prostaglandins
Nitric Oxide-Donating Prostaglandin
F2-Alpha PGA s:
◦ Pfizer/Nicox Research are investigating
NO-Donating Bimatoprost 0.004% (NCX 470)
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
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7/15/2015
Rho Kinase Inhibitors
Rho Kinase Inhibitors
Several companies with phase I to III trials
Likely not to be packaged with BAK
Amenable to alternative delivery modes:
◦ 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 calciumindependent manner
◦ ROCK inhibitors reduce IOP by enhancing
aqueous humor drainage through the trabecular
meshwork
◦ Punctal plugs, gel vehicle etc.
Rho Kinase Inhibitors
Current status:
Mechanism:
Rho Kinase Inhibitors
◦ April 2014: Rhopressa Phase 3 Trial (Rocket 1)
Misses Primary Endpoint
Current status:
◦ Roclatan:
Essentially, Rhopressa + Latanoprost
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 + Latanoprost
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
Adenosine Receptor Agonists
Like ROCK inhibitors, these molecules can
work on the TM but much less is known of
them
A3 adenosine receptor (A3AR) agonists:
◦ A3 agonists have been found to protect normal
cells from undergoing apoptosis via the down
regulation of death signals
Therefore, potentially neuroprotective
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7/15/2015
Adenosine Receptor Agonists
A1 receptors:
Adenosine Receptor Agonists
◦ Stimulation of A1 adenosine receptor in the TM
causes a improvement in metabolic activity
which helps to clear the pathway for the aqueous
to flow out of the eye (lowering IOP)
A1 Adenosine receptor agonists:
◦ Trabodenoson (Inotek INO-8875)
Appears to work primarily by increasing the outflow
of aqueous via the TM pathway
This metabolic activity takes the form of an increase or
upregulation of proteases - such as Protease A or MMP2 - that digest and remove accumulated proteins which
can block the flow of aqueous humor out of an eye with
glaucoma
RNAi (RNA Interference)
Interference RNA (RNAi) is a promising
technology with therapeutic applications
◦ Sylentis is developing a treatment based on
silencing the action of genes involved in aqueous
humor production and/or genes which regulate its
drainage, so as to reduce IOP
Discovered in plants in the 1990s, RNAi
consists of highly efficient selective &
specific inhibition of gene expression
Drug Class
Prostaglandins
ROCK Inhibitors
Sustained
Delivery
Other
RNAi (RNA Interference)
RNAi is mediated by small fragments of
double-stranded RNA, consisting of 1923 nucleotides, which promote degradation
of mRNA, thus inhibiting synthesis of the
proteins for which they code
As this mechanism is used naturally by cells
to regulate gene expression in a way that is
both non-toxic and highly effective, RNAi
has great therapeutic potential
Product (Company)
PF-4217329 (EP2-agonist, Pfizer) d/c’ed
EP2-agonist, (Allergan’s Butaprost)
NCX 116 (B&L’s Vesneo)
NCX 470 (Nicox & Pfizer)
Latanoprost & AR-13324 combo (Aerie’s Roclatan)
AR-13324 (Aerie’s Rhopressa)
AR-12286 & AR-13165 (Aerie) d/c’ed
AMA0076 Amakem
K-115 (Kowa’s Ripasudil (Glanatec) in Europe)
H-1337 (Isoquinoline Sulf ROCK by D.Western Therpeutics)
Y39983/SNJ1656/RKI-983 (Senji-Novartis) d/c’ed
DE-104 (Santen-Ube) d/c’ed
ATS907 (Altheos) d/c’ed
DDS subtenon implant (Allergan)
Punctal plugs Latanoprost (Mati)
Punctal plugs Travoprost (Ocular Therapeutix)
AC-262271 Muscarinic selective compounds (Acadia-Allergan)
SAD 448 (cannabinoid CV 1/2 agonist, Novartis) d/c’ed
INO-8875 (adenosine-1 agonist, Inotek’s Trabodenoson)
Clinical Ophthalmology 2014:8
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7/15/2015
Surgical Management
Interpreting the GLT Results
Is ALT/SLT a better option than primary Tx
than medication?
Early decisions were based on the Glaucoma
Laser Trial (GLT) of 1995
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
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
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
◦ 20% - 30% IOP reduction from baseline
Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417
Controversies in Treatment
Dude….Can you prescribe medical
marijuana for my glaucoma?
Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417
History of MJ use
Since 1996, voters have approved the
medical use of marijuana
◦ These state ballot initiatives, and the wider
discussion they spawned about appropriate
national policies regulating marijuana, have been
sharply divisive
◦ 2010 = 12 states (3 provisionals)
◦ 2012 = 16 states + D.C.
30 states looking to modify laws by 2013
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7/15/2015
History of MJ use
The director of the White House Office of
National Drug Control Policy (ONDCP)
asked the Institute of Medicine (IOM) to
review the evidence for the potential benefits
and risks associated with the use of
marijuana
History of MJ use
The report of the 18-month IOM study was
first released to both the ONDCP and the
public in March 1999
◦ There is remarkable consensus about the
potential of cannabinoid drugs for medical use
◦ There are far less convincing data about proven
medical benefits
◦ The IOM is a non-governmental, apolitical, nonprofit organization of scientists
MJ & Glaucoma
MJ & Glaucoma
Glaucoma ranks among the most frequently
cited reasons for using medical marijuana
and is one of the indications for which the
federal government once granted permission
for compassionate marijuana use
Research findings from as early as the 1970s
show that both marijuana and THC reduce
IOP
Despite its illegality, millions of Americans
use marijuana regularly
Reported medical uses of marijuana
MJ & Glaucoma
The first such reports generated considerable
interest because at the time conventional
medications for glaucoma caused a variety of
adverse side effects
◦ Pilocarpine and Diamox were among the few drugs
available to treat glaucoma in the late 1970s
Currently other treatments for the disorder have
since eclipsed marijuana-based medicines
MJ & Glaucoma
Several clinical studies have found that
synthetic cannabinoids or marijuana reduce
IOP as well as do most conventional
glaucoma medications
◦ This is true whether administered orally (eaten),
intravenously or by inhalation
◦ NOT when they are applied directly to the eye
◦ In most trials a single dose of marijuana or
cannabinoid maintained this effect for three to
four hours
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7/15/2015
MJ & Glaucoma
MJ & Glaucoma
Researchers have yet to explain how
marijuana and cannabinoids reduce IOP
Marijuana reduces blood pressure and
reduced blood pressure could decrease blood
flow to the optic nerve, counteracting the
benefits of reducing IOP
MJ & Glaucoma
MJ & Glaucoma
There is no question that marijuana-based
medicines can be used to lower IOP but, like
several other glaucoma medications that have
fallen into disuse, their drawbacks outweigh
their benefits
This was not the case when the first reports of
marijuana's effects on IOP were published in
the 1970s when there were relatively few drugs
(all of which caused troubling side effects) were
available to treat the condition
Societal Concerns
Societal Concerns
So for glaucoma…..
◦ There are far better management regimens now
available
The short duration of effect means that
marijuana-based medicines must be taken up
to 8 X per day, which most patients are
unlikely to do!
◦ Other medicines reduce IOP equally well and
need only be taken once or twice a day
This is an important difference because
patients need to control IOP continuously
due to the progressive nature of glaucoma
Those drugs have since been superseded by
more effective and less problematic
medications which seems the likely fate of
marijuana-based treatments for glaucoma as
well
The use of Medical Marijuana is currently
being worked through
3-4 hr efficacy ≠ good control
Constant intoxication ≠ good citizens
Health concerns ≠ future safety profile
◦ Colorado ODs can be certified for DEA
Schedules 3 narcotic – 5
Marijuana is still Schedule 1
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7/15/2015
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 …”
Societal Trends
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 of up to 20 ounces of cannabis oil
if a doctor signs off on the treatment
Societal Concerns
Wide Variability In Potency Plagues
Medical Marijuana Edibles, JAMA Study
(Forbes 6/23/2015 @ 5:06PM)
Full legalization of marijuana….
◦ 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
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!
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