GLAUCOMA: ADVANCES AND CONTROVERSIES
| MAKING SENSE OF THE EUROPEAN GLAUCOMA PREVENTION STUDY AND THE OCULAR HYPERTENSION
TREATMENT STUDY —Richard K. Parrish II, MD, Professor of Ophthalmology and Associate Dean for Graduate
Medical Education, University Miami, Miller School of Medicine, Bascom Palmer Eye Institute
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| Background: European Glaucoma Prevention Study (EGPS)—goal to evaluate efficacy of intraocular pressure (IOP) reduction
in patients with ocular hypertension; Ocular Hypertension Treatment Study (OHTS)—goal to lower IOP at
least 20%; question whether IOP reduction with single agent altered development, prevented, or delayed progression
from ocular hypertension to manifest primary open angle glaucoma (POAG)
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European Glaucoma Prevention Study
| Inclusion criteria: IOP 22 to 29 mm Hg; ≥2 normal and reliable visual fields based on Octopus or Humphrey criteria; normal
optic nerve; randomization—patients received dorzolamide (Trusopt) or vehicle for dorzolamide; efficacy end
point—2 confirmatory visual fields that demonstrate difference, or optic disc change on single follow-up photograph;
safety end point—IOP >35 mm Hg on 2 consecutive examinations; follow-up—>300 of 1081 patients lost from follow-
up (question whether results can be generalized to entire study population)
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| Outcomes: after 6 mo, IOP reduced 15% (with placebo, IOP reduced 9%); after 5 yr, percentage IOP reduction in placebo
group nearly as great as that in dorzolamide group (what went awry?); high number of adverse events (21%; 9% in placebo);
group that withdrew from study disproportionately large; number of IOP determinations (at baseline, 536; at 60
mo, 192); IOP same for placebo and dorzolamide
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| Risk of reaching glaucomatous end point (disc or field change): confusing; proportion in dorzolamide group not statistically
different based on hazard ratios and confidence intervals; same risk of worsening whether patients received drug
or placebo; rate of progression in placebo and dorzolamide groups comparable; allowing for people who exited study due
to IOPs >35 mm Hg, still no significant difference in proportion that reached glaucomatous end point
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| Reason for failure to show difference: main problem of study that patients followed more often had lower IOPs at outset
and throughout study; conversely, if IOP higher, patients exempted from study; not surprising not much difference in
IOPs; patients with higher IOPs more likely to develop damage, but less likely to be followed; no statistically significant
difference in proportion of eyes that reached glaucoma or safety end point; study well-designed (problem in follow-up);
corneal thickness in dorzolamide group same as placebo group (baseline IOPs same); average IOP of all visits statistically
significant, but far less than anticipated, based on expected efficacy; more patients in placebo group left study because
IOPs >35 mm Hg; proportion of eyes with disc or field changes not different
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Discrepant Results Between OHTS and EGPS
| Different populations involved: loss from follow-up—OHTS lost 14% (EGPS more than double that); inclusion
criteria—OHTS (IOP ≥24 mm Hg in one eye; ≥22 mmHg in other); EGPS (IOP ≥22 mm Hg); 65% of patients in EGPS not
eligible for OHTS
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| EGPS (conclusion): authors take optimistic view of remarkable efficacy of placebo and suggest that other clinical trials
(eg, Early Manifest Glaucoma Trial [EMGT] and OHTS) be repeated with placebo control; speaker not convinced placebo
to blame (problem that different patients followed)
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| Speaker’s view: patients with marginally elevated IOPs at outset most likely to be followed; method for checking IOPs in
OHTS unusual; individual measuring IOP same who recorded it; may have been tendency to overestimate or underread
IOP at beginning (would muddle results); highly experienced technician may be more accurate than physician at reading
photograph of optic disc; finally, OHTS recruited 25% black patients (prevalence of POAG 4- or 5-fold higher); EGPS
had no black patients (EMGT had 1)
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| THE MOLECULAR GENETICS OF GLAUCOMA —Wallace L. M. Alward, MD, Professor and Vice-Chair of Ophthalmology,
and Director, Glaucoma Service, University of Iowa School of Medicine, Iowa City
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| Promises of genetic research: 1) better understanding of pathophysiology of glaucoma; 2) better tests for glaucoma; 3)
better treatments for glaucoma
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| How are we doing? researchers know more about molecular genetics of glaucoma than decade ago; POAG loci and
genes—7 known genetic loci (GLC1A through GLC1G); 3 known genes (WDR36 most recent; not confirmed); other
glaucoma genes—primary congenital glaucoma (CYP1B1)
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Better Understanding of Pathophysiology of Glaucoma
| Axenfeld-Rieger (A-R) syndrome: diverse system-wide involvement (effects do not fit together in 1 gene); many
changes in anterior segment of eye; unusual dentition and umbilicus; empty sella syndrome or growth retardation
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| Transcription factor genes: regulate expression of other genes; PAX6 (aniridia); PITX2 and FOXC1 (A-R syndrome); if
awry, can affect many structures in body not necessarily tied together genetically
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| Myocilin gene: involved in POAG; 3% to 5% of patients with POAG have mutations in myocilin; gene has 3 exons; importance
in glaucoma not clear; myocilin expressed throughout trabecular meshwork, other parts of eye, and muscular
structures throughout body; lower concentrations in retina and optic nerve; some patients with normal-tension glaucoma
have myocilin mutations; myocilin protein increased in eye of patients with glaucoma and in response to steroids and
stress; normal (wild type) myocilin secreted from cells into extracellular matrix; mutated myocilin 1) not secreted and 2)
blocks wild-type secretion; 2 more genes discovered in POAG (smaller players); possibly dozens or hundreds of genes
part of pathway (mutations in any one could cause glaucoma)
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Developing Better Tests for Glaucoma
 | Families with known mutations: physicians already make genetic diagnoses; eg, GLC1A mapped in family; mother of 2
children had glaucoma since 16 yr of age (surgery at 18 yr of age); 100% certainty that daughter will develop glaucoma
(no increased risk in son)
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| Speaker’s approach: genetic testing for glaucoma not done routinely; occasionally, speaker tests for myocilin mutations;
optineurin mutations rare cause of glaucoma; speaker sometimes tests for developmental genes (PITX2 or FOXC1 [A-
R syndrome] or PAX6 [aniridia])
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| Case: girl 9 yr of age diagnosed with primary congenital glaucoma; hypoplastic irises (more prominent with age); patient
small for age; younger brother had recent heart valve replacement surgery; patient tested for mutations in A-R genes
(PITX2 and FOXC1); PITX2 mutations associated with growth hormone (GH) deficiency (treat systemically); FOXC1 mutations
associated with heart valve defects; finding—patient had FOXC1 mutation
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| If myocilin mutation suspected: physician can send sample for analysis; cost $126; takes 8 to 10 wk for result
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| To determine prognosis: test for myocilin.mt1 promoter polymorphism (OcuGene); sequence variation “upstream” from
actual coding sequence of gene; recently described as measure of disease severity, but others not able to replicate finding
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| Requirements for genetic screening: ideally, limited number of genes that cause large percentage of glaucoma (so far, 3
genes collectively cause only 5% or 6% of glaucoma); limited number of disease-causing mutations to avoid screening
through entire gene (expensive; even myocilin has >50 reported mutations); inexpensive screening technology
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Developing Better Treatments for Glaucoma
| Gene replacement therapy: glaucoma may not be severe enough to warrant gene replacement therapy; DNA from jellyfish
successfully delivered into trabecular meshwork of monkey; clinical use far down horizon
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| Small molecule therapy: identify defective protein and replace it, or interrupt defective pathway before axons start to die;
may discover medication to treat myocilin glaucoma, but will not be helpful in eg, optineurin glaucoma
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| RISK MANAGEMENT IN GLAUCOMA —Paul P. Lee, MD, James Pitzer Gills III, MD, and Joy Gills Professor of Ophthalmology,
Duke University Eye Center, Duke University School of Medicine, Durham, North Carolina
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Basics of Malpractice
| Source of standards: case law dictates most decisions in malpractice (short of statutory limitations); but case law can
change; state-by-state determination (no federal standard for malpractice; exception federal employees)
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| Essential elements of malpractice: 1) duty (arises if doctor-patient relationship established); 2) failure to meet applicable
standard of care; 3) causation; and, 4) injury that law recognizes
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| When is duty established? relationship established if physician advises patient, and he or she relies on physician’s expertise
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| Breach of duty occurs when physician fails to provide adequate care: standard of care varies from state to state and
from case to case; reliance on expert testimony imprecise and unreliable way of determining applicable standard; practice
guidelines provide more objective measure; physician vicariously liable for statements or actions by staff relating to care
(use training protocols); breach must cause recognizable injury; many states recognize nonphysical injuries (eg, emotional
trauma) even in absence of physical injury
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| Determining standard of care: guidelines—have some weight in malpractice litigation, but not dispositive; in recent
survey, two thirds of attorneys used guidelines to decide whether to take case; if guideline not followed, physician may
need to explain why (through documentation or subsequently); by definition, guideline not mandate; target IOP
ranges—help show consistency in cure patterns and treatment of patient (inconsistent notes problematic if patient getting
worse); help document that physician has some idea of what he or she trying to achieve from treatment; if not in
chart or notes inconsistent, physician has high threshold to overcome in court
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Keys to Avoiding Malpractice Liability
| Communications: most common reason why people sue is feeling that physicians and hospitals not talking to them and/or
withholding information; communication skills of physician most important influence on choice of physician and ratings
of patient satisfaction; dispelling myths—patients talk forever (if allowed to talk, patients usually “run down” within 2.5
min); first complaint most important (often not true); I let patient talk enough (typically, physician interrupts patient
within 20 sec); I can tell what’s bothering patient (do not assume; always appropriate to ask); social factors—in recent
study, black patients more likely than white patients to believe they are being experimented on without consent; key
points—do not assume (ask); patients’ number one complaint “my doctor doesn’t listen to me”
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| Documentation: write it down (“if you don’t write it down, it wasn’t done”); handling phone calls—all calls (even refill
requests) recorded on sheet that gets attached to chart for physician to look at and approve; do not include billing or financial
problems in chart; documenting “no-shows”—chart stamped; follow-up phone call or letter to reschedule; if serious
condition, return receipt or registered letter stating medical necessity of return visit, including potential
consequences of lack of treatment; if continued noncompliance, withdrawal may be warranted (avoid abandonment)
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| COMPARISON OF METHODS TO DETECT GLAUCOMATOUS VISUAL FIELD PROGRESSION— Kouros Nouri-
Mahdavi, MD, Visiting Assistant Professor of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine
at the University of California, Los Angeles
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Paper by Nouri-Mahdavi et al
| Purpose: to compare 3 methods for detection of glaucomatous visual field progression; 1) Glaucoma Change Probability
Analysis (GCPA); 2) pointwise linear regression (PLR) analysis; 3) Advanced Glaucoma Intervention Study (AGIS)
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| Parameters: 156 eyes of 156 patients from AGIS; ≥8 yr follow-up; baseline AGIS visual field score ≤16; ≥6 visual field
examinations during first 4 yr (≥6 additional visual field examinations from 4 to 8 yr)
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| Methods: surrogate standard used for determining time of visual field progression and whether progression occurred at all;
GCPA flagged changes in threshold sensitivity at single test location (exceeding fluctuation) in stable glaucomatous
eyes; definition of progression at 8 yr required change in ≥3 test locations on last 3 examinations (locations did not have
to be adjacent); to make PLR analysis comparable to GCPA, similar criteria used to define change (≥3 points showing
change over last 3 examinations); in PLR, threshold sensitivity plotted at single point over time and compared to follow-
up; trend or slope accompanied by probability (p) values; if single test location had decrease in slope >1 decibel (dB) and
p value of ≤0.01, test location progressive; use of AGIS criteria—progression at 8 yr defined as worsening of visual field
≥4 points over last 3 yr; mean AGIS visual field score at baseline 7.7 (roughly equal to mean deviation of -11 dB); median
18 visual fields available during follow-up
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| Results: about one third of progressing test locations detected by PLR and GCPA simultaneously (AGIS detected ≈22%);
only 14% of eyes progressive by all 3 methods; at 8 yr, agreement of PLR and GCPA much better than agreement of either
with AGIS; k value for agreement fairly good (0.58)
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| Conclusions: over last decade, most published comparisons suggest AGIS most conservative method (however, during first
few years, AGIS detected more progressing eyes, compared to PLR and GCPA); as length of follow-up increases, PLR and
GCPA detection increased; spatial pattern of progression (PLR vs GCPA)—37 eyes defined as progressive by both
methods; median time to first confirmed progression (AGIS, 3.8 yr; GCPA, 4.7 yr; PLR, 5.1 yr); median number of progressing
test locations at time of first detection same for both methods; however, only 34% of test locations same (therefore,
spatial pattern of progression different); all methods show low false-positive rate
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Educational Objectives
| The goal of this program is to educate the listener about advances and controversies in managing glaucoma. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Compare the results of the European Glaucoma Prevention Study with the Ocular Hypertension Treatment Study.
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| 2. Describe the role of molecular genetics in the pathophysiology of glaucoma.
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| 3. Describe the essential elements of medical malpractice.
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| 4. Describe strategies for avoiding malpractice litigation.
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| 5. Compare the efficacy of different methods for detecting glaucomatous visual field progression.
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Discussed on This Program
Dorzolamide [Trusopt]
Dorzolamide HCl and timolol maleate [Cosopt]
Resources
Carverlabs.org
Suggested Reading
Alward WL et al: Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol
136:904, 2003; Alward WL: Variations in the myocilin gene in patients with open-angle glaucoma. Arch Ophthalmol
120:1189, 2002; Borges AS et al: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from
Brazil. J Glaucoma 11:51, 2002; Dawn AG et al: Development of a patient satisfaction survery for outpatient care: a brief
report. J Med Pract Manage 19:166, 2003; Dawn AG et al: Patient expectations regarding eye care: development and results
of the Eye Care Expectation Survey (ECES). Arch Ophthalmol 123:534, 2005; Dawn AG, Lee PP: Patient expectations
for medical and surgical care: a review of the literature and applications to ophthalmology. Surv Ophthalmol 49:513,
2004; Fingert JH et al: Myocilin glaucoma. Surv Ophthalmol 47:547, 2002; Gordon MO et al: The Ocular Hypertension
Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120:714,
2002; Gordon MO, Kass MA: The Ocular Hypertension Treatment Study: design and baseline description of the participants.
Arch Ophthalmol 117:573, 1999; Kass MA et al: The Ocular Hypertension Treatment Study: a randomized trial determines
that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch
Ophthalmol 120:701, 2002; Koucheki B et al: Visual field changes after cataract extraction: the AGIS experience. Am J
Ophthalmol 138:1022, 2004; Miglior S et al: Results of the European Glaucoma Prevention Study. Ophthalmology
112:366, 2005; Miglior S et al: The European Glaucoma Prevention Study design and baseline description of the participants.
Ophthalmology 109:1612, 2002; Nouri-Mahdavi K et al: Comparison of methods to detect visual field progression
in glaucoma. Ophthalmology 104:1228, 1997; Nouri-Mahdavi K et al: Pointwise linear regression for evaluation of visual
field outcomes and comparison with the advanced glaucoma intervention study methods. Arch Ophthalmol 123:193,
2005; Nouri-Mahdavi K et al: Prediction of visual field progression in glaucoma. Invest Ophthalmol Vis Sci 45:4346,
2004; Nouri-Mahdavi K et al: Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention
Study. Ophthalmology 111:1627, 2004; Sloan FA et al: Monitoring visual status: why patients do or do not
comply with practice guidelines. Health Serv Res 39:1429, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. Dr. Parrish has been a consultant
for Alcon, Merck and Pfizer; Dr. Lee has received research grants from, and has been a consultant to Pfizer, Allergan,
and Merck.
Drs. Parrish, Alward, and Lee were recorded at the 27th Annual Midwest Glaucoma Symposium and 10th Annual Spring
Symposium, Glaucoma: Current Management and Updates, presented May 21, 2005, in Cincinnati by the Department of
Ophthalmology, University of Cincinnati College of Medicine, and the Cincinnati Eye Institute; Dr. Nouri-Mahdavi was recorded
at the Jules Stein Clinical and Research Seminar 2005, presented May 20-21, 2005, in Los Angeles by the Jules
Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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