HOT TOPICS
Educational Objectives
| The goal of this program is to improve the management of myopic progression, optic neuropathy, and nonarteritic ischemic
optic neuropathy (NAION). After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Recognize risk factors for progression of myopia.
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| 2. Advise patients about the prospect of reducing myopic progression.
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| 3. Describe recent advances in neuroprotection for patients with glaucoma.
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| 4. Recognize signs and symptoms of NAION.
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| 5. Evaluate recent research correlating use of phosphodiesterase-5 inhibitors with an increased risk for NAION.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Tsai has
been a consultant to Alcon, Allergan, Merck, and Pfizer. Drs. Fredrick and Tomsak and the planning committee reported
nothing to disclose.
Acknowledgments
Dr. Fredrick was recorded at the 2008 Ophthalmology Symposium, presented June 7, 2008, in Los Angeles, CA, by the
Southern California Permanente Medical Group; Dr. Tsai was recorded at the 58th Annual Post-Graduate Review
Course in Ophthalmology, presented November 30 to December 1, 2007, in Syracuse, NY, by the State University of
New York, Upstate Medical University; Dr. Tomsak was recorded at the 26th Annual Update for the Comprehensive
Ophthalmologist 2008, presented May 16, 2008, in Cleveland, OH, by University Hospitals Case Medical Center,
Case Western Reserve University School of Medicine. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
| Slowing Myopia Progression
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| Douglas Fredrick, MD, Clinical Professor of Ophthalmology and Pediatrics, Stanford University School of Medicine, Stanford
University Medical Center and Lucile Packard Children’s Hospital, Palo Alto, CA
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| Pathologic myopia: myopia > -6 to -8 diopters (D); macular and retinal changes; higher risk for retinal detachment, and
higher incidence of glaucoma; in some countries, incidence of pathologic myopia high (in Japan, >1 million people affected);
Blue Mountains Eye Study—looked at prevalence and progression of pathologic myopia in older population; at -
7 to -9 D, high prevalence of myopic maculopathy (rate 54%; in lower levels of myopia, rate 3%); in 5-yr period, progression
of macular degeneration seen in large percentage of patients; among patients with >9 D myopia, 50% had myopic
maculopathy (>40% had visual acuity <20/40); >9% had progressive vision loss; consequences of pathologic myopia include
thinning of sclera, choroid, and retina
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| Genetic factors and refractive status
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| Incidence or prevalence of myopia varies widely: Asian countries have higher incidence than Western countries; in China
(as in other countries), children start out with low degrees of myopia, but by age 14 or 15 yr, rate up to 50%;
hypothesis—myopia genetically predetermined
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| Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study Group: Asian-Americans had
highest rate of myopia; (whites second; blacks and Hispanics third and fourth); prevalence of myopia increasing
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| Twin studies: (Teikeri, 1991; Hammond, 2001): subjects monozygotic and dizygotic twins; findings—high heritability of
myopic or hyperopic refractive error
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| Studies by Zadnik: parental history of myopia strongest risk factor; other risk factors—low hyperopia at 4 yr of age; high
accommodative convergence-accommodation (AC/A) ratio; near-point esophoria
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| Visual experience and ocular growth: prevalence of myopia low in minimally literate indigenous populations (rate
3%-4%); among grandchildren educated in Western-style schools, prevalence of myopia increased; environment changed
(more reading in dimmer light); close or near work can drive eyes toward myopia; increased years of education correlates
with increased levels of myopia (average graduate student becomes 1 D more myopic during course of study); higher
achievement in school performance also correlated with more myopia; rate of myopia progression decreases during summer
vacation; prevalence of myopia higher among children who live in urban areas, compared to rural areas; people with
jobs that require much near work (eg, microscopists, editors) have more myopia than those who do not; 2 hypotheses—1)
prolonged accommodation due to effect of constriction of ciliary body leads to myopia, or 2) myopes underaccommodate;
in studies of induced blur, myopes have poorer facility of accommodation than hyperopes or emmetropes (may lead
to defocus on retina)
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| Study by Young: monkeys placed in restraining chairs; first group allowed to see 20 ft to infinity; second group presented
with checkerboard patterns that required eyes to accommodate several hours during day; near-view group became
more myopic than infinite-view group; supports idea that near work or accommodation can lead to myopia
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| Studies by Hubel and Wiesel: striate cortex examined to assess effect of early vision deprivation on brain; study eyes subjected
to early eyelid closure much more myopic than fellow eyes (eyelids not closed); visual deprivation led to axial
elongation
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| Primate study: contact lenses placed in eyes of young chimpanzees; whether positive or negative lenses used to induce
blur, eye grew in direction needed to maintain emmetropia
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| Avian model: translucent goggles placed over eyes to blur vision of chickens; within days after occluding vision of newborn
chick, eyes shifted towards myopia; when goggles removed after 3 wk, eyes moved back toward emmetropia;
when one-half of visual axis occluded, only occluded side became myopic (suggests that focal process at level of retina,
choroid, and sclera, driving eye growth)
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Optical Interventions
| Specific interventions: overcorrection; undercorrection; part-time correction; use of bifocals
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| Undercorrection to prevent progression of myopia: randomized controlled trial, 2002—myopes randomized to
full correction or undercorrection by 0.75 D; undercorrected group became more myopic than group with full correction;
monovision study—one eye undercorrected, fellow eye fully corrected; however, undercorrected eye became less myopic;
comment—give full cycloplegic retinoscopic refraction (not manifest refraction); give patients what they need (no
more, no less)
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| Do bifocals decrease rate of progression of myopia? Correction of Myopia Evaluation Trial (COMET, 2001)—
≈500 children randomized to progressive (bifocal) lenses or single-vision lenses; excellent follow-up; benefit small and
does not warrant change in clinical practice; however—posthoc reviews of data suggest that power of lenses used in
study too weak to produce significant results
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| Use of contact lenses to inhibit myopic progression
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| Orthokeratology (ortho-K): series of proprietarily designed contact lenses used to exert pressure on cornea to flatten corneal
curvatures (Ks); lenses worn at night; many cases of infectious keratitis leading to permanent vision loss reported);
theory that ortho-K changes peripheral cornea by inducing hyperopic defocus so that eye does not elongate (no
scientific rationale); topography of patients very irregular; some patients see better, but no evidence that myopia prevented
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| Rigid gas-permeable (RGP) contact lenses and myopic progression: Khoo, 1999—children randomized to rigid gas-permeable
(RGP) contact lenses or spectacles; no effect; Contact Lens and Myopia Progression (CLAMP) study—patients
randomized to RGP or spectacles; RGP had no significant long-term effect in prevention of myopia; soft contact
lenses—do not prevent myopia
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| Pharmacologic interventions (antimuscarinics)
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| Atropine: proposed mechanism of action—initial theory that preventing accommodation decreases physical effect on eye
that causes elongation; new theory that anticholinergic properties of atropine prevent retinal, scleral, or choroidal
growth; atropine blocks all receptors (in contrast, pirenzepine selective antimuscarinic); Kennedy, 1995, 2000—at end
of trial, atropinized eyes had ≈1.0 D less progression of myopia than controls, and rate of progression decreased from
0.5 D/yr, to ≈0.1 D/yr
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| Pirenzepine: orphan drug; used in trials in Asia (not in United States); causes less mydriasis and cycloplegia than atropine;
studies—gel used twice per day; good follow-up; 1-yr and 2-yr data show that effect not as strong as with atropine,
but myopic progression decreased ≈50%
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| Other strategies: scleral sling—donor sclera used to shrink eye; can shorten eye but it does not decrease myopic maculopathy;
acoustic biofeedback—feeling good about your life does not decrease myopia; selective absorption of wavelengths
of light to decrease accommodative stimulus—no impact
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| Night light scare: Quinn, 1999—findings suggested that incidence of myopia higher among children who slept with
night lights, compared to those who did not; problem of selection bias—study did not look at refractive error of parents
(myopic parents more likely to provide night lights for their children)
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| Summary: risk factors for progression of myopia include young age at onset of myopia, more severe myopia at baseline,
near work, myopic parents, and poor accommodation; use cyclopentolate for refractive assessment (not tropicamide);
speaker uses atropine and progressive transition lenses with UV block to minimize risk for UV damage in
patients with long-term pupil dilation; patients with high myopia tolerate atropine well; more tips—do not hold text
too close; use adequate lighting; rest 10 min per 30 min of reading; increase physical exercise
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| Neuroprotection: New Frontiers in Glaucoma Therapy
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| James C. Tsai, MD, Robert R. Young Professor and Chair, Department of Ophthalmology and Visual Science, Yale University
School of Medicine, New Haven, CT
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| Current therapy for glaucoma: focuses on lowering intraocular pressure (IOP); clinical outcome variable; loss of
retinal ganglion cell (RGC) layer seen in patients with glaucoma
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| Potential neuroprotective strategies include: gene therapy; stem cell therapy; medical therapy—brimonidine, memantine;
erythropoietin (EPO); brain-derived neurotrophic factor
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| Brimonidine: unpublished paper by Gandolfi (presented 2004)—patients with progressive open-angle glaucoma randomized
to laser trabeculoplasty or brimonidine; findings—brimonidine group had greater stability of visual fields despite
having less IOP reduction
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| Memantine: memantine is glutamate N-methyl-D-aspartate (NMDA)-receptor blocker; effective if NMDA elevated to
pathologic levels; pearl—supplementation with magnesium can achieve similar calcium channel-blocker effect (in patients
with progressive normal-tension glaucoma, check magnesium levels); studies by Hare et al, 2004 (monkey model)—
chronic ocular hypertension induced by argon laser treatment; memantine safe and effective for reduction of functional
loss and structural changes associated with experimental glaucoma; ongoing study by Shields—>2000 patients enrolled
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| Introduction: EPO blocks apoptosis and reduces production of inducible nitrous oxide synthetase, which is deleterious to
RGCs
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| Intravitreal administration of EPO and preservation of RGCs in experimental rat model of glaucoma (Tsai et al, 2005):
rats that received EPO had less loss of RGCs than groups that received normal saline or no treatment; issue whether
EPO stimulates neovascularization (problem not seen in study); more research needed to demonstrate safety of EPO
therapy
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| Summary: various levels of EPO found in ocular system, including retina and anterior segment (less in posterior segment
[choroidal region]); dose toxicity (in rabbit model, no untoward effects seen on angiography; investigations still preliminary);
EPO potential neuroprotective agent (more data needed)
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| Inhibition of Nogo-receptor function: next era of research in glaucoma; mechanism neuroregeneration (not neuroprotection);
recent research has identified some of reasons why central nervous system (CNS) axons do not regenerate;
mechanism involves active inhibition in CNS; paper by Kim, 2004—in control media, axon sends dendrites outward;
however, in myelin environment, axons stop regenerating; Nogo receptor throughout CNS and mediated by ligands in
myelin (Nogo-66, oligodendrocyte-myelin glycoprotein [OMgp], and myelin-associated glycoprotein [MAG] actively inhibit
neurite growth)
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| Ischemic Optic Neuropathy Update
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| Robert L. Tomsak, MD, PhD, Professor of Neurology and Ophthalmology, Case Western Reserve University School of
Medicine, and Program Director, Neuro-ophthalmology, University Hospitals Case Medical Center, Cleveland, OH
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| Case presentation: 50-yr-old white man complains of visual loss in left eye; no vascular risk factors (eg, hypertension,
diabetes, dyslipidemia, smoking); patient awakened one morning with visual field loss in left eye; had taken phosphodiesterase
(PDE)-5 inhibitor (sildenafil [Viagra]) night before for erectile dysfunction; denied pain, headache, jaw
claudications, scalp tenderness, diplopia, or other visual or neurologic symptoms; color vision and acuity in both eyes (at
distance and near) excellent; subtle visual field defect in left eye; pupils equal and round; no afferent pupillary defect
(central acuity preserved); mild nuclear lens sclerosis; normal right optic nerve, abnormal left optic nerve; slight edema,
especially upper nasally; small-to-absent physiologic cup; visual fields normal on right and minimally abnormal on left;
IOPs normal, remainder of neurologic examination normal, no carotid bruit; initial diagnosis—nonarteritic anterior ischemic
optic neuropathy (NAION); issue—whether NAION secondary to use of PDE-5 inhibitor
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| Diagnosis: NAION most common form of ION; symptoms—sudden painless visual loss, often noted on awakening (suggests
nighttime drop in blood pressure; altitudinal visual field loss (usually lower fields affected); natural history—60%
of patients remain at same visual acuity and visual field level (30% improve slightly; 10% worsen over first 6 wk); fellow
eye involved in ≈15% of cases; more florid ION—diffusely swollen disc; nerve-fiber layer infarct
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| Pathophysiology: optic nerve structure plays role in disease; lack of cup predisposes optic nerve to infarction later in
life; nocturnal hypotension probably plays role; atherosclerotic risk factors, eg, hypertension, diabetes, hypercholesterolemia,
likely play role; thrombosis of vessels does not occur; in most cases, vessels patent after event (underlying cause
of NAION probably autoregulation phenomenon); in normal optic nerve, cup/disc ratio 0.2 or 0.3; in disc at risk, cup/disc
ratio <0.1; PDE-5 inhibitors’ ability to potentiate ION may be related to hypotension during night; some patients with retinitis
pigmentosa (RP) have PDE-6 gene defect (in those patients, PDE-5 inhibitor contraindicated)
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| PDE-5 inhibitors and development of ION
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| Case reports in small series: most cases occurred after use of sildenafil (several other cases after use of tadalafil [Cialis]);
most patients awoke with visual loss in morning, but some noted visual loss few days later; other risk factors for
NAION—small cup/disc ratio; other vascular risk factors (eg, erectile dysfunction)
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| Larger studies: tend to diminish association; in postmarketing data from Pfizer, >100 clinical trials reviewed (only 1 case of
NAION found); in retrospective age- and sex-matched case-control study, male patients with NAION not more likely to be
using sildenafil; in Veterans Health Administration (VHA) study, risk for NAION slightly increased if patient prescribed
PDE-5 inhibitor, but diagnosis suspected in many cases
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| Recommendations: all patients who have risk factors for NAION should be warned of risk; use extreme caution when
prescribing PDE-5 inhibitors to patients, especially if they have disc at risk, history of NAION, or other active optic nerve
or retinal diseases; retinal disease—central serous choroidopathy reported in few patients who had taken sildenafil; because
of PDE-6 crossover inhibition, patient with RP should not take PDE-5 inhibitors
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| Treatment: no evidence-based studies showing that any treatment effective for managing NAION; Ischemic Optic Neuropathy
Decompression Trial showed that optic nerve sheath decompression not effective and may increase risk for progressive
visual loss; identify and address risk factors for atherosclerotic complications; antiplatelet therapy, control of
vascular risk factors, and neuroprotective agents all of no proven benefit
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Suggested Reading
Diether S et al: Changes in contrast sensitivity induced by defocus and their possible relations to emmetropization in the
chicken. Invest Ophthalmol Vis Sci 42:3072, 2001; Guzowski M et al: Five-year refractive changes in an older population:
the Blue Mountains Eye Study. Ophthalmology 110:1364, 2003; Hyman L et al: The Correction of Myopia Evaluation Trial
(COMET): design and general baseline characteristics. Control Clin Trials 22:573, 2001; Khoo CY et al: A 3-year study on
the effect of RGP contact lenses on myopic children. Singapore Med J 40:230, 1999; Kim JE et al: Nogo-66 receptor prevents
raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron 44:439, 2004; McGee
AW, Strittmatter SM: The Nogo-66 receptor: focusing myelin of axon regeneration. Trends Neurosci 26:193, 2003;
Thurtell MJ, Tomsak RL: Nonarteritic anterior ischemic optic neuropathy with PDE-5 inhibitors for erectile dysfunction.
Int J Impot Res [Epub ahead of print], 2008; Tsai JC et al: Intravitreal administration of erythropoietin and preservation of retinal
ganglion cells in an experimental rat model of glaucoma. Curr Eye Res 30:1025, 2005; Vongphanit J et al: Prevalence
and progression of myopic retinopathy in an older population. Ophthalmology 109:704, 2002; Zadnik K et al: The effect of
parental history of myopia on children’s eye size. JAMA 271, 1323, 1994.
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