GLAUCOMA THERAPY: YESTERDAY, TODAY, AND TOMORROW
| THE DOCTOR-PATIENT RELATIONSHIP IN GLAUCOMA— George L. Spaeth, MD, Esposito Research Professor,
and Director, Glaucoma Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia,
PA
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| Introduction: definition of glaucoma has evolved; patient concerns—dependence; expense of treatment; inconvenience
of frequent follow-up; on horizon, genetic factors; inability to perform activities of daily living (ADL); physician
definition—optic neuropathy
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| Cup-to-disc ratios: study (data points show cup-disc ratio in glaucoma patients compared to normal patients); meaning
of “mean”—ratios larger in patients with glaucoma than people without (but patient with smallest cup-disc ratio has
glaucoma); data points used to show means, but data points (ie, experience of individual patients) cannot be extrapolated
from means
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| Synechial closure (study): in subjects with chronic angle-closure glaucoma, greater peripheral anterior synechiae and
narrowing of drainage angle associated with higher intraocular pressure (IOP) without treatment, but person in study with
10 hr of closure had IOP 20 mm Hg (another had almost no closure, but IOP 40 mm Hg); on individual basis, amount of
synechial closure useless measure for predicting IOP
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| Pattern electroretinography (PERG): mean—correlation between PERG abnormality and known risk factors for
glaucoma (PERG potentially predictive for development and/or progression of disease); data points—except for 3 cases,
test worthless; does not distinguish between individuals who have glaucoma and those who do not (physicians care for individuals)
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| Broader definition of glaucoma: process (not findings); can cause disability due to loss of visual function related to
ocular tissue damage (especially optic nerve); at least partially related to IOP, but disability can be caused by emotional
aspects (person diagnosed with glaucoma has immediate decrease in quality of life [QOL])
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| Role of physician: to create environment that promotes health and prevents disability; if disability present, to prevent
worsening; to achieve goals, physician must know likely outcomes with and without treatment; without intervention,
worsening will continue; patients not getting worse, probably will not worsen further, unless something changes
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| Estimating lifespan: based on varying lifespan, one patient may become disabled while another fine despite more rapid
progression; avoidance of disability is treatment success, even if visual field loss occurs; average life expectancy of person
77 yr of age almost 10 yr; with change in lifestyle or health status, modify estimate; critical question—who already
is disabled and who will become disabled?
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| Prognosis based on corneal thickness and IOP? IOP 24 mm Hg and corneal thickness 550 µm (risk of visual field
loss ≈3%); thin central cornea and IOP slightly elevated (risk ≈8%); more elevated IOP and average corneal thickness
(prognosis appears worse); but two thirds of people with IOP 28 mm Hg and thin cornea do not develop visual field loss
within 8 yr (so if used as predictors of visual field loss, physician wrong two thirds of time); visual field loss—surrogate
marker for development of disability
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| Classic risk factors: not good predictive indicators of disability; worsening of optic disc—most reliable sign of
whether person actually has glaucoma (damage already present); relative afferent pupillary defect (RAPD)—present in
67% of glaucoma patients; highly sensitive indicator of optic nerve damage (not glaucoma)
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| Who is going to get worse? existing damage tells whether patient going to get worse; keys—starting point (stage),
rate of change, and how long change will continue; communicating with patients—“what can be said at all can be said
clearly; what cannot be said clearly we must pass over in silence”
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| Study by Caprioli: review of Advanced Glaucoma Intervention Study (AGIS) data; rate of change in visual field—
highly correlated with whether people continued to get worse; high correlation with age (extent of damage present); correlation
found between mean IOP and fluctuation in IOP; visual fields rapidly getting worse, will continue to worsen; as
with cup/disk ratio, eyes that got worse had higher mean; but oldest person did not get worse (age useless; cannot move
from means to data points); high IOP (ie, >30 mm Hg) useful, otherwise IOP tells little; issue whether patients going to
lose vision and become disabled (diagnosis and care must be based on rate of change (not “snapshot”); for some patients
at later stage, any change intolerable; others at earlier stage can have progression in visual field and optic disc without becoming
disabled; population statistics cannot be applied to individuals (in comparison of cup/disc ratios, means different,
but patient with smallest cup had glaucoma); individualize care and concentrate on essentials
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| More advances: Cordera starting to count number of disabled retinal ganglion cells (may be better measure; visual fields
do not change early in glaucoma)
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| Disc Damage Likelihood Scale (DDLS): used to detect progression, identify stage, and calculate rate of change; system
based on rim and size of disc; consider width of rim at thinnest point; measure in rim/disc units and note size of disc; if
no rim, consider circumferential extent of rim absence; disc size easy to measure; multiply figure by 0.9 for a +60 D lens or
by 1.3 for a +90 D lens; speaker uses +66 D lens to measure size directly without need for correction factor; compares more
validly than cup/disc ratios or Heidelberg retina tomography (HRT) against visual fields; reproducible; summary—
measure disc size; identify area where rim narrowest or absent; nomogram addresses 3 disc sizes (consider small discs separately
from larger discs); detection of real change requires progression ≥2 scale units; objective and quantitative (documents
disc changes that correlate well with field changes)
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| Conclusion: concentrate on essentials in managing glaucoma; central glaucoma causes blindness needlessly; concentrate
on disability; to gauge disability, ask patients directly about ADLs (standardized tests being developed); all other signs
are surrogates (progressive disc damage and visual field loss); what are patient’s needs/wants and lifespan? need “video,”
not “snapshot”
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| OCULAR NEUROPROTECTION IN PRACTICE: IS THIS NEW DRUG GOOD FOR MY PATIENT ?—Ivan Goldberg,
MBBS, Clinical Associate Professor of Ophthalmology, University of Sydney; Director, Eye Associates and Director,
Glaucoma Services, Sydney Eye Hospital, Sydney, NSW, AUS
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| Why drugs may fail in clinical trials: in vitro models and animal studies may not mimic disease adequately in humans;
in phase 1 trials patients may be too young, in phase 2 number too small, and in phase 3 too old; multiple mechanisms
of disease; cascading nature of secondary degenerations; inclusion criteria too wide; patient variations in—
mechanisms; severity of insult; age and general condition; comorbidities and concurrent medications
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| Key questions: efficacy of neuroprotectants—does agent bind receptors relevant to neuronal survival? is it protective
in animal models? does it achieve sufficient tissue concentration with clinically relevant dosing and methods of dosing?
has it been demonstrated to be neuroprotective in controlled clinical trials in humans? clinical assessment—is disease
present? is it diagnosable? if so, what grade of damage?
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| Proposed application of neuroprotection: to augment current therapeutic strategies
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 | Advanced glaucomatous damage where fixation and mobility threatened due to visual field loss: prompt intervention indicated;
introduce usual hypotensive therapy; add neuroprotectant
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| Moderate damage, fixation and mobility not threatened, but with high risk factors: usual hypotensive therapy and add
neuroprotectant
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| Moderate damage, but lower risk profile: consider usual hypotensive therapy; hold off on neuroprotectant, pending assessment
of tolerance and compliance issues; questions—patient physically able to instill drops? any response to hypotensive
treatment with adequate achievement of target IOP? progression over time? patient allergic to preservatives?
introduce neuroprotectant—if patient not able to take medications, progression occurs despite treatment, or risk factors
for progression present
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| Glaucoma diagnosed at early stage with mild damage: usual hypotensive treatment; introduce neuroprotectant if patient
unable to use medications or progression occurs despite treatment
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| No glaucoma present, structurally or functionally: consider usual hypotensive treatment; treat depending on risk profile;
consider neuroprotectant if—indicated based on patient preference; patient at very high risk; patient one-eyed; family
history of blinding glaucoma; patient young
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| NEUROPROTECTION AND NEUROLOGY: LESSONS LEARNED —Christopher A. Girkin, MD, Professor of Ophthalmology,
and Director, Glaucoma Service and Optic Nerve Imaging Center, Callahan Eye Foundation Hospital, University
of Alabama, Birmingham, School of Medicine
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| Introduction: in glaucoma, neuronal death similar to that in other neurologic conditions; neurotrophin deprivation exciting
event; several secondary messengers (eg, glutamate, free radicals); finally, mitochondrial failure; similar cascade of
events occurs in variety of conditions throughout central nervous system (CNS)
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| Neuroprotection and stroke: >25 phase 3 trials in humans (many cancelled because of dose-limiting side effects
of N-methyl-D-aspartate [NMDA]-antagonist drugs or lack of significant benefit); despite success in animal models,
effects have not translated well into clinical studies; axogenic and somagenic injury—in stroke (somagenic), nerve cell
bodies destroyed early in disease (smaller window of opportunity to provide neuroprotectant); with glaucoma (axogenic),
more time in which to apply neuroprotectant to preserve integrity of nerve cell body
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| Spinal cord injury: also axogenic; some success in treating spinal cord injury by blocking lipid peroxidation; in animal
models, methylprednisolone and naloxone improve outcome
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| Second National Acute Spinal Cord Injury Study (NASCIS II): if given within 8 hr, methylprednisolone improved neurologic
recovery; naloxone showed no overall benefit, but postoperative analysis showed some benefit in patients with
incomplete paresis; study criticisms—no significant overall effect with methylprednisolone; significant but modest
improvement in outcome in spinal cord injury; no functional QOL end point used; problems with high-dose glucocorticoid
therapy—secondary damage can occur to injured CNS by addition of methylprednisolone; in animal models,
methylprednisolone can inhibit axonal sprouting (8-hr window critically important); immunologic suppression can
create life-threatening complications; careful dosing required (low dose can increase serum glucose and anaerobic metabolism;
high dose can increase metabolism by stimulating gluconeogenesis)
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| NASCIS III trial: initiated with discovery of tirilazad; drug lacks glucocorticoid receptor activity; in models, similar efficacy
to methylprednisolone; 24-hr dosing of methylprednisolone vs 48-hr dosing vs bolus followed by 24-hr infusion
of tirilazad; combination therapy demonstrated similar efficacy, with extended perfusion, without glucocorticoid side
effects; also illustrates “treatment window effect” (when initiated within 3 hr, 24-hr infusion equivalent, when >3 hr,
48-hr infusion better)
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| Other neurodegenerative diseases: in stroke and spinal cord injury, primary injury occurs early in course of disease
(spinal cord injury involves trauma; with stroke, perfusion injury occurs in few minutes); secondary and delayed injury
occurs over hours, days and weeks; in glaucoma, primary process occurs over many years, so secondary and delayed neurodegenerative
cascades extend over longer period; much more success in, eg, Alzheimer’s disease in developing neuroprotection;
in Parkinson’s disease, NMDA antagonist can improve symptoms (may have some effect on progression);
levodopa (L-dopa) may have effect on progression; in amyotrophic lateral sclerosis (ALS), riluzole increases survival
and decreases deterioration; for Alzheimer’s disease, memantine improves function and decreases progression
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| L-dopa and carbidopa: can improve symptoms of Parkinson’s disease, but may not have true neuroprotective effect
(neurodegenerative decline continues); L-dopa therapy might improve symptoms short term, but causes neurodegeneration
and secondary toxicity; comparison of 2 doses of L-dopa and carbidopa (study)—one of few studies to use single-photon
emission computed tomography (SPECT) and brain imaging as biomarkers for neural injury; results—
dissociation between 2 measures (symptomatic and physiologic); functional measures (symptomatology and progressive
neurologic functional decline) improved with both levels of treatment; still, extent of effect dose dependent; SPECT
showed worsening of dopamine transport within striatum; study controversial; need biomarkers of neuroimaging studies
validated against functional measures; need better quantitative end points
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| Alzheimer’s disease: (Cochrane Collaboration review)—in moderate-to-severe disease, drug primarily useful for cognitive/functional
behavior and in clinical impression (modest improvement); in mild-to-moderate disease, effect less
pronounced and not seen across all categories of measure; unlike other glutamate antagonists, memantine extremely
well tolerated, with mild side effects (dizziness most common); drug applied to other diseases (eg, Parkinson’s, nenonatal
stroke, epilepsy)
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| ALS: some early clinical evidence that memantine neuroprotective; works by blocking glial uptake of glutamate, increasing
transsynaptic glutamate and glutamate excitotoxicity
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Educational Objectives
| The goal of this program is to educate the listener about current and future management of glaucoma. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Communicate more effectively with patients about glaucoma.
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| 2. Prioritize the risk for disability in making management decisions.
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| 3. Utilize the Disc Damage Likelihood Scale (DDLS) as a prognostic indicator of progression in glaucoma.
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| 4. Describe recent research on medical therapy for ocular neuroprotection.
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| 5. Describe neuroprotective strategies in neurodegenerative disease that may lead to breakthroughs in ocular neuroprotection.
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Discussed on This Program
Carbidopa [Lodosyn]
Carbidopa, levodopa, entacapone [Stalevo 50, Stalevo 100, Stalevo 150]
Levodopa (L -dopa) [Dopar, Larodopa]
Levodopa and carbidopa [Parcopa, Sinemet-10/100, Sinemet-25/100, Sinemet-25/250, Sinemet CR]
Memantine HCl [Namenda]
Methylprednisolone [Medrol]
Methylprednisolone acetate [several formulations and trade names]
Methylprednisolone sodium succinate [A-Methapred, Solu-Medrol]
Naloxone HCl [Narcan]
Riluzole [Rilutek]
Tirilazad mesylate [Freedox] (investigational)
Suggested Reading
Cohen JS et al: Evolving paradigms in the medical treatment of glaucoma. Int Ophthalmol 25:253, 2004; Danesh-
Meyer HV et al: Comparison of disc damage likelihood scale, cup to disc ration, and Heidelberg retina tomograph in the
diagnosis of glaucoma. Br J Ophthalmol 90:437, 2006; Danesh-Meyer HV et al: Regional correlation of structure and
function in glaucoma, using the Disc Damage Likelihood Scale, Heidelberg Retina Tomograph, and visual fields. Ophthalmology
113:603, 2006; Glisson CC: Capturing the benefit of vision restoration therapy. Curr Opin Ophthalmol 17:504,
2006; Kim J et al: The Advanced Glaucoma Intervention Study (AGIS): 14. Distinguishing progression of glaucoma
from visual field fluctuations. Ophthalmlology 111:2109, 2004; Osborne NN et al: Optic nerve and neuroprotection
strategies. Eye 18:1075, 2004; Spaeth GL et al: Systems for staging the amount of optic nerve damage in glaucoma: a
critical review and new material. Surv Ophthalmol 51:293, 2006; Spaeth GL, Shields MB: The stages of glaucoma.
Am J Ophthalmol 141:147, 2006; Spaeth GL: Controlling patient expectations: important in maximizing patient satisfaction.
Ophthalmic Surg Lasers Imaging 37:270, 2006; Spaeth GL: Teaching and learning ethics. Arch Ophthalmol
121, 1342, 2004; Spaeth GL: The disc damage likelihood scale: reproducibility of a new method of estimating the
amount of optic nerve damage caused by glaucoma. Trans Am Ophthalmol Soc 100:181, 2002.
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. Goldberg has participated
on speaker panels for Alcon, Allergan, Ellex Lasers, and Pfizer, and on advisory boards for Alcon, Allergan, Pfizer,
and VisionGroup.
Dr. Spaeth was recorded at the 10th Annual Glaucoma Symposium, presented February 11, 2006, in San Francisco,
by the Glaucoma Research and Education Group, San Francisco, CA; Drs. Goldberg and Girkin were recorded at the
International Ocular Neuroprotection Symposium, presented October 14, 2006, by the University of Toronto, Department
of Ophthalmology and Visual Sciences, Toronto, Ontario, CAN. The Audio-Digest Foundation thanks Drs.
Spaeth, Goldberg, and Girkin, and the sponsors, for their cooperation in the production of this program.
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