CHALLENGES IN NEURO-OPHTHALMOLOGY
| ASSESSMENT AND MANAGEMENT OF NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY —Neil
R. Miller, MD, Professor of Ophthalmology, Neurology, and Neurosurgery, and Frank B. Walsh Professor of Neuro-Ophthalmology,
Johns Hopkins Medical Institutions, Baltimore, MD
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| Ischemic optic neuropathy (ION): case—man, 67 yr of age, awakens with onset of blurred vision in superior field of
right eye but no history of headache or ocular discomfort; visual acuity of affected eye 20/80; opposite eye unaffected; optic
disc of affected eye swollen and hyperemic; contralateral eye has small optic disc with no cup; prevalence—common
cause of optic neuropathy (second only to glaucoma); types of anterior ischemic optic neuropathy—nonarteritic; perioperative;
arteritic
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| Nonarteritic anterior ischemic optic neuropathy (NAION): usually occurs in older patients, with same frequency
in men and women; most patients have underlying vascular disease (not always diagnosed or considered problematic); unilateral
presentation; eye pain rare (mild when present); pain with eye movement very rare; most cases untreated; vision loss—
loss in visual acuity varies (mild to severe); changes in color vision usually parallel changes in acuity (as opposed to optic neuritis);
altitudinal or arcuate field defect typically present; physical findings—disc usually hyperemic; peripapillary hemorrhages
often present; optic disc and optic cup of opposite eye small or absent (“disc at risk”)
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| Pathophysiology: underlying vasculopathy (eg, hypertension, hypercholesterolemia, diabetes) usually present, but not
always diagnosed; prevalence of NAION likely to increase because of obesity epidemic in United States; risk factors—
congenital anomaly (eg, disc at risk) plus systemic vasculopathy, resulting in vascular compromise; pathogenesis not
well understood; ischemia occurs at prelaminar or laminar portion of optic disc; no evidence of obstruction in short posterior
ciliary arteries (SPCAs); compartment syndrome may occur, resulting in partial or complete ischemia
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| Nonsurgical anemia and NAION: hypotension may not accompany anemia; cases reported in patients on dialysis
and patients with epistaxis or uterine bleeding; vision improves after restoration of hematocrit (no evidence that restoration
of hematocrit helps in cases of perioperative ischemic optic neuropathy [ION])
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| Sleep apnea syndrome (SAS): relationship suspected because of impaired vision upon awakening; both conditions
associated with nocturnal hypotension; SAS characterized by episodic obstruction of upper airway; episodes last 10 sec
to 2 min and induce hypoxia and sleep deprivation; comorbidity—71% of patients with NAION diagnosed with SAS;
treatment—continuous positive airway pressure (CPAP) effective treatment for SAS, but may not protect against
NAION; history—question spouse or partner about snoring habits and nocturnal waking; consider sleep studies for patients
with suspected SAS
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| Hyperhomocysteinemia: important risk factor for some vascular diseases (eg, stroke, cardiac disease, especially in
younger patients); etiology—deficiency in vitamin B12 or B6 (involved in metabolism of homocysteine) or in enzyme
along metabolic pathway results in accumulation of homocysteine, causing atherogenic and thrombogenic damage to
vascular structures; comorbidity—condition reported to occur in 0% to 50% of patients with NAION; speaker recommends
measuring serum homocysteine in patients with NAION, especially young patients without apparent risk factors
and older patients with cardiac disease
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| Erectile dysfunction drugs: sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) associated with ischemic
optic neuropathy; drugs cause vasodilation, which can result in hypotension; although NAION rare adverse effect, some
association (based on challenge-rechallenge cases) certain; risk—most cases to date involve patients with disc at risk
(possible role for screening); screening—ask men with apparent NAION about use of these drugs; inform patients about
risk
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| Amiodarone: has long half-life and accumulates in lysosomes; ocular symptoms typically minor and include blue-green
halos around lights; study found accumulation of amiodarone in lysosomes in human eyes, including retinal ganglia;
study following 447 patients taking amiodarone reported 13 cases of ION; most patients had edema of optic disc, identical
to that seen with AION; risk—patients taking amiodarone have 6-fold risk of developing optic neuropathy; by 1990,
≈100 reports published linking amiodarone to optic neuropathy; package insert lists permanent blindness as possible adverse
event; optic neuropathy—amiodarone-associated optic neuropathy differs from standard NAION in that it has insidious
onset (occurring over weeks to months), typically affects both eyes simultaneously, and has slower resolution of
optic disc swelling; effects on visual acuity vary (as in standard NAION); conclusion—although some controversy exists,
amiodarone possible cause of optic neuropathy; counseling—inform patients who develop optic neuropathy about possible
association with amiodarone; contact cardiologist so he or she can decide whether to continue medication
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| UNIFIED THEORY OF PATHOPHYSIOLOGY —Howard Krauss, MD, Clinical Professor of Ophthalmology and Neurosurgery,
David Geffen School of Medicine at the University of California, Los Angeles
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| Proposed etiology: ischemia of optic nerve head, anterior to lamina cribrosa, caused by compartment syndrome; anatomic
irregularities in scleral canal or optic nerve head may result in constriction; hypertension—patients with hypertension
have increased risk; patients who take blood pressure medication at night at risk for nocturnal hypotension
(awaken with visual dysfunction); patients with microvascular disease appear to have increased risk
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 | Anatomic predisposition: 15% to 25% of patients with NAION in 1 eye subsequently develop NAION in other eye, but only
1% of patients have second attack in same eye; disc at risk—crowded optic nerve head with cup-to-disc ratio of zero
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| Other predisposing factors: vasculopathy—patients with postoperative hypotony or postoperative ocular hypertension
after cataract surgery have increased risk for cataract-associated ischemic optic neuropathy; preischemic vitreopapillary
traction phenomena—occur in some patients; Valsalva—repeated Valsalva events (eg, standing on head as
part of yoga practice) may contribute to manifestation of disease; medications—amiodarone and erectile dysfunction
drugs (some controversy about causality)
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| Failed therapeutic modalities: steroids (topical and oral); neuroprotective drugs; hyperbaric O2 ; optic nerve sheath fenestration
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| Prognosis: ≈33% of patients improve; ≈33% worsen; ≈33% remain stable; no treatment in most cases; disc edema resolves
over 2 mo; sectoral optic atrophy remains; protective effect—resulting atrophy likely creates space (ie, alleviates
compartment syndrome) and prevents second episode; patients who have second episode tend to have history of mild initial
episode (ie, little damage and atrophy)
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| Compartment syndrome: tightness (caused by anatomic limitations) leads to increased tissue pressure in confined space;
ischemic damage results; extremities—capillary tension in muscle tissue normally ≈30 mm Hg; injury may result in increased
tissue pressure; although distal pulses remain palpable, ischemic damage may occur in compartment; optic nerve—
increased pressure in optic nerve head may damage capillary perfusion; higher pressure in central retinal artery maintains retinal
circulation
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| Possible treatments: although controlled clinical trials not yet performed, some patients treated with transvitreal optic
neurotomy or radial sclerotomy; useful studies—cadaver studies looking at relationship between cup-to-disc ratio and
circumference of scleral ring or tissue compliance of optic nerve head; controlled clinical trials looking at effects of surgical
procedures (compared to sham); future—if surgery proven successful in controlled trials, question about benefit of
prophylactic surgery for contralateral eye
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| Questions and answers: patient counseling—many patients have disc at risk, but only small percentage develop
NAION; information about increased risk with erectile dysfunction drugs and amiodarone important; extensive counseling
unnecessary; relationship between scleral canal and cup-to-disc ratio—size relationship unknown, but patients with
large scleral canals seem to have larger cups; patients with absent cup and compact nerve head have less space (ie, at risk
for problems if congestion occurs); triamcinolone injections—treatment performed on compassionate basis, but no prospective
trials to date; prophylactic panretinal photocoagulation (PRP) on fellow eye—evidence insufficient to conclude
benefit; but reducing congestion around nerve head may help
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| OPTIC NEURITIS AND MULTIPLE SCLEROSIS —Lynn K. Gordon, MD, Assistant Professor, Department of Ophthalmology,
David Geffen School of Medicine at the University of California, Los Angeles
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| Multiple sclerosis (MS): chronic relapsing and remitting disease involving focal destruction of myelin, axonal loss,
and inflammatory infiltrate within central nervous system (CNS); onset—disease usually manifests in patients 20 to
50 yr of age (more common in women); ≈5% of patients have early onset (<16 yr of age)
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| Involvement of visual pathway: oculomotor nerve and optic nerve most commonly affected, but disease may affect any
part of visual pathway; oculomotor deficits—intranuclear ophthalmoplegia most common (but sometimes subtle);
first manifestation of MS in some cases
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| Optic neuritis: variable signs and symptoms, but relative afferent pupillary defect always occurs in patients with asymmetric
involvement; presentation—average age at onset 32 yr (but may manifest at any age); condition more common
in women; optic neuritis and MS—initial clinical manifestation of MS in ≈20% of patients; ≈50% of patients with MS
have optic neuritis during course of disease (more common in patients with early onset of MS); vision loss—subacute
onset, typically monocular, occurs over hours to days; nadir typically reached within 2 wk of onset; spontaneous improvement
generally begins within first month; ophthalmologic findings—optic disc appears normal in 65% to 70% of
patients, but sometimes pale or swollen; ≈30% of patients have papillitis
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| Differential diagnosis: swollen disc may indicate different diagnosis; infectious disease—eg, cat scratch fever, Lyme
disease, typically present with swollen disc and macular star; inflammatory disease—eg, sarcoidosis; ischemic
disease—eg, NAION
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| Pain: occurs in 92% of patients; may precede or coincide with onset of optic neuritis; provoked or worsened with eye
movement; does not correspond to clinical course, severity, loss of vision, or potential for recovery; lasts for days, not
weeks
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| Visual dysfunction: visual acuity may range from 20/20 to no light perception (NLP); ≈33% of patients present with visual
acuity better than 20/40; ≈50% of patients have impaired contrast sensitivity; most patients have abnormalities in
color vision (eg, desaturation); defects in visual field typically diffuse or altitudinal (generally not central scotoma); clinical
course—nadir reached within ≈2 wk, then vision stabilizes for several weeks; visual acuity often recovers to near-normal
within 6 to 8 wk, but other defects (eg, contrast sensitivity, color abnormalities) may persist; recurrence—≈33% of patients
have recurrence of optic neuritis within 10 yr
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| Red flags: atypical features indicate diagnosis other than optic neuritis; simultaneous bilateral involvement; severe loss of
vision (including no light perception [NLP]) without early recovery; progressive deterioration or absence of recovery after
3 wk; worsening of vision after withdrawal of steroid; absence of pain; severe or persistent pain that lasts \>2 wk; severe
disc edema; edema with macular star; presence of other retinal lesions or vitreous cells
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| Diagnostic evaluation: imaging—magnetic resonance imaging (MRI) useful for assessing risk for clinically definite
MS (look for bright plaques of demyelination, but remember that ≈5% of patients with MS have no findings on MRI
when they initially present); gadolinium-enhanced, fat-suppressed images recommended for imaging optic nerve (remember,
involvement of optic nerve does not predict recovery); lumbar puncture (LP)—useful for diagnosing MS, but
5% to 10% of patients have no characteristic findings; laboratory tests—especially important for ruling out other diagnoses
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| Optic Neuritis Treatment Trial (ONTT): 457 patients, 18 to 46 yr of age, enrolled in study within 8 days of onset
of optic neuritis; subjects had no history of optic neuritis in affected eye, no history of steroid treatment, and no other systemic
diseases; patients randomized to treatment with 14 days of oral prednisone, 3 days of intravenous (IV) methylprednisolone
followed by oral corticosteroids, or 14 days of oral placebo; results—IV methylprednisolone hastened visual
function, but did not affect final outcome; patients receiving IV therapy had lower rate of conversion to clinically defined
MS during first 2 yr, but benefit lost after 3 yr; oral prednisone (alone) contraindicated; disease progression—≈56% of
patients with 1 lesion on MRI and 22% of patients with no findings on MRI progressed to clinically defined MS over 10
yr
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| Controlled High-Risk Avonex Multiple Sclerosis Prevention Surveillance (CHAMPS) study: randomized
double-blind trial looking at effect of interferon beta-1a after first demyelinating event (eg, optic neuritis); patients
had ≥2 lesions visible on MRI; primary end points—conversion to clinically defined MS or appearance of \>1 new lesion;
results—statistically significant reduction in rate of conversion at 3 yr (50% of patients in placebo group; 38% of
patients in treatment group)
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| Treatment overview: short-term treatment with corticosteroids speeds recovery but does not affect final outcome; oral
prednisone alone contraindicated (associated with higher rate of recurrence); early treatment with systemic immunomodulatory
drugs may delay MS events, but questions about adverse effects, cost, and timing remain
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Educational Objectives
| The goal of this activity is to educate the clinician about nonarteritic anterior ischemic optic neuropathy (NAION)
and optic neuritis. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the typical findings in patients with NAION.
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| 2. Discuss the association of NAION with vascular disease, sleep apnea syndrome (SAS), and drugs for erectile
dysfunction.
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| 3. Explain compartment syndrome as a proposed etiology of NAION.
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| 4. Diagnose patients with optic neuritis.
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| 5. Recognize optic neuritis as a presenting manifestation of multiple sclerosis and counsel patients accordingly.
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Discussed on This Program
Amiodarone HCl [Cordarone, Pacerone]\
Interferon beta-1a (recombinant) [Avonex, Rebif]
Methylprednisolone [Medrol]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred DS]
Sildenafil (Revatio, Viagra)
Tadalafil (Cialis)
Triamcinolone acetonide (several trade names)
Vardenafil HCl (Levitra)
Suggested Reading
Atkins EJ, et al: The natural history of optic neuritis. Rev Neurol Dis 3:45, 2006; de la Cruz J, Kupersmith
MJ: Clinical profile of simultaneous bilateral optic neuritis in adults. Br J Ophthalmol 90:551, 2006; Dickersin K,
et al: Surgery for nonarteritic anterior ischemic optic neuropathy. Cochrane Database Syst Rev Jan 25:CD001538,
2006; Fraser C, et al: Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis.
Arch Neurol 63:847, 2006; Fraunfelder FW, et al: Nonarteritic anterior ischemic optic neuropathy and
sildenafil. Arch Ophthalmol 124:733, 2006; Gorkin L, et al: Sildenafil citrate use and the incidence of nonarteritic
anterior ischemic optic neuropathy. Int J clin Pract 60:500, 2006; Hayreh SS, Zimmerman B: Visual field abnormalities
in nonarteritic anterior ischemic optic neuropathy: their pattern and prevalence at initial examination. Arch
Ophthalmol 123, 1554, 2005; Janaky M, et al: Electrophysiological findings in patients with nonarteritic anterior ischemic
optic neuropathy. Clin Neurophysiol 117:1158, 2006; Purvin V, et al: Optic neuropathy in patients using amiodarone.
Arch Ophthalmol 124:696, 2006; Rubiera M, et al: Neuromyelitis optica diagnosis in clinically isolated
syndromes suggestive of multiple sclerosis. Neurology 66:1568, 2006; Sotgiu S, et al: Multiple sclerosis-associated
retrovirus and optic neuritis. Mult Scler 12:357, 2006; Wilhelm B, et al: Efficacy and tolerability of 0.2% brimonidine
tartrate for the treatment of acute non-arteritic anterior ischemic optic neuropathy: a 3-month double-masked, randomised
placebo-controlled trial. Graefes Arch Clin Exp Ophthalmol 244:551, 2006.
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. For this issue,
the faculty reported nothing to disclose.
Dr. Miller was recorded in Napa, CA, at the 29th Annual Ophthalmology Symposium, sponsored by the University of
California, Davis, Health System, Office of Continuing Medical Education, and Department of Ophthalmology and
Vision Science, and held May 19-20, 2006; Drs. Krauss and Gordon were recorded in Los Angeles, CA, at the Jules
Stein Eye Institute Clinical and Research Seminar, sponsored by the Jules Stein Eye Institute, and held May 19-20,
2006. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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