JOBNAME: cno 25#1 2005 PAGE: 1 OUTPUT: Fri February 11 20:34:45 2005lww/cno/94412/WNO160361Prod #: WNO160361
Howard D. Pomeranz, MD, PhD and Abdhish R. Bhavsar, MD
Abstract: Seven patients, aged between 50 and 69 years,
had typical features of nonarteritic anterior ischemic optic
The medical records of seven patients in whom
neuropathy (NAION) within 36 hours after ingestion of
NAION developed subsequent to ingestion of sildenafil
sildenafil citrate (Viagra) for erectile dysfunction. Six
were identified between 1999 and 2003 and reviewed in
patients had vision loss within 24 hours after use of the
a nonmasked manner at the University of Minnesota. All
agent. Final visual acuity in the affected eye ranged from
seven patients received complete ophthalmic examinations
20/20 to light perception. Both eyes were affected in
including visual field testing. Medications, medical history,
one individual. All affected individuals had pre-existing
the time of development of ocular symptoms after ingestion
hypertension, diabetes, elevated cholesterol, or hyperlipid-
of sildenafil, visual acuity, pupil examination, visual field
emia. Seven similar cases have been previously reported.
testing, and optic disc appearance at the time of pre-
Sildenafil may provoke NAION in individuals with an
sentation and on follow-up examination were recorded.
Inclusion in this study was not dependent on a requiredlength of follow-up.
Sildenafil citrate (Viagra; Pfizer Pharmaceuticals, New
York, NY) is a selective phosphodiesterase 5 inhibitor
The characteristics of the seven patients are
and partial phosphodiesterase 6 inhibitor prescribed for
summarized in Table 1 together with those of the seven
erectile dysfunction. Use of sildenafil leads to smooth
previously described patients (3,6,7). All patients presented
muscle relaxation in the corpus cavernosum, allowing
with blurred vision and loss of visual field. In some cases,
inflow of blood to the penis during sexual stimulation.
the loss of visual acuity and visual field was progressive
Headache and flushing are the most frequently reported
over days or weeks. The patients ranged in age from 50 to
adverse events associated with use of this drug. Sildenafil
69 years. All had at least one arteriosclerotic risk factor,
use is contraindicated in patients taking nitrates (1).
including hypertension, diabetes, hypercholesterolemia, or
Sildenafil has been reported to cause transient
hyperlipidemia. The dose of sildenafil was either 25 mg, 50
changes in perception of color hue or brightness through
mg, or 100 mg. Some of the patients had been using the
a presumed action on phosphodiesterase type 6 in retinal
agent intermittently for months or years for treatment of
photoreceptor outer segments (2). Seven cases of non-
erectile dysfunction before the occurrence of acute visual
arteritic anterior ischemic optic neuropathy (NAION) asso-
loss. Other individuals had only recently been prescribed
ciated with sildenafil use have been previously reported (3–7).
sildenafil and had used one or a few doses before visual loss
This report adds an additional seven cases.
developed. In six patients, visual loss occurred within 24hours after the use of sildenafil, most commonly onawakening the next morning. An ophthalmologist exam-ined each patient soon after the acute visual loss. In affected
Department of Ophthalmology (H.D.P., A.R.B.), University of
eyes, visual acuity varied between 20/20 and light
Minnesota Medical School, Minneapolis, MN; Retina Center (A.R.B.),PA, and Phillips Eye Institute, Minneapolis, MN.
perception (median 20/180). Visual field loss was present
Address correspondence to Howard Pomeranz, MD, PhD, University of
in all patients, as was optic disc edema in the affected eye,
Minnesota Medical School, Department of Ophthalmology, MMC 493, 420
often with associated nerve fiber layer hemorrhages. All
Delaware Street SE, Minneapolis, MN 55455; E-mail: [email protected]
patients had small cup-to-disk ratios in the fellow eye. Giant
Supported in part by an unrestricted grant from Research to Prevent
cell arteritis was ruled out by history, laboratory testing, or,
Blindness Inc, New York, New York to the Department of Ophthalmologyat the University of Minnesota Medical School.
in some cases, by temporal artery biopsy.
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TABLE 1. Characteristics of 14 reported cases of nonarteritic ischemic optic neuropathy occurring shortly after sildenafil use
AM = morning; CAD = coronary artery disease; HTN = hypertension; DM = diabetes mellitus; MI = myocardial infarction; RD = retinal detachment;
The visual loss was disabling for several patients.
The next day, examination disclosed visual acuities of
One patient (Case 1) had bilateral sequential NAION with
20/20 OU. A right afferent pupillary defect was present.
final visual acuities of hand movements in one eye and
Humphrey 30-2 visual field testing revealed an inferior
light perception in the other eye, despite treatment with
altitudinal defect OD. The visual field OS was normal.
intravenous corticosteroids. Another patient (Case 4) had
Diffuse optic disc edema was present OD. The optic disc
a final visual acuity of 20/160 in the affected eye and dense
OS was normal. The sedimentation rate was 72 mm/h.
amblyopia secondary to optic nerve hypoplasia in the
ANA was negative. Cholesterol and triglycerides were
fellow eye, reducing visual acuity to hand movements.
elevated at 246 and 226 mg/dL, respectively. One week
Several patients attributed the visual loss to sildenafil
later, visual field testing revealed extension of the inferior
and subsequently stopped using it. Other individuals
altitudinal visual field deficit to the superior half of the
continued to use sildenafil after the occurrence of NAION.
One of these individuals had bilateral sequential NAION
A temporal artery biopsy result was negative, but he
was treated for 3 days with methylprednisolone 1 g/d intra-venously, followed by prednisone 80 mg/d. One week later,
visual acuity was 20/70 OD. An MRI scan of the brain and
A 59-year-old man was prescribed 50 mg sildenafil
orbits was normal. The patient continued to experience
18 months before presentation. Because this dose caused
a decline in vision OD. Six days later, visual acuity was
severe headaches, the dose was lowered to 25 mg 15
light perception OD and 20/60 OS. Humphrey 30-2 visual
months before presentation. The patient used sildenafil
field testing revealed an inferior altitudinal defect OS. A fluo-
sporadically. Medical history was significant for erectile
rescein angiogram showed late leakage in the optic disc OS.
dysfunction, headaches, depression, gastric reflux, and skin
The prednisone dose was tapered over several months.
cancer. Medications were sertraline and omeprazole. One
A repeat sedimentation rate a few months later was 3 mm/h.
day before presentation, he took one 25 mg sildenafil tablet
Four months after initial presentation, the patient noted
before intercourse after not having used the medication for
progressive visual loss OS. Visual acuities were light
several months. A few hours later after intercourse, he saw
perception OD and 20/70 OS. Fundus examination revealed
bright colors, followed by loss of vision in the OD and
optic disc pallor OD and optic disc edema OS. Two weeks
later, visual acuity had decreased to 20/100 OS. A repeat
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Nonarteritic Ischemic Optic Neuropathy After Use of Viagra
MRI scan of the brain and orbits was negative. Complete
side effects. On the third day, at approximately 11:00 pm,
blood count, antinuclear antibody, angiotensin-converting
he took two 50-mg tablets of sildenafil. The next day, he
enzyme, and syphilis serology were negative. The sedi-
sensed ‘‘a flashbulb go off in my eyes’’ with persistent
mentation rate was 7 mm/h. Three weeks later, the patient
glare. During the early hours of the next morning, 30 hours
took another 25-mg dose of sildenafil and subsequently
after his last ingestion of sildenafil, he noted sudden
engaged in sexual intercourse. A few hours later, he noted
color changes with the OS, followed by loss of vision. A few
Nine years earlier, visual acuity had been 20/20 OS
days later, visual acuity was counting fingers OS, the optic
with a normal Goldmann visual field but he had finger
disc OS was diffusely edematous, and the visual field OS
counting visual acuity OD from optic nerve hypoplasia.
was severely constricted. He was retreated with intravenous
Past medical history was significant for renal stones, benign
methylprednisolone. The sedimentation rate was 6 mm/h.
prostatic hypertrophy, and arthritis. Medications were
Three months later, visual acuity was hand movements OS
terazosin, gabapentin, and metaxalone.
and the optic disc was pale. Final visual acuities 1 year later
Examination on the day of visual loss OS showed
were light perception OD and hand movements OS.
visual acuities of finger counting OD and 20/70 OS. Anafferent pupillary defect was present OS. The optic nerve
OD was hypoplastic and the optic disc OS was swollen.
A 58-year-old man used 50 mg of sildenafil, engaged
Three days later, visual acuity had decreased to 20/160 OS.
in sexual activity with his wife and headache developed
Humphrey visual field testing revealed inferior altitudinal
almost immediately. He noted that his face was ‘‘beet red’’
and central defects OS. There were no symptoms of giant
and that he could not see out of his OD. He had a history
of amblyopia OS, lowering visual acuity to 20/40. He had
An erythrocyte sedimentation rate was 1 mm/h. Lipid
remote epistaxis caused by dehydrational mucositis, hyper-
profile, rheumatoid factor, antinuclear antibody, glucose
cholesterolemia, and erectile dysfunction. Medications
levels, blood pressure, carotid and vertebral ultrasound
studies, echocardiograms (transthoracic and transesopha-
Nine days after acute visual loss OD, visual acuity
geal), magnetic resonance angiogram, and magnetic
was hand movements OD and 20/40 OS. There was a right
resonance imaging of the brain and orbits were normal.
afferent pupillary defect and optic disc swelling with
He was treated with anticoagulation and oral prednisone
hemorrhages OD. He denied symptoms of temporal
without improvement in vision. One week later, visual
arteritis. The erythrocyte sedimentation rate was 43 mm/h.
acuity had declined to finger counting OS. Goldmann
A temporal artery biopsy sample and carotid and vertebral
visual field testing revealed a small island of visual field
artery ultrasound studies were normal. Two months later,
temporal to fixation OS. Four months later, pallor of the left
visual acuity was unchanged and the optic disc OD was
optic disc was noted. Several years later, visual acuities and
A 67-year-old man awakened with decreased vision
OD 1 day after he had used 50 mg sildenafil. He had beenusing the drug intermittently for 5 weeks. His medical
history was significant for hypertension and a seizure disor-
A 69-year-old man used a single 50-mg sildenafil
der. Medications included metoprolol, enalapril, sertraline,
tablet and reported acute visual loss OS the next day. He
bisoprolol, nifedipine, nortryptiline, doxazosin, phenobar-
had used 50 mg sildenafil once per week for 3 months. He
had undergone retinal buckle surgery 3 months earlier OS
One week after acute visual loss OD, best-corrected
with postoperative visual acuities of 20/32 OD and 20/100
visual acuities were 20/200 OD and 20/25 OS. The right
OS. His medical history was significant for hypertension,
pupil was poorly reactive to light. The optic disc OD was
atrial flutter, prostate cancer treated with radioactive plaque,
edematous and the optic disc OS was normal. Visual field
and occasional erectile dysfunction. Medications included
testing revealed a depression in the superior aspect of the
chlorthalidone, warfarin, digoxin, and diltiazem.
visual field OD. Two and one-half years later, the visual
Visual acuities 1 day after the acute visual loss OS
were 20/32 OD and 2/200 OS. The optic disc OS wasedematous with peripapillary nerve fiber layer hemor-
rhages. Six months later, visual acuities were 20/32 OD and
A 50-year-old man took one 50-mg tablet of
in 20/125 OS. The optic disc OS was pale and the retina
sildenafil in the evening for 2 consecutive days without
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A 66-year-old man experienced acute visual loss OD
with spontaneous NAION, as many of our patients did,
while exercising. He had used sildenafil 36 hours earlier
but an ischemic effect of sildenafil on the optic nerve is
and had noted flushing and headache the next day. He had
a history of no light perception OS because of a traumatic
This drug is a selective phosphodiesterase 5 inhibitor
retinal detachment. Medical history was significant for
causing vasomotor effects through its action on the nitric
diabetes, hypertension, and hypercholesterolemia. Medi-
oxide-cyclic GMP pathway. In 12 normal adults, it
cations were glipizide, metformin, lisinopril, furosemide,
increased pulsatile ocular blood flow, a result of filling
the choroidal circulation (8). Grunwald et al. (9,10) did not
Four days after the acute visual loss OD, visual acuity
find any significant change in optic nerve rim or foveolar
was 20/25 OD and no light perception OS. The optic disc
choroidal blood flow (9) or retinal vessel caliber (10) after
OD was swollen and the optic disc OS was flat and pale.
treatment with sildenafil, but Pache et al. (11) found that
Complete blood count, erythrocyte sedimentation rate, and
sildenafil caused significant dilation of retinal arteries and
serum protein electrophoresis were normal. Carotid ultra-
veins in healthy individuals. One healthy, young woman in
sound demonstrated no significant stenosis or plaque. Thirty
another study (12) had severe flushing, headache, and
months later, visual acuity was 20/30 OD and the optic disc
visual field defects after ingestion of 200 mg of sildenafil,
suggesting that the effect on the optic nerve is acutely andtemporally related to ingestion of the medication.
Morgan et al. (13) reported the occurrence of
a transient ischemic attack in a 50-year-old man 2 hours
after ingesting 50 mg sildenafil. On re-challenging himself
A 60-year-old man reported a ‘‘shade coming down
with 100 mg sildenafil 6 days later, permanent neurologic
over the OD’’ on awakening the morning after using
deficits from an ischemic stroke developed.
sildenafil (exact dose unknown). He had used sildenafil
Studies by Pfizer (published in the Physicians Desk
sporadically over the past year. Medical history was
Reference and available through the Food and Drug
significant for obesity, cardiac dysrhythmia, and hyper-
Administration [FDA] web site) show that sildenafil
cholesterolemia. Medications were metoprolol, simvas-
reaches a peak plasma concentration within 2 hours (30–
120 min) during fasting and over a longer period of time in
Examination on the day of acute visual loss OD
the presence of lipid (2). Elevated levels of sildenafil and its
disclosed visual acuities of 20/20 OU. An afferent pupillary
active metabolite are present in the blood for 8 to 12 hours
defect was present OD. The optic disc OD was swollen with
after ingestion. Therefore, if sildenafil is ingested at
nerve fiber layer hemorrhages; the optic disc OS was nor-
night, sufficient drug levels may be present during sleep
mal. Humphrey 24-2 visual field testing revealed a superior
or the next morning. Many of our patients recognized
altitudinal defect OD and a normal field OS.
visual loss on awakening, implying that it took place
Complete blood count, erythrocyte sedimentation
rate, thyroid stimulating hormone, and C-reactive protein
Because of the lack of a model in which to test for
were normal. Electrolytes were normal except for blood
a relationship between sildenafil and NAION, a definite
urea nitrogen of 21 mg/dL and a creatinine of 1.5 mg/dL.
causal relationship cannot be established at this time. An
Cholesterol and triglyceride levels were 286 and 624
animal model for NAION has been developed (14) and may
mg/dL, respectively. Two weeks later, Humphrey 24-2
provide an experimental paradigm. In view of the fact that
visual field testing revealed a new inferior defect OD.
other medications for treatment of erectile dysfunction,
Carotid ultrasound did not reveal any significant stenosis. A
such as tadalafil and vardenafil, have undergone clinical
trial of levodopa did not result in visual improvement.
trials for FDA approval and are now available by
Three months later, visual acuity was 20/20 OD through
prescription, it is critical that irreversible ocular side effects
a small central island. Pallor of the optic nerve OD was
such as NAION be ruled out in this class of drugs.
Pfizer’s postmarketing experience with sildenafil led
to the addition of the following statements to the PhysiciansDesk Reference in 2002:
‘‘Serious cardiovascular, cerebrovascular, and vascu-
The onset of NAION within hours after ingestion of
lar events, including myocardial infarction, sudden cardiac
sildenafil in our seven patients supports an association
death, ventricular arrhythmia, cerebrovascular hemorrhage,
between use of this agent and NAION. We recognize that
transient ischemic attack, hypertension, subarachnoid and
patients with erectile dysfunction are more likely to have
intracerebral hemorrhages, and pulmonary hemorrhage
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Nonarteritic Ischemic Optic Neuropathy After Use of Viagra
have been reported post marketing in temporal association
with the use of Viagra. Most, but not all, of these patients
1. Physicians Desk Reference, 55th ed. Montvale: Medical Economics;
had preexisting cardiovascular risk factors. Many of these
events were reported to occur during or shortly after sexual
2. Center for Drug Evaluation and Research. A double-blind, random-
ized, placebo-controlled, four-period crossover study to assess the
activity, and a few were reported to occur shortly after the
effect of orally administered sildenafil (50, 100, and 200 mg) on visual
use of Viagra without sexual activity. Others were reported
function in healthy mail volunteers: study 148–223 Viagra (Sildenafil):
to have occurred hours to days after the use of Viagra and
Joint Clinical Review for NDA-20–895. Washington DC: Food andDrug Administration; 1998:160–1.
sexual activity. It is not possible to determine whether these
3. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafil-associated
events are directly related to Viagra, sexual activity, to the
nonarteritic anterior ischemic optic neuropathy. Ophthalmology.
patient’s underlying cardiovascular disease, to a combina-
4. Egan RA, Pomeranz HD. Sildenafil (Viagra) associated anterior
tion of these factors, or to other factors (2).’’
ischemic optic neuropathy. Arch Ophthalmol. 2000;118:291–2.
Based on the fact that 14 cases of NAION have now
5. Cunningham AV, Smith KH. Anterior ischemic optic neuropathy
been reported soon after use of sildenafil, we believe that
associated with Viagra. J Neuroophthalmol. 2001;21:22–5.
6. Dheer S, Rekhi GS, Merlyn S. Sildenafil associated anterior ischemic
ophthalmologists should ask all men with NAION about
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the use of sildenafil, given that this information may not be
7. Boshier A, Pambakian N, Shakir SA. A case of nonarteritic ischemic
volunteered without specific inquiry. We recommend that
optic neuropathy (NAION) in a male patient taking sildenafil. Int JPharmacol Ther. 2002;40:422–423.
patients with a history of monocular NAION be cautioned
8. Sponsel WE, Paris G, Sandoval SS, et al. Sildenafil and ocular
that sildenafil may increase the risk of NAION in the fellow
perfusion [letter]. N Engl J Med. 2000;342:1680.
eye. We also suggest that physicians report cases of ocular
9. Grunwald JE, Siu KK, Jacon SS, et al. Effect of sildenafil citrate (Viagra)
on the ocular circulation. Am J Ophthalmol. 2001;131:751–755.
ischemia in patients using sildenafil to the National
10. Grunwald JE, Metelitsina T, Grunwald L. Effect of sildenafil citrate
Registry of Drug-Induced Ocular Side Effects and that
(Viagra) on retinal blood vessel diameter. Am J Ophthalmol. 2002;
Pfizer consider investigating this association.
11. Pache M, Meyer P, Prunte C, et al. Sildenafil induces retinal
vasodilatation in healthy subjects. Br J Ophthalmol. 2002;86:156–158.
12. McCulley TJ, Lam BL, Marmor MF, et al. Acute effects of sildenafil
(Viagra) on blue-on-yellow and white-on-white Humphrey perimetry. J Neuroophthalmol. 2000;20:227–8.
13. Morgan JC, Alhatou M, Oberlies J, et al. Transient ischemic attack and
stroke associated with sildenafil (Viagra) use. Neurology. 2001;
The contribution of cases by Gary Cowan, MD,
14. Bernstein SL, Guo Y, Kelman SE, et al. Functional and cellular
David H. Zackon, MD, and Michael Zgrabik, MD is
responses in a novel rodent model of anterior ischemic optic
neuropathy. Invest Ophthalmol Vis Sci. 2003;44:4153–4162.
Finnish philosopher Georg Henrik von Wright (1916-2003) is one of the foremost logicians of the 20th century, whose status was truly set in stone when he succeeded Ludwig Wittgenstein (1889-1951) at Cambridge. Outside the action typologies, von Wright’s logic is too technical and too deep into the realm of analytic philosophy for me to fully understand. But then it is not as an analytical philos
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