Prefrontal Mechanisms in Extinction of Conditioned Fear Gregory J. Quirk, René Garcia, and Francisco González-Lima Interest in the medial prefrontal cortex (mPFC) as a source of behavioral inhibition has increased with the mounting evidence for afunctional role of the mPFC in extinction of conditioned fear. In fear extinction, a tone-conditioned stimulus (CS) previously pairedwith a footshoc
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Centralfloridaurology.comJOBNAME: 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.
JOBNAME: cno 25#1 2005 PAGE: 2 OUTPUT: Fri February 11 20:34:46 2005lww/cno/94412/WNO160361 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 JOBNAME: cno 25#1 2005 PAGE: 3 OUTPUT: Fri February 11 20:34:47 2005lww/cno/94412/WNO160361 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 JOBNAME: cno 25#1 2005 PAGE: 4 OUTPUT: Fri February 11 20:34:47 2005lww/cno/94412/WNO160361 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 JOBNAME: cno 25#1 2005 PAGE: 5 OUTPUT: Fri February 11 20:34:48 2005lww/cno/94412/WNO160361 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 optic neuropathy. J Assoc Physicians India. 2002;50:265.
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.
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