Sequential Nonarteritic Anterior Ischemic Optic Neuropathy after Vardenafil
Corresponding author: Dr. Arturo Carta, Fernando Onofrio Avellis, Stefano Gandolfi Section of Ophthalmology, University of Par- ma, 14, Via Gramsci 43126 Parma, Italy, Tel: 00390521703721; E-mail: firstname.lastname@example.org
Vardenafil (Levitra, Bayer Pharmaceuticals, Leverkusen, Germany) is one of the phosphodiesterase type 5 inhibitors (PDE-5i) approved for the treatment of erectile dysfunc- tion. Several case reports (other than small case series) have described a possible causative effect between PDE-5i inhibitors assumption and Non-Arteritic Ischemic Optic Neuropathy (NAION) since 2006. Following these reports, two main clinical trials have been conducted on this topic [1-3]; unfortunately, these studies have not really clarified the risk of developing NAION after PDE-5i intake report- ing that weekly use of PDE-5i increase the annual NAION
incidence up to three cases per 100,000 in men 50 years old or older .
Moreover, the occurrence of sequential or simultaneous bi- lateral NAION after assumption of such class of drugs have never been investigated despite some cases have been re- cently documented [5-7]. acute bilateral NAION following the use of Vardenafil in a case of a relatively young patient; to the best of our knowledge, this is the first description of such association.
A 52-year-old white man with erectile dysfunction expe- rienced NAION in the left eye (LE) on awakening. Patient was diagnosed as NAION according to the Ischemic Optic Neuropathy Decompression Trial (IONDT) criteria . The patient reported assumption of Vardenafil 20 mg 4 times during the 10 days before the onset of the visual symptoms. He took the last pill 24-hours before the beginning of visual symptoms and without sexual intercourse. There was no significant local risk factor for NAION (hyperopia), whereas systemic risk factors were diabetes, hypertension and overweight. A previously documented bilateral mild non proliferative diabetic retinopathy was stable since two years. At the same time, diabetes and hypertension were under control at the time of the NAION onset as demonstrated by the glycosilated hemoglobin levels and by 24-hour blood pressure monitoring. Three days after first eye involve- ment patient manifested in the right eye (RE) transient visual obscurations lasting seconds and, two weeks later, he developed NAION in the fellow eye. On this occasion he denied assumption of Vardenafil as he had stopped taking the drug after the visual symptoms onset in the LE.
Patient was screened for coagulative disorders other than for protective factors against NAION as glucose-6-phosphatase de- hydrogenase (G6PD) deficiency and for mean platelets volume with all these assessments negative [9-10]. An arteritic form of anterior ischemic optic neuropathy was ruled out investigating clinical and laboratory data, mainly erythrocyte sedimentation rate, C-reactive protein and differential leukocyte count; furthermore, clinical findings and neuroimaging were consistent with NAION.
An oral treatment with Pentoxifylline 400 mg/die was started. The three months’ follow-up visit showed a Best Corrected Visual Acuity (BCVA) stable since the acute to the atrophic phase of the disease in each eye with 20/200 in the LE and 20/20 in the RE. The optic disc appearance showed a diffuse optic atrophy in the LE whereas fundus copy revealed a segmental optic atrophy in the fellow eye (Figures 1, 2, 3). Visual field testing showed a bilateral inferior altitudinal defect (Figure 4).
Figure 1. Red free retinography. Optic nerve image of the right (A) and left eye (A) in late phase.
Figure 2 A B
Figure 3 A B
Figures 2 and 3. TD OCT. Optic nerve volumes of the right (Figure 2) and left eye (Figure 3) in acute phase (A), late phase (B)
Figure 4. 24-2 Humphrey visual field perimetry. A, inferior altitudinal defect of the left eye (acute phase). B, inferior altitudinal defect of right eye (late phase)
tension were under control) other than the early second eye involvement suggest a role of Vardenafil in this case of bilateral NAION
NAION is the most common form of acute optic neuropathy in people aged 60 years or over and one of the most notable form of optic nerve disease. In this case report we describe for the first time to the best of our knowledge an association between Vardenafil assumption and NAION sequentially occurred in both eyes of a relatively young patient.
Some evidences suggested a possible role of Vardenafil in- take as triggering or worsening factor for neuropathy’s later- alization. The temporal link between PDE5i assumption and NAION’s episodes onset was very close and the visual impair- ment was extremely severe in the first eye. Finally, the neurop- athy became bilateral very early despite the systemic param- eters were compensated (diabetes and high blood pressure). Since the introduction of the first molecule of PDE-5i, many case reports describing monocular visual loss due to NAION within hours after drug ingestion suspected a cause- effect relationship. This hypothesis is supported from the features of optic nerve head blood flow, from the various factors that influence it and from the systemic vascular effects of 5-PDE in- hibitors. Studies on the blood supply of the optic nerve head, as well as experimental, pathologic, and clinical findings, have all shown that NAION is caused by ischemia of the ONH. NAION is a multifactorial disease, with many risk factors playing a role in its development [11-16].
While a bilateral optic nerve involvement in forms of NAION arisen after taking PDE-5i has been already reported, the cor- relation between the drug assumption and the binocular isch- emic event has not been clearly demonstrated yet. Further- more, it’s currently unknown how the drug assumption might weigh in relation to other NAION risk factors that was often contextual in the analyzed literature .
A fellow eye’s NAION in not so common as demonstrated by IONDT; factors as age, sex, smoking or use of aspirin could be not involved unlike poor baseline visual acuity in the first affected eye, blood pressure’s dropping down and diabetes seems to increase incidence of .
In conclusion the causal connection between drug intake and bilateral NAION occurrence should be considered in PDE-5i users with risk factors for NAION.
Further studies are needed in order to clarify the relationship between PDE-5i and NAION avoiding possible patient’s sight loss as much providing correct information about the possible side effects of such class of drugs.
- Pfizer. A Study to Assess Whether PDE5 Inhibitors Increase the Chance of Triggering the Onset of Acute NAION. In: Clin- icalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Jul 02]. Available from: https://clinicaltrials.gov/ct2/show/NCT00759174. Identifi- er: NCT00759174.
- Bayer. PDE5 Inhibitor Use and Non-arteritic Anterior Isch- emic Optic Neuropathy (NAION). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Jul 02]. Available from: https://clinicaltrials.gov/show/NCT00867815.Identifier: NCT00867815.
- Eli Lilly and Company. A Study to Determine if There is a Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) and Phosphodiesterase Type 5 (PDE5) Inhibitors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Jul 02]. Available from: https://www.clinicaltrials.gov/ct2/show/ NCT01131104. Identifier: NCT01131104.
- Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D et al. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015, 12(1): 139-151.
- Moschos MM, Margetis I. Bilateral simultaneous anterior ischemic optic neuropathy associated with sildenafil. Case Rep Ophthalmol. 2011, 2(2): 262-265.
- Su DH, Ang PS, Tow SL. Bilateral posterior ischemic optic neuropathy associated with use of sildenafil. J Neuroophthal- mol. 2008, 28(1): 75.
- Galvez-Ruiz A, Arishi N. Sequential, non-arteritic anterior ischemic optic neuropathy in patients taking sildenafil: a re- port of ten cases. Saudi J Ophthalmol. 2013, 27(4): 241-246.
- Arnold AC. Ischemic optic neuropathy. In: Miller NR, New- man NJ, Biousse V, Kerrison JB, editors. Walsh & Hoyt’s Clinical Neuro-Ophthalmology. 6th ed. I. Philadelphia: Lippincott Wil- liams & Wilkins; 2005. pp. 349-384.
- Pinna A, Solinas G, Masia C, Zinellu A, Carru C et al. Glu- cose-6-phosphate dehydrogenase (G6PD) deficiency in nonar- teritic anterior ischemic optic neuropathy in a Sardinian popu- lation. Italy.Invest Ophthalmol Vis Sci. 2008, 49(4): 1328-1332.
- ªahin M, ªahin A, Elbey B, Yüksel H, Türkcü FM et al. Mean Platelet Volume in Patients with Nonarteritic Anterior Isch- emic Optic Neuropathy. J Ophthalmol. 2016, 2016: 5.
- SS Hayreh. Erectile dysfunction drugs and non-arteritic an- terior ischemic optic neuropathy: is there a cause and effect relationship? J Neuro-Ophthalmol. 2005, 25(4): 295-298.
- NM Peter, MV Singh, PD Fox. Tadalafil-associated anterior ischaemic optic neuropathy. Eye. 2005, 19: 715-717.
- SS Hayreh. Non-arteritic anterior ischaemic optic neurop- athy and phosphodiesterase-5 inhibitors. Br J Ophthalmol. 2008, 92(12): 1577-1580.
- AR Rao, A Thwaini, HU Ahmed, IS Shergill, S Minhas. The Phosphodiesterase inhibitors and non-arteritic anterior isch- aemic optic neuropathy: increased vigilance is necessary. BJU Int. 2007, 100(1): 3-4.
- Not Just for Men N Molina Prat, BF. Sanchez-Dalmau, R Fo- roozan. Survey of Ophthalmology 2011; 56: 173-177.
- HD Pomeranz, KH Smith, WM Hart, RA Egan. Sildenafil-as- sociated nonarteritic anterior ischemic optic neuropathy. Oph- thalmology. 2002, 109(3): 584-587
- Pomeranz HD. Cases of Ischemic Optic Neuropathy Associ- ated with Phosphodiesterase-5 Inhibitor Use Reported to the Food and Drug Administration Adverse Event Reporting Sys- tem. J Neuroophthalmol. 2016, 36(2): 221-222.
- Newman NJ1, Scherer R, Langenberg P, Kelman S, Feldon S et al. The fellow eye in NAION: report from the ischemic op- tic neuropathy decompression trial follow-up study. Ischemic Optic Neuropathy Decompression Trial Research Group. Am J Ophthalmol. 2002, 134(3): 317-328.