Fourth Cranial Nerve Palsy Associated With Sildenafil Citrate

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Fourth Cranial Nerve Palsy Associated With Sildenafil Citrate Yumi Lee, MD, Kyung-Ah Park, PhD, Sei Yeul Oh, PhD, Ju-Hong Min, PhD, Byoung Joon Kim, PhD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/04/2022 P hosphodiesterase-5 inhibitors (PDE5i) have been developed for the treatment of coronary artery disease, but they are now widely used for the treatment of erectile dysfunction. Unfortunately, these drugs are also known to cause several ocular side effects. Among those symptoms that may be experienced, a nonarteritic anterior ischemic optic neuropathy (NAION) is the most common neuroophthalmological complication, and the prevalence is 0.09%–0.18% (1). To date, an occurrence of a fourth cranial nerve palsy has not been reported in the literature. The authors report a fourth cranial nerve palsy after sildenafil administration in a patient. A 50-year-old previously healthy man was referred to our clinic with a presumed diagnosis of a left fourth cranial nerve palsy. The patient developed an acute diplopia on his down gaze 20 days ago. He had a medical history of a right facial palsy that occurred 12 years ago and it recovered spontaneously, and there was no significant medical history such as diabetes mellitus, hypertension, hyperlipidemia, or cardiovascular disorder, excepting an erectile disorder. There was no significant surgical history or social history such as tobacco use. He denied any trauma history. The only medication that the patient was taking at that time was sildenafil. The day before the onset of the diplopia, he had taken sildenafil at 50 mg for erectile dysfunction. On review of the system, there were no other symptoms except that he experienced a flushing sensation and a headache right after the intake of sildenafil, which was noted as having been 1 day before the onset of the experience of diplopia, according to the patient’s statement. On ocular examination, his visual acuity was noted as having been 20/20 in both eyes, and the measured intraocular pressure was normal range in both eyes. The distance and near deviation angles at that time were both orthotropia. A left hypertropia of 8 prism diopters (PDs) was measured in down gaze, and a 2 PD of left hypertropia was measured on dextroversion. The patient was orthoDepartments of Ophthalmology (YL, K-AP, SYO), and Neurology (J-HM, BJK), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. The authors report no conflicts of interest. Address correspondence to Kyung-Ah Park, PhD, Department of Ophthalmology, Samsung Medical Center, #81 Irwon-ro, Kangnamgu, Seoul 06351, Republic of Korea; E-mail: [e-mail] Lee et al: J Neuro-Ophthalmol 2021; 41: e79-e80 phoric on other gazes. On the Bielschowsky head tilt test, the patient was orthophoric on a right head tilt and showed a 8 PD of the left hypertropia on a left head tilt. On the extraocular motility test, it was considered as notable for full ductions of his right eye, but 75% of the normal superior oblique muscle function was observed in the left eye. Both of the patient’s pupils reacted normally to the direct light, and no disability in the afferent pupillary reaction was observed. The anterior segment examination showed normal findings, and the fundus examination revealed a healthy appearing optic nerve with 0.3 cup-to-disc ratio in both eyes, a mild excyclotorsion in the left eye, and otherwise unremarkable findings in both eyes of the retina. Upon review of a performed high-resolution pre- and post-contrast cranial nerve MRI with 3-dimensional sequences using a 3-T system (Magnetom Skyra; Siemens Healthineers, Erlangen, Germany) with a 32-channel phased-array head coil, this test revealed no abnormality in fourth cranial nerve pathway, and no abnormality was found on an MRA. Laboratory tests showed a hemoglobin level of 15.8 g/dL, white blood cell count of 5.32 · 103 mL (segmented neutrophil 58.8%, lymphocyte 36.3%, and monocyte 3.4%), and normal electrolytes. The erythrocyte sedimentation rate and C-reactive protein levels were noted also to be as normal. The fasting blood glucose level was noted as 96 mg/dL. Under this circumstance, the serological investigations revealed a positive result of antinuclear antibody, whereas the patient’s anti-neutrophil cytoplasmic antibody showed a negative result. The anticardiolipin antibody, ganglioside antibody, thyroid antibody, and acetylcholine receptor antibody were all noted to have been within normal range. Other tests—liver, renal, and coagulation panel —were also noted as being normal. Although the antinuclear antibody showed positive findings, there were no symptoms representing rheumatic diseases such as dry eye, dry mouth, ulcer, and arthritis. Based on the above results, the patient was diagnosed as sildenafil-associated left fourth cranial nerve palsy. By preventing the cyclic guanosine monophosphates (cGMP) degradation, PDE5i enhance the vascular smooth muscle relaxation. In addition, since nitric oxide (NO) is required for cGMP to be produced, the PDE5i amplify the role of NO donors by interfering with cGMP degradation (2). e79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Therefore, patients with cardiovascular disease who take nitrates should be cautious when taking sildenafil together because there may be serious side effects along with severe hypotension, and some of these side effects may even result in the death of the patient if left untreated (3). The incidence of cranial nerve palsy after the administration of sildenafil is very rare to occur in a patient, and only a few cases have been reported. Oculomotor nerve palsy (4) and the case of a combined oculomotor nerve palsy and abducens nerve palsy (5) have been reported in 1 case each. According to the previous case reports, preceded by headache, the diplopia appeared within 1 hour to 1 day after taking the medicine, whereby the condition shown to have improved within 3 months (4,5). In our case, the patient felt a headache immediately after taking sildenafil. The next day, diplopia caused by a fourth nerve palsy had developed. In all 3 cases, including our case, an acute cranial nerve palsy occurred within 1 day after taking sildenafil-based drugs, but the likelihood of temporal coincidence cannot be excluded as Donahue et al (4) mentioned. PDE5i also have been reported to increase the risk of NAION, which is caused by ischemia of the optic nerve head. It is known that PDE5 is widely expressed in the corpora cavernosa of penis, systemic arteries and veins, the pulmonary arteries, the myocardium, the skeletal muscles, e80 and in the platelets, and the PDE5i can cause hypotension. Our case along with previously reported cases suggests that PDE5i can induce neurologic dysfunction probably related with systemic hypotension, even in patients without concomitant intake of nitrates (4). In conclusion, we report a case of fourth cranial nerve palsy a day after sildenafil administration. When treating patients with fourth nerve palsy, PDE5i may need to be scrutinized because the patients themselves may be reluctant to speak on these issues and PDE5i may be able to interact with underlying diseases or other drugs that it was taken. REFERENCES 1. Liu B, Zhu L, Zhong J, Zeng G, Deng T. The association between phosphodiesterase type 5 inhibitor use and risk of non-arteritic anterior ischemic optic neuropathy: a systematic review and meta-analysis. Sex Med. 2018;6:185–192. 2. Glossmann H, Petrischor G, Bartsch G. Molecular mechanisms of the effects of sildenafil (VIAGRA (R)). Exp Gerontol. 1999;34:305–318. 3. Chrysant SG. Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension. Curr Hypertens Rep. 2013;15:475–483. 4. Donahue SP, Taylor RJ. Pupil-sparing third nerve palsy associated with sildenafil citrate (Viagra). Am J Ophthalmol. 1998;126:476–477. 5. van Landingham SW, Singman EL. A case report: consecutive cranial neuropathies following the use of phosphodiesterase-5 inhibitors. Am Orthopt J. 2015;65:109–114. Lee et al: J Neuro-Ophthalmol 2021; 41: e79-e80 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.