1524 | Intracerebral Hemorrhage after Sildenafil Citrate Use: An Incidental Association? Giyas Ayberk,1 Mehmet Faik Ozveren,1 Mesut Emre Yaman,2 Hakan Tosun1 Corresponding Author: Gıyas Ayberk, MD Department of Neurosurgery, Ataturk Training and Research Hospital, 06800 Bilkent, Ankara, Türkiye. Tel: +90 312 291 2525 Fax: +9 312 291 2705 E-mail: giyas67@hotmail.com Received March 2013 Accepted June 2013 1 Department of Neurosurgery, Ataturk Training and Research Hospital, 06800 Bilkent, Ankara, Türkiye. 2 Department of Neurosur- gery, Kecioren State Hospital, Ankara, Türkiye. Keywords:‎cerebral‎hemorrhage;‎disability‎evaluation;‎sildenafil;‎incidental‎findings. INTRODUCTION The‎most‎common‎causes‎of‎intracerebral‎hemorrhage‎(ICH)‎are‎structural‎vascular‎anomalies‎and‎dysfunctional‎coagulation.‎ICH‎caused‎by‎sildenafil‎is‎rarely‎reported‎in‎the‎literature.‎Sildenafil‎is‎a‎selective‎phosphodiesterase-5‎(PDE-5)‎enzyme‎in- hibitor,‎and‎causes‎an‎increase‎in‎cyclic‎guanosine‎monophosphate‎(cGMP)‎in‎the‎vascular‎ smooth‎muscle‎of‎the‎corpus‎cavernosum,‎leading‎to‎muscle‎relaxation‎and‎vasodilation.‎ Sildenafil‎has‎same‎effects‎on‎intracranial‎vasculature‎by‎way‎of‎PDE-1‎and‎2‎enzymes.‎ Overdose‎of‎sildenafil‎or‎use‎over‎an‎extended‎period‎of‎time‎increases‎the‎likelihood‎of‎ intracerebral‎hemorrhage. CASE REPORT A‎35-year-old‎male‎was‎admitted‎to‎the‎emergency‎department‎in‎a‎disoriented‎state‎and‎with‎ a‎serious‎headache.‎His‎wife‎reported‎that‎he‎had‎noticed‎a‎serious‎headache‎two‎hours‎after‎ taking‎50‎mg‎of‎sildenafil‎without‎having‎sexual‎activity.‎He‎had‎used‎the‎drug‎for‎nearly‎a‎ month,‎two‎to‎three‎times‎in‎a‎day‎without‎supervision‎of‎an‎urologist.‎He‎had‎no‎hyperten- sion,‎family‎history‎of‎cerebral‎arteriovenous‎malformation,‎cerebral‎aneurysms,‎or‎ICH.‎On‎ CASE REPORT Case Report 1525Vol. 11 | No. 02 | March- April 2014 |U R O LO G Y J O U R N A L Sildenafil and Stroke | Ayberk et al admission,‎blood‎pressure‎was‎120/90‎mm‎Hg,‎and‎pulse‎ rate‎ was‎ 90‎ beats/minute.‎ The‎ Glasgow‎ coma‎ score‎ was‎ 12.‎The‎neurological‎examination‎was‎normal,‎with‎the‎ex- ception‎of‎mild‎neck‎stiffness.‎Routine‎blood‎examination,‎ platelet‎count‎and‎coagulation‎factors‎were‎normal.‎Cranial‎ computed‎ tomography‎(CT)‎scan‎revealed‎hemorrhage‎ in‎ the right nucleus caudatus, which opened in the lateral and third‎ ventricles‎ (Figure‎ 1).‎ CT‎ scan‎ angiography‎ and‎ the‎ cerebral‎digital‎subtraction‎angiography‎(DSA)‎revealed‎no‎ vascular‎pathology‎(Figure‎2).The‎patient‎was‎consulted‎by‎ a‎cardiology‎department‎to‎rule‎out‎cardiac‎causes,‎and‎re- ported‎as‎normal‎findings.‎He‎admitted‎to‎the‎intensive‎care‎ unit‎for‎observation,‎and‎discharged‎after‎five‎days‎with‎nor- mal‎neurologic‎examination. DISCUSSION Sildenafil‎is‎a‎PDE-5‎enzyme‎inhibitor,‎and‎causes‎an‎in- crease‎in‎cGMP‎in‎the‎vascular‎smooth‎muscle‎of‎the‎corpus‎ cavernosum.‎The‎nitric‎oxide‎(NO)-cGMP‎pathway‎may‎be‎ responsible‎for‎cerebral‎vasodilation‎by‎similar‎mechanisms‎ in the brain.(3)‎It‎has‎been‎suggested‎that‎sildenafil‎also‎acts‎ on‎the‎PDE-1‎and‎PDE-2‎enzymes,‎which‎are‎involved‎in‎ the‎control‎of‎cerebral‎vasculature.(4)‎There‎are‎many‎re- ported‎side‎effects‎of‎sildenafil‎ in‎ the‎literature‎including‎ headache,‎ visual‎ and‎ retinal‎ disturbances,‎ dizziness,‎ and‎ a‎pupil-sparing‎third‎nerve‎palsy,‎which‎explain‎systemic‎ distribution‎into‎the‎microvasculature.(5) Hypertension and sexual‎activity‎are‎known‎risk‎factors‎for‎ICH.(6) The‎ingestion‎of‎sildenafil‎and‎onset‎symptoms‎after‎three‎ hours‎without‎sexual‎activity‎suggests‎that‎sildenafil‎may‎be‎ related‎to‎the‎ICH‎in‎this‎patient.‎The‎cranial‎CT‎angiog- raphy‎and‎DSA‎did‎not‎reveal‎any‎vascular‎anomalies‎ex- plaining‎the‎cause‎of‎ICH.‎The‎relationship‎between‎the‎ICH‎ and‎sildenafil‎ingestion‎is‎speculative‎in‎the‎literature.(7) It is‎known‎that‎sildenafil‎increases‎the‎response‎of‎cerebral‎ vasculature‎to‎C02‎and‎causes‎increased‎cerebral‎blood‎flow‎ and‎cerebral‎blood‎volume‎intracranially.(8) Altered cerebro- vascular‎reactivity‎causes‎a‎vasodilatory‎response‎and‎blood‎ flow‎modifications.‎The‎effects‎of‎sildenafil‎on‎cerebral‎ar- terial‎diameter‎are‎not‎hemodynamically‎significant‎at‎rest,‎ but‎hypercapnia‎decreases‎the‎mean‎arterial‎pressure‎5‎to‎15‎ mm‎Hg.(2)‎In‎hypertensive‎patients,‎these‎effects‎are‎much‎ more‎prominent‎and‎dose‎dependent.(9)‎Increased‎blood‎C02 tension‎was‎not‎considered‎as‎a‎cause‎of‎ICH,‎due‎to‎the‎pa- tient’s‎lack‎of‎strenuous‎activity.‎It‎was‎shown‎that‎sildenafil‎ modulates‎NO-cGMP‎pathways‎in‎the‎rat‎brain,‎and‎endog- Figure 1. Cranial computed tomography scan demonstrates hemorrhage in the right nucleus caudatus. Figure 2. Computed tomography scan angiography and the cerebral digital subtraction angiography show no vascular pathology. 1526 | Case Report enous‎NO‎releasing‎is‎potentiated‎by‎sildenafil.(10,4) Modula- tion‎of‎the‎NO-cGMP‎pathway‎may‎potentiate‎the‎effect‎of‎ sildenafil‎and‎cause‎bleeding‎in‎cerebral‎blood‎vessels.‎ CONCLUSION To‎ conclude,‎ taking‎ sildenafil‎ for‎ an‎ unusually‎ extended‎ period‎of‎time,‎and‎at‎a‎high‎dose‎may‎cause‎persistent‎va- sodilatation‎on‎cerebral‎vasculature‎which‎may‎increase‎the‎ probability‎of‎ICH.‎Additionally,‎it‎may‎be‎an‎incidental‎side‎ effect‎as‎presented‎case. CONFLICT OF INTEREST None declared. REFERENCES 1. Johnston KC. Effect of sildenafil (Viagra) on cerebral blood vessels. Neurology. 2005;65:785. 2. Diomedi M, Sallustio F, Rizzato B, Ferrante F. Sildenafil increases cerebrovascular reactivity: A transcranial doppler study. Neurology. 2005;65:919-21. 3. McHugh J, Cheek DJ. Nitric oxide and regulation of vascular tone; Pharmacological and physiological consideration. Am J Crit Care. 1998;7:131-40. 4. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effect of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isoenzymes. J Urol. 1998;159:2164-71. 5. Donahue SP, Taylor RJ. Pupil sparing third nerve palsy associated with sildenafil citrate (Viagra). Am J Ophthalmol. 1998;126:476-7. 6. Monastero R, Pipia C, Camarda LKC, Camarda R. Intracerebral hem- orrhage associated with sildenafil citrate. J Neurol. 2001;248:141-2. 7. Buxton N, Flannery T, Wild D, Bassi S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg. 2001;15:347-9. 8. Jimenez-Caballereo PE, Segura T. Normal values of cerebral vasomotor reactivity using the breath-holding test. Rev Neurol. 2006;43:598-602. 9. 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