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Nonaneurysmal Subarachnoid Hemorrhage after Udenafil Intake
Case Report
Nonaneurysmal Subarachnoid Hemorrhage after Udenafil Intake Eun-Kee Bae, MD, Jong-Hyeon Ahn, MD, and Jeong-Jin Park, MD
We report a 67-year-old man who presented with severe headache after taking 50 mg of udenafil, a new phosphodiesterase 5 inhibitor. Computed tomographic imaging of the brain revealed a small amount of acute subarachnoid hemorrhage localized around basal cisterns (anterior to midbrain and pons). There were no aneurysms in the cerebral arteries, although vein of Galen stenosis was suspected after magnetic resonance venography. This case anecdotally suggests that phosphodiesterase 5 inhibition might trigger perimesencephalic subarachnoid hemorrhage with venous hypertension possibly associated with vein of Galen stenosis. Key Words: Cerebral veins— phosphodisesterase 5 inhibitors—subarachnoid hemorrhage—udenafil. Ó 2013 by National Stroke Association
Nonaneurysmal subarachnoid hemorrhage (NA-SAH) differs from aneurysmal subarachnoid hemorrhage (SAH) in both clinical course and outcome. In spite of many reports and case series since the first description in 1985,1 the etiology of NA-SAH remains uncertain in 15% of cases with spontaneous SAH.2 Udenafil is a new oral selective phosphodiesterase 5 (PDE5) inhibitor that, like sildenafil, was developed for the treatment of erectile dysfunction.3 Although headache is one of its common side effects,3 SAH after udenafil intake has not been reported. We present a case of NA-SAH after udenafil intake with underlying vein of Galen stenosis.
Case Report A 63-year-old man with a medical history of chronic hypertension presented with severe headache after taking 50 mg of udenafil for the first time. Thirty minutes after From the Department of Neurology, Inha University Hospital, Incheon, Korea. Received February 20, 2013; revision received April 5, 2013; accepted April 6, 2013. Address correspondence to Eun-Kee Bae, MD, Department of Neurology, Inha University Hospital, 7-206, 3-Ga, Sinheung-Dong, Jung-Gu, Incheon, 400-711, Republic of Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.04.002
taking the drug, he had a severe headache that was accompanied by nausea and vomiting. He did not have any focal neurologic abnormalities. He was first treated with painkillers after undergoing a noncontrast computed tomographic (CT) scan of the brain at a nearby hospital. Because his headache did not subside for 1 week, he visited our hospital. Although the initial CT scan of his brain showed high attenuation, suggesting acute hemorrhage localized around the basal cisterns (anterior to midbrain and pons; Figs 1, A and B), the follow-up brain CT scan 1 week later revealed no abnormalities (Figs 1, C and D). A magnetic resonance imaging (MRI) scan of the brain revealed hyperintensity along with the sulci of left frontal, bilateral parieto-occipital lobes and perimsencephalic space on fluid-attenuated inversion recovery (FLAIR) and a hypointense rim along the brain surface on gradient echo T2-weighted images, suggesting superficial siderosis. Brain magnetic resonance angiography (MRA) and catheter angiography revealed no arterial abnormalities, including aneurysms. However, magnetic resonance venography (MRV) revealed stenosis at the junction of the vein of Galen and the straight sinus (Fig 1, E). The opening pressure of lumbar puncture was increased to 265 mm H2O, and the gross appearance of cerebrospinal fluid (CSF) was yellow-brown (xanthochromic). CSF analysis revealed the presence of red blood cells (110/mm3) and white blood cells (30/mm3; lymphocyte-dominant). The
Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 8 (November), 2013: pp e647-e649
e647
e648
E.-K. BAE ET AL.
Figure 1. Noncontrast computed tomographic scan of the brain at symptom onset (A and B) and 1 week later (C and D). The initial computed tomographic scan revealed a small amount of acute hemorrhage localized around the basal cisterns (anterior to midbrain and pons), and this hemorrhage disappeared after 1 week. Magnetic resonance venography (E) revealed stenosis at the junction of the vein of Galen with the straight sinus (arrow).
protein content was 60 mg/dL and the glucose concentration was 69 mg/dL in the CSF. His headache subsided after 5 days of mannitol therapy, and then he discharged without any neurologic sequelae.
Discussion Idiopathic NA-SAH can be divided into 2 groups according to the bleeding pattern on CTscans of the brain: perimesencephalic and nonperimesencephalic. NA-SAH with a perimesencephalic pattern of bleeding has a benign course and excellent short- and long-term prognosis.2 A venous source of bleeding has been postulated because of
the normal arteriography, the limited extension of hemorrhage, and the invariably mild clinical features at onset.4 This is supported by several case series and reports of abnormal venous structures and primitive drainages patterns associated with perimesencephalic SAH.4-6 However, there was only 1 report of 2 cases suggesting vein of Galen stenosis as an etiologic factor of perimesencephalic SAH.5 Although we could not verify the presence of venous hypertension and the causal relationship, our case strengthens the evidence linking perimesencephalic SAH with venous hypertension associated with vein of Galen stenosis. In addition, udenafil, a PDE5 inhibitor, might trigger this process in the presence of underlying venous stenosis through
NONANEURYSMAL SAH AFTER UDENAFIL INTAKE
its hemodynamic effects via PDE5 inhibition resulting in nitric oxide–dependent vascular smooth muscle cell relaxation in our case. Because this was the patient’s first time taking udenafil and because his symptoms occurred immediately after taking the drug, we postulated that there was little probability that udenafil caused the cerebral venous stenosis. Because the PDE5 isoenzyme is expressed in platelets and in the blood vessels of brain,7 udenafil could also contribute to SAH through platelet inhibition. There are several reports of cerebral hemorrhage associated other PDE5 inhibitors, such as sildenafil8 and tadalafil.9 This is the first report of SAH associated with udenafil. In conclusion, our case is the first report of NA-SAH as an adverse event caused by udenafil. It might contribute to understanding the pathophysiology of NA-SAH and suggest the potential risk of cerebral hemorrhage when taking PDE5 inhibitors.
References 1. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: A nonaneurysmal and benign
e649
2.
3.
4.
5.
6.
7.
8.
9.
form of subarachnoid hemorrhage. Neurology 1985; 35:493-497. Canovas D, Gil A, Jato M, et al. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol 2012;19:457-461. Ding H, Du W, Wang H, et al. Efficacy and safety of udenafil for erectile dysfunction: A meta-analysis of randomized controlled trials. Urology 2012;80:134-139. van der Schaaf IC, Velthuis BK, Gouw A, et al. Venous drainage in perimesencephalic hemorrhage. Stroke 2004; 35:1614-1618. Mathews MS, Brown D, Brant-Zawadzki M. Perimesencephalic nonaneurysmal hemorrhage associated with vein of Galen stenosis. Neurology 2008;70:2410-2411. Watanabe A, Hirano K, Kamada M, et al. Perimesencephalic nonaneurysmal subarachnoid haemorrhage and variations in the veins. Neuroradiology 2002;44:319-325. Lin CS, Lin G, Xin ZC, et al. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006; 12:3439-3457. Alpsan MH, Bebek N, Ciftci FD, et al. Intracerebral hemorrhage associated with sildenafil use: A case report. J Neurol 2008;255:932-933. Sheikh-Taha M, Alaywa RA. Subarachnoid hemorrhage associated with tadalafil. Am J Health Syst Pharm 2011; 68:1195-1196.
Nonaneurysmal Subarachnoid Hemorrhage after Udenafil Intake Eun-Kee Bae, MD, Jong-Hyeon Ahn, MD, and Jeong-Jin Park, MD
We report a 67-year-old man who presented with severe headache after taking 50 mg of udenafil, a new phosphodiesterase 5 inhibitor. Computed tomographic imaging of the brain revealed a small amount of acute subarachnoid hemorrhage localized around basal cisterns (anterior to midbrain and pons). There were no aneurysms in the cerebral arteries, although vein of Galen stenosis was suspected after magnetic resonance venography. This case anecdotally suggests that phosphodiesterase 5 inhibition might trigger perimesencephalic subarachnoid hemorrhage with venous hypertension possibly associated with vein of Galen stenosis. Key Words: Cerebral veins— phosphodisesterase 5 inhibitors—subarachnoid hemorrhage—udenafil. Ó 2013 by National Stroke Association
Nonaneurysmal subarachnoid hemorrhage (NA-SAH) differs from aneurysmal subarachnoid hemorrhage (SAH) in both clinical course and outcome. In spite of many reports and case series since the first description in 1985,1 the etiology of NA-SAH remains uncertain in 15% of cases with spontaneous SAH.2 Udenafil is a new oral selective phosphodiesterase 5 (PDE5) inhibitor that, like sildenafil, was developed for the treatment of erectile dysfunction.3 Although headache is one of its common side effects,3 SAH after udenafil intake has not been reported. We present a case of NA-SAH after udenafil intake with underlying vein of Galen stenosis.
Case Report A 63-year-old man with a medical history of chronic hypertension presented with severe headache after taking 50 mg of udenafil for the first time. Thirty minutes after From the Department of Neurology, Inha University Hospital, Incheon, Korea. Received February 20, 2013; revision received April 5, 2013; accepted April 6, 2013. Address correspondence to Eun-Kee Bae, MD, Department of Neurology, Inha University Hospital, 7-206, 3-Ga, Sinheung-Dong, Jung-Gu, Incheon, 400-711, Republic of Korea. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.04.002
taking the drug, he had a severe headache that was accompanied by nausea and vomiting. He did not have any focal neurologic abnormalities. He was first treated with painkillers after undergoing a noncontrast computed tomographic (CT) scan of the brain at a nearby hospital. Because his headache did not subside for 1 week, he visited our hospital. Although the initial CT scan of his brain showed high attenuation, suggesting acute hemorrhage localized around the basal cisterns (anterior to midbrain and pons; Figs 1, A and B), the follow-up brain CT scan 1 week later revealed no abnormalities (Figs 1, C and D). A magnetic resonance imaging (MRI) scan of the brain revealed hyperintensity along with the sulci of left frontal, bilateral parieto-occipital lobes and perimsencephalic space on fluid-attenuated inversion recovery (FLAIR) and a hypointense rim along the brain surface on gradient echo T2-weighted images, suggesting superficial siderosis. Brain magnetic resonance angiography (MRA) and catheter angiography revealed no arterial abnormalities, including aneurysms. However, magnetic resonance venography (MRV) revealed stenosis at the junction of the vein of Galen and the straight sinus (Fig 1, E). The opening pressure of lumbar puncture was increased to 265 mm H2O, and the gross appearance of cerebrospinal fluid (CSF) was yellow-brown (xanthochromic). CSF analysis revealed the presence of red blood cells (110/mm3) and white blood cells (30/mm3; lymphocyte-dominant). The
Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 8 (November), 2013: pp e647-e649
e647
e648
E.-K. BAE ET AL.
Figure 1. Noncontrast computed tomographic scan of the brain at symptom onset (A and B) and 1 week later (C and D). The initial computed tomographic scan revealed a small amount of acute hemorrhage localized around the basal cisterns (anterior to midbrain and pons), and this hemorrhage disappeared after 1 week. Magnetic resonance venography (E) revealed stenosis at the junction of the vein of Galen with the straight sinus (arrow).
protein content was 60 mg/dL and the glucose concentration was 69 mg/dL in the CSF. His headache subsided after 5 days of mannitol therapy, and then he discharged without any neurologic sequelae.
Discussion Idiopathic NA-SAH can be divided into 2 groups according to the bleeding pattern on CTscans of the brain: perimesencephalic and nonperimesencephalic. NA-SAH with a perimesencephalic pattern of bleeding has a benign course and excellent short- and long-term prognosis.2 A venous source of bleeding has been postulated because of
the normal arteriography, the limited extension of hemorrhage, and the invariably mild clinical features at onset.4 This is supported by several case series and reports of abnormal venous structures and primitive drainages patterns associated with perimesencephalic SAH.4-6 However, there was only 1 report of 2 cases suggesting vein of Galen stenosis as an etiologic factor of perimesencephalic SAH.5 Although we could not verify the presence of venous hypertension and the causal relationship, our case strengthens the evidence linking perimesencephalic SAH with venous hypertension associated with vein of Galen stenosis. In addition, udenafil, a PDE5 inhibitor, might trigger this process in the presence of underlying venous stenosis through
NONANEURYSMAL SAH AFTER UDENAFIL INTAKE
its hemodynamic effects via PDE5 inhibition resulting in nitric oxide–dependent vascular smooth muscle cell relaxation in our case. Because this was the patient’s first time taking udenafil and because his symptoms occurred immediately after taking the drug, we postulated that there was little probability that udenafil caused the cerebral venous stenosis. Because the PDE5 isoenzyme is expressed in platelets and in the blood vessels of brain,7 udenafil could also contribute to SAH through platelet inhibition. There are several reports of cerebral hemorrhage associated other PDE5 inhibitors, such as sildenafil8 and tadalafil.9 This is the first report of SAH associated with udenafil. In conclusion, our case is the first report of NA-SAH as an adverse event caused by udenafil. It might contribute to understanding the pathophysiology of NA-SAH and suggest the potential risk of cerebral hemorrhage when taking PDE5 inhibitors.
References 1. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: A nonaneurysmal and benign
e649
2.
3.
4.
5.
6.
7.
8.
9.
form of subarachnoid hemorrhage. Neurology 1985; 35:493-497. Canovas D, Gil A, Jato M, et al. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol 2012;19:457-461. Ding H, Du W, Wang H, et al. Efficacy and safety of udenafil for erectile dysfunction: A meta-analysis of randomized controlled trials. Urology 2012;80:134-139. van der Schaaf IC, Velthuis BK, Gouw A, et al. Venous drainage in perimesencephalic hemorrhage. Stroke 2004; 35:1614-1618. Mathews MS, Brown D, Brant-Zawadzki M. Perimesencephalic nonaneurysmal hemorrhage associated with vein of Galen stenosis. Neurology 2008;70:2410-2411. Watanabe A, Hirano K, Kamada M, et al. Perimesencephalic nonaneurysmal subarachnoid haemorrhage and variations in the veins. Neuroradiology 2002;44:319-325. Lin CS, Lin G, Xin ZC, et al. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006; 12:3439-3457. Alpsan MH, Bebek N, Ciftci FD, et al. Intracerebral hemorrhage associated with sildenafil use: A case report. J Neurol 2008;255:932-933. Sheikh-Taha M, Alaywa RA. Subarachnoid hemorrhage associated with tadalafil. Am J Health Syst Pharm 2011; 68:1195-1196.