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  • br Conclusions br Statement of authorship br Nonaneurysmal


    Statement of authorship
    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, the etiology of NA-SAH remains uncertain in 15% of cases with spontaneous SAH. Udenafil is a new oral selective phosphodiesterase 5 (PDE5) inhibitor that, like sildenafil, was developed for the treatment of erectile dysfunction. Although headache is one of its common side effects, 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 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 LDN-212854 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 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 CT scans 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. 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. This is supported by several case series and reports of abnormal venous structures and primitive drainages patterns associated with perimesencephalic SAH.4, 5, 6 However, there was only 1 report of 2 cases suggesting vein of Galen stenosis as an etiologic factor of perimesencephalic SAH. 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 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, udenafil could also contribute to SAH through platelet inhibition. There are several reports of cerebral hemorrhage associated other PDE5 inhibitors, such as sildenafil and tadalafil. 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.