ARTICLE IN PRESS Case Studies Tacrolimus-Induced Reversible Cerebral Vasoconstriction Syndrome with Delayed Multi-Segmental Vasoconstriction Satoshi Kodama, MD,* Tatsuo Mano, MD, PhD,* Akihiro Masuzawa, MD,† Yasutaka Hirata, MD, PhD,† Yuki Nagasako, MD,* Kagari Koshi Mano, MD,* Masashi Hamada, MD, PhD,* Yasuo Terao, MD, PhD,* Toshihiro Hayashi, MD, PhD,* Minoru Ono, MD, PhD,† and Shoji Tsuji, MD, PhD* Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve. Key Words: Vasoconstriction—stroke—subarachnoid hemorrhage—magnetic resonance imaging—angiography—calcineurin inhibitor. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. From the *Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and †Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Received January 8, 2017; revision received February 6, 2017; accepted March 3, 2017. Consent for publication: The patient’s legal guardian provided consent for publication. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Tatsuo Mano, MD, PhD, Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: tatsuomano@ gmail.com. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.03.006 Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by transient multi-segmental constrictions of the cerebral arteries.1,2 Its main symptoms are characteristic thunderclap headaches accompanied by various neurological complications resulting from ischemic and hemorrhagic strokes.3 We describe a patient with tacrolimus-induced RCVS who had delayed progression of cerebral vasoconstrictions despite improvement of her symptoms. This case may provide valuable insights into the pathophysiology and management of this condition. Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■ 1 ARTICLE IN PRESS S. KODAMA ET AL. 2 Case Report A 15-year-old girl, who underwent orthotropic heart transplantation for dilated cardiomyopathy 8 days before, presented with a generalized seizure. She had no medical history other than cardiac failure, including stroke or mi- graine, and her postoperative course had been uneventful until the seizure. She was taking methylprednisolone 20 mg, tacrolimus 4 mg, and mycophenolate mofetil 500 mg per day for prophylaxis of rejection of the transplanted heart; and diltiazem 100 mg, enalapril 2.5 mg, bisoprolol 1.25 mg, furosemide 20 mg, and spironolactone 25 mg as well for Figure 1. (A) Electroencephalogram on day 1 demonstrating the epileptic focus in the left parietal region. (B) Head computed tomography (CT) performed immediately after symptom onset showing a thin subarachnoid hemorrhage (arrowheads). Enlarged view of the lesion was shown in the right panel. (C, D) Magnetic resonance imaging (MRI) performed 2 hours after symptom onset showing cortical hyperintensity lesions in both medial parietal lobes on the fluid-attenuated inversion recovery image (C) and a thin subarachnoid hemorrhage (arrowheads) at the right parietal convexity on the T2-weighted MRI image (D). (E-G) Magnetic resonance angiograms with vasoconstrictions in the cerebral arteries (arrowheads) 2 hours after symptom onset (E), on day 3 (F), and on day 11 (G). Multi-segmental vasoconstrictions were limited to the left posterior cerebral artery at the onset (E), spread throughout the cerebral arteries including the bilateral anterior cerebral arteries (A1 segment), middle cerebral arteries (M1, M2 segments), without involvement of basilar and vertebral arties on day 3 (F). These vasoconstrictions had completely disappeared on day 11 (G). ARTICLE IN PRESS RCVS WITH DELAYED VASOCONSTRICTION cardiac failure. The seizure initiated from the right leg without headache, vomiting, or visual disturbance, to become immediately generalized, which promptly relieved after intravenous administration of diazepam. At the onset of the seizure, her blood pressure was 165/ 65 mm Hg, and neurological examination revealed right Babinski sign, which was considered to be due to Todd’s paralysis. She had no thunderclap headache. The electroencephalogram demonstrated an epileptic focus (Fig 1, A). Head computed tomography showed a thin subarachnoid hemorrhage (SAH) on the left convexity (Fig 1, B). Using magnetic resonance imaging (day 1, 2 hours after the seizure), we observed hyperintensity lesions bilaterally in the medial parietal lobe on the fluidattenuated inversion recovery image (Fig 1, C) and SAH was also confirmed on the T2-weighted image (Fig 1, D). A few focal vasoconstrictions suggestive of RCVS were detected using magnetic resonance angiography (Fig 1, E). On therapeutic drug monitoring, the serum concentration of tacrolimus sharply increased to 16.2 ng/mL (target range 10-15 ng/mL) from 6.3 ng/mL on the day of the seizure; thus, tacrolimus was likely the cause of RCVS. Although the discontinuation of tacrolimus resulted in improvement of her neurological conditions, multisegmental vasoconstrictions spread throughout the cerebral arteries bilaterally on day 3 (Fig 1, F). Diltiazem, which was initially administered for cardiac failure preoperatively, was continued as a vasodilator; the vasoconstrictions disappeared on day 11 (Fig 1, G). Discussion The onset of RCVS in this case coincided with the rapid increase in the serum tacrolimus concentration, which strongly suggested tacrolimus as the cause. Calcineurin inhibitors can injure endothelial cells of the cerebral arteries,4 which may be a potential triggering factor for RCVS.5-7 Additionally, they may induce vascular inflammation through toll-like receptor 4 signaling.8 Previous studies have demonstrated that 21% of patients had normal initial magnetic resonance angiography findings,3 and cerebral vasoconstrictions reached their 3 maximum at an average of 16 days after symptom onset.9 Ducros et al hypothesized that the initial vasospastic condition starts in small distal arteries, which induces seizure, brain edema, and SAH, and progresses to mediumsized and large arteries, leading to ischemic stroke.3 Vasoconstriction may progress despite clinical improvement, suggesting that it is important to consider the administration of vasodilating agents to prevent further worsening of clinical symptoms.10 References 1. Miller TR, Shivashankar R, Mossa-Basha M, et al. 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