Barkhof, F

Golay, X

Haller, S

Lovblad, K-O

Thomas, D

Zaharchuk, G

UCL Discovery

FULL TITLE PAGE Manuscript title Acetazolamide arterial spin labeling to estimate cerebrovascular reserve in Moyamoya disease and syndrome  Manuscript type Response  Authors Sven HALLER1,2,3,4, Frederik BARKHOF5,6,7, David THOMAS8, Karl-Olof LOVBLAD9, Xavier GOLAY8, Greg ZAHARCHUK10,  Affiliations 1 Affidea Centre de Diagnostic Radiologique de Carouge CDRC, Geneva, Switzerland 2 Faculty of Medicine of the University of Geneva, Switzerland 3 Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden 4 Department of Neuroradiology, University Hospital Freiburg, Germany 5 Neuroradiological Academic Unit, Dept of Brain Repair and Rehabilitation, Institute of Neurology UCL, London, UK 6 Dept of  Healthcare Engineering, UCL, London, UK 7 Dept of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, NL 8 Institute of Neurology, University College Hospital, London, UK  9 Neuroradiology, University Hospitals Geneva, Switzerland 10 Stanford University, Stanford, CA 94305-5488  Word count  Manuscript   351 Figures:    0 Tables:   0 References:   11  Disclosure No conflicts of interest   Corresponding authors Prof. Dr. M.Sc. Sven Haller Service neuro-diagnostique et neuro-interventionnel DISIM University Hospitals of Geneva Rue Gabrielle Perret-Gentil 4 1211 Geneva 14 Email : sven.haller@hcuge.ch Tel. +41 (0) 22 37 23311; Fax +41 (0) 22 37 27072   Acetazolamide arterial spin labeling to estimate cerebrovascular reserve in Moyamoya disease and syndrome  We thank Dr. Mugikura and colleagues for their interest.  We agree with them that, like any medical intervention, acetazolamide administration is associated with risk, which must be interpreted relative to benefit. However, it is important to point out that this risk is small. Mugikura et al. in a prior letter (1) cite Japanese literature suggesting that acetazolamide was related to 6 fatalities in 400,000 to 600,000 administrations (0.001 -0.0015%) (2, 3). For reference, the estimated lifetime-adjusted cancer risk from radiation administered during a brain single photon emission tomography (SPECT) examination is at least 100 times greater (4). The only study examining acetazolamide risk in English reported no adverse events in > 1000 studies (5). A more recent study examining MR diffusion changes following acetazolamide in a small cohort of Moyamoya patients could not detect any deleterious effects (6).  In Moyamoya, the most common surgical treatment is external carotid – internal carotid (EC-IC) bypass, a complex procedure with non-negligible risk. Cerebrovascular reserve (CVR) assessment might inform on the optimal timing for surgery (7–9). In this context, where a low-risk diagnostic test identifies patients who may benefit from a higher risk surgical intervention, the risk–benefit ratio is likely justified. If CVR studies are performed, our article highlights that using arterial spin labeling (ASL) MRI instead of SPECT and PET will reduce cancer risk by avoiding the need for radioactivity.  Alternative approaches to acetazolamide for CVR are currently being evaluated. These include breath-holding and carbon dioxide inhalation, and have frequently used blood oxygenation-level dependent (BOLD) as a surrogate CVR marker (10, 11). These approaches can be hard to implement and require patient compliance levels not necessary for acetazolamide studies.  Finally, the authors suggest indirectly assessing CVR using contrast-perfusion MRI or the ‘ivy sign’ on fluid-attenuated inversion recovery (FLAIR). While interesting, this has limitations. We suggest considering ASL instead of GD enhanced MR perfusion, which might avoid the need of repetitive contrast injections. Evaluating the ‘ivy sign’ does not require contrast, but is qualitative and has not been directly compared to CVR.  These alternatives to acetazolamide CVR testing hold promise, but must still be validated in larger cohorts.  References 1. Mugikura S, Fujimura M, & Takahashi S. (2016). Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan. (279(2)). Departments of Diagnostic Radiology * and. Neurosurgery, † Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan 980-8574. Departments of Diagnostic Radiology * and. 2. Emergency warnings of the serious adverse effects of intravenous acetazolamide (diamox) administration [in Japanese]. (Japan Stroke Society, Japan Neurosurgical Society, Japanese Society of Neurology, and Japanese Society of Nuclear Medicine). Available from: https://www.neurology-jp.org/news/pdf/news_20140618_01_01.pdf. 3. Guideline of the adequate use of intravenous acetazolamide administration [in Japanese]. Joint Committee on the Adequate Use of Intravenous Acetazolamide (diamox) Administration (Japan Stroke Society, Japan Neurosurgical Society, Japanese Society of Neurology, and Japanese Society of Nuclear Medicine). Available from: http://www. jsts.gr.jp/img/acetazolamide.pdf. 4. Brix G, Nekolla EA, Borowski M et al. Radiation risk and protection of patients in clinical SPECT/CT. Eur J Nucl Med Mol Imaging 2014; 41 Suppl 1S125-36. 5. Piepgras A, Schmiedek P, Leinsinger G et al. A simple test to assess cerebrovascular reserve capacity using transcranial Doppler sonography and acetazolamide. Stroke 1990; 21(9):-1306-1311. 6. Federau C, Christensen S, Zun Z et al. Cerebral blood flow, transit time, and apparent diffusion coefficient in moyamoya disease before and after acetazolamide. Neuroradiology 2017; 59(1):-5-12. 7. Conklin J, Fierstra J, Crawley AP et al. Impaired cerebrovascular reactivity with steal phenomenon is associated with increased diffusion in white matter of patients with Moyamoya disease. Stroke 2010; 41(8):-1610-1616. 8. Kang KH, Kim HS, & Kim SY. Quantitative cerebrovascular reserve measured by acetazolamide-challenged dynamic CT perfusion in ischemic adult Moyamoya disease: initial experience with angiographic correlation. AJNR Am J Neuroradiol 2008; 29(8):-1487-1493. 9. Antonucci MU, Burns TC, Pulling TM et al. Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease. AJNR Am J Neuroradiol 2016; 37(2):-228-235. 10. Pellaton A, Bijlenga P, Bouchez L et al. CO2BOLD assessment of moyamoya syndrome: Validation with single photon emission computed tomography and positron emission tomography imaging. World J Radiol 2016; 8(11):-887-894. 11. Su P, Mao D, Liu P et al. Multiparametric estimation of brain hemodynamics with MR fingerprinting ASL. Magn Reson Med 2016;   

Further Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan Response

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Further Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan Response

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