高分辨磁共振血管壁成像技术在烟雾病中的研究进展
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摘要
烟雾病(moyamoya disease,MMD)是一种病因不明的慢性脑血管闭塞性疾病。目前诊断烟雾病的金标准是数字减影血管造影术(digital subtraction angiography,DSA),但其只能反映颅内动脉疾病的狭窄或闭塞,无法对颅内动脉疾病的血管壁进行成像。近年来,高分辨磁共振(high resolution magnetic resonance imaging,HR-MRI)的应用越来越广泛,其可以对颅内血管的管壁进行成像,已经成为烟雾病鉴别诊断的有用工具。烟雾病的高分辨磁共振研究提供了对烟雾病更深入的了解,有助于在颅内血管壁上评估其病理变化。本文对高分辨磁共振成像技术在烟雾病中的研究进展做一综述。
Moyamoya disease is an unexplained,chronic progressive cerebrovascular occlusive disease.The current gold standard for the diagnosis of moyamoya disease is digital subtraction angiography,but it can only reflect the stenosis or occlusion of intracranial artery disease,and can not image the blood vessel wall of intracranial artery disease.In recent years,the application of high-resolution magnetic resonance has become more and more extensive.It can image the wall of intracranial blood vessels and has become a useful tool for differential diagnosis of moyamoya disease.High-resolution magnetic resonance studies of moyamoya disease provide a deeper understanding of moyamoya disease and help to assess pathological changes in the intracranial vessel wall.This article reviews the research progress of high resolution magnetic resonance imaging in moyamoya disease.
Moyamoya disease is an unexplained,chronic progressive cerebrovascular occlusive disease.The current gold standard for the diagnosis of moyamoya disease is digital subtraction angiography,but it can only reflect the stenosis or occlusion of intracranial artery disease,and can not image the blood vessel wall of intracranial artery disease.In recent years,the application of high-resolution magnetic resonance has become more and more extensive.It can image the wall of intracranial blood vessels and has become a useful tool for differential diagnosis of moyamoya disease.High-resolution magnetic resonance studies of moyamoya disease provide a deeper understanding of moyamoya disease and help to assess pathological changes in the intracranial vessel wall.This article reviews the research progress of high resolution magnetic resonance imaging in moyamoya disease.
引文
[1] ESPERT R,GADEA M,ALINO M,et al.Moyamoya disease:clinical,neuroradiological,neuropsychological and genetic perspective[J].REVISTA DE NEUROLOGIA,2018,66:S57-S64.
[2] Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis.Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis)[J].Neurol Med Chir,2012,52(5):245-266.
[3] FUKUI M,KONO S,SUEISHI K,et al.Moyamoya disease[J].Neuropathology,2000,20(s1):61-64.
[4] SUZUKI J,TAKAKU A.Cerebrovascular "moyamoya" disease.Disease showing abnormal net-like vessels in base of brain[J].Arch Neurol,1969,20(3):288-299.
[5] KIM T,LEE H,BANG J S,et al.Epidemiology of Moyamoya Disease in Korea:Based on National Health Insurance Service Data[J].J Korean Neurosurg Soc,2015,57(6):390-395.
[6] LIU X,ZHANG D,WANG S,et al.Clinical features and long-term outcomes of moyamoya disease:a single-center experience with 528 cases in China[J].J Neurosurg,2015,122(2):392-399.
[7] KAZUMATA K,ITO M,UCHINO H,et al.Proposal for a Prospective Registry for Moyamoya Disease in Japan[J].Neurol Med Chir (Tokyo),2017,57(2):66-72.
[8] DUAN L,BAO X Y,YANG W Z,et al.Moyamoya disease in China:its clinical features and outcomes[J].Stroke,2012,43(1):56-60.
[9] BABA T,HOUKIN K,KURODA S.Novel epidemiological features of moyamoya disease[J].J Neurol Neurosurg Psychiatry,2008,79(8):900-904.
[10] LEE S,RIVKIN M J,KIRTON A,et al.Moyamoya Disease in Children:Results From the International Pediatric Stroke Study[J].J Child Neurol,2017,32(11):924-929.
[11] BANG O Y,RYOO S,KIM S J,et al.Adult Moyamoya Disease:A Burden of Intracranial Stenosis in East Asians?[J].PLoS One,2015,10(6):e130663.
[12] MORIOKA M,HAMADA J,KAWANO T,et al.Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are predictors of hemorrhage in adult moyamoya patients[J].Stroke,2003,34(1):90-95.
[13] KIM J S.Moyamoya Disease:Epidemiology,Clinical Features,and Diagnosis[J].J Stroke,2016,18(1):2-11.
[14] TAN H W,CHEN X,MAINGARD J,et al.Intracranial Vessel Wall Imaging with Magnetic Resonance Imaging:Current Techniques and Applications[J].World Neurosurg,2018,112:186-198.
[15] PINHO M C,HALL J T,CROSS J C,et al.Intracranial Vessel Wall MRI in Clinical Practice:Technical Considerations,Current and Emerging Applications,and Clinical Pearls and Pitfalls[J].Neurographics,2018,8(2):97-118.
[16] 娄昕,姜卫剑,马林,等.重度颅内动脉狭窄活体高分辨磁共振成像初探[J].中华内科杂志,2008,47(6):478-481.
[17] 李树合,周定标,娄昕,等.高分辨MRI对颈动脉粥样硬化斑块成分显示的病理对照研究[J].中华神经外科杂志,2007,23(7):38-40.
[18] PUPPINI G,FURLAN F,CIROTA N,et al.Characterisation of carotid atherosclerotic plaque:comparison between magnetic resonance imaging and histology[J].Radiol Med,2006,111(7):921-930.
[19] BHATTI L,HOANG J K,DALE B M,et al.Advanced magnetic resonance techniques:3 T[J].Radiol Clin North Am,2015,53(3):441-455.
[20] SWARTZ R H,BHUTA S S,FARB R I,et al.Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI[J].Neurology,2009,72(7):627-634.
[21] MUGLER J R.Optimized three-dimensional fast-spin-echo MRI[J].J Magn Reson Imaging,2014,39(4):745-767.
[22] TAKAGI Y,KIKUTA K,NOZAKI K,et al.Histological features of middle cerebral arteries from patients treated for Moyamoya disease[J].Neurol Med Chir (Tokyo),2007,47(1):1-4.
[23] CHMELOVA J,KOLAR Z,PROCHAZKA V,et al.Moyamoya disease is associated with endothelial activity detected by anti-nestin antibody[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2010,154(2):159-162.
[24] LIN R,XIE Z,ZHANG J,et al.Clinical and immunopathological features of Moyamoya disease[J].PLoS One,2012,7(4):e36386.
[25] MASUDA J,OGATA J,YUTANI C.Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moy amoya disease[J].Stroke,1993,24(12):1 960-1 967.
[26] TAKEKAWA Y,UMEZAWA T,UENO Y,et al.Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease[J].Neuropathology,2004,24(3):236-242.
[27] HOUKIN K,YOSHIMOTO T,ABE H,et al.Role of basic fibroblast growth factor in the pathogenesis of moyamoya disease[J].Neurosurg Focus,1998,5(5):e2.
[28] KAKU Y,MORIOKA M,OHMORI Y,et al.Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image:is arterial constrictive remodeling a major pathogenesis?[J].Acta Neurochir (Wien),2012,154(12):2 151-2 157.
[29] SCHOENHAGEN P,ZIADA K M,KAPADIA S R,et al.Extent and direction of arterial remodeling in stable versus unstable coronary syndromes:an intravascular ultrasound study[J].Circulation,2000,101(6):598-603.
[30] XU W,LI M,GAO S,et al.In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis[J].Atherosclero-sis,2010,212(2):507-511.
[31] RYU C W,JAHNG G H,KIM E J,et al.High resolution wall and lumen MRI of the middle cerebral arteries at 3 tesla[J].Cerebrovasc Dis,2009,27(5):433-442.
[32] CHUNG G H,KWAK H S,HWANG S B,et al.High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis[J].European Journal of Radiology,2012,81(12):4 069-4 074.
[33] KAKU Y,MORIOKA M,OHMORI Y,et al.Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image:is arterial constrictive remodeling a major pathogenesis?[J].Acta Neurochir (Wien),2012,154(12):2 151-2 157.
[34] AOKI S,HAYASHI N,ABE O,et al.Radiation-induced Arteritis:Thickened Wall with Prominent Enhancement on Cranial MR Images—Report of Five Cases and Comparison with 18 Cases of Moyamoya Disease[J].Radiology,2002,223(3):683-688.
[35] RYOO S,CHA J,KIM S J,et al.High-Resolution Magnetic Resonance Wall Imaging Findings of Moyamoya Disease[J].Stroke,2014,45(8):2 457-2 460.
[36] KIM Y J,LEE D H,KWON J Y,et al.High resolution MRI difference between moyamoya disease and intracranial atherosclerosis[J].European Journal of Neurology,2013,20(9):1 311-1 318.
[37] MOSSA-BASHA M,DE HAVENON A,BECKER K J,et al.Added Value of Vessel Wall Magnetic Resonance Imaging in the Differentiation of Moyamoya Vasculopathies in a Non-Asian Cohort[J].Stroke,2016,47(7):1 782-1 788.
[38] WASSERMAN B A.Advanced contrast-enhanced MRI for looking beyond the lumen to predict stroke:building a risk profile for carotid plaque[J].Stroke,2010,41(10 Suppl):S12-S16.
[39] KERWIN W S,O'BRIEN K D,FERGUSON M S,et al.Inflammation in carotid atherosclerotic plaque:a dynamic contrast-enhanced MR imaging study[J].Radiology,2006,241(2):459-468.
[40] EDJLALI M,GENTRIC J C,REGENT-RODRIGUEZ C,et al.Does aneurysmal wall enhancement on vessel wall MRI help to distinguish stable from unstable intracranial aneurysms?[J].Stroke,2014,45(12):3 704-3 706.
[41] SLUIMER J C,KOLODGIE F D,BIJNENS A P,et al.Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage[J].J Am Coll Cardiol,2009,53(17):1 517-1 527.
[42] CHEN X Y,WONG K S,LAM W W M,et al.Middle Cerebral Artery Atherosclerosis:Histological Comparison between Plaques Associated with and Not Associated with Infarct in a Postmortem Study[J].Cerebrovascular Diseases,2008,25(1/2):74-80.
[43] LARSEN N,VON DER BRELIE C,TRICK D,et al.Vessel Wall Enhancement in Unruptured Intracranial Aneurysms:An Indicator for Higher Risk of Rupture?High-Resolution MR Imaging and Correlated Histologic Findings[J].American Journal of Neuroradiology,2018,39(9):1 617-1 621.
[44] BLEY T A,UHL M,VENHOFF N,et al.3-T MRI reveals cranial and thoracic inflammatory changes in giant cell arteritis[J].Clinical Rheumatology,2007,26(3):448-450.
[45] QIAO Y,ETESAMI M,ASTOR B C,et al.Carotid Plaque Neovascularization and Hemorrhage Detected by MR Imaging are Associated with Recent Cerebrovascular Ischemic Events[J].Am J Neuroradiol,2012,33(4):755-760.
[46] LIM M,CHESHIER S,STEINBERG G K.New vessel formation in the central nervous system during tumor growth,vascular malformations,and Moyamoya[J].Curr Neurovasc Res,2006,3(3):237-245.
[47] QIAO Y,ZEILER S R,MIRBAGHERI S,et al.Intracranial Plaque Enhancement in Patients with Cerebrovascular Events on High-Spatial-Resolution MR Images[J].Radiology,2014,271(2):534-542.
[48] SKARPATHIOTAKIS M,MANDELL D M,SWARTZ R H,et al.Intracranial Atherosclerotic Plaque Enhance-ment in Patients with Ischemic Stroke[J].Am J Neuroradiol,2013,34(2):299-304.
[49] WANG M,YANG Y,ZHOU F,et al.The Contrast Enhancement of Intracranial Arterial Wall on High-resolution MRI and Its Clinical Relevance in Patients with Moyamoya Vasculopathy[J].Scientific Reports,2017,7:44 264.
[50] MURAOKA S,ARAKI Y,TAOKA T,et al.Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy:Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging[J].World Neurosurg,2018,116:1 114-1 121.
[51] DIELEMAN N,VAN DER KOLK A G,ZWANENBURG J J,et al.Imaging intracranial vessel wall pathology with magnetic resonance imaging:current prospects and future directions[J].Circulation,2014,130(2):192-201.
[2] Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis.Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis)[J].Neurol Med Chir,2012,52(5):245-266.
[3] FUKUI M,KONO S,SUEISHI K,et al.Moyamoya disease[J].Neuropathology,2000,20(s1):61-64.
[4] SUZUKI J,TAKAKU A.Cerebrovascular "moyamoya" disease.Disease showing abnormal net-like vessels in base of brain[J].Arch Neurol,1969,20(3):288-299.
[5] KIM T,LEE H,BANG J S,et al.Epidemiology of Moyamoya Disease in Korea:Based on National Health Insurance Service Data[J].J Korean Neurosurg Soc,2015,57(6):390-395.
[6] LIU X,ZHANG D,WANG S,et al.Clinical features and long-term outcomes of moyamoya disease:a single-center experience with 528 cases in China[J].J Neurosurg,2015,122(2):392-399.
[7] KAZUMATA K,ITO M,UCHINO H,et al.Proposal for a Prospective Registry for Moyamoya Disease in Japan[J].Neurol Med Chir (Tokyo),2017,57(2):66-72.
[8] DUAN L,BAO X Y,YANG W Z,et al.Moyamoya disease in China:its clinical features and outcomes[J].Stroke,2012,43(1):56-60.
[9] BABA T,HOUKIN K,KURODA S.Novel epidemiological features of moyamoya disease[J].J Neurol Neurosurg Psychiatry,2008,79(8):900-904.
[10] LEE S,RIVKIN M J,KIRTON A,et al.Moyamoya Disease in Children:Results From the International Pediatric Stroke Study[J].J Child Neurol,2017,32(11):924-929.
[11] BANG O Y,RYOO S,KIM S J,et al.Adult Moyamoya Disease:A Burden of Intracranial Stenosis in East Asians?[J].PLoS One,2015,10(6):e130663.
[12] MORIOKA M,HAMADA J,KAWANO T,et al.Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are predictors of hemorrhage in adult moyamoya patients[J].Stroke,2003,34(1):90-95.
[13] KIM J S.Moyamoya Disease:Epidemiology,Clinical Features,and Diagnosis[J].J Stroke,2016,18(1):2-11.
[14] TAN H W,CHEN X,MAINGARD J,et al.Intracranial Vessel Wall Imaging with Magnetic Resonance Imaging:Current Techniques and Applications[J].World Neurosurg,2018,112:186-198.
[15] PINHO M C,HALL J T,CROSS J C,et al.Intracranial Vessel Wall MRI in Clinical Practice:Technical Considerations,Current and Emerging Applications,and Clinical Pearls and Pitfalls[J].Neurographics,2018,8(2):97-118.
[16] 娄昕,姜卫剑,马林,等.重度颅内动脉狭窄活体高分辨磁共振成像初探[J].中华内科杂志,2008,47(6):478-481.
[17] 李树合,周定标,娄昕,等.高分辨MRI对颈动脉粥样硬化斑块成分显示的病理对照研究[J].中华神经外科杂志,2007,23(7):38-40.
[18] PUPPINI G,FURLAN F,CIROTA N,et al.Characterisation of carotid atherosclerotic plaque:comparison between magnetic resonance imaging and histology[J].Radiol Med,2006,111(7):921-930.
[19] BHATTI L,HOANG J K,DALE B M,et al.Advanced magnetic resonance techniques:3 T[J].Radiol Clin North Am,2015,53(3):441-455.
[20] SWARTZ R H,BHUTA S S,FARB R I,et al.Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI[J].Neurology,2009,72(7):627-634.
[21] MUGLER J R.Optimized three-dimensional fast-spin-echo MRI[J].J Magn Reson Imaging,2014,39(4):745-767.
[22] TAKAGI Y,KIKUTA K,NOZAKI K,et al.Histological features of middle cerebral arteries from patients treated for Moyamoya disease[J].Neurol Med Chir (Tokyo),2007,47(1):1-4.
[23] CHMELOVA J,KOLAR Z,PROCHAZKA V,et al.Moyamoya disease is associated with endothelial activity detected by anti-nestin antibody[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2010,154(2):159-162.
[24] LIN R,XIE Z,ZHANG J,et al.Clinical and immunopathological features of Moyamoya disease[J].PLoS One,2012,7(4):e36386.
[25] MASUDA J,OGATA J,YUTANI C.Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moy amoya disease[J].Stroke,1993,24(12):1 960-1 967.
[26] TAKEKAWA Y,UMEZAWA T,UENO Y,et al.Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease[J].Neuropathology,2004,24(3):236-242.
[27] HOUKIN K,YOSHIMOTO T,ABE H,et al.Role of basic fibroblast growth factor in the pathogenesis of moyamoya disease[J].Neurosurg Focus,1998,5(5):e2.
[28] KAKU Y,MORIOKA M,OHMORI Y,et al.Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image:is arterial constrictive remodeling a major pathogenesis?[J].Acta Neurochir (Wien),2012,154(12):2 151-2 157.
[29] SCHOENHAGEN P,ZIADA K M,KAPADIA S R,et al.Extent and direction of arterial remodeling in stable versus unstable coronary syndromes:an intravascular ultrasound study[J].Circulation,2000,101(6):598-603.
[30] XU W,LI M,GAO S,et al.In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis[J].Atherosclero-sis,2010,212(2):507-511.
[31] RYU C W,JAHNG G H,KIM E J,et al.High resolution wall and lumen MRI of the middle cerebral arteries at 3 tesla[J].Cerebrovasc Dis,2009,27(5):433-442.
[32] CHUNG G H,KWAK H S,HWANG S B,et al.High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis[J].European Journal of Radiology,2012,81(12):4 069-4 074.
[33] KAKU Y,MORIOKA M,OHMORI Y,et al.Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image:is arterial constrictive remodeling a major pathogenesis?[J].Acta Neurochir (Wien),2012,154(12):2 151-2 157.
[34] AOKI S,HAYASHI N,ABE O,et al.Radiation-induced Arteritis:Thickened Wall with Prominent Enhancement on Cranial MR Images—Report of Five Cases and Comparison with 18 Cases of Moyamoya Disease[J].Radiology,2002,223(3):683-688.
[35] RYOO S,CHA J,KIM S J,et al.High-Resolution Magnetic Resonance Wall Imaging Findings of Moyamoya Disease[J].Stroke,2014,45(8):2 457-2 460.
[36] KIM Y J,LEE D H,KWON J Y,et al.High resolution MRI difference between moyamoya disease and intracranial atherosclerosis[J].European Journal of Neurology,2013,20(9):1 311-1 318.
[37] MOSSA-BASHA M,DE HAVENON A,BECKER K J,et al.Added Value of Vessel Wall Magnetic Resonance Imaging in the Differentiation of Moyamoya Vasculopathies in a Non-Asian Cohort[J].Stroke,2016,47(7):1 782-1 788.
[38] WASSERMAN B A.Advanced contrast-enhanced MRI for looking beyond the lumen to predict stroke:building a risk profile for carotid plaque[J].Stroke,2010,41(10 Suppl):S12-S16.
[39] KERWIN W S,O'BRIEN K D,FERGUSON M S,et al.Inflammation in carotid atherosclerotic plaque:a dynamic contrast-enhanced MR imaging study[J].Radiology,2006,241(2):459-468.
[40] EDJLALI M,GENTRIC J C,REGENT-RODRIGUEZ C,et al.Does aneurysmal wall enhancement on vessel wall MRI help to distinguish stable from unstable intracranial aneurysms?[J].Stroke,2014,45(12):3 704-3 706.
[41] SLUIMER J C,KOLODGIE F D,BIJNENS A P,et al.Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage[J].J Am Coll Cardiol,2009,53(17):1 517-1 527.
[42] CHEN X Y,WONG K S,LAM W W M,et al.Middle Cerebral Artery Atherosclerosis:Histological Comparison between Plaques Associated with and Not Associated with Infarct in a Postmortem Study[J].Cerebrovascular Diseases,2008,25(1/2):74-80.
[43] LARSEN N,VON DER BRELIE C,TRICK D,et al.Vessel Wall Enhancement in Unruptured Intracranial Aneurysms:An Indicator for Higher Risk of Rupture?High-Resolution MR Imaging and Correlated Histologic Findings[J].American Journal of Neuroradiology,2018,39(9):1 617-1 621.
[44] BLEY T A,UHL M,VENHOFF N,et al.3-T MRI reveals cranial and thoracic inflammatory changes in giant cell arteritis[J].Clinical Rheumatology,2007,26(3):448-450.
[45] QIAO Y,ETESAMI M,ASTOR B C,et al.Carotid Plaque Neovascularization and Hemorrhage Detected by MR Imaging are Associated with Recent Cerebrovascular Ischemic Events[J].Am J Neuroradiol,2012,33(4):755-760.
[46] LIM M,CHESHIER S,STEINBERG G K.New vessel formation in the central nervous system during tumor growth,vascular malformations,and Moyamoya[J].Curr Neurovasc Res,2006,3(3):237-245.
[47] QIAO Y,ZEILER S R,MIRBAGHERI S,et al.Intracranial Plaque Enhancement in Patients with Cerebrovascular Events on High-Spatial-Resolution MR Images[J].Radiology,2014,271(2):534-542.
[48] SKARPATHIOTAKIS M,MANDELL D M,SWARTZ R H,et al.Intracranial Atherosclerotic Plaque Enhance-ment in Patients with Ischemic Stroke[J].Am J Neuroradiol,2013,34(2):299-304.
[49] WANG M,YANG Y,ZHOU F,et al.The Contrast Enhancement of Intracranial Arterial Wall on High-resolution MRI and Its Clinical Relevance in Patients with Moyamoya Vasculopathy[J].Scientific Reports,2017,7:44 264.
[50] MURAOKA S,ARAKI Y,TAOKA T,et al.Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy:Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging[J].World Neurosurg,2018,116:1 114-1 121.
[51] DIELEMAN N,VAN DER KOLK A G,ZWANENBURG J J,et al.Imaging intracranial vessel wall pathology with magnetic resonance imaging:current prospects and future directions[J].Circulation,2014,130(2):192-201.