De Novo Cerebral Microbleeds and Cognitive Decline in Cerebral Hyperperfusion After Direct Revascularization for Adult Moyamoya Disease



      Adult patients with moyamoya disease (MMD) occasionally develop cognitive decline due to cerebral hyperperfusion following direct revascularization surgery. However, how the hyperperfusion phenomenon contributes to declines in cognitive function remains unclear. The present supplementary analysis of a prospective study aimed to determine whether cerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion leads to development of de novo cerebral microbleeds (CMBs) and whether postoperative cognitive decline is related to these CMBs.

      Materials and Methods

      In total, 32 patients who underwent direct revascularization surgery also underwent T2*-weighted magnetic resonance imaging (T2*WI) and neuropsychological testing before and 2 months after surgery. Development of cerebral hyperperfusion and hyperperfusion syndrome following surgery was defined based on brain perfusion single-photon emission computed tomography (SPECT) findings and clinical symptoms.


      Cerebral hyperperfusion on brain perfusion SPECT (95% confidence interval [CI], 1.1–10.8; p = 0.0175) or cerebral hyperperfusion syndrome (95%CI, 1.3–15.3; p = 0.0029) was significantly associated with postoperatively increased CMBs on T2*WI. Postoperatively increased CMBs were significantly associated with postoperative cognitive decline (95%CI, 1.8–20.4, p = 0.0041). For patients with cerebral hyperperfusion on brain perfusion SPECT, the incidence of postoperative cognitive decline was significantly greater in patients with than in those without postoperatively increased CMBs (p = 0.0294).


      Cerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion contributes to the development of de novo CMBs and postoperative cognitive decline is related to these CMBs.

      Key Words

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        • Suzuki J
        • Takaku A.
        Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain.
        Arch Neurol. 1969; 20: 288-299
      1. Research Committee on the Pathology and treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Intractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (Spontaneous occlusion of the circle of Willis).
        Neurol Med Chir (Tokyo). 2012; 52: 245-266
        • Fujimura M
        • Tominaga T.
        Current status of revascularization surgery for moyamoya disease: special consideration for its ‘internal carotid-external carotid (IC-EC) conversion’ as the physiological reorganization system.
        Tohoku J Exp Med. 2015; 236: 45-53
        • Guzman R
        • Lee M
        • Achrol A
        • et al.
        Clinical outcome after 450 revascularization procedures for moyamoya disease.
        J Neurosurg. 2009; 111: 927-935
        • Miyoshi K
        • Chida K
        • Kobayashi M
        • et al.
        Two-year clinical, cerebral hemodynamic, and cognitive outcomes of adult patients undergoing medication alone for symptomatically ischemic moyamoya disease without cerebral misery perfusion: A prospective cohort study.
        Neurosurgery. 2019; 84: 1233-1241
        • Narisawa A
        • Fujimura M
        • Tominaga T.
        Efficacy of the revascularization surgery for adult-onset moyamoya disease with the progression of cerebrovascular lesions.
        Clin Neurol Neurosurg. 2009; 111: 123-126
        • Lai PMR
        • Patel NJ
        • Frerichs KU
        • et al.
        Direct vs indirect revascularization in a North American cohort of moyamoya disease.
        Neurosurgery. 2021; 89: 315-322
        • Lee SB
        • Kim DS
        • Huh PW
        • et al.
        Long-term follow-up results in 142 adult patients with moyamoya disease according to management modality.
        Acta Neurochir (Wien). 2012; 154: 1179-1187
        • Zeifert PD
        • Karzmark P
        • Bell-Stephens T
        • et al.
        Neurocognitive performance after cerebral revascularization in adult moyamoya disease.
        Stroke. 2017; 48: 1514-1517
        • Yanagihara W
        • Chida K
        • Kobayashi M
        • et al.
        Impact of cerebral blood flow changes due to arterial bypass surgery on cognitive function in adult patients with symptomatic ischemic moyamoya disease.
        J Neurosurg. 2018; 131: 1716-1724
        • Ogasawara K
        • Komoribayashi N
        • Kobayashi M
        • et al.
        Neural damage caused by cerebral hyperperfusion after arterial bypass surgery in a patient with moyamoya disease: case report.
        Neurosurgery. 2005; 56: E1380
        • Shimada Y
        • Kojima D
        • Yoshida J
        • et al.
        Transient symptomatic downregulation of cortical neurotransmitterreceptor function due to cerebral hyperperfusion after arterial bypass surgery for a patient with ischemic moyamoya disease.
        Neurol Med Chir (Tokyo). 2018; 58: 481-484
        • Gustavsson AM
        • Stomrud E
        • Abul-Kasim K
        • et al.
        Cerebral microbleeds and white matter hyperintensities in cognitively healthy elderly: a cross-sectional cohort study evaluating the effect of arterial stiffness.
        Cerebrovasc Dis Extra. 2015; 5: 41-51
        • Mackey J
        • Wing JJ
        • Norato G
        • et al.
        High rate of microbleed formation following primary intracerebral hemorrhage.
        Int J Stroke. 2015; 10: 1187-1191
        • Wilson D
        • Charidimou A
        • Ambler G
        • et al.
        Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: a meta-analysis.
        Neurology. 2016; 87: 1501-1510
        • Werring DJ
        • Frazer DW
        • Coward LJ
        • et al.
        Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI.
        Brain. 2004; 127: 2265-2275
        • Fazekas F
        • Kleinert R
        • Roob G
        • et al.
        Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds.
        AJNR Am J Neuroradiol. 1999; 20: 637-642
        • Ishikawa T
        • Kuroda S
        • Nakayama N
        • et al.
        Prevalence of asymptomatic microbleeds in patients with moyamoya disease.
        Neurol Med Chir (Tokyo). 2005; 45: 495-500
        • Kikuta K
        • Takagi Y
        • Nozaki K
        • et al.
        Asymptomatic microbleeds in moyamoya disease: T2*-weighted gradient-echo magnetic resonance imaging study.
        J Neurosurg. 2005; 102: 470-475
        • Kikuta K
        • Takagi Y
        • Nozaki K
        • et al.
        The presence of multiple microbleeds as a predictor of subsequent cerebral hemorrhage in patients with moyamoya disease.
        Neurosurgery. 2008; 62: 104-111
        • Kuroda S
        • Kashiwazaki D
        • Ishikawa T
        • et al.
        Incidence, locations, and longitudinal course of silent microbleeds in moyamoya disease: a prospective T2*-weighted MRI study.
        Stroke. 2013; 44: 516-518
        • Kazumata K
        • Shinbo D
        • Ito M
        • et al.
        Spatial relationship between cerebral microbleeds, moyamoya vessels, and hematoma in moyamoya disease.
        J Stroke Cerebrovasc Dis. 2014; 23: 1421-1428
        • Akoudad S
        • Wolters FJ
        • Viswanathan A
        • et al.
        Association of cerebral microbleeds with cognitive decline and dementia.
        JAMA Neurol. 2016; 73: 934-943
        • Yamashiro K
        • Tanaka R
        • Okuma Y
        • et al.
        Cerebral microbleeds are associated with worse cognitive function in the nondemented elderly with small vessel disease.
        Cerebrovasc Dis Extra. 2014; 4: 212-220
        • Tanaka A
        • Ueno Y
        • Nakayama Y
        • et al.
        Small chronic hemorrhages and ischemic lesions in association with spontaneous intracerebral hematomas.
        Stroke. 1999; 30: 1637-1642
        • Akoudad S
        • de Groot M
        • Koudstaal PJ
        • et al.
        Cerebral microbleeds are related to loss of white matter structural integrity.
        Neurology. 2013; 81: 1930-1937
        • Fukui M.
        Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan.
        Clin Neurol Neurosurg. 99. 1997: S238-S240
        • Gregoire SM
        • Chaudhary UJ
        • Brown MM
        • et al.
        The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds.
        Neurology. 2009; 73: 1759-1766
        • Banerjee G
        • Kim HJ
        • Fox Z
        • et al.
        MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden.
        Brain. 2017; 140: 1107-1116
        • Shinagawa F
        • Kobayashi S
        • Fujita K.
        Japanese Wechsler Adult Intelligence Scale-Revised.
        Tokyo: Nihon Bunka Kagakusha. 1990;
        • Koyama M.
        Clinical psychology of brain damage.
        Gakuen Sha, Tokyo1985
        • Lezak MD.
        Neuropsychological assessment.
        3rd ed. Oxford University Press, New York1995
        • Khana NI
        • Saherwalaa AA
        • Chen M
        • et al.
        Prevalence of and risk factors for cerebral microbleeds in moyamoya disease and syndrome in the American population.
        Cerebrovasc Dis Extra. 2019; 9: 139-147
        • Wenz H
        • Wenz R
        • Maros M
        • et al.
        Incidence, locations, and longitudinal course of cerebral microbleeds in European moyamoya.
        Stroke. 2017; 48: 307-313
        • Yamamoto S
        • Kuroda S.
        Long‑term effect of surgical revascularization on silent microbleeds in adult moyamoya disease: A case report.
        Surg Neurol Int. 2017; 8: 99
        • Igarashi S
        • Ando T
        • Takahashi T
        • et al.
        Development of cerebral microbleeds in patients with cerebral hyperperfusion following carotid endarterectomy and its relation to postoperative cognitive decline.
        J Neurosurg In press. 2021;
        • Mansour A
        • Rashad S
        • Niizuma K
        • et al.
        A novel model of cerebral hyperperfusion with blood-brain barrier breakdown, white matter injury, and cognitive dysfunction.
        J Neurosurg. 2020; 133: 1460-1472
        • Alessandro N
        • Kaku Y
        • Julia O
        • et al.
        In vivo demonstration of blood-brain barrier impairment in Moyamoya disease.
        Acta Neurochirurgica. 2019; 161: 3718
        • Fujimura M
        • Niizuma K
        • Inoue T
        • et al.
        Minocycline prevents focal neurological deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease.
        Neurosurgery. 2014; 74: 163-170
        • Tashiro R
        • Fujimura M
        • Katsuki M
        • et al.
        Prolonged/delayed cerebral hyperperfusion in adult patients with moyamoya disease with RNF213 gene polymorphism c.14576G>A (rs112735431) after superficial temporal artery-middle cerebral artery anastomosis.
        J Neurosurg. 2021; 135: 417-424
        • Hara S
        • Kudo T
        • Hayashi S
        • et al.
        Improvement in cognitive decline after indirect bypass surgery in adult moyamoya disease: implication of 15O-gas positron emission tomography.
        Ann Nucl Med. 2020; 34: 467-475