Cerebral Hemodynamics and Stroke in HIV-associated TB Meningitis.

摘要 在低收入和中等收入国家，结核性脑膜炎(TBM)对人们的影响不成比例， 与高发病率和高死亡率有关。中风是重型颅脑损伤的常见并发症，可导致严重的 不可逆转的神经性残疾。然而，关于脑脊液相关卒中病理的研究一直是重点。 主要针对未感染艾滋病毒的个人。这项提议的总体目标是使用经颅多普勒和 脑成像以了解脑血管和脑血流量的变化，以确定 脑血管反应性的变化，表征中风的类型，并描述长期 HIV相关TBM的神经认知结果。中心假设是，在感染艾滋病毒的人中， TBM导致广泛的脑血管狭窄和脑血管反应性受损，降低 大脑血液流动，最终导致中风。核心假设将通过追求三个具体目标来检验： 1)描述HIV相关TBM患者脑血管反应性的变化；2)描述 HIV相关TBM中的卒中并确定其是否与血管病变和/或损害有关 脑血管反应性；以及3)确定脑血管反应性受损是否预示着长期的 HIV相关性TBM的神经系统结局。在目标1下，将使用经颅多谱勒 重复测量大脑中动脉血流速度和搏动指数。研究的一个子集 受试者还将根据刺激(吸入二氧化碳、血液变化)进行动态测量 压力和运动任务)。我们将确定HIV患者的脑血管反应性是否受损- 通过将测量结果与没有神经系统感染的对照患者的测量结果进行比较，将其与TBM相关联。在……下面 目的2，所有研究对象都将在TBM治疗的头两周内进行脑部MRI检查，以确定 大脑动脉卒中的存在和相关的大脑动脉区域。我们会比较TCD 中风患者和非中风患者之间的读数。在目标3下，我们将研究TCD测量如何在 研究登记与第二个月的神经认知测试和一个月的功能评估的结果有关 6.最终，该提案的长期目标是描述脑血管反应性如何受损 HIV相关的TBM有助于中风的发展和由此导致的神经认知障碍和 残疾。本申请中提出的研究具有创新性，因为它结合了 床边的经颅多谱勒，可实时用于脑脊髓炎患者的护理。建议数 研究具有重要意义，因为它有望为发展 未来的临床试验将测试有针对性的干预措施，以改善脑血管反应并预防 人类免疫缺陷病毒相关性脑脊髓炎患者卒中的发生。归根结底，这种知识有可能防止 发展不可逆转的神经损伤，改善短期和长期结果。

Abstract Tuberculous meningitis (TBM) disproportionally affects people in low- and middle-income countries and is associated with high morbidity and mortality. Stroke is a common complication in TBM and can lead to severe irreversible neurological disability. Studies on TBM-associated stroke pathology, however, have focused primarily on HIV-uninfected individuals. The overall objective of this proposal is to use transcranial doppler and brain imaging to understand changes in cerebral blood vessels and cerebral blood flow in order to determine changes in cerebrovascular responsiveness, characterize patterns of stroke, and describe long-term neurocognitive outcomes in HIV-associated TBM. The central hypothesis is that in HIV-infected individuals, TBM causes extensive cerebral vascular narrowing and impaired cerebrovascular responsiveness, decreased cerebral blood flow, and ultimately stroke. The central hypothesis will be tested by pursuing three specific aims: 1) describe changes in cerebrovascular responsiveness in HIV-associated TBM; 2) characterize the patterns of stroke in HIV-associated TBM and determine whether it is associated with vasculopathy and/or impairments in cerebrovascular responsiveness; and 3) determine if impaired cerebrovascular responsiveness predicts long- term neurological outcome in HIV-associated TBM. Under Aim 1, transcranial doppler will be used to take repeated measurements of the middle cerebral artery flow velocity and pulsatility index. A subset of study subjects will also have dynamic measurements made in response to stimuli (inhaled CO2, changes in blood pressure, and motor tasks). We will determine whether cerebrovascular responsiveness is impaired in HIV- associated TBM by comparing measurements to those of control patients with no neurological infection. Under Aim 2, all study subjects will have a brain MRI performed within the first 2-weeks of TBM treatment to identify the presence of a cerebral artery stroke and the associated cerebral artery territory. We will compare TCD readings between participants with or without stroke. Under Aim 3, we will examine how TCD measurements at study enrolment relate to the results of neurocognitive testing at month 2 and functional assessment at month 6. Ultimately, the long-term goal of the proposal is to describe how impaired cerebrovascular responsiveness in HIV-associated TBM contributes to the development of strokes and resulting neurocognitive impairment and disability. The research proposed in this application is innovative because it incorporates the use of transcranial doppler at the bedside, to be used in real time, in the care of subjects with TBM. The proposed research is significant because it is expected to provide strong scientific justification for the development of future clinical trials testing targeted interventions to improve cerebrovascular responsiveness and prevent the development of strokes in HIV-associated TBM. Ultimately, such knowledge has the potential of preventing the development of irreversible neurological injury and improving both short and long-term outcomes.