【摘要】：第一部分:對比增強(qiáng)TCD診斷右向左分流的方法學(xué)優(yōu)化近年來,研究發(fā)現(xiàn)右向左分流(right-to-left shunt,RLS)可能與缺血性卒中、偏頭痛、減壓病、斜臥呼吸-直立型低氧血癥、外周動脈栓塞、阻塞性睡眠呼吸暫停綜合征等疾病相關(guān)。對比增強(qiáng)經(jīng)顱多普勒超聲(contrast-enhanced transcranial Doppler,c-TCD)以靈敏度高、安全無創(chuàng)、易于重復(fù)操作的特點(diǎn),廣泛應(yīng)用于RLS的診斷。然而,c-TCD方法學(xué)方面仍存在較大差異。本部分研究就以下幾方面對c-TCD診斷RLS方法學(xué)進(jìn)行優(yōu)化:1.常規(guī)經(jīng)顳窗監(jiān)測大腦中動脈(middle cerebral artery,MCA)不適用于顳窗穿透不良的患者,而頸動脈嚴(yán)重狹窄也會影響常規(guī)RLS診斷。近期還有研究表明RLS相關(guān)缺血性卒中患者的缺血灶及梗死灶多位于后循環(huán)椎基底動脈系統(tǒng)。為探討c-TCD診斷RLS中椎動脈(vertebral artery,VA)監(jiān)測的可行性,我們同步對比了c-TCD經(jīng)枕窗監(jiān)測VA與經(jīng)顳窗監(jiān)測MCA診斷RLS的差異。2.Valsalva動作是c-TCD探查RLS過程中的輔助手段,其執(zhí)行方式及效力評判標(biāo)準(zhǔn)關(guān)乎潛在型RLS的檢出。目前c-TCD探查RLS研究多沿用傳統(tǒng)的Valsalva動作,以MCA流速下降20~25%作為評判其效力的標(biāo)準(zhǔn)。然而,百分比并不適合操作過程中的快速評判。為此,我們比較了傳統(tǒng)的Valsalva動作與改良的Valsalva動作對c-TCD探查RLS的影響,并進(jìn)一步測量了Valsalva動作過程中血流速度的變化差值。1.對比增強(qiáng)TCD診斷右向左分流中椎動脈監(jiān)測的可行性本研究從臨床實(shí)際出發(fā),以2015年2月至4月在吉林大學(xué)第一醫(yī)院神經(jīng)內(nèi)科就診的318名需行c-TCD篩查RLS情況的患者為主要研究對象,對滿足入排標(biāo)準(zhǔn)的194名患者行c-TCD同步監(jiān)測VA和MCA,以進(jìn)一步探討c-TCD診斷RLS中VA監(jiān)測的可行性。主要研究結(jié)果表明:1c-TCD中VA監(jiān)測與MCA監(jiān)測相比,總體、固有型及潛在型RLS檢出情況均無統(tǒng)計(jì)學(xué)差異,靈敏度和特異性均較高;2c-TCD中VA監(jiān)測比MCA監(jiān)測探查的RLS等級略低,但差異無統(tǒng)計(jì)學(xué)意義(P=0.079);3c-TCD靜息狀態(tài)及Valsalva動作下VA監(jiān)測RLS第一個(gè)微氣泡出現(xiàn)均比MCA監(jiān)測略晚(P0.001)。2.對比增強(qiáng)TCD檢查過程中改良Valsalva動作的價(jià)值探討及血流評判標(biāo)準(zhǔn)的建立本研究從臨床實(shí)際出發(fā),以2014年11月至12月在吉林大學(xué)第一醫(yī)院神經(jīng)內(nèi)科就診的317名需行c-TCD篩查RLS情況的患者為主要研究對象,對滿足入排標(biāo)準(zhǔn)的298名患者行c-TCD隨機(jī)完成以下3段監(jiān)測:1)靜息狀態(tài);2)傳統(tǒng)的Valsalva動作:深吸氣后緊閉聲門下的屏氣動作,持續(xù)10秒;3)改良的Valsalva動作:向連通壓力計(jì)的管子用力吹氣,使壓力計(jì)達(dá)到40 mm Hg維持10秒。通過比較RLS陽性檢出率、RLS等級及第一個(gè)微氣泡出現(xiàn)的時(shí)間,探討改良Valsalva動作的價(jià)值。進(jìn)一步回顧性分析,線下回放c-TCD監(jiān)測記錄,對滿足入排標(biāo)準(zhǔn)的共114例患者,選取并記錄壓力計(jì)控制的Valsalva動作下血流趨勢曲線上流速最高和最低點(diǎn)對應(yīng)的收縮期流速與平均流速,計(jì)算差值變化,以期建立Valsalva動作效力的血流評判標(biāo)準(zhǔn)。主要研究結(jié)果表明:1靜息狀態(tài)、傳統(tǒng)的Valsalva動作和改良的Valsalva動作下,c-TCD探查RLS檢出率分別為21.8%、36.9%和47.3%,改良的Valsalva動作下RLS檢出率高于傳統(tǒng)的Valsalva動作(P=0.010);2改良的Valsalva動作下c-TCD探查RLS等級較高(P0.001);3改良的Valsalva動作下第一個(gè)微氣泡出現(xiàn)略晚于傳統(tǒng)的Valsalva動作(P0.05)。4收縮期流速變化為30±9.7cm/s(95%置信區(qū)間為28.2~31.5);5平均流速變化為24±5.3 cm/s(95%置信區(qū)間為22.6~24.5)。結(jié)論:1c-TCD監(jiān)測左側(cè)VA與MCA相比,在靜息狀態(tài)和Valsalva動作下對RLS診斷的靈敏度、特異性均較高,可以作為一種替代方法,應(yīng)用于顳窗穿透不良或頸內(nèi)動脈嚴(yán)重狹窄患者的RLS探查。2通過對比兩種不同Valsalva動作對RLS探查的影響,研究發(fā)現(xiàn)改良的Valsalva動作比傳統(tǒng)的Valsalva動作RLS陽性檢出率及檢出等級更高。改良的Valsalva動作可以作為一種替代方法,尤其是對難以配合傳統(tǒng)Valsalva動作但高度懷疑存在RLS的患者。3正常左側(cè)MCA監(jiān)測下收縮期流速降低30 cm/s或平均流速降低25 cm/s可作為c-TCD操作過程中快速評判Valsalva動作效力的血流參考指標(biāo)。第二部分:PFO封堵治療RLS相關(guān)偏頭痛安全性與療效評估近年來,大量報(bào)道指出偏頭痛,尤其是先兆偏頭痛與卵圓孔未閉(patent foramen ovale,PFO)相關(guān)。假說機(jī)制為神經(jīng)遞質(zhì)或微栓子避過肺部的濾過滅活經(jīng)PFO隨右向左分流(right-to-left shunt,RLS)進(jìn)入顱內(nèi)循環(huán)引發(fā)偏頭痛發(fā)作或降低其閾值。有研究表明PFO封堵手術(shù)可減輕偏頭痛,但其適用人群及封堵器選擇存在爭議。目前,我國在此領(lǐng)域仍缺乏大樣本前瞻性研究。本研究旨在評估PFO封堵手術(shù)對偏頭痛的安全性和長期療效,同時(shí)驗(yàn)證c-TCD在診斷RLS相關(guān)的偏頭痛及PFO封堵治療術(shù)后隨訪殘余分流方面的重要作用。本部分研究從臨床實(shí)際出發(fā),前瞻性連續(xù)納入2013年至2015年在吉林大學(xué)第一醫(yī)院神經(jīng)內(nèi)科就診的偏頭痛患者,基線HIT-6評分后行c-TCD探查RLS,中至大量RLS患者進(jìn)一步行心臟超聲明確PFO后,根據(jù)患者意愿分為手術(shù)組和對照組,并隨訪1年內(nèi)HIT-6評分。滿足入排標(biāo)準(zhǔn)的患者共258例,130例要求或同意手術(shù)的患者入手術(shù)組,其余128例拒絕手術(shù)的患者入對照組。術(shù)后患者需口服阿司匹林6個(gè)月并于1個(gè)月、3個(gè)月、6個(gè)月和1年隨訪復(fù)查c-TCD。主要研究結(jié)果表明:1共241例患者完成了隨訪,手術(shù)組125例,對照組116例。125例均成功置入封堵器,僅1例出現(xiàn)心包填塞,無嚴(yán)重不良反應(yīng);21年隨訪期間復(fù)查c-TCD的殘余分流患者85.71%轉(zhuǎn)為陰性或小量分流;3封堵器內(nèi)皮化不完全所致的殘余分流和安慰效應(yīng)在1年時(shí)基本消除;4術(shù)后1年患者頭痛HIT-6隨訪最終評級92例(73.6%)降低、31例(24.8%)未變動、2例(1.6%)升高;5剔出基線HIT-6評分影響,手術(shù)組與對照組隨訪最終HIT-6評分比較表明手術(shù)組患者長期頭痛緩解更明顯(48.77 vs.57.85,P0.001);6手術(shù)組患者HIT-6基線評分與1年后的差值減少程度明顯大于對照組(16.35 vs.5.59,P0.001);7除男性及潛在型RLS組外,其他亞組分析進(jìn)一步驗(yàn)證了手術(shù)組療效優(yōu)于對照組。結(jié)論:本研究表明PFO封堵手術(shù)是一項(xiàng)安全有效治療RLS相關(guān)偏頭痛的手段,同時(shí)c-TCD在診斷RLS相關(guān)的偏頭痛及PFO封堵治療后隨訪殘余分流方面具有重要的指導(dǎo)及預(yù)測價(jià)值。
[Abstract]:The first part: In recent years, the right-to-left shunt (RLS) of the right-to-left shunt (RLS) may be associated with ischemic stroke, migraine, decompression sickness, oblique-lying breathing-orthostatic hypoxemia, peripheral arterial embolism, Obstructive sleep apnea syndrome. Contrast-enhanced transcranial Doppler (c-TCD) is widely used in the diagnosis of RLS. However, there are still significant differences in the c-TCD methodology. This part studies the optimization of the method for the diagnosis of RLS with c-TCD in the following aspects:1. The middle cerebral artery (MCA) in the middle cerebral artery (MCA) is not suitable for the patients with bad through-window penetration, and the carotid artery stenosis will also affect the conventional RLS diagnosis. Recent studies have shown that the ischemic range and the infarct focus of patients with RLS-associated ischemic stroke are located in the posterior circulation vertebrobasilar system. In ord to investigate that feasibility of c-TCD in the diagnosis of the vertebral artery (VA) in the RLS, we compare the difference between the monitor VA of c-TCD and the diagnostic RLS of the MCA through the window.2. Valsalva's action is the aid of c-TCD in the exploration of RLS. At present, the traditional Valsalva maneuver is used to explore the RLS in the C-TCD exploration, and the MCA flow rate is reduced by 20-25% as the criterion for judging its effectiveness. However, the percentage is not suitable for rapid evaluation during operation. To this end, we compared the traditional Valsalva's action with the modified Valsalva's action on the detection of RLS by c-TCD, and further measured the difference of blood flow velocity during Valsalva's motion. In contrast, the feasibility of contrast-enhanced TCD in the diagnosis of the right-to-left shunt in the right-to-left shunt is the main study of the 318 patients who need c-TCD to screen the RLS in the first hospital of Jilin University from February to April,2015. The VA and MCA were monitored by c-TCD in 194 patients who met the entry criteria to further investigate the feasibility of VA monitoring in the diagnosis of RLS with c-TCD. The results showed that VA monitoring in 1c-TCD did not have statistical difference, sensitivity and specificity were higher than that of MCA, and VA monitoring in 2c-TCD was lower than that of MCA, but the difference was not significant (P = 0.079). In the 3-TCD resting state and Valsalva's operation, the first micro-bubble in the VA-monitored RLS was slightly lower than that of the MCA (P 0.001). In order to improve the value of Valsalva's motion and the establishment of the criteria for the evaluation of blood flow in the course of enhancing the TCD examination, the clinical practice of the study is to study 317 patients with RLS in the neurology of the first hospital in Jilin University from November to December of 2014 as the main research object. the following three monitoring:1) resting state for 298 patients meeting the entry criteria:1) resting state;2) conventional valsalva motion: a breath-holding action under the closed acoustic door after deep inhalation for 10 seconds; and 3) an improved valsalva motion: a forced air blow to the tube in communication with the pressure gauge, Maintain the pressure gauge up to 40 mm Hg for 10 seconds. The value of modified Valsalva's action was discussed by comparing the positive rate of RLS, the level of RLS and the time of the first micro-bubble. Further retrospective analysis, offline playback of c-TCD monitoring records, a total of 114 patients who met the entry criteria, the systolic flow rate and the mean flow rate corresponding to the highest and lowest points on the blood flow trend curve under the control of the pressure gauge were selected and recorded, and the difference was calculated. So as to establish a blood flow evaluation standard for Valsalva's action effectiveness. The results showed that the detection rate of RLS was 21.8%, 36.9% and 47.3%, respectively, and that of the modified Valsalva was higher than that of the traditional Valsalva (P = 0.010). The first micro-bubble in the modified Valsalva maneuver was higher than that of the traditional Valsalva (P.001). The first micro-bubble in the modified Valsalva maneuver was slightly later than that of the traditional Valsalva (P0.05). The change of systolic velocity was 30-9.7 cm/ s (95% confidence interval was 28.2-31.5), and the mean flow rate was 24-5.3 cm/ s (95% confidence interval is 22.6-24.5). Conclusion: The sensitivity and specificity of 1c-TCD in the diagnosis of RLS under the action of resting and Valsalva can be used as an alternative. By comparing the effects of two different Valsalva actions on the detection of RLS, the results show that the improved Valsalva's action is higher than that of the traditional Valsalva. the modified valsalva action can be used as an alternative, In particular, patients with difficulty in matching the traditional Valsalva maneuver but highly suspected of RLS. The systolic flow rate at normal left MCA monitoring was reduced by 30 cm/ s or the mean flow rate was reduced by 25 cm/ s as the blood flow reference index for the rapid evaluation of the efficacy of the Valsalva operation during the c-TCD operation. The second part: The safety and curative effect of PFO occlusion in the treatment of RLS-associated migraine has been reported in recent years, and it is reported that the migraine, especially the migraine with aura, is associated with the patent foramen ovale (PFO). The hypothesis mechanism is that neurotransmitters or microemboli escape through the PFO with the right-to-left shunt (RLS) into the intracranial cycle to trigger a migraine attack or to reduce its threshold. Studies have shown that PFO occlusion can reduce migraine, but there is a dispute between the appropriate population and the device choice. At present, there is still a lack of large-sample prospective studies in this field in our country. The purpose of this study was to evaluate the safety and long-term efficacy of PFO occlusion in the treatment of migraine and to verify the important role of c-TCD in the diagnosis of RLS-associated migraine and the follow-up residual shunt in the treatment of PFO. This part of the study, from the clinical practice, was forward-looking and continuously included in the first hospital of the first hospital of Jilin University from 2013 to 2015, and after the baseline HIT-6 score, c-TCD was used to explore the RLS, and the middle to large number of RLS patients further underwent cardiac ultrasound to clear the PFO. The patient's will was divided into the surgical group and the control group, and the HIT-6 score was followed for 1 year. Of the 258 patients who met the criteria of entry,130 patients who required or agreed to the procedure were enrolled in the operation group, and the remaining 128 patients who refused to be operated were enrolled in the control group. The postoperative patient was given an aspirin for 6 months and the c-TCD was reviewed at 1 month,3 months,6 months, and 1 year follow-up. The results showed that:1 total of 241 patients had completed the follow-up,125 cases in the operation group and 116 in the control group. 3. The residual shunt and the comfort effect caused by the endothelialization of the occluder were substantially eliminated at 1 year; the final rating of the HIT-6 follow-up in 1 year after the operation was decreased in 92 (73.6%),31 (24.8%) did not change,2 (1.6%) increased, and 5 the baseline HIT-6 score was removed. The result of the follow-up HIT-6 score of the operation group and the control group showed that the long-term headache response of the patients in the operation group was more obvious (48.77 vs. 57.85, P0.001), and the difference between the HIT-6 baseline score and the 1-year post-treatment group in the 6-operation group was significantly higher than that of the control group (16.35 vs. 5.59, P0.001), and that in addition to the male and potential RLS groups, The other subgroup analyses further demonstrated that the efficacy of the surgical group was superior to that of the control group. Conclusion: The study shows that PFO occlusion is a safe and effective means for the treatment of RLS-associated migraine, while c-TCD has important guidance and predictive value in the diagnosis of RLS-associated migraine and the follow-up of residual shunt after PFO occlusion treatment.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R747.2

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