多發性硬化症顱內外靜脈回流系統型態與血流量化分析

Abstract

一．研究背景與目的 多發性硬化症一直被認為是自體免疫脫髓鞘病變，義大利的科學家Dr Zamboni針對多發性硬化症的病人，，利用頸部與經顱都普勒超音波檢測發現慢性腦脊髓靜脈功能不全(chronic cerebrospinal venous insufficiency)發生率極高，且和正常對照組相比有顯著的差異性。因此他提出了一個新的假說：就是所謂慢性腦脊髓血流靜脈循環不全(chronic cerebral spinal venous insufficiency) 來解釋多發性硬化症的病理生理變化。但是也有一些研究抱持著反對意見，認為這兩者的關連性不高。但之前的研究多著重在顱外靜脈且使用超音波檢查為主，我們利用核磁共振靜脈造影研究多發性硬化症病人與健康受試者的頭頸部靜脈，由靜脈型態與流向的特徵，分析是否這些病人較常發生靜脈回流的異常，同時也由顱內外靜脈血流的量化指標比較病人與對照組之間的差異。 二．研究方法 本研究經倫理委員會同意進行，我們收集了二十七位多發性硬化症的病人與三十位年齡與性別盡量配對的健康受試者，進行一般頭部核磁共振造影與顯影劑顯像及相位對比靜脈造影，由顯影劑顯像的靜脈造影我們可以分析頭頸部靜脈回流的型態與狹窄與否，相位對比靜脈造影可得到在兩側內頸靜脈和顱內硬腦膜靜脈竇包含兩側橫竇、上矢狀竇、直竇的血流流向、血流尖峰速率、平均速率與平均流量的資料，我們也分析了病患腦內斑塊的體積，還有收集病患的臨床資料包含患病時間，第一次發作時間，疾病覆發頻率，以及行為能力殘缺量表(EDSS)。 在病例組與對照組顱內外血流量化指標的比較是用Mann-Whitney test來分析，在病患的顱內外血流量化指標與臨床資料和腦部斑塊的相關性分析是利用Pearson correlation test。多發性硬化症相對於健康受試者的危險因子研究是用logistic regression分析。 三．研究結果 病例組與對照組在顱內外靜脈型態分析發現有部份比例的人有內頸靜脈狹窄，病例組有七人，對照組有16人，病例組有一人懷疑左側內頸靜脈有靜脈瓣功能不全，在硬腦膜靜脈竇的型態上，病例組有三人有橫竇狹窄，對照組有一人，在顱內外靜脈的流向分析方面，病例組有三人在內頸靜脈出現逆流，對照組也有三人，在靜脈型態的比較上，病例組與對照組無明顯的差別。關於病例組與對照組在顱內外靜脈血流量化指標的比較，在直竇的尖峰速率與平均速率和左橫竇之尖峰速率有統計上顯著的差異。病例組在臨床病況指標與腦部斑塊和顱內外靜脈血流量化指標的相關性分析得到第一次發病的年齡和上矢狀竇與直竇的血流呈中度負相關，斑塊體積與上矢狀竇、直竇與左橫竇血流相關，病患年齡也與上矢狀竇的平均流量成中度負相關，同時病患的第一次發病年齡與其年齡呈現高度正相關。 四．結論 我們運用核磁共振靜脈影像檢查發現顱內靜脈竇之直竇的流速在多發性硬化症與健康對照組有顯著的差異，且直竇引流的腦部區域恰好對應於與多發性硬化症的腦部斑塊好發部位，而推測直竇的血行力學變化在此疾病的病因扮演著重要角色。顱內靜脈竇的血流量化指標和多發性硬化症的腦部斑塊體積與第一次發病年齡有中度相關性，暗示顱內靜脈回流可能是影響此病的原因之一或是長期病程演化而導致靜脈流量減少的結果，其因果關係尚未明朗。再來是多發性硬化症病人其顱外靜脈的型態與流向分析病未發現與健康對照組有顯著的差異。

Purpose Multiple sclerosis was a disease combined with chronic inflammation, demyelination and neurodegeneration of the central venous system, and was heterogeneity in clinical course, imaging findings, and treatment response among patients. Diversity in the risk factors of multiple sclerosis was existed and the pathogenesis was still investigated. It was reported strong association between multiple sclerosis and chronic cerebrospinal venous insufficiency examined by Doppler by Zomboni in 2009 and angioplasty seemed to play a role in the functional improvement of these patients. However, some studies with opposite opinions were also published. The prior studies focused mainly on the abnormality of extracranial veins examined by ultrasound. We used contrast-enhanced and phase contrast MR venography to study the intra- and extracranial venous hemodynamics in multiple sclerosis, and found if anomalous cerebrospinal venous return occur more frequently in multiple sclerosis than normal control. The relationship of flow pattern of cerebrocervical veins on phase contrast MR and plaque burden was also investigated. Method The study was approved by National Taiwan University Hospital Research Ethics Committee and informed consent was obtained. There were 27 patients diagnosed with multiple sclerosis according to the revised Mcdonald’s criteria enrolled and 26 patients were classified relapsing-remission type and one secondary progressive type. Neuromyelitis optica and clinical isolated syndrome were excluded. The health control group included 21 females and 9 males. Routine brain MR protocol, phase contrast and contrast-enhanced MRV involving the cerebrocervical region were performed. 2D Phase contrast MRV slices were positioned at coronal plane for bilateral transverse and superior sagittal sinuses, oblique coronal plane perpendicular to straight sinus for SS, and axial plane at C2-3 level for bilateral internal jugular veins. The plaque burden was calculated by summation of manually selected region of interest on a series of parallel axial planes separated by a fixed distance on fluid-attenuated inversion-recovery (FLAIR) imaging, and included the supratentorial region and brainstem. Morphologic analysis was performed by the contrast-enhanced MRV of the cerebrocervical veins. Stenosis of IJV was defined absent or pinpoint flow on contrast-enhanced MRV. Flow direction, peak velocity, average velocity and average flow were recorded for the target dural sinuses and bilateral internal jugular veins on PC MRV. Mann-Whiney test was used for comparison of the difference of flow parameters between patients and control group. Pearson correlation test was used for the association between flow parameters, plaque burden, disease duration, first event age as well as age. Result The anomalous morphology of the patient group included absent or pinpoint flow in 7 patients. Stenosis at transverse sinus was noted in 3 patients, valve incompetence of IJV in 1, and fenestrated IJV in 1. Of the control group, anomalous morphology of IJV was found in 16 people, stenosis at transverse sinus in 1, and fenestrated IJV in 1. Reversed flow of IJV was found in 3 of the patient group and 3 of the control group. The flow parameters between the patient and control groups were significantly different in peak velocity of SS (p=0.048), average velocity of SS (p=0.026) and peak velocity of left transverse sinus (p=0.035). The correlation analysis of intracranial venous flow quantification and disease characters in MS patients showed moderate correlation between first event age and average flow and velocity of SSS, first event age and peak and average velocity of SS, plaque volume with peak velocity of superior sagittal and left transverse sinuses and average flow of straight sinus. Patient age also had moderate reverse correlation with average velocity and average flow of SSS. The relationship between flow parameters and age showed moderate correlation with average flow of SSS in the health control group. Conclusion The morphologic analysis of intra- and extracranial veins revealed a substantial abnormal morphology and reversed flow of IJV in both the patient and control groups. Significant lower velocity of SS and left transverse sinus in the patient group as compared with the health controls hinted that decreased velocity of intracranial venous drainage may play a role in the pathogenesis of multiple sclerosis. The disease condition of multiple sclerosis, like plaque volume, first event age and patients’ age had moderate reverse correction with the hemodynamics of intracranial venous drainage.