DS is clinically the most useful technique for detecting, localizing, and evaluating peripheral venous obstruction and venous valvular incompetence [57, 58]. The sensitivity and specificity of venous DS for symptomatic proximal deep vein thrombosis exceeds 90 % [59, 60]. Spectral analysis of the DS signal is used to confirm the presence or absence of flow and indicates its direction and the patterns. Spectral analysis of DS signal and color DS are used to confirm the presence of reflux. Several DS studies have shown a relationship between IJV drainage abnormalities, characterized by JVR and specific neurological diseases of undetermined etiology along with a higher prevalence of brain WM hyperintensities in elderly people ([8, 12, 32, 61]). An increased prevalence of JVR, dilated vessel lumen, and slowed flow velocity in the left IJV, as well as decreased time-averaged mean velocity of bilateral IJV was found in those over 70 years of age ([12, 32]).

Because of the advantages of the DS in detecting intraluminal venous pathology, it was initially promoted as a method of choice for screening of extracranial venous abnormalities and developmental variants, indicative of CCSVI [17, 62]. The diagnosis of CCSVI is both based on hemodynamic and imaging findings that utilize DS to study the deep cerebral veins, the IJVs, and the VVs in both erect and supine positions. Recent findings suggest that the majority of CCSVI pathology is confined to the intraluminal portion of extracranial veins which can be visualised with high resolution B-mode imaging while visible “stenoses” (Fig. 4) or extraluminal venous abnormalities most likely develop more frequently with the progression of the disease or age [7, 56, 63].

The prevalence of CCSVI and JVR, as well as their relationship to clinical findings in CNS disorders, emphasizes the need for more quantitative and reproducible measures for the integration of morphological and functional anomalies. These include blood flow as well as velocity and blood volume measurements that could be potentially more reliable in assessing the degree of venous outflow obstruction in the IJVs and azygos vein (Fig. 5). Monti et al. performed quantitative evaluation of cerebral venous blood outflow in the supine and sitting positions and found significant alterations in cerebral venous outflow in MS patients in comparison with healthy controls and patients with other neurological diseases ([64, 65]).

While the value of these CCSVI VH criteria in detecting venous abnormalities or developmental variants is uncertain and operator dependent, no other validated criteria have been proposed at this time [23]. Recently, the International Society for Neurovascular Disease (ISNVD) developed a more comprehensive consensus document that included the participation of more than 60 international experts in DS imaging [23]. DS was proposed as a standardized screening tool for determining CCSVI status. The protocol proposes also the use of quantitative measures for the definition of functional anomalies such as blood flow velocity and volume (Fig. 5) that could be potentially more reliable in assessing the degree of venous outflow obstruction in the IJVs. It also refines originally proposed VH criteria. A novel technology called Quality Doppler Processing (QDP) [62, 66] designed to insonate the veins at the base of the skull may become useful in the near future, because it is difficult to visualize the superior petrosal sinus, the inferior petrosal sinus, and the contralateral inferior and superior petrosal sinuses. Because insonation of the petrosal sinuses requires a Doppler angle close to 90°, detection of reflux in the form of bidirectional flow can be made only using a multi-angle Doppler system. The QDP technology enables the operator to determine the direction of blood flow within the examined cerebral veins and make an adjustment of the pulse repetition frequency (PRF) to clearly visualize the direction without background Doppler noise. But because of its limited availability, QDP technology can only be considered as an additional criterion for diagnosis of CCSVI.

Also recently, the European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) expressed considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS [19] and proposed the central blinded DS reading as part of a recent multicenter Italian CoSMo study investigating the prevalence of CCSVI in MS patients, healthy controls, and patients with other neurologic diseases (OND) [67].

Dynamic contrast-enhanced exams can potentially increase the value of DS by overcoming the operator-dependent analysis of the ultrasonic signal [68]. Unlike the diffusible agents commonly used in MR imaging and computed tomography (CT), DS contrast agents are true intravascular agents that remain entirely within the vascular space and possess intravascular characteristics similar to those of red blood cells. This technique allows registration of changes in ultrasonic signal intensity during and after intravenous injection of a contrast agent. Time dependence of enhancement can be shown in a time-intensity curve (TIC) where the average signal from a region of interest (ROI) is plotted as a function of time. Tissue and vascular uptake, transit times, and washout of the contrast agent can also be obtained from a TIC [69, 70]. Mancini et al. used contrast-enhanced ultrasonography of the internal jugular vein with TIC analysis and revealed significantly reduction of washout rate in IJVs in MS patients compared to healthy controls [68].

DS has the advantage among other diagnostic techniques of being noninvasive, providing high-resolution images with real-time dynamic information such as flow and velocity, showing intraluminal as well as extraluminal abnormalities and developmental variants (Fig. 4), and being considerably less expensive than other noninvasive imaging techniques. DS imaging can also be readily applied in the follow-up period of subjects undergoing endovascular treatment because it can recognize the associated complications (residual stenosis, restenosis, or venous thrombosis) (Fig. 4) [2, 5, 13, 22, 71]. DS can also assess the hemodynamic consequences of outflow derangement, while B-mode ultrasound detects structural venous intraluminal anomalies (Fig. 4) [22, 71].

The main criticism of the recommended DS protocol is that its reproducibility depends on the training level and skills of the operator and it is not easy to be blinded and standardized in either a research or clinical setting [7, 19, 72, 73]. Moreover, the value of the CCSVI VH criteria is controversial because they combine functional and structural intra- and extracranial venous abnormalities/developmental variants in a single binary composite. Further, the assessment of the second CCSVI criterion (reflux in deep cerebral veins) (Fig. 6) is particularly controversial because the direction of the blood flow in veins connecting cortical with deep veins may vary considerably as a consequence of the physiologic interindividual variation of the cerebral venous anatomy [72].

DS also has limits regarding extracranial vein characterization, since findings can be influenced by hydration status. It is a very time-consuming method, and visualization of the central veins, particularly in the thorax and abdomen, is often limited and cannot give the global view of vein anatomy. Although it can detect extracranial collateral veins which are probably associated with CCSVI, it is not technically feasible to follow the complete course of the collateral veins which can be more easily visualized with the use of magnetic resonance venography (MRV), computed tomography venography (CTV), or CV. Other pitfalls in DS imaging include the misidentification of veins. Additionally, overlying bone and muscle may prevent continuous imaging (cannot visualize suitably the confluence of the IJVs and the subclavian vein because the clavicle commonly blocks direct visualization). Similarly, the cervical part of IJV and the jugular bulb cannot be visualized by DS because of the limited acoustic window resulting from the spine, mandible, and skull. So far, none of the recently published DS studies have reproduced the originally reported CCSVI prevalence, regardless of diagnostic DS method utilized [5, 48, 71, 74, 75].

During the past decade, catheter-based digital subtraction angiography, as the preferred method for imaging of the intracranial venous anatomy, has been increasingly supplanted by MRV, an often overlooked and underappreciated noninvasive and safe method for the evaluation of head and neck veins [76, 77]. In the absence of better noninvasive techniques for the imaging of the dural venous sinuses, well-known and documented pitfalls associated with flow-sensitive MR techniques have been tolerated [34, 56, 78–81]. Furthermore, simple protocols that incorporate two-dimensional time-of-flight (2D-TOF) pulse sequence have already improved their accuracy for the diagnosis of deep venous thrombosis involving the femoral, popliteal, or iliac veins [82]; however, experience with MRV techniques in the cervical veins remains still limited.

The CCSVI concept triggered several MRV studies that emphasized the value of MRV as a comprehensive, noninvasive, and relatively operator-independent technique which provided a 3D structural assessment of the intra- and extracranial vasculature for the potential identification of stenosis and quantification of blood flow through major veins [7, 48, 56, 78, 79, 81, 83–90]. But so far almost none of the MRV studies found significant differences in extracranial vein morphology between MS patients and controls. It could be hypothesized that those so-called abnormalities in venous outflow likely reflect normal developmental anatomic variants. Further, the findings of these studies suggest also that MRV morphologic information by itself may be insufficient to allow conclusions to be drawn about the presence of venous abnormalities and their relationship to CCSVI in MS.

TOF venography has the advantage of simplicity because no special pulse sequences are required, and this technique is available on nearly every MRI system. TOF pulse sequences are spoiled gradient-echo or gradient-echo acquisitions performed sequentially, i.e., all “phase-encode” steps are played out in a single slice before moving on to the next slice, which results in much greater suppression of stationary tissue [34, 77, 82]. It also has the advantage of avoiding the need for the use of contrast agents, and it remains the technique of choice in the evaluation of the pregnant patient with suspected dural sinus thrombosis [34, 78]. Furthermore, the accompanying conventional MR study is more sensitive in terms of the detection of cortical venous infarction than a CT [91]. The axial orientation of the acquisition allows for high in-plane resolution, which is ideal for cross-sectional area (CSA) measurements of the veins (Fig. 7). However, the TOF sequence is easily affected by motion artifacts, especially from the patient’s breathing, swallowing, snoring, or head motion [87, 92]. Relative insensitivity to in-plane flow is another limitation of the TOF technique. Regarding the direction of flow, the optimal acquisition plane lies orthogonal, which is inefficient from the standpoint of acquisition time and not always achievable. Although it has a higher spatial resolution, 2D TOF may overestimate stenosis in the setting of turbulent or slow flow [78]. All in all, standard conventional MRV techniques are more prone to artifacts than phase-contrast MRV and multidirectional TOF angiography [34, 56]. These techniques can potentially alleviate some of the usual MRV artifacts and provide more detailed flow information. One obvious improvement is to image at higher field strength, such as 3 T, because this increases signal-to-noise ratio and better characterizes slow flow.

In contrast to TOF techniques, which rely mainly on flow-related enhancement for producing vascular images, phase-contrast MR angiography (PC-MRA) uses velocity-induced phase shifts imparted upon the moving spins to distinguish flowing blood from the surrounding stationary tissue, thus providing information regarding both anatomy and flow (Fig. 8). The major advantage of PC-MRI angiography is excellent background suppression as well as quantitative determination of blood velocities [93, 94]. However, it requires long imaging times and a prior estimate of blood flow velocity. Furthermore, it may also be more sensitive to signal loss due to turbulence or intravoxel dephasing. So far there are only a few studies that used PC-MRI to quantify venous flow in MS patients compared to healthy controls [92, 95, 96]. More studies are needed to validate the venous flow at the upper neck level on an adequate number of age- and gender-matched healthy controls with heterogeneous age groups.