Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS).1 The pathology of MS includes focal demyelination with relative preservation of axons, a variable degree of inflammation, remyelination, and astrogliosis. These histological features are encompassed by the term MS lesion. Although MS may affect any part of the CNS, including the so-called normal appearing white matter (WM)2 and the gray matter,3–6 focal WM demyelination is considered the pathological hallmark of MS.
For nearly 150 years, a topographic relationship has been noted between focal MS lesions in the WM and cerebral veins,7, 8 although as many MS lesions become confluent over time, their venocentric nature may become less apparent. Evidence suggests the topographic association between focal demyelination and cerebral veins in MS arises from a disruption of the blood-brain barrier in the course of an immune response. Whether this response reflects an early event in the pathogenesis of lesion formation,9 or rather a secondary phenomenon, for example initiated through unmasking of (auto-)antigens following oligodendrocyte apoptosis,10 has yet to be clarified.
Based on findings using venous ultrasound and selective venography studies of cerebrospinal veins, an alternative hypothesis has recently emerged claiming to explain the association between cerebral veins and the distribution of demyelinating MS lesions as a result of chronically impaired venous drainage from the CNS.11, 12 A subsequent study by the same group assessed the effect of endovascular angioplasty in patients with MS and what they coined chronic cerebrospinal venous insufficiency (CCSVI).12
The reported findings are remarkable in that (1) the observation of CCSVI seemed to perfectly match with a diagnosis of MS (100% sensitivity, 100% specificity, 100% positive and 100% negative predictive value)11 and (2) clinical outcomes appeared to improve in a significant proportion of MS patients (35 of 65) following percutaneous transluminal angioplasty of assumed extracranial venous stenoses followed for up to 18 months.13–15 If confirmed, these findings would have significant impact on the understanding of MS pathogenesis and the treatment of this disabling condition that affects >2.5 million people worldwide.
We were intrigued by these observations, which in our laboratory seemed to have gone unnoticed despite our experience in the use of Doppler ultrasound as a clinical and research tool, particularly of the cerebral venous system.16–19
Against the backdrop of the huge interest in the hypothesis of CCSVI as a possible cause of MS by the media and Internet fora, and given that endovascular treatments based on this hypothesis have led to 2 serious adverse events,20 independent evaluation of CCSVI in patients with MS has been identified as an urgent need.21
The aim of this study was to (1) evaluate the ultrasound findings reported by Zamboni and coworkers suggesting a role of CCSVI in the pathogenesis of MS and (2) to extend the studies they performed through acquisition of additional ultrasound indices such as blood volume flow (BVF) and internal jugular venous valve competence (Valsalva maneuver [VM]) to more comprehensively evaluate the hemodynamic effects of any suspected cerebrocervical venous congestion.
Intracranial Veins and Sinuses
The insonation rates of intracranial veins and sinuses varied according to the assessed vessel (see Table 2). In the BVR, the DMCV, and the SS, the blood flow was orthograde in all patients and controls. Retrograde blood flow was observed in the left TS in 1 patient with RRMS. In this patient, blood flow in the TS turned into a physiological direction during manual compression of the contralateral IJV. No changes of blood flow direction were observed due to postural reaction in any vein or sinus.
CBF and Blood Flow Direction in the IJV and VV
The mean global CBF in patients was 618ml/min (SD, 81ml/min) compared to 658 (SD, 72ml/min) in controls (p = 0.063). Blood flow direction in the IJVs and VVs during normal breathing was unidirectional toward the heart in the supine as well as in the upright body position in 55 of 56 patients and in all subjects of the reference cohort. In 1 patient, bidirectional flow in the left IJV was observed in a supine body position only.
Assessment of IJVVI and IJV Stenosis
Of 34 patients in whom a VM was performed, pathological reflux of >0.88 seconds was found in 13 (38%). In these patients, reflux was unilateral in 11 (9 on the right, 2 on the left) and bilateral in 2. Of 20 subjects in the reference cohort, 6 (30%) were found to have a pathological reflux during VM (5 unilateral and 1 bilateral). A stenosis of the IJVs according to the CCSVI criteria was detected in none of the subjects included in this study (patients and reference cohort).
BVF in the IJV and VV of Patients
Supine Body Position
Bilateral BVF in the IJVs was detected in 54, and unilateral BVF in 2 patients (Tables 4 and 5). The mean BVF was 325 (SD, 167) ml/min in the right and 181 (SD, 115) ml/min in the left IJV. BVF was higher in the right IJV in 44 patients (79%). The drainage of venous blood via the IJVs as a proportion of the global CBF was >⅔ in 38 patients (68%) and <⅓ in 3 patients (5%). Bilateral BVF in the VVs was detected in 16 patients (29%), and unilateral BVF in 17 patients (30%). In 23 patients (41%), no flow was detected in either VV. BVF in the right and left VV was 9 (SD, 12) ml/min and 5 (SD, 8) ml/min, respectively. No significant correlation was found between global CBF and BVF in the IJVs and VVs (p = 0.52).
Table 4. Postural Changes of BVF, BFV, and CSA in the Internal Jugular Veins in 56 Patients with Multiple Sclerosis
Table 5. Postural Changes of BVF, BFV, and CSA in the Vertebral Veins in 56 Patients with Multiple Sclerosis
Upright Body Position
BVF in the IJVs was bilateral in 44 (79%), unilateral in 10 (18%), and not detectable in 2 patients (3%). The mean BVF was 197 (SD, 200) ml/min in the right and 125 (SD, 126) ml/min in the left IJV. These values translate into a decrease of 40% on the right and 30% on the left side. BVF in the VVs was bilateral in 48 (86%), unilateral in 3 (5%), and missing in 5 (9%) of MS patients. The mean BVF was 35 (SD, 24) ml/min in the right and 26 (SD, 20) ml/min in the left VV. Compared to the recumbent position, this is an increase of 289% on the right and of 440% on the left side. Postural changes from the supine to the upright body position led to a typical decrease of BVF in the IJVs in 44 patients (79%) and an increase in 12 patients (21%), whereas BVF in the VVs increased in 50 patients (89%) and remained unchanged in 6 (11%).
CSA in the IJV and VV of Patients
Mean CSA of the IJVs in the upright position decreased from 86 (SD, 37) mm2 to 28 (SD, 16) mm2 (p < 0.001) (see Tables 4 and 5). The right IJV decreased from 51 (SD, 28) mm2 to 15 (SD, 11) mm2 (p < 0.001), and the left IJV from 36 (SD, 24) mm2 to 12 (SD, 9) mm2 (p < 0.001). An atypical increase of the IJV diameter was observed in 4 patients (7%). In 2 patients, the increase was observed in the right and in 3 in the left IJV, respectively. An increase in diameter of both IJVs was detected in 1 MS patient.
An inverse change of the mean CSA was found in the VVs (see Tables 4 and 5). Postural changes of BFV were much more heterogeneous, especially in the IJVs (see Tables 4 and 5).
CCSVI Criteria in Patients
We detected a lack of postural lumen reduction in the IJV in 4 patients, missing flow in the VV in 5 patients, and a retrograde flow in the TS of 1 patient (see Table 3). A single patient had no detectable flow in the VVs in combination with a bidirectional flow in the left IJV (in supine position only). In none of the patients were ≥2 of these criteria detected.
BVF in the IJVs and VVs of Controls
Supine Body Position
In 18 subjects, BVF was detected in both IJVs, and in 2 subjects in 1 IJV in the supine position (right IJV: 346 (SD, 140) ml/min; left IJV: 149 (SD, 120) ml/min, right-sided dominance in 90%) (Tables 6 and 7). The drainage of venous blood via the IJVs as a proportion of the global CBF was >⅔ in 11 (55%) and <⅓ in 1 (5%) subjects. The BVF in the VVs was bilateral in 9 (45%), unilateral in 6 (30%), and not detectable in 5 (25%) subjects (right VV: 8 [SD, 7] ml/min; left VV: 8 [SD, 8] ml/min). No significant correlation was found between global CBF and BVF in the IJVs and VVs (p = 0.69).
Table 6. Postural Changes of BVF, BFV, and CSA in the Internal Jugular Veins in 20 Reference Subjects
Table 7. Postural Changes of BVF, BFV, and CSA in the Vertebral Veins in 20 Reference Subjects
Upright Body Position
In the upright body position, BVF was 80 (SD, 69) ml/min in the right and 44 (SD, 62) ml/min in the left IJV (decrease in right IJV = 77%; decrease in left IJV = 70%), compared to 40 (SD, 34) ml/min and 27 (SD, 21) ml/min in the right and left VV, respectively (increase in right VV = 400%; increase in left VV = 238%). In the IJVs, BVF was detectable bilaterally in 12 (60%), unilaterally in 7 (35%), and absent on both sides in 1 patient (5%). The corresponding values for the VVs were 17 (85%), 2 (10%), and 1 (5%) patient, respectively. A typical shift of BVF toward the VVs in the upright position was observed in all controls. The BVF in the IJVs after postural changes to the upright position decreased in all subjects, whereas in the VVs, BVF increased in 19 subjects (95%) and remained unchanged in 1 subject (5%).
CSA in the IJVs and VVs of Controls
Mean CSA of the IJVs in the upright position decreased from 82 (SD, 27) mm2 to 27 (SD, 12) mm2 (p < 0.001) (see Tables 6 and 7). An atypical unilateral increase of the IJV diameter was observed in 3 patients (15%). An increase in diameter of both IJVs was not seen.
An inverse change of the mean CSA was found in the VVs.
CCSVI Criteria in Controls
Four subjects fulfilled 1 CCSVI criterion each; 3 subjects showed no postural lumen reduction in the IJV, and 1 subject showed no detectable flow in the VVs. In none of the reference subjects were 2 or more of these criteria detected. No difference in the prevalence of CCSVI criteria was detected between patients and reference subjects (see Table 3).
CSA, BFV, and BVF values are summarized in Tables 4 to 7. No differences between patients and reference subjects were detected in a lying position for BVF and CSA of the IJVs and VVs. Sitting up from a lying position resulted in a decrease of BVF in both IJVs and an increase in both VVs. In IJVs, this decrease was less pronounced in patients than in reference subjects. No significant differences between groups were detected regarding the BFVs in the intracranial venous structures (BVR, DMCV, SS, and TS).
The most important finding of our study is that we were unable to detect a significant difference of the cerebral and cervical venous drainage between patients with MS and healthy subjects for all except 2 venous indices analyzed. Compared to the reference cohort, we detected higher BVF in patients with MS in an upright position, whereas in a lying position no difference emerged in BVF between patients and reference subjects (Table 8). Consistent with this finding, the decrease of the BVF in patients was less pronounced after moving from a lying to an upright position. We hypothesize that this finding might reflect vascular dysregulation, perhaps due to MS affecting the autonomous nervous system,31 and this result warrants further investigation. If anything, however, higher BVF in patients should suggest a better than normal cerebral venous drainage (at least in an upright position) in MS. Our results therefore call into question the existence of CCSVI—certainly in a large proportion of patients with MS—and do not underpin a role of cerebral venous congestion leading to reflux of blood into the CNS in the pathophysiology of MS.
Table 8. Indices of Venous BVF and BFV and Estimates of Blood Vessel Diameters (CSA) Compared between 56 Patients with Multiple Sclerosis and 20 Reference Subjects (Controls)
Although not statistically significant, a trend difference emerged in CBF, with higher values in reference subjects compared to patients with MS. Provided this trend would, in a larger cohort, reach statistical significance, it could reflect lower energy demand in patients with MS due to brain atrophy.32
The anatomy of the cerebral venous system can be divided into a superficial and a deep venous drainage component. The largest vessel of the superficial system is the superior sagittal sinus (SSS), which receives blood from the ascending superior cerebral veins, including the vein of Trolard, via the venous network of the pia mater.33 The SSS drains toward the confluens sinuum, where it merges with venous blood from the SS, and then via the paired transverse and sigmoid sinuses into the IJVs or—alternatively or in conjunction with the former—into extrajugular pathways. Further drainage of venous blood through the superficial venous system occurs via the vein of Labbé into the TS as well as Sylvian veins toward the sphenoparietal sinus, the cavernous sinus, and subsequently—mainly via the superior and inferior petrosal sinus—toward the IJVs.
The deep venous drainage system collects blood from the more basal brain regions via the inferior cerebral veins. The anterior cerebral veins merge with the DMCVs to form the paired BVRs. Together with the internal cerebral veins, the BVRs form the unpaired vein of Galen, which along with the inferior sagittal sinus feeds into the SS.34 There is considerable individual variation of the venous drainage from white matter regions. This drainage can even occur via the deep and/or the superficial venous system.
At the level of the skull base, the blood from the brain may drain through the IJVs and/or via condylar and emissary veins into the extrajugular system, which itself consists of an intra- and extraspinal compartment extending throughout the vertebral column.35–38 The relevance of extrajugular pathways for venous drainage and the capacity to compensate for the drainage via the IJVs have been demonstrated in previous studies.17–19
At the level of the skull base, the total CSA of the nonjugular pathways surpasses that of both IJVs.39 A blood volume capacity of approximately 1,000ml has been estimated for the extrajugular venous system,40 allowing it to take over the entire cerebral venous drainage.41, 42 Further, there is evidence that in >1 of 5 healthy subjects, venous drainage via the IJVs in a supine body position accounts for <⅔ and in 6% for <⅓ of the total CBF.19 These findings have been further underpinned by a study showing that bilateral manual compression of the IJVs immediately causes significant increase of BVF in the VV. This phenomenon is even more pronounced when additional pressure is applied to the deep neck veins.18 Finally, the removal of 1 or both IJVs in patients who underwent radical neck dissection is generally well tolerated, with only a few patients having persistent clinical signs of raised intracranial pressure. Although observation times may be too short to draw definitive conclusions, no association with MS has been reported in this patient population.41, 43, 44
The evidence summarized above as well as our anatomical considerations underpin the huge capacity of extrajugular pathways for cerebral venous drainage and make it unlikely that IJV stenosis would lead to venous congestion in the CNS.
There are conditions that potentially do affect the venous drainage of the brain, including cerebral venous thrombosis, radical neck dissection with removal of 1 or both IJVs, idiopathic intracranial hypertension, and chronic obstructive pulmonary disease. However, there is no evidence that these disorders are associated with an increased risk of developing MS, or that they have a detrimental effect on the course of established MS through cerebral venous congestion.21
Why are the results of our study in line with the evidence described above, whereas the results presented by Zamboni and coworkers appear to provide strong evidence for cerebral venous congestion as a condition frequently associated with MS? A comparison of methodological approaches and the interpretation of findings reveal a number of differences between our study and the work by Zamboni et al that may, at least in part, explain these discrepancies.
First, Zamboni and coworkers describe pathological reflux in veins of the subcortical gray matter in MS patients but not in healthy controls.11, 12 However, there is no agreement in the Doppler literature about how to define the veins draining from the ventricular plane toward the cortical or subcortical gray matter. The blood flow direction in veins connecting cortical with deep veins may vary considerably (in line with the physiological interindividual variation of the cerebral venous anatomy). Criteria to identify these veins using Doppler ultrasound do not exist, and hence no reference values regarding blood flow direction and BFV can be given.
Moreover, the reflux in veins of the subcortical gray matter suggested by Zamboni et al was assessed using the color-coded duplex technique only.11, 12 However, the lack of blood flow analysis using the Doppler spectrum may lead to misinterpretation of the blood flow direction, especially if the course of the vessel can only be investigated over a very short distance.
On the other hand, in intracranial veins and sinuses well-characterized by TCCS, including the DMCV, BVR, SS, and TS, Zamboni et al did not report BFVs potentially underpinning their findings, which would make them comparable with reference values from other laboratories.
Considering the well-characterized DMCV, BVR, SS, and TS, blood flow direction was orthograde in all but 1 vessel in 1 MS patient. Furthermore, there was no difference in BFVs, neither compared to our reference cohort, nor in comparison to values reported in the literature.16, 30, 45 Zamboni et al reported reflux in the DCVs in 50%, reflux in the IJVs and/or VVs in 70% and IJV stenosis in 28%.11 However, it remains unclear whether these observations were made in the same or mainly in different patients.
Second, using B-mode Duplex imaging, Zamboni et al defined reduction of the CSA at least 50% as an IJV stenosis.11 This definition, however, may lead to numerous false-positive results. The wall of the IJV is very thin and thus can easily be compressed either manually (eg, by the ultrasound transducer) or by surrounding anatomical structures (eg, the neck muscles or the carotid artery). The IJV shows physiological variations of its diameter. It is dilated at the craniocervical junction (superior bulb) and distally (inferior bulb), and might appear narrowed within the region of the normally developed internal jugular vein valves. The diameter also depends on the position of a subject's body17 and intrathoracic and central venous pressures,29 and as described above the anatomy of the jugular and extrajugular venous system varies widely in the normal population.46 Hence, the significance of a suspected IJV stenosis cannot be established solely by measuring the CSA. Only the additional assessment of BFV and BVF provides sufficient information to make a diagnosis of venous outflow obstruction. In our study, no difference was detected in BVF in the IJV between patients with MS and reference subjects. The high percentage of BVF in the IJVs (as a proportion of the global CBF) of 79% further underpins unrestricted drainage via these veins.17, 19, 47
Third, in only 4 patients included in our study did we not detect any blood flow in the VVs, whereas in all patients at least low BFV and BVF were detectable in the IJVs. Zamboni and coworkers did not detect any flow in 52% of the patients' IJVs and/or VVs.12 Previous ultrasound analyses have shown that physiologically most subjects have a predominantly jugular drainage pattern, but in a small percentage of subjects venous blood mainly drains via extrajugular vessels even in a supine body position.19 These observations are in line with the findings in our current study (patients and reference subjects). The differences between the observations from Zamboni and our findings may, again, be explained by different methodology. Whereas Zamboni and coworkers reported use of the color-coded duplex mode only to detect blood flow in the IJVs and VVs, we additionally acquired BFV and BVF. Depending on different ultrasonographic indices, for example, the pulse repetition frequency, blood flow may not be detectable using the duplex technique, especially when the BFV is low. The BFV is often low in the VVs and also decreases with age, leading to a lower detection rate in the elderly.48 With respect to the IJVs, a wide vessel lumen and/or a state of exsiccation (leading to low central venous pressure) may reduce the BFV immensely and render detection of the vessel in the duplex mode impossible.
Fourth, in a single patient with RRMS, we detected a constant bidirectional flow in the left IJV in a supine position. This flow pattern turned into an orthograde flow when sitting up. In contrast to our findings, Zamboni et al reported a reflux of >0.88 seconds in the IJVs and/or VVs in any body position in 70% of the patients with MS.11, 12 The Doppler-sonographic observation of bidirectional flow in parts of the IJVs may be caused by a pulsation artifact from the nearby carotid artery and hence be misinterpreted as a venous reflux, particularly if blood flow measurements were not assessed along the entire IJV.
VM testing seems a adequate method by which to detect venous reflux. In our study, we detected IJVVI in 38% of MS patients, slightly more often than in our reference cohort as well as compared to values reported earlier.29 As Zamboni and coworkers did not report analysis of IJV valve competence using VM, it cannot be excluded that what they detected as reflux was rather caused by IJVVI then by stenosis.
Fifth, in a healthy individual, the CSA of the IJV typically decreases when changing body position from supine to upright due to a partial collapse of the vein. This postural response is associated with a reduction of BVF in the IJVs and a simultaneous blood flow increase in extrajugular pathways such as the VVs.17 Nine percent of patients with MS and 15% of the reference subjects in our study showed greater CSA of the IJV in an upright position, either uni- or bilaterally. However, taking the bilateral IJV CSA measurements together, greater CSA of the IJV in an upright position was observed in 1 patient only. The CSA changes of IJVs as well as VVs were similar across patients and controls. By contrast, Zamboni and coworkers reported a paradoxical increase of the CSA in the vertical position in 55 to 58% of their MS patients, suggesting that their postural regulation of venous diameter was impaired.11, 12 However, analysis of postural BVF changes—a much more suitable index than CSA alone to estimate the hemodynamic significance of postural changes in IJV anatomy—was not performed in their studies.
Limitations of Our Study
Our study has several limitations. First, it was carried out in a single center, and—although authors who performed the Doppler studies were not involved in the clinical management of the patients—the investigators were not blinded to subject's status (patients/reference subjects). In the future, attempts could be made to mask investigators for subject status, for example, by separating investigators from handling of subjects prior to ultrasound measurements, covering subjects with a blanket, and keeping conversations between subjects and investigators to a minimum. The success of such blinding measures may, however, be limited and should be evaluated. Second, as our study focused on data acquisition using cerebral and neck Doppler ultrasound only, we are unable to comment on any pathology potentially affecting thoracic veins, for example, the azygous and cava veins. Such studies could be performed using conventional magnetic resonance imaging and magnetic resonance venography, but should also include flow assessment parameters. Third, in future studies the reproducibility of venous Doppler data should be assessed as has been done for arterial blood flow indices.49 Finally, our patient cohort included patients with either RRMS or SPMS only. In the future, further patient subgroups should be investigated. However, we do not think the above limitations significantly compromise the validity of our findings.
In conclusion, our results suggest that the cerebral venous drainage in patients with MS is not restricted and thus challenge the hypothesis that venous congestion plays a significant role in the pathogenesis of MS. Against this backdrop, we discourage interventional procedures as more work is done to investigate CCSVI and its possible role in MS.