Venous and Cerebrospinal Fluid Flow in Multiple Sclerosis: A Case-Control Study

Peter Sundstrom, MD, PhD(1), Anders Wåhlin, MSc(2), Khalid Ambarki, MSc, PhD(2), Richard Birgander, MD, PhD, Anders Eklund, MSc, PhD(2,3,4), and Jan Malm, MD, PhD(1).

The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing-remitting multiple sclerosis cases and 20 healthy controls with phasecontrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrastenhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis.
ANN NEUROL 2010;68:255–259

A new hypothesis about the etiopathogenesis in multiple sclerosis (MS), chronic cerebrospinal venous insufficiency (CCSVI), has in a short time gained enormous attention in the media, among patients as well as in the scientific community. MS-CCSVI suggests that MS may develop secondarily to an impaired venous outflow from the central nervous system (CNS) (1). Stenoses of the internal jugular vein (IJV), possibly treatable by angioplasty or stenting, have been suggested as a cause of this impaired outflow (2,3). Zamboni et al used ultrasound and transcranial Doppler to show that venous reflux is a common finding in MS, but never seen in controls (4). The hypothesis is that venous reflux may lead to the accumulation of iron in the CNS, triggering secondary autoimmune events leading to MS (1).

A marked decrease of MS cerebrospinal fluid (CSF) flow through the cerebral aqueduct, correlating with the Doppler sonography pattern, is also described (5,6). MS-CCSVI and the vascular hypothesis of MS have been questioned (7). Does imbalance of venous outflow have etiological relevance for MS, or are the findings just a secondary phenomenon compatible with the prevailing view on MS etiopathogenesis? Magnetic resonance imaging with phase contrast (PC-MRI) makes it possible to noninvasively and accurately evaluate the flow direction and flow rate of intracranial blood and CSF (8-13). Using contrastenhanced magnetic resonance angiography (CE-MRA), venous anatomy and pathology can be described as well.
The present study is a joint project between a hydrocephalus research group specializing in CSF dynamics and blood flow, and the MS research group at Umeå University. To test the most vital part of the vascular MS hypothesis, that is, the obstructed IJV flow, blood flow of the internal carotid arteries, the vertebral arteries, and the IJVs, as well as the anatomy of the vessels, was assessed in 21 MS patients and 20 healthy controls.

Subjects and Methods

MS Patients and Controls

Twenty-one relapsing-remitting MS (RRMS) patients fulfilling the revised McDonald diagnostic criteria (14), and in whom a new MRI examination was clinically motivated, were invited during February to April 2010. All patients accepted participation. The MS population at the Department of Neurology, Umeå University Hospital, is clinically well characterized15; here, the MS diagnosis was supported by MRI (at least 3 of 4 MRI criteria fulfilled) in 17 cases and CSF electrophoresis analyses in all 21 cases (14). Twenty healthy volunteers (friends, colleagues, and spouses to colleagues) were recruited and examined with the axial T2-weighted (T2W) turbo spin echo (TSE) sequence from the clinical MS protocol to assess the criteria set for inclusion as healthy controls. The local ethics committee approved the study, and all participants gave their written consent.

MRI Investigation

A 3T Philips Achieva (Philips Medical Systems, Best, the Netherlands) with an 8-channel head coil was used for all measurements. MS cases were examined with CE-MRA, a 3-dimensional fast-field echo sequence with bolus timing technique to image the intracranial and cervical venous system. Images, covering the intracranial space as well as the cervical region (C0–C7/Th1), were obtained in the coronal plane with an acquisition matrix of 400 x 340. Following the CE-MRA, cases were examined with the local clinical MS protocol including in-plane high-resolution 3mm T2W TSE, sagittally obtained 1mm fluid attenuated inversion recovery, and T1W turbo field echo volumes, performed after intravenous contrast administration. CE-MRA was not performed in healthy controls, as we did not want to expose these to intravenous contrast.
All 41 subjects underwent identical 2-dimensional PCMRI scans to assess blood and CSF flows. Blood flow of the internal carotid arteries, the vertebral arteries, and the IJVs were imaged at the C2–C3 level using a velocity sensitization of 70cm/s. The blood measurement section was placed perpendicularly to the flow direction as determined by a sagittal 2-dimensional angiographic scout image. CSF flow was imaged using a velocity sensitization of 20cm/s and measurement section placed perpendicular to the cerebral aqueduct.
The PC-MRI sequences had a field of view of 140 x 140 to 150 x 150mm2, a matrix size of 128 x 128 to 160 x 160 pixels, a 5 to 6mm section thickness, a 10- to 16-millisecond repetition time, a 6- to 11-millisecond echo time, a flip angle of 10 to 15°, and 2-fold signal averaging. Retrospective cardiac triggering using a peripheral sensor was used to synchronize the PC-MRI sequence. No breath holding was employed. Thirtytwo phases were reconstructed to represent a full cardiac cycle.

MRI Analysis

Visual assessments, using source images, multiplanar and maximum intensity projection reconstructions of the CE-MRA, were used by the neuroradiologist (R.B.) to evaluate occurrence of stenoses in the venous system. For the PC-MRI analysis, 1 operator (A.W.), only accessing anonymized and unlabeled data sets, performed vessel lumen delineation.
Total cerebral blood flow (tCBF) was calculated by summation of the average volume flow rate of the internal carotid and vertebral arteries. Total IJV blood flow (tJBF) was calculated by summation of the average volume flow rate of each IJV.
To control for differences in tCBF between cases and controls, the fraction of the cerebral blood flow that returns through the IJVs was calculated as tJBF/tCBF. Reflux was defined as present in subjects who at any time during the cardiac cycle had a retrograde flow in either IJV. The aqueduct CSF flow stroke volume and net flow were calculated using the volume flow rate curve (16,17).

Statistical Analysis

Differences between groups were assessed using the t test or the Mann-Whitney test where appropriate. The chi-square test was used for cross-tab calculations. p values < 0.05 were regarded as statistically significant.

Results

PC-MRI Measurements

There were no significant differences between cases and controls regarding tJBF, the fraction of the cerebral blood flow returning through both IJVs (tJBF/tCBF) or either of the IJVs, the prevalence of IJV reflux, or any of the studied CSF flow parameters. There were no significant differences between sexes for any of these parameters. All subjects, both cases and controls, with reflux had a markedly decreased IJV blood flow on the affected side. The Figure also illustrates the lateralization of IJV blood flow; a decreased blood flow fraction in 1 of the IJVs was generally accompanied by a compensatory increase of the contralateral flow. The distributions of cases and controls were highly overlapping.

MS Venous MRA

The CE-MRA examination of the MS cases revealed no signs of venous stenoses in 18 cases and a venous stenosis in 3 cases. All these stenoses were located in the mid portion of the IJV. These 3 cases also had a corresponding decreased IJV flow as measured by PC-MRI.

Discussion

With focus on IJV flow in the supine position, this study failed to reproduce the findings associated with MSCCSVI, as we expected them to appear by PC-MRI.
There were no clear indications of decreased IJV flow or reflux being more common in MS patients. There were no significant differences regarding the proportion of blood leaving the brain through the IJVs, or any differences between cases and controls regarding CSF flow parameters. In both cases and controls, the right IJV most frequently conducted the major part of the internal jugular drainage, which is in accordance to the literature (18). A decreased cerebral venous outflow in MS may be secondary to a decreased arterial inflow. Magnetic reso- nance perfusion studies in MS show significantly decreased CBF (19). Moreover, decreased CBF has been associated with brain atrophy (20), which is common in RRMS (21). In this study, tCBF tended to be lower among cases, but this was not significant.
There was no typical pattern for MS. However, in a post hoc analysis we were able to construct a centrally located region, based on the distribution in controls, where the MS cases were underrepresented. This may indicate a more prominent lateralization of IJV outflow in MS, and/or an altered balance between flow in IJV and other veins. Due to the small sample size of the present study and the overlapping distributions, this tendency was impossible to ininterpret and merely encourages further investigation, but does not support any vascular treatment procedures. As MS-CCSVI has been described, with IJV insufficiency in 94% (33 of 35) of RRMS cases, and almost never present in controls, this case-control study should have had sufficient power to detect a difference (2). We did not investigate all aspects of the MS-CCSVI hypothesis, but impaired IJV flow is reported as central (2), and we believe that PCMRI is an optimal method to assess the presence of pathogenically significant venous reflux or stenoses.
In conclusion, by the use of PC-MRI we were not able to reproduce the findings reported to be associated with the suggested vascular MS hypothesis MS-CCSVI. In particular, we were unable to see the pronounced differences previously noted between MS cases and controls.
Further and larger case-control studies of MS venous flow are still needed and may include estimation of azygous venous flow by PC-MRI. If MS-CCSVI is an entity associated with MS, the association is likely to be weaker than previously reported, and most importantly, we found no support for a treatment rationale of endovascular procedures like angioplasty or stenting.

Acknowledgments

This project was funded by the Swedish research council, Vinnova, and the Foundation for Strategic Research, through their joint initiative Biomedical Engineering for Better Health, and by the Objective 2 Norra Norrland– European Union Structural Fund.

Authorship

P.S. and A.W. contributed equally.

Potential Conflicts of Interest

Nothing to report.

References

1. Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab 2009;29:1867–1878.
2. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.
3. Zamboni P, Galeotti R, Menegatti E, et al. A prospective openlabel study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009;50:1348.e1–3–1358. e1–3.
4. Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci 2009;282:21–27.
5. Zamboni P, Menegatti E, Weinstock-Guttman B, et al. The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Funct Neurol 2009;24:133–138.
6. Doepp F, Paul F, Valdueza JM, et al. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010; 68:173–183.
7. Khan O, Filippi M, Freedman MS, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010;67: 286–290.
8. Pelc LR, Pelc NJ, Rayhill SC, et al. Arterial and venous blood flow: noninvasive quantitation with MR imaging. Radiology 1992; 185:809–812.
9. McCauley TR, Pena CS, Holland CK, et al. Validation of volume flow measurements with cine phase-contrast MR imaging for peripheral arterial waveforms. J Magn Reson Imaging 1995;5: 663–668.
10. Barkhof F, Kouwenhoven M, Scheltens P, et al. Phase-contrast cine MR imaging of normal aqueductal CSF flow. Effect of aging and relation to CSF void on modulus MR. Acta Radiol 1994;35: 123–130.
11. van Everdingen KJ, Visser GH, Klijn CJ, et al. Role of collateral flow on cerebral hemodynamics in patients with unilateral internal carotid artery occlusion. Ann Neurol 1998;44:167–176.
12. Wåhlin A, Ambarki K, Birgander R, et al. Assessment of craniospinal pressure-volume indices. Am J Neuroradiol (in press).
13. Evans AJ, Iwai F, Grist TA, etal. Magnetic resonance imaging of blood flow with a phase subtraction technique. In vitro and in vivo validation. Invest Radiol 1993;28:109-115.
14. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria.”.Ann Neurol 2005;58:840–846.
15. Sundstrom P, Svenningsson A, Nystrom L, Forsgren L. Clinical characteristics of multiple sclerosis in Vasterbotten County in northern Sweden. J Neurol Neurosurg Psychiatry 2004;75: 711–716.
16. Bradley WG Jr, Scalzo D, Queralt J, etal. Normal-pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at MR imaging. Radiology 1996;198:523–529.
17. Enzmann DR, Pelc NJ. Cerebrospinal fluid flow measured by phase-contrast cine MR. AJNR Am J Neuroradiol 1993;14: 1301–1307; discussion 1309–1310.
18. Stoquart-Elsankari S, Lehmann P, Villette A, et al. A phasecontrast MRI study of physiologic cerebral venous flow. J Cereb Blood Flow Metab 2009;29:1208–1215.
19. Inglese M, Adhya S, Johnson G, et al. Perfusion magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis. J Cereb Blood Flow Metab 2008;28:164–171.
20. Appelman AP, van der Graaf Y, Vincken KL, et al. Total cerebral blood flow, white matter lesions and brain atrophy: the SMART-MR study. J Cereb Blood Flow Metab 2008;28:633–639.
21. Chard DT, Griffin CM, Rashid W, etal. Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis. Mult Scler 2004;10:387–391.