Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis

Abstract

Background: The extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have not previously been investigated.

Methods: Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases and older controls not affected by neurological diseases but scheduled for venography (HAV-C) blindly underwent a combined transcranial and extracranial colour-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCS-ECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement.

Results: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29 to 65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; this provides a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated with CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher.

Conclusion: CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterised by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.

Figure 1

B-mode detection of venous stenosis. (A) Right cervical side, high-resolution B-mode image, transversal access: common carotid artery (CC) with cerebral inflow (red), and right internal jugular vein (IJVr) with regular cerebral outflow (blue). (B) Same patient, left side: stenoses of the left internal jugular vein (IJVl) due to annulus (black arrows) with reflux (red) and severe reduction of the lumen.

Figure 2

(A) Selective venography of the azygous vein in a control case (HAV-C) (a) and in MS cases (b, c, d). (a) Normal azygous vein, azygous arch and descending trunk (AZY); H, heart; SVC, superior vena cava. (b) Twisting (arrow) just below the azygous arch. (c) Membranous obstruction (arrow) at the junction of the AZY with the SVC. (d) Septum (arrow) of the proximal AZY. (B) Selective venography of the internal jugular vein (IJV) in a control case (HAV-C) (e) and in multiple sclerosis (MS) cases (f, g, h). (e) Normal right IJV (IJVr) with normal outflow and without stenosis after injection. (f) Annulus of the left jugular vein, JVl (IJVl, arrow) at the junction with the brachiocephalic trunk (BCT). (g) Closed stenosis of the IJVl (arrow) with reflux after injection and collateral circles (CC) depicted by small arrows. (h) Annulus of the IJVr (arrow) with reflux and activation of numerous cervical collateral circles involving the thyroid veins (CC); one of them re-enters the SVC. (C) Selective venography of the lumbar veins in a control case (HAV-C) (i) and in MS cases (j, k, l). (i) Selective venography of the ascending lumbar vein (LV) from the iliac vein (IV): normal appearance with characteristic hexagonal shape of the intrarachidian plexus draining outward into the LV and upward to the azygous system. (j, k, l) Dramatic bare venous lumbar tree in MS cases with combination of agenesia and atresia. This picture is further associated with multilevel stenosis of the azygous system configuring the chronic cerebrospinal venous insufficiency type D pattern.

Figure 3

Patterns of chronic cerebrospinal venous insufficiency observed in multiple sclerosis (MS) cases. Normal: example of normal extracranial venous outflow direction. In particular, the black arrows depict the drainage of the internal jugular vein (IJV) system into the superior vena cava (SVC), and of the vertebral plexus (Vplex) outward from the spinal cord into the azygous system (AZY). Type A (30%): this pattern is characterised by a steno-obstruction of the proximal azygous, associated with a closed stenosis of one of the two IJVs (red crosses). Reflux is always present, under all postural conditions, in the stenosed IJV (red arrow), with a compensatory controlateral IJV that appears with an ample cross-sectional area of the IJV. Reflux in the deep cerebral veins (DCVs) was detected by means of transcranial colour-coded Doppler sonography in 60% of cases. In the azygous vein the reflux has an effect as far as the lumbar veins, being able to re-enter the caval circle either through the system of the hemiazygous vein–left renal vein, or by rising again inside the rachis. Type B (38%): this pattern is characterised by significant stenoses of both IJVs and the proximal azygous (red crosses). Reflux is present in all three venous segments (red arrows). Cerebral venous outflow for overcoming the IJVs stenosis re-enters the heart mainly through cervical collateral circles (fig 1B); for the hampered azygous vein outflow, the collateral circles include again the intrarachidian pathway, or the system of the renal-hemiazygous. Type C (14%): this pattern is characterised by bilateral stenosis in both IJVs, with a normal azygous system (red crosses). Reflux (red arrows) occurs in the IJVs but not in the vertebral veins, with cervical or intracranial collateral circles that shunt blood towards the superior vena cava or the azygous vein system, respectively. The resulting overload of the azygous system is depicted by black bold arrows. Type D (18%): in this pattern the azygous system was constantly affected in various segments (red crosses), resulting in a forced venous drainage towards the intrarachidian circles in an upward direction (red arrows). The vertebral veins appeared to be refluent, and the intracranial collateral circles seek to gain the IJVs, as confirmed by reflux detection in DCVs in 90% of cases. At times, the IJVs were also affected (six cases, 50%), causing an additional obstruction in these patients. IVC, inferior vena cava; L-REN, left renal vein.

Figure 4

Selective venography and MRI in a clinically defined multiple sclerosis case with chronic cerebrospinal venous insufficiency pattern D. Left: selective venography showing membranous obstruction of the outlet of the azygous vein (AZY) combined with atresia of the descending azygous vein (arrow). Due to multilevel obstruction of the azygous system, the vertebral plexus is dilated below the atresia, and the blood is drained through intrarachidian collateral circles (IRC) in an upward direction. Top right: sagittal T1 weighted imaging after gadolinium injection of the same case, showing typical multiple sclerosis lesions of the spinal cord. The enhanced gadolinium image shows intrarachidian venous plexuses in the form of small spots. Bottom right: axial merge T2 of the same patient at the cervical level with dilated extrarachidian venous plexuses. SVC, superior vena cava.