Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis

P Zamboni, R Galeotti, E Menegatti, A M Malagoni, G Tacconi, S Dall'Ara, I Bartolomei, F Salvi, P Zamboni, R Galeotti, E Menegatti, A M Malagoni, G Tacconi, S Dall'Ara, I Bartolomei, F Salvi

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.

Conflict of interest statement

Competing interests: None.

Figures

Figure 1
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
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
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
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.

References

    1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000;343:938–52
    1. Frohman EM, Racke MK, Raine CS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 2006;354:942–55
    1. Ge Y, Zohrabian VM, Grossman RI. Seven-Tesla magnetic resonance imaging. New vision of microvascular abnormalities in multiple sclerosis. Arch Neurol 2008;65:812–16
    1. Kermode AG, Thompson AJ, Tofts P, et al. Breakdown of the blood–brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 1990;113:1477–89
    1. Kidd D, Barkhof F, McConnell R, et al. Cortical lesions in multiple sclerosis. Brain 1999;122:17–26
    1. Tan IL, van Schijndel RA, Pouwels PJ. MR venography of multiple sclerosis. Am J Neuroradiol 2000;21:1039–42
    1. Fog T. The topography of plaques in multiple sclerosis with special reference to cerebral plaques. Acta Neurol Scand Suppl 1965;15:1–161
    1. Schaller B. Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Rev 2004;46:243–60
    1. Valdueza JM, von Munster T, Hoffman O, et al. Postural dependency of the cerebral venous outflow. Lancet 2000;355:200–1
    1. Gisolf J, van Lieshout JJ, van Heusden K, et al. Human cerebral venous outflow pathway depends on posture and central venous pressure. J Physiol 2004;560:317–27
    1. Schreiber SJ, Lurtzing F, Gotze R, et al. Extrajugular pathways of human cerebral venous blood drainage assessed by duplex ultrasound. J Appl Physiol 2003;94:1802–5
    1. Doepp F, Schreiber SJ, von Münster T, et al. How does the blood leave the brain? A systematic ultrasound analysis of cerebral venous drainage patterns. Neuroradiology 2004;46:565–70
    1. Nedelmann M, Eicke BM, Dieterich M. Functional and morphological criteria of internal jugular valve insufficiency as assessed by ultrasound. J Neuroimaging 2005;15:70–5
    1. Sander K, Sander D. New insights into transient global amnesia: recent imaging and clinical findings. Lancet Neurol 2005;4:437–44
    1. Lichtenstein D, Saïfi R, Augarde R, et al. The Internal jugular veins are asymmetric. Usefulness of ultrasound before catheterization. Intensive Care Med 2001;27:301–5
    1. Baumgartner RW, Nirkko AC, Müri RM, et al. Transoccipital power-based color-coded duplex sonography of cerebral sinuses and veins. Stroke 1997;28:1319–23
    1. Stolz DE, Kaps M, Kern A, et al. Reference data from 130 volunteers transcranial color-coded duplex sonography of intracranial veins and sinuses. Stroke 1999;30:1070–5
    1. Zamboni P, Menegatti E, Bartolomei I, et al. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res 2007;4:252–8
    1. Menegatti E, Zamboni P. Doppler haemodynamics of cerebral venous return. Curr Neurovasc Res. In press.
    1. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” Ann Neurol 2005;58:840–6
    1. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006;129:606–16
    1. Lublin DF, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907–11
    1. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability scale (EDSS). Neurology 1983;33:1444–52
    1. Raju S, Hollis K, Neglen P. Obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. J Vasc Surg 2006;44:820.
    1. Lee BB, Villavicencio L, Kim YW, et al. Primary Budd–Chiari syndrome: outcome of endovascular management for suprahepatic venous obstruction. J Vasc Surg 2006;43:101–8
    1. Uflacker R. Atlas of vascular anatomy. An angiographic approach Philadephia: Lippincot, Williams & Wilkins, 1997:81–112, 131–42
    1. Leriche H, Aubin ML, Aboulker J. Cavo-spinal phlebography in myelopathies. Stenoses of internal jugular and azygos veins, venous compressions and thromboses. Acta Radiol Suppl 1976;347:415–17
    1. Tzuladze II. The selective phlebography of the large tributaries of the vena cava system in the diagnosis of venous circulatory disorders in the spinal complex. Zh Vopr Neirokhir Im N N Burdenko 1999;2:8–13
    1. Franceschi C. Physiopathologie hémodinamique de l’insuffisance veineuse des membres inferieurs. Kieffer E, Bahnini A, eds. Chirurgie des veines des membres inferieurs Paris: Editions AERCV; 1996:19–53
    1. Brex PA, Ciccarelli O, O'Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;17:158–64
    1. Ingle GT, Stevenson VL, Miller DH, et al. Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain 2003;126:2528–36
    1. Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. The clinical features and natural history of primary progressive multiple sclerosis. Brain 1999;122:625–39
    1. Schelling F. Damaging venous reflux into the skull or spine: relevance to multiple sclerosis. Med Hypotheses 1986;21:141–8
    1. Talbert DG. Raised venous pressure as a factor in multiple sclerosis. Med Hypotheses 2008;70:1112–17
    1. Labropoulos N, Borge M, Pierce K, et al. Criteria for defining significant central vein stenosis with duplex ultrasound. J Vasc Surg 2007;46:101–7
    1. Zamboni P. Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 2006;99:589–93
    1. Saphir O, Lev M. Venous valvulitis. AMA Arch Pathol 1952;53:456–69
    1. Tremlett HL, Oger J. Ten years of adverse drug reaction reports for the multiple sclerosis immunomodulatory therapies: a Canadian perspective. Mult Scler 2008;14:94–105

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe