Pathophysiology and treatment of chronic cerebrospinal venous insufficiency: a review of new concepts

Reviewed by
Marian SIMKA, Katowice, Poland

Multiple sclerosis (MS) is a chronic disease of the central nervous system of as yet undetermined etiology. For the time being the ruling MS paradigm is the autoimmune one, which means that that this disease is caused by autoimmune attack against nervous tissue. How such an autoimmune reaction is initiated, however, remains unclear. Moreover, several findings from human studies, especially regarding the neurodegenerative aspect of MS, do not fit into this autoimmune dogma.

Recently, a unique vascular pathology called chronic cerebrospinal venous insufficiency (CCSVI) has been described.⁴ It comprises of stenoses and occlusions in extracranial veins (primarily: the internal jugular veins and the azygous vein) draining the central nervous system. Since CCSVI has been found to be highly associated with MS, this coexistence has shed new light on the potential cause of MS. Consequently, it has been suggested that CCSVI may be responsible for initiation and/or progression of inflammatory and neurodegenerative processes. This hypothetical role for CCSVI is not necessarily contrary to the currently accepted model of MS, since it is known, for example, that chronic venous insufficiency in the lower extremities also triggers an inflammatory reaction in the affected tissues. Mechanisms by which CCSVI evokes neurological pathology remain unknown, but some hypotheses have been proposed. For example, it was suggested that inflammation and neurodegeneration may develop due to the excess iron that is stored within nervous parenchyma in settings of venous insufficiency. Also, it was conjectured that a pathologic pattern of venous flow leads to disassembling of the blood-brain barrier, which in turn allows penetration of nervous tissue by immune cells and by glutamate (substance known to be toxic to neurons). Also, CCSVI was suspected to be the main cause of brain hypoperfusion, the phenomenon thought to be responsible for MS symptoms such as chronic fatigue, depression and impaired cognitive functions.⁶ Yet, the question whether CCSVI directly triggers MS, or only contributes to its further progression, while other factors are responsible for initiation of pathologic processes, should be elucidated by future studies.

Similarly, our knowledge of the clinical significance of CCSVI is very limited. We know that the prevalence of CCSVI among MS patients is very high: CCSVI was found in over 90% of MS patients assessed by catheter venography.³ Yet, we do not know how high this prevalence is in a “healthy” population. Moreover, we do not know if CCSVI found in a person without neurologic symptoms and without lesions revealed by brain MRI is of any clinical relevance.

Currently, Doppler sonography is the main diagnostic test in screening for and diagnosing CCSVI.⁴ However, this imaging technique is highly operator-dependent and the results of this examination, especially if performed by an inexperienced sonographer, should be interpreted with caution. To improve the reliability of Doppler tests, the Consensus Document on ultrasonographic screening for CCSVI has been recently accepted by the International Society for Neurovascular Diseases. Since strong scientific evidence of the specificity and sensitivity of the proposed Doppler criteria is still lacking, it is planned to verify the reliability of these criteria. For this purpose, Doppler sonographic findings will be compared with catheter venography, with the latter serving as the “gold standard”.

Magnetic resonance venography (MRV) is the other commonly used noninvasive test to diagnose CCSVI. Theoretically, MRV could potentially replace other diagnostic methods, it can be combined with structural and functional imaging of the brain and cerebral vessels. Yet as yet there are no widely accepted MRV protocols for the assessment of CCSVI. Moreover, while some researchers have found MRV useful and reliable,¹ others have reported unsatisfactory results.⁷ We should expect that in the future MRV protocols fulfilling the criteria of reliable, noninvasive, and inexpensive diagnostic tools will be elaborated.

Endovascular procedures, primarily balloon angioplasty, remain the main treatment modality for CCSVI. It should be remembered, however, that these treatments are in their infancy and only results of open-label studies have been published so far. Still, all these reports demonstrate the safety of the procedures^3,5 and the positive effects of the treatments,^2,5 thus warranting further studies on this topic. Importantly, two multicenter, prospective, randomized, sham-controlled studies on endovascular treatment for CCSVI in MS patients will be conducted very soon (one in Italy and one in the USA). It is hoped that these studies will verify the safety and clinical efficacy of vascular treatment for CCSVI in patients with associated MS. It is expected also that―at least in some subgroups of the patients―the beneficial effect of such treatments will be proven.

Regarding additional aspects of the detection of CCSVI, it has recently been suggested that further studies, especially on the anatomical distribution and severity of vascular abnormalities, may help identify unique subgroups of MS patients who can benefit from currently available pharmacological treatments.

Figure. Click to enlarge

Complete blockage of the left internal jugular vein caused by a stenotic valve (black arrow) in the junction with the left brachiocephalic vein. The catheter is inserted into the left internal jugular vein (gray arrow), but contrast is flowing out through the collateral network (thin black arrows) and via cerebral sinuses to the right internal jugular vein (white arrow).

References:
1. Hartel M, Kluczewska E, Simka M, et al. Magnetic resonance venography of chronic cerebrospinal venous insufficiency in patients with associated multiple sclerosis Pol Przegl Radiol. 2011;76:59-62.
2. Ludyga T, Kazibudzki M, Latacz P, et al. Early results of a prospective open-label study on endovascular treatments for chronic cerebrospinal venous insufficiency in the patients with associated multiple sclerosis Przeg Flebol. 2011;19:9-14.
3. Ludyga T, Kazibudzki M, Simka M, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology. 2010;25:286-295.
4. 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.
5. Zamboni P, Galeotti R, Menegatti E, et al. Endovascular treatment of chronic cerebrospinal venous insufficiency, A prospective open-label study. J Vasc Surg. 2009;6:1348-1358.
6. Zamboni P, Menegatti E, Weinstock-Guttman B, et al. Hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report BMC Med. 2011:9:22.
7. Zivadinov R, Lopez-Soriano A, Weinstock-Guttman B, et al. Use of MR venography for characterization of the extracranial venous system in patients with multiple sclerosis and healthy control subjects. Radiology. 2011;258:562-570.