Chronic Cerebrospinal Venous Insufficiency

Chronic cerebrospinal venous insufficiency (CCSVI), the new vascular theory of multiple sclerosis (MS) set forward by Zamboni,^1,2 has raised a wave of controversy, leading to numerous publications aiming to define the pathology and its causes, as well as offering strategies to correct it. Zamboni’s vascular hypothesis states that MS is caused by the obstruction at different vein levels, namely the internal jugular veins (IJVs), azygos vein (AV), and vertebral veins.^1,2

In a recent review article, ³ our group presented strong evidence that the route of CCSVI might stem from cardiovascular autonomic system (ANS) dysfunction in general and sympathetic dysfunction in particular. ANS dysfunction could lead to dysregulation in the arterial blood pressure^4,5 and cerebral perfusion pressure, reducing cerebral blood flow.^6,7 The dysfunction of this system can also impair cerebral autoregulation, ⁸ reducing transmural pressure and increasing the critical closure pressure (CrCP).^9,10 Alterations in the CrCP have the potential to contribute to the compression or the collapse of the cerebral venous system, especially that of the IJVs because of their cytoarchitectural construction. Furthermore, the low sympathetic outflow leads also to suboptimal central venous pressure, hindering the reopening of the IJVs after their collapse due to orthostatic challenge. ¹¹

The relationship between CCSVI and ANS dysfunction is further strengthened by the coexistence of CCSVI with clinical symptoms, such as cognitive impairment, fatigue, sleeping disorders, headache on awakening, and thermal intolerance. ⁵ Cardiovascular ANS dysfunction is known to contribute to these clinical entities.^12–16 Furthermore, the coexistence of CCSVI and cardiovascular ANS dysfunction has been reported in other autoimmune and neurological diseases.^17,18

We propose that ANS dysfunction–derived hemodynamic impairment can lead to morphological and metabolic changes, recently observed in the IJVs. ¹⁹ A series of studies by Zamboni and colleagues^20–22 report morphological changes involving IJV calcification, often observed in the adventitia microvessels. ²⁰ The calcification patterns resemble those observed in the arterial system using similar analytical techniques.^23,24 In addition, changes in the structure of the IJVs’ endothelial cells and alterations in the patterns of their deposition were observed. ²⁰ Endothelial cells were often absent in the intraluminal obstacles and replaced by fibrous lamina; the latter was encapsulated with microreticulate-containing spheric lipid particles. ²¹

The same group also reported an increase in the proportions of type III to type I collagen within the adventitia, ²² with possible adverse effects on the vessel wall elastic properties and vessel wall thickness. These venous-related pathological changes have close similarity to hemodynamic impairment–induced arterial remodeling, arterial hardening, and stenosis, a process known as atherosclerosis. ²⁵

The involvement of ANS dysfunction in venous remodeling is supported by a study involving a porcine model of progressive central pulmonary venous (PV) obstruction. PV banding is known to be associated with pulmonary venous remodeling, involving alterations in elastin and collagen structure and an increase in their synthesis. ²⁶ In addition, a surgically created arteriovenous (AV) fistula, used to treat kidney failure patients, is a common example where hemodynamic alterations can lead to vessel remodeling and AV graft stenosis. ²⁷

We propose that ANS dysfunction–induced hemodynamic impairment is a trigger for the venous remodeling, leading ultimately to “venosclerosis.” However, the comparison between IJVs from patients with MS and control subjects did not uncover significantly higher T cell infiltrates in the diseased veins compared with the control veins.

A recent study involving a porcine AV fistula model showed an early increase in macrophage infiltration on the second day after the creation of the AV fistula, with a rapid disappearance of the infiltrate on the seventh day. ²⁸ These results suggest that immune cell infiltration may occur early in the process of venous remodeling and be transient in nature. Furthermore, in a porcine model of coronary artery injury, Bayes-Genis et al ²⁹ reported the transformation of the early macrophage infiltrates into myofibroblasts. Whether the microreticulate-containing spheric lipid particles observed by the Zamboni group ²¹ present the transformation of early macrophage infiltrates into fibrotic tissue is currently unknown.

The absence of immune cell infiltrates in the diseased veins may also be related to the differences in the flow dynamics between the arterial and venous systems. In the porcine model of the AV fistula, created between the femoral artery and vein, the level of macrophage infiltration closely correlated with the level of vessel wall shear stress. ²⁸ Therefore, in the venous system, which has 15 times less physiological shear stress compared with artery (1 vs 15 dyne/cm², respectively), ³⁰ one can expect little or no macrophage infiltration.

Whether ANS dysfunction–induced hemodynamic impairment contributes to the reported high rate of cerebral venous thromboembolic events, observed especially in patients with progressive MS^31,32 is unknown. Although these occurrences are attributed to lumbar puncture and the use of high dose steroids, the underlying causes remain mostly obscure. ³³ In addition, the lower-than-normal sympathetic outflow has the potential to reduce the risk of ischemic stroke, ³⁴ ischemic heart disease, and myocardial infarction ³⁵ in patients with MS, although some studies report otherwise.^31,35,36

Modalities that improve ANS function and prevent venous remodeling may be effective in minimizing, preventing, and perhaps correcting CCSVI. ³⁷ Consistent with this conclusion, our group has recently shown that venous angioplasty normalizes blood pressure deviation in CCSVI-positive MS patients. ⁵ Our results suggest that the reported efficacy of venous angioplasty in MS patients may be related to the improvement in ANS function.

Venous angioplasty can activate the sympathetic branch of the ANS by increasing the central venous pressure, which can in turn activate the high pressure baroreceptors. ³⁸ However, venous distention alone has been shown to activate the sympathetic function, independent of changes in volume. ³⁹ In addition, the efficacy of 25-hydroxy vitamin D in MS may be related to its ability to beneficially influence ANS function, ⁴⁰ preventing subsequent venous remodeling, ⁴¹ a pathological process associated with the occurrence of CCSVI lesions.