Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system of unknown origin. Since the time of Charcot, a relationship between the cerebral veins and the inflammatory lesions associated with MS has been consistently reported (1,2). Observations have been made that the periventricular lesions of MS seem to extend along cerebral veins and that the cortical lesions occur within territory drained by cortical veins (1,3-5). Additional post-mortem studies have confirmed the relationship between the lesions of MS and the small veins of the CNS (6-8). For example, Fog showed that MS plaques arise from segments of large epiventricular veins and then extend into the cerebral hemispheres along the cerebral veins (6). In addition, Putnam showed plaques lined with gliotic tissue containing large veins, surrounded by hematogenous pigment (7). While these observations imply a connection between the cerebral veins and MS, this connection was felt to be interesting but was largely ignored.
As MRI became a primary way of evaluating patients with MS, the potential connection between the cerebral venous circulation and MS was once again observed. Studies showed that patients with MS have cerebral blood flow disturbances, including decreased cerebral blood flow, decreased cerebral blood volume, and a prolonged mean transit time (9-12). These findings were felt by some to be due to vascular pathology and not a result of decreased metabolic demand (10,13). However, the cause of the abnormal flow was never fully explained. MR venography has also been helpful in directly demonstrating the relationship between the inflammatory lesions of MS and the cerebral veins (14).
Histologic studies of the venous system in MS have potentially shed some light on this relationship. These studies have shown evidence of both pericapillary fibrin cuffs and perivenous iron deposits in the form of extracellular hemosiderin and iron-laden macrophages (8,15,16). In addition, MRI has been able to detect these perivenous iron deposits (17-19). Iron is known to be important for CNS physiology since it is a cofactor for neural metabolism and ATP production and because it is involved in myelination and oligodendrocyte development (20,21). In addition, a role for iron in the pathophysiology of senile toxicity and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has been described (22-24), possibly due to oxidative stress and free-radical generation (18,25,26).
Interestingly, there appears to be a possible role for iron in the inflammation associated with MS, although investigations into this role are limited (20). For example, Grant, et al. found that the incidence of encephalomyelitis (EAE) in mice, which is often used as an experimental for MS, was 60-70% in mice with a normal iron level and in iron-overloaded mice, but 0% in iron-deficient mice, suggesting that iron-deficiency is protective against EAE (27). Similarly, Sfagos found higher levels of serum ferritin and soluble transferring receptors in active MS than in controls (28). Both of these findings support the hypothesis that local iron-overload may be the initial signal of the inflammatory chain in MS (2).
This relationship between the venous circulation and iron deposition has been better explored in patients with chronic venous insufficiency in the lower extremities (2). In the lower extremities, venous reflux and venous obstruction are known to cause multiple problems including varicose veins, edema, skin changes (including pigmentation, lipodermatosclerosis, etc.), and ultimately venous ulcers. Studies have demonstrated a relationship between tissue iron accumulation and the inflammatory changes associated with chronic venous insufficiency (29-32). In the lower extremities, venous stasis can lead to extravasation of red blood cells. The degradation of these cells causes iron to be released, ultimately leading to its incorporation into ferritin, hemosiderin deposition, and inflammatory change (2). In addition, both chronic venous reflux and local iron overload may activate matrix metalloprotease (MMP) in the vein wall, which can lead to the degradation of collagen, elastin, and laminin, resulting in tissue breakdown and ulcer formation (33-36). Finally, the presence of a pericapillary fibrin cuff has been shown around the lower extremity vasculature in these patients and is considered a marker of insufficient venous drainage.
One of the reasons why the correlation between venous abnormalities and MS has been explored recently is because histologic changes similar to those seen in chronic venous insufficiency of the lower extremities have been found in association with MS. A pericapillary fibrin cuff is consistently found in patients with MS (8,15,16), which is important since fibrin deposition is thought to exacerbate axonal injury in MS patients (37). In addition, it is known that MMP activation has a role in MS by digesting basement-membrane collagen and fibronectin, thereby facilitating the migration of cells and proteins into the CNS, perhaps inciting the inflammatory response characteristic of MS (38-40). Cellular migration may involve red blood cells and their degradation can lead to increased iron deposition. As stated previously, perivenous iron deposits have been found on both MR imaging studies and histologic studies in MS patients.
While the histologic findings described above seem to support similarities between MS and chronic venous insufficiency, recent descriptions of venous abnormalities in MS patients have lent additional support to the theory of Chronic Cerebrospinal Venous Insufficiency (CCSVI). Zamboni, et al used Doppler ultrasound to evaluate the venous circulation in patients with MS (41,42). The findings that were seen significantly more often in MS patients than in normal controls included constant reflux in the internal jugular and/or vertebral veins, reflux in the deep cerebral veins, indetectable flow in the internal jugular and/or vertebral veins, and a defined stenosis of the internal jugular veins. Patients with positive Doppler examinations were subsequently studied with selective venography, which showed that CCSVI is characterized by multiple extracranial stenoses involving the internal jugular and azygous veins (43). More recently, Zivadinov, et al reported on the preliminary data from the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study at the 2010 meeting of the American Academy of Neurology (44). This study evaluated 441 patients (280 patients with MS and 161 healthy controls) and found that the prevalence of CCSVI in MS patients was 56.4% and in healthy controls, it was 22.4%. When the 10.2% of subjects in which the results were borderline were excluded, the percentage of affected MS patients rose to 62.5% compared to 25.9% of healthy controls.
Zamboni, et al were able to define four main patterns of extracranial disease in MS patients based on involvement of the internal jugular and/or azygous veins. It was felt that these disease patterns may occur more frequently in different forms of MS (41,45). For example, the form involving the azygous vein may be more common in patients with the primary progressive form of MS, which correlates with the fact that spinal plaques are often seen in these patients. It was therefore theorized that the location of venous obstruction might play a key role in determining the clinical course of MS.
Importantly, the internal jugular and azygous veins represent the primary routes for venous outflow from the CNS. Extracranial Doppler studies have shown that the internal jugular veins are the predominant pathways for drainage when a patient is in the supine position and that the vertebral veins are the primary pathways when a patient is upright (46,47). When flow in the internal jugular veins and/or azygous vein is compromised, it can have physiologic implications for cerebral blood flow. Collateral vessels develop in order to prevent the development of intracranial venous hypertension (48,49). However, even with these collateral pathways in place, the venous drainage is insufficient and the transit time is prolonged, as confirmed by MR perfusion studies (10,48,49). This can lead to several problems. Since normal CSF circulation depends on efficient venous drainage from the CNS (50-52), insufficient venous drainage can lead to lower net CSF flow. This is supported by the increases in the volume of the lateral and third ventricles in MS patients (51). Insufficient venous drainage can also cause retrograde venous flow and reflux into the CNS (49), which has been demonstrated in the deep cerebral veins and transverse sinus in MS patients (53). Based on the Doppler studies performed by Zamboni, et al, the reflux occurs in any body position and without being elicited by a forced movement, which suggests that the reflux is due to a stenosis or occlusion as opposed to valvular incompetence (41).
The presence of chronic reflux and flow reversal in the cerebral venous system can lead to increases in the peak diastolic velocity of blood, which increases the resistance to flow (53). The microcirculation can then become overloaded and transmural pressure becomes increased (35,54). Even before any discussions about CCSVI, venous hypertension was thought to play a role in the pathogenesis of MS (55,56). It is thought that slight increases in venous pressure can lead to venous dilatation, which can potentially separate the endothelial cells forming the blood brain barrier (57). This can enable cells, including red blood cells, to pass through the blood brain barrier and initiate the perivenular inflammatory process that is seen in MS (2,53). In MS, changes in microcirculatory perfusion parameters on MRI have been shown to precede plaque formation (58). These ideas may explain the venous distribution of MS lesions.
With this in mind, Zamboni, et al treated 65 MS patients with CCSVI that was diagnosed on Doppler ultrasound (59). These patients underwent selective venography of the internal jugular and azygous veins from a common femoral vein approach. A significant stenosis was considered a venous lumen reduction >50%, which correlated with a pressure gradient of 2.2 cm/H20. All of these procedures were performed as outpatient procedures. All patients were treated with angioplasty, which led to improved luminal diameter and reduced venous pressures. Six patients reported a post-operative headache, which resolved spontaneously in all patients. No other operative or postoperative complications were reported. Patients were followed with repeat Doppler ultrasound and venography at 18 months. At the completion of follow-up 96% of lesions treated in the azygous vein were patent and 53% of lesions treated in the internal jugular veins were patent; many of these patients underwent secondary angioplasty but the long-term patency after this second intervention has not yet been studied. Zamboni also showed sustained clinical improvement in relapsing-remitting patients as evidenced by significant improvement in the Multiple Sclerosis Functional Composite (MSFC). However, only limited improvement was seen in patients with primary and secondary progressive MS. All of the relapsing-remitting patients with continued patency of the internal jugular and azygous veins at 18 months were relapse-free. In addition, there were reductions in enhancing lesions on the MRI studies performed in these patients one year after treatment. This study concluded that endovascular treatment of CCSVI using angioplasty is feasible and safe.
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