En videnskabelig artikel, på engelsk, som på fremragende vis forklarer hvad CCSVI er:
(Kopieret fra
CCSVI Locator)
Denise Manley:
Background Information on CCSVI all in one place!Posted by Ken Torbert
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.
References
1.Charcot JM. Histology of "sclerose en plaque" (in French). Gazette Hosp (Paris) 1868l 41:554-566
2.Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J Royal Soc Med 2006; 99:589-593
3.Barnett MH, Sutton I. The pathology of multiple sclerosis: a paradigm shift. Curr Opin Neurol 2006; 19:242-247
4.Dawson JW. The histology of disseminated sclerosis. Trans R Soc Edinb 1916; 50:517
5.Kidd D, Barkhof F, McConnell R, et al. Cortical lesions in MS. Brain 1999; 122:17-26
6.Fog T. The topography of plaques in multiple sclerosis with special reference to cerebral plaques. Acta Neurol Scand 1965; 15(Suppl):1-161
7.Putnam TJ. Lesions of “encephalomyelitis†and multiple sclerosis. Venous thrombosis as the primary alteration. JAMA 1937; 108:1477
8.Adams CW, Poston RN, Buk SJ. Pathology, histochemistry, and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci 1989; 92:291-306
9.Simka M, Zaniewski. Reinterpreting the magnetic resonance signs of hemodynamic ipairment in the brains of mutiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins. J Neurosci Res 2010
10.Law M, Saindane AM, Ge Y, et al. Microvascular abnormality in relapsing-remitting MSL perfusion MR imaging findings in normal-appearing white matter. Radiology 2004; 231:645-652
11.Varga AW, Johnson G, Babb JS, et al. White matter hemodynamic abnormalities precede sub-cortical gray matter changes in MS. J Neurol Sci 2009; 282:28-33
12.Adhya S, Johnson G, Herbert J, et al. Pattern of hemodynamic impairment in MS: dynamic susceptibility contrast perfusion MR imaging at 3.0T. Neuroimage 2006; 33:1029-1035
13.Ge Y, Law M, Johnson G, et al. Dynamic susceptibility contrast perfusion MR imaging of MS lesions: characterizing hemodynamic impairment and inflammatory activity. Am J Neuroradiol 2005; 26:1539-1547
14.Tan IL, van Schijndel RA, Pouwels PJ. MR venography of multiple sclerosis. Am J Neuroradiol 2000; 21:1039-42
15.Adams CW. Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry 1988; 51:260-5
16.Zamboni P. Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 2006; 99:589-593
17.Haacke EM, Cheng NY, House MJ, et al. Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging 2005; 23:1-25
18.Tjoa CW, Benedict RH, Weinstock-Gutman B, et al. MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J Neurol Sci 2005; 234:17-24
19.Brass SD, Chen NK, Mulkern RV et al. Magnetic resonance imaging of iron deposition in neurological disorders. Top Magn Reson Imaging 2006; 17:31-40
20.Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cerebral Blood Flow and Metabol 2009; 29:1867-1878
21.Todrich B, Pasquini JM, Garcia CI, et al. Oligodendrocytes and myelination: the role of iron. GLIA 2009; 57:467-478
22.Altamura S, Muckenthaler MU. Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease, and atherosclerosis. J Alzheimer Dis 2009; 16:879-895
23.Bush AI. Metals and neuroscience. Curr Opin Chem Biol 2000; 4:184-191
24.Stankiewicz J, Panter SS, Neema M, et al. Iron in chronic brain disrders: imaging and neurotherapeutic implications. Neurotherapeutics: J Am Soc Exp Neurother 2007; 34:371-386
25.Ke Y, Ming, Qian Z. Iron misregulation in the brain a primary cause of neurodegenerative disorders. Lancet Neurol 2003; 4:246-253
26.Thomas M, Jankovic J. Neurodegenerative disease and iron storage in the brain. Curr Opin Neurol 2004; 4:437-442
27.Grant SM, Wiesinger JA, Beard JL, et al. Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutri 2003; 133:2635-2638
28.Sfagos C, Makis AC, Chaidos A, et al. Serum ferritin, transferring, and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler 2005; 11:272-275
29.Zamboni P, Tognazzo S, Izzo M, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 2005; 42:309-314
30.Wenk J, Fotizik A, Achterberg V, et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix degrading metalloproteinase I and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing. Concept J Invest Dermatol 2001; 116:833-839
31.Ackerman Z, Seidenbaum M, Loewenthal E et al. Overload of iron in the skin of patients with venous ulcers. Possible contributing role of iron accumulation in progression of the disease. Arch Dermatol 1988; 124:1376-1378
32.Zamboni P, Izzo M, Fogato L, et al. Urine haemosiderin: a novel marker to assess the severity of chronic venous disease. J Vasc Surg 2003; 37:132-136
33.Zamboni P, Scapoli G, Lanzara V, et al. Serum iron and MMP-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg 2005; 31:644-649
34.Gurjar MV, Deleon J, Sharma RV, et al. Role of reactive oxygen species in IL-1 stimulated sustained ERK activation and MMP-9 inducation. Am J Phys 2001; 281:H2568-H2574
35.Bergen JJ, Schmid-Schonbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med 2006; 355:488-498
36.Sansilvestri-Morel P, Fioretti F, Rupin A, et al. Comparison of extracellular matrix in skin and Saphenous veins from patients with varicose veins: does the skin reflect venous matrix changes? Clin Sci (Lond) 2007; 112:229-239
37.Gveric D, Hanemaaijer R, Newcombe J, et al. Plasminogen activators in multiple sclerosis lesions. Implications for the inflammatory response and axonal damage. Brain 2001; 124:1978-1988
38.Frohman EM, Racke MK, Raine CS. Multiple-sclerosis – the plaque and its pathogenesis. N Engl J Med 2006; 354:942-955
39.Minagar A, Jy W, Jimenez JJ, et al. Multiple sclerosis as a vascular disease. Neurol Res 2006; 28:230-235
40.Fainardi E, Castellazzi M, Bellini T, et al. Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Multiple Sclerosis 2006; 12:294-301
41.Zamboni P, Galeotti P, Menegtti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80:392-399
42.Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci 2009; 282:21-27
43.Zamboni P, Menegatti E, Weinstock-Guttman, et al. The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Functional Neurol 2009; 24:133-13823
44.Zivadinov, R, et al. Preliminary report of the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. 2010 Meeting of the American Academy of Neurology. Toronto, Canada. April, 2010
45.Simka M, Kostecki J, Zaniewski M, et al. Preliminary report on pathologic flow patterns in the internal jugular and vertebral veins of patients with multiple sclerosis. Przegl Flebol 2009; 17:61-64
46.Gisolf J, von Lieshout JJ, van Heusden K, et al. Human erebral venous outflow pathway depends on posture and central venous pressure. J Physiol 2004; 560:317-327
47.Valdueza JM, von Munster T, Hoffman O, et al. Postural dependency of the cerebral venous outflow. Lancet 2000; 355:200-201
48.Zamboni P, Consorti G, Galeotti R, et al. Venous collateral circulation of the extracranial cerebrospinal outflow routes. Curr Neurovasc Res 2009; 6:204-212
49.Franceschi C. The unsolved puzzle of multiple sclerosis and venous function. J Neurol Neurosurg Psychiatry 2009; 80:358
50.Schaller B. Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Rev 2004; 46:243-260
51.Ursino M, Lodi CA. A simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics. J Appl Physiol 1997; 82:1256-1269
52.Kim J, Thacker NA, Bromiley PA, et al. Prediction of the jugular venous waveform using a model of CSF dynamics. Am J Neuroradiol 2007; 28:983-989
53.Zamboni P, Menegatti E, Bartolomei I, et al. Intracranial venous haemodynamics in MS. Curr Neurovasc Res 2007; 4:252-258
54.Zamboni P, Lanzara S, Mascoli F, et al. Inflammation in venous disease. Int Angiol 2008; 27:361-369
55.Schelling F. Damaging venous reflux into the skull or spine: relevance to multiple sclerosis. Med Hypotheses 1986; 21:141-148
56.Talbert DG. Raised venous pressure as a factor in multiple sclerosis. Med Hypotheses 2008; 70:1112-1117
57.West JB, Tsukimoto K, Matheu-Costello O, et al. Stress failure in pulmonary capillaries. J Appl Physiol 1991; 70:1731-1742
58.Wuerfel J, Bellmann-Strobl J, Brunecker P, et al. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 2004; 127:111-119
59.Zamboni P, Galeotti R, Menegatti E, et al. A prospective open label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009; 50:1348-1358
