Venöse Multiple Sklerose | CCSVI

Die Liste der Publikationen zur venösen Multiple Sklerose (MS). Die zu Beginn empfohlenen und besonders wichtigen Forschungsartikel sind kursiv und blau geschrieben. Die Publikationen sind zeitlich geordnet. Falls nicht anders angegeben sind sie in Englisch.

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Publikationen (CCSVI, MRA/MRV, SWI, 2006 – jetzt)

1. [simka10a] Simka M, and Zaniewski M: Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins. J Neurosci Res. 2010 Feb. PMID 20127806, doi:10.1002/jnr.22350.
   Private Healthcare Institution SANA, Department of Angiology, Pszczyna, Poland.
   Abstract

   Multiple sclerosis patients examined with perfusion magnetic resonance (MR) imaging techniques have been found to have patterns of abnormal blood flow. These include prolonged mean transit time, a trend toward decreased cerebral blood flow in the area of plaques, and decreased cerebral blood flow and prolonged mean transit time within normal-appearing white matter. In-creased cerebral blood flow and volume and decreased mean transit time (compared with the baseline values before the relapse) were found to precede the development of plaques. In addition, susceptibility-weighted imaging utilizing deoxyhemoglobin as the contrast has revealed that venous blood in cerebral veins of multiple sclerosis patients is less deoxygenated compared with healthy controls. All these findings were traditionally interpreted as a sign of local flow disturbances mediated by inflammatory and neurodegenerative processes. However, recent findings of significant stenoses in the extracranial veins that drain the brain and spinal cord shed new light on these MR results. With the assumption that a majority, if not all, of multiple sclerosis patients exhibit such extracranial venous obstacles, the perfusion MR images of multiple sclerosis patients should be reinterpreted. Perhaps ongoing MR studies with respect to extracranial venous hemodynamics may decipher some of the unsolved puzzles related to this neurologic disease. (c) 2010 Wiley-Liss, Inc.
2. [qiu10] Qiu W, Raven S, Wu JS, Carroll WM, Mastaglia FL, and Kermode AG: Wedge-shaped medullary lesions in multiple sclerosis. J Neurol Sci. 2010 Jan. PMID 20056253, doi:10.1016/j.jns.2009.12.017.
   Centre for Neuromuscular and Neurological disorders, University of Western Australia, Australia; Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Department of Neurology, the Third Affiliated Hospital of Sun yat-sen University, Guangzhou, China.
   Abstract

   Multiple sclerosis (MS) is a heterogeneous disease with variable clinical features and magnetic resonance imaging (MRI) findings. We report four MS cases with unusual wedge-shaped lesions in the paramedian ventral medulla oblongata demonstrated on MRI. The clinical features and MRI characteristics of the medullary lesions suggest an impairment of venous drainage. We propose that the formation of these wedge-shaped lesions may be related to the pattern of venous drainage in the ventral medulla and raised venous pressure due to chronic cerebrospinal venous insufficiency which has recently been described in MS.
3. [lee09a] Lee BB, Bergan J, Gloviczki P, Laredo J, Loose DA, Mattassi R, Parsi K, Villavicencio JL, and Zamboni P: Diagnosis and treatment of venous malformations Consensus Document of the International Union of Phlebology (IUP)-2009. Int Angiol. 2009 Dec;28(6):434-51. Montecarlo September 4th 2009 [uip09]. This document was approved by experts from 47 different countries. PMID 20087280. PDF$
   Division of Vascular Surgery, Department of Surgery, Center for Vein, Lymphatics, and Vascular Malformation, Georgetown University School of Medicine, Washington, DC, USA.
   Extracts

   The International Union of Phlebology (IUP), the largest international organization devoted to the investigation and management of venous disorders, established an expert panel to formulate guidelines for physicians and health care professionals around the world on the evaluation and treatment of venous malformations (VMs).

   The aim of this document is to provide recommendations for the diagnosis and treatment of VMs based on the best currently available scientific evidence. When scientific evidence was lacking or weak, a consensus of opinions among expert members of the panel was reached to support the recommendations.
   …

   Truncular lesions of obstructive nature (webs, hypoplasia) may have different hemodynamic impacts on their relevant vascular systems depend ing upon their location, extent/severity, and natural compensation through collaterals. Chronic venous insufficiency develops in the territory drained by the truncular vein. Stenosing truncular lesions produce venous obstruction leading to a reduction in venous drainage. Membranous obstruction of the inferior vena cava in primary Budd-Chiari Syndrome is an example of a primary obstructive VM affecting a major vein.

   Truncular VM lesions may also occur in veins with the same embryologic origin or draining the same territory (e.g., stenosing lesions of the extracranial jugular veins, superior vena cava, and azygos vein system along the main outflow pathways of the cerebro-spinal venous system as suspected cause of multiple sclerosis).^96-99
   …

   ⁹⁸ = [zamboni09b]

   Info

   A Consensus Conference on Venous Malformations – headed by Prof. Byung B Lee from Georgetown – and experts from 47 countries – studied the evidence and unanimously voted in favour of officially including the stenosing lesions found in CCSVI in the new Consensus document and Guidelines.
4. [zamboni09h] Zamboni P, Menegatti E, Weinstock-Guttman B, Schirda C, Cox JL, Malagoni AM, Hojanacki D, Kennedy C, Carl E, Dwyer MG, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, and Zivadinov R: The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Funct Neurol. 2009 Jul-Sep ;24(3):133-8. PMID 20018140. PDF.
   Abstract

   Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular picture that shows a strong association with multiple sclerosis (MS). The aim of this study was to investigate the relationship between a Doppler cerebral venous hemodynamic insufficiency severity score (VHISS) and cerebrospinal fluid (CSF) flow dynamics in 16 patients presenting with CCSVI and relapsing-remitting MS (CCSVI-MS) and in eight healthy controls (HCs). The two groups (patients and controls) were evaluated using validated echo-Doppler and advanced 3T-MRI CSF flow measures. Compared with the HCs, the CCSVI-MS patients showed a significantly lower net CSF flow (p=0.027) which was highly associated with the VHISS (r=0.8280, r2=0.6855; p=0.0001). This study demonstrates that venous outflow disturbances in the form of CCSVI significantly impact on CSF pathophysiology in patients with MS.
5. [zamboni09g] Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, and Salvi F: A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009 Dec;50(6):1348-58.e1-3. PMID 19958985, doi:10.1016/j.jvs.2009.07.096. Presented at the Thirty-first Charing Cross Symposium, London, United Kingdom, Apr 3–7, 2009 [cx09]. Abstract, PDF, Deutsche Übersetzung, preliminary results: [zamboni09c]
   Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
   Abstract

   OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by combined stenoses of the principal pathways of extracranial venous drainage, including the internal jugular veins (IJVs) and the azygous (AZY) vein, with development of collateral circles and insufficient drainage shown by increased mean transit time in cerebral magnetic resonance (MR) perfusion studies. CCSVI is strongly associated with multiple sclerosis (MS). This study evaluated the safety of CCSVI endovascular treatment and its influence on the clinical outcome of the associated MS. METHODS: Sixty-five consecutive patients with CCSVI, subdivided by MS clinical course into 35 with relapsing remitting (RR), 20 with secondary progressive (SP), and 10 with primary progressive (PP) MS, underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months. Vascular outcome measures were postoperative complications, venous pressure, and patency rate. Neurologic outcome measures were cognitive and motor function assessment, rate of MS relapse, rate of MR active positive-enhanced gadolinium MS lesions (Gad+), and quality of life (QOL) MS questionnaire. RESULTS: Outpatient endovascular treatment of CCSVI was feasible, with a minor and negligible complication rate. Postoperative venous pressure was significantly lower in the IJVs and AZY (P < .001). The risk of restenosis was higher in the IJVs compared with the AZY (patency rate: IJV, 53%; AZY, 96%; odds ratio, 16; 95% confidence interval, 3.5-72.5; P < .0001). CCSVI endovascular treatment significantly improved MS clinical outcome measures, especially in the RR group: the rate of relapse-free patients changed from 27% to 50% postoperatively (P < .001) and of MR Gad+ lesions from 50% to 12% (P < .0001). The Multiple Sclerosis Functional Composite at 1 year improved significantly in RR patients (P < .008) but not in PP or SP. Physical QOL improved significantly in RR (P < .01) and in PP patients (P < .03), with a positive trend in SP (P < .08). Mental QOL showed significant improvement in RR (P < .003) and in PP (P < .01), but not in SP. CONCLUSIONS: PTA of venous strictures in patients with CCSVI is safe, and especially in patients with RR, the clinical course positively influenced clinical and QOL parameters of the associated MS compared with the preoperative assessment. Restenosis rates are elevated in the IJVs but very promising in the AZY, suggesting the need to improve endovascular techniques in the former. The results of this pilot study warrant a subsequent randomized control study.
6. [zamboni09f] Zamboni P, Menegatti E, Weinstock-Guttman B, Schirda C, Cox JL, Malagoni AM, Hojanacki D, Kennedy C, Carl E, Dwyer MG, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, and Zivadinov R: The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Funct Neurol. 2009 Jul-Sep ;24(3):133-8. PMID 20018140. PDF$
   Abstract

   Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular picture that shows a strong association with multiple sclerosis (MS). The aim of this study was to investigate the relationship between a Doppler cerebral venous hemodynamic insufficiency severity score (VHISS) and cerebrospinal fluid (CSF) flow dynamics in 16 patients presenting with CCSVI and relapsing-remitting MS (CCSVI-MS) and in eight healthy controls (HCs). The two groups (patients and controls) were evaluated using validated echo-Doppler and advanced 3T-MRI CSF flow measures. Compared with the HCs, the CCSVI-MS patients showed a significantly lower net CSF flow (p=0.027) which was highly associated with the VHISS (r=0.8280, r2=0.6855; p=0.0001). This study demonstrates that venous outflow disturbances in the form of CCSVI significantly impact on CSF pathophysiology in patients with MS.
7. [zivadinov09] Pirko I, and Zivadinov R: Transcranial sonography of deep gray nuclei: a new outcome measure in multiple sclerosis? Neurology. 2009 Sep;73(13):1006-7. Epub 2009 Aug 26. Type: Comment. PMID 19710403, doi:10.1212/WNL.0b013e3181bb1de9. Article$
8. [tallantyre09] Tallantyre EC, Morgan PS, Dixon JE, Al-Radaideh A, Brookes MJ, Evangelou N, and Morris PG: A comparison of 3T and 7T in the detection of small parenchymal veins within MS lesions. Invest Radiol. 2009 Sep;44(9):491-4. PMID 19652606, doi:10.1097/RLI.0b013e3181b4c144.
   Department of Clinical Neurology, Medical School, University of Nottingham, Nottingham, United Kingdom.
   Abstract

   OBJECTIVE: Histologic examination of multiple sclerosis (MS) brain lesions reveals heterogeneity including the presence or absence of a central blood vessel. Recent work has shown that T2* weighted magnetic resonance imaging at 7T allows the identification of small parenchymal veins within MS lesions. The aims of this study were (1) to compare whether a comparable sequence at 3T was also capable of demonstrating parenchymal veins within MS brain lesions, and (2) to investigate the potential of 7T T2* weighted imaging to differentiate between MS white matter lesions and age-related vascular lesions seen in controls. MATERIALS AND METHODS: Seven patients with demyelinating brain disease and 7 healthy volunteers were scanned at 3T and 7T. Fluid attenuated inversion recovery (FLAIR) images acquired at 3T were used to identify each brain lesion in each patient. A comparison of images from both field strengths was then made to determine whether white matter lesions seen in 3T FLAIR images could be identified in T2*-weighted images, and whether a central vein could be detected. RESULTS: A total of 358 brain lesions were identified in the brains of the 7 patients using 3T FLAIR images. The 3T T2* sequence detected 89% of FLAIR lesions compared with 94% using the 7T T2* sequence (P = 0.0002). A central vessel could be identified in 45% of visible lesions using 3T T2* and 87% of visible lesions using 7T T2* (P < 0.0001). Using 7T T2* imaging, a central vein was evident in only 8% of the discrete white matter lesions found in the brains of healthy volunteers. DISCUSSION: This study suggests that ultra high field imaging is advantageous in demonstrating detailed structural anatomy of MS lesions. 7T T2* imaging can be used in the future to investigate the pathogenesis of MS lesions. The potential for ultra high field imaging to discriminate between MS white matter lesions and microangiopathic lesions warrants further investigation as this would represent a clinically useful application.
9. [khalil09] Khalil M, Enzinger C, Langkammer C, Tscherner M, Wallner-Blazek M, Jehna M, Ropele S, Fuchs S, and Fazekas F: Quantitative assessment of brain iron by R(2)* relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis. Mult Scler. 2009 Sep;15(9):1048-54. Epub 2009 Jun 25. PMID 19556316, doi:10.1177/1352458509106609. PDF
   Department of Neurology and Department of Radiology (Division of Neuroradiology), Medical University of Graz, Graz, Austria.
   Abstract

   BACKGROUND: Increased iron deposition has been implicated in the pathophysiology of multiple sclerosis (MS), based on visual analysis of signal reduction on T(2)-weighted images. R(2)* relaxometry allows to assess brain iron accumulation quantitatively. OBJECTIVE: To investigate regional brain iron deposition in patients with a clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) and its associations with demographical, clinical, and conventional magnetic resonance imaging (MRI) parameters. METHODS: We studied 69 patients (CIS, n = 32; RRMS, n = 37) with 3T MRI and analyzed regional R(2)* relaxation rates and their correlations with age, disease duration, disability, T(2) lesion load, and normalized brain volumes. RESULTS: Basal ganglia R(2)* relaxation rates increased in parallel with age (r = 0.3-0.6; P < 0.01) and were significantly higher in RRMS than in CIS (P < 0.05). Using multivariate linear regression analysis, the rate of putaminal iron deposition was independently predicted by the patients' age, disease duration, and gray matter atrophy. CONCLUSIONS: Quantitative assessment by R(2)* relaxometry suggests increased iron deposition in the basal ganglia of MS patients, which is associated with disease duration and brain atrophy. This technique together with long-term follow-up thus appears suited to clarify whether regional iron accumulation contributes to MS morbidity or merely reflects an epiphenomenon.
10. [walter09] Walter U, Wagner S, Horowski S, Benecke R, and Zettl UK: Transcranial brain sonography findings predict disease progression in multiple sclerosis. Neurology. 2009 Sep;73(13):1010-7. Epub 2009 Aug 5. Type: Controlled Clinical Trial. PMID 19657105, doi:10.1212/WNL.0b013e3181b8a9f8. Abstract, Article$
    Department of Neurology, University of Rostock, Rostock, Germany.
    Abstract

    OBJECTIVE: In multiple sclerosis (MS), an early neurodegenerative affection of subcortical gray matter has been suggested. Transcranial sonography (TCS) shows hyperechogenic lesions of substantia nigra (SN) and basal ganglia, thought to reflect iron accumulation, in a number of primary neurodegenerative diseases. The present study deals with the question of whether TCS can also display deep gray matter lesions in patients with MS and whether sonographic findings relate to severity and progression of MS. METHODS: We prospectively studied 75 patients with different courses of MS and 55 age-matched healthy subjects clinically and with TCS. Twenty-three patients additionally had 1.5-T MRI at the time of TCS. Disease progression was assessed clinically 2 years after TCS. RESULTS: Abnormal hyperechogenicity of SN, lenticular nucleus (LN), caudate nucleus, and thalamus was found in 41%, 54%, 40%, and 8% of the patients with MS, with similar frequency in patients with relapsing-remitting and primary or secondary progressive MS if corrected for disease duration, but only in 13%, 13%, 5% (each, p < 0.001), and none (p = 0.028) of the control subjects. Hyperechogenicity of SN and LN correlated with more pronounced MRI T2 hypointensity, thought to reflect iron deposition. Larger bilateral SN echogenic area was related to higher rate of disease progression, whereas small SN echogenic area (SN hypoechogenicity) predicted a disease course without further progression within 2 years. CONCLUSIONS: Neurodegenerative disease-like deep gray matter lesions can be frequently detected by transcranial sonography (TCS) in patients with multiple sclerosis (MS). Findings suggest that TCS shows changes of brain iron metabolism which correlate with future progress of MS.
11. [zamboni09e] Singh AV, and Zamboni P: Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009 Dec;29(12):1867-78. Epub 2009 Sep 02. PMID 19724286, doi:10.1038/jcbfm.2009.180. PDF
    Department of Physics, European School of Molecular Medicine (SEMM), IFOM-IEO Campus, Centro Interdisciplinare Materiali e Interfacce Nanostrutturati, University of Milan, Milan, Italy.
    Abstract

    Multiple sclerosis (MS) is primarily an autoimmune disorder of unknown origin. This review focuses iron overload and oxidative stress as surrounding cause that leads to immunomodulation in chronic MS. Iron overload has been demonstrated in MS lesions, as a feature common with other neurodegenerative disorders. However, the recent description of chronic cerebrospinal venous insufficiency (CCSVI) associated to MS, with significant anomalies in cerebral venous outflow hemodynamics, permit to propose a parallel with chronic venous disorders (CVDs) in the mechanism of iron deposition. Abnormal cerebral venous reflux is peculiar to MS, and was not found in a miscellaneous of patients affected by other neurodegenerative disorders characterized by iron stores, such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis. Several recently published studies support the hypothesis that MS progresses along the venous vasculature. The peculiarity of CCSVI-related cerebral venous blood flow disturbances, together with the histology of the perivenous spaces and recent findings from advanced magnetic resonance imaging techniques, support the hypothesis that iron deposits in MS are a consequence of altered cerebral venous return and chronic insufficient venous drainage.
12. [zamboni09d] Zamboni P, Consorti G, Galeotti R, Gianesini S, Menegatti E, Tacconi G, and Carinci F: Venous collateral circulation of the extracranial cerebrospinal outflow routes. Curr Neurovasc Res. 2009 Aug;6(3):204-12. Epub 2009 Aug 1. Type: Review. PMID 19534716. Full article (PDF)
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
    Abstract

    A new nosologic vascular pattern that is defined by chronic cerebrospinal venous insufficiency (CCSVI) has been strongly associated with multiple sclerosis. The picture is characterized by significant obstacles of the main extracranial cerebrospinal veins, the jugular and the azygous system, and by the opening of substitute circles. The significance of collateral circle is still neglected. To the contrary, substitute circles are alternative pathways or vicarious venous shunts, which permit the drainage and prevent intracranial hypertension. In accordance with the pattern of obstruction, even the intracranial and the intrarachidian veins can also become substitute circles; they permit redirection of the deviated flow, piping the blood toward available venous segments outside the central nervous system. We review the complex gross and radiological anatomy of collateral circulation found activated by the means of EchoColor-Doppler and selective venography in the event of CCSVI, focusing particularly on the suboccipital cavernous sinus (SCS), the condylar venous system, the pterygoid plexus, the thyroid veins, and the emiazygous-lumbar venous anastomosis with the left renal vein.
13. [zamboni09c] Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Mascoli F, Dall'Ara S, Bartolomei I, and Salvi F: Rationale and preliminary results of endovascular treatment of multiple sclerosis, the liberation procedure. 2009, in 1978–2009 -31 years- Vascular and Endovascular Controversies Update 31st International Symposium – CX Charing Cross, pp. 71–79. [cx09] Full article (PDF), final results: [zamboni09f], Deutsche Übersetzung
14. [simka09] Simka M: Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis. Curr Neurovasc Res. 2009 May;6(2):132-9. Type: Review. PMID 19442163. Abstract, PDF
    Department of Angiology, Private Healthcare Institution SANA, Pszczyna, Poland.
    Abstract

    Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammation and demyelination within the central nervous system. The mechanism that triggers the disease remains elusive. However, recent findings may indicate that multiple sclerosis, at its source, could be a hemodynamic disorder. It has been found that multiple sclerosis patients exhibit significant stenoses in extracranial veins draining the central nervous system (in azygous and internal jugular veins), which are associated with significant pressure gradients measured across strictures. Such anatomic venous abnormalities were not found in the control group of healthy subjects. In this review, it is hypothesized that pathological refluxing venous flow in the cerebral and spinal veins increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the cerebrovascular endothelium. This, in turn, could lead to the increased permeability of the blood-brain barrier. Inflamed and activated endothelium could secrete proinflammatory cytokines, including GM-CSF and TGF-beta In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells. Consequently, a potential therapeutic option for multiple sclerosis could be pharmacotherapy with either substances that strengthen the tight-junctions barrier, or with agents that reduce the expression of adhesion molecules. In addition, surgical correction could be an option in some anatomical variants of pathologic venous outflow. We are optimistic that a hemodynamic approach to the multiple sclerosis pathogenesis can open a new chapter of investigations and treatment of this debilitating neurologic disease.
15. [haacke09d] Ge Y, Zohrabian VM, Osa EO, Xu J, Jaggi H, Herbert J, Haacke EM, and Grossman RI: Diminished visibility of cerebral venous vasculature in multiple sclerosis by susceptibility-weighted imaging at 3.0 Tesla. J Magn Reson Imaging. 2009 May;29(5):1190-4. PMID 19388109, doi:10.1002/jmri.21758. PDF
    Department of Radiology/Center for Biomedical Imaging, NYU School of Medicine, New York, New York 10016, USA.
    Abstract

    Multiple sclerosis (MS) is a disease of the central nervous system characterized by widespread demyelination, axonal loss and gliosis, and neurodegeneration; susceptibility-weighted imaging (SWI), through the use of phase information to enhance local susceptibility or T2* contrast, is a relatively new and simple MRI application that can directly image cerebral veins by exploiting venous blood oxygenation. Here, we use high-field SWI at 3.0 Tesla to image 15 patients with clinically definite relapsing-remitting MS and to assess cerebral venous oxygen level changes. We demonstrate significantly reduced visibility of periventricular white matter venous vasculature in patients as compared to control subjects, supporting the concept of a widespread hypometabolic MS disease process. SWI may afford a noninvasive and relatively simple method to assess venous oxygen saturation so as to closely monitor disease severity, progression, and response to therapy.
16. [franceschi09] Franceschi C: The unsolved puzzle of multiple sclerosis and venous function. J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):358. Type: Comment. PMID 19289474, doi:10.1136/jnnp.2008.168179. Extract, Article$
17. [zamboni09b] Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, and Salvi F: Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):392-9. Epub 2008 Dec 5. PMID 19060024, doi:10.1136/jnnp.2008.157164. Full article, PDF, Deutsche Übersetzung
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
    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.
18. [haacke09c] Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, and Grossman RI: Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging. 2009 Mar;29(3):537-44. PMID 19243035, doi:10.1002/jmri.21676. Full article, PDF, [spin09]
    Department of Radiology, Wayne State University, Detroit, Michigan 48201, USA.
    Abstract

    PURPOSE: To investigate whether the variable forms of putative iron deposition seen with susceptibility weighted imaging (SWI) will lead to a set of multiple sclerosis (MS) lesion characteristics different than that seen in conventional MR imaging. MATERIALS AND METHODS: Twenty-seven clinically definite MS patients underwent brain scans using magnetic resonance imaging including: pre- and postcontrast T1-weighted imaging, T2-weighted imaging, FLAIR, and SWI at 1.5 T, 3 T, and 4 T. MS lesions were identified separately in each imaging sequence. Lesions identified in SWI were reevaluated for their iron content using the SWI filtered phase images. RESULTS: There were a variety of new lesion characteristics identified by SWI, and these were classified into six types. A total of 75 lesions were seen only with conventional imaging, 143 only with SWI, and 204 by both. From the iron quantification measurements, a moderate linear correlation between signal intensity and iron content (phase) was established. CONCLUSION: The amount of iron deposition in the brain may serve as a surrogate biomarker for different MS lesion characteristics. SWI showed many lesions missed by conventional methods and six different lesion characteristics. SWI was particularly effective at recognizing the presence of iron in MS lesions and in the basal ganglia and pulvinar thalamus.
19. [zamboni09a] Zamboni P, Menegatti E, Galeotti R, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, and Salvi F: The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci. 2009 Jul;282(1-2):21-7. Epub 2009 Jan 13. PMID 19144359, doi:10.1016/j.jns.2008.11.027. Abstract, PDF
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
    Abstract

    Iron stores in the white and deep grey matter in course of multiple sclerosis (MS) have never been explained and could be related to abnormalities in venous drainage, but this possibility has never before been investigated. From an initial cohort of 320 subjects, after application of exclusion criteria, we selected 109 patients affected by MS, and 177 controls respectively composed by age- and sex-matched, healthy aged, and patients affected by other neurological diseases. They blindly underwent transcranial and extracranial Color-Doppler sonographic examination (TCCS-ECD), aimed at investigating five parameters related to normal cerebral venous outflow haemodynamics. Overall we analyzed 1430 TCSS-ECD parameters. In controls we found 861 normal parameters of cerebral venous return vs. 24 anomalous, whereas in MS 288 parameters were normal and 257 anomalous, respectively. Consequently, each of the considered Doppler haemodynamic parameters, when compared to revised McDonald criteria as a gold standard of MS diagnosis, showed separately a highly significant sensitivity and a noteworthy specificity. However, the detection >or=2 parameters in the same subject, never observed in controls, perfectly overlapped the diagnosis of MS (value, 95%CI: sensitivity 100%, 97-100; specificity 100%, 98-100; positive predictive value 100%, 97-100, negative predictive value 100%, 98-100; p<0.0001). Moreover, this study demonstrates a significant impairment of cerebral venous drainage in patients affected by MS, a mechanism potentially related to increased iron stores.
20. [haacke09b] Mittal S, Wu Z, Neelavalli J, and Haacke EM: Susceptibility-weighted imaging: technical aspects and clinical applications, part 2. AJNR Am J Neuroradiol. 2009 Feb;30(2):232-52. Epub 2009 Jan 8. Type: Review. PMID 19131406, doi:10.3174/ajnr.A1461. Full article, PDF, [spin09]
    Department of Neurosurgery, Wayne State University, Detroit, MI 48201, USA.
    Abstract

    SUMMARY: Susceptibility-weighted imaging (SWI) has continued to develop into a powerful clinical tool to visualize venous structures and iron in the brain and to study diverse pathologic conditions. SWI offers a unique contrast, different from spin attenuation, T1, T2, and T2* (see Susceptibility-Weighted Imaging: Technical Aspects and Clinical Applications, Part 1). In this clinical review (Part 2), we present a variety of neurovascular and neurodegenerative disease applications for SWI, covering trauma, stroke, cerebral amyloid angiopathy, venous anomalies, multiple sclerosis, and tumors. We conclude that SWI often offers complementary information valuable in the diagnosis and potential treatment of patients with neurologic disorders.
21. [haacke09a] Haacke EM, Mittal S, Wu Z, Neelavalli J, and Cheng YC: Susceptibility-weighted imaging: technical aspects and clinical applications, part 1. AJNR Am J Neuroradiol. 2009 Jan;30(1):19-30. Epub 2008 Nov 27. Type: Review. PMID 19039041, doi:10.3174/ajnr.A1400. Full article, PDF, [spin09]
    Department of Radiology, Wayne State University, Detroit, MI, USA.
    Abstract

    Susceptibility-weighted imaging (SWI) is a new neuroimaging technique, which uses tissue magnetic susceptibility differences to generate a unique contrast, different from that of spin density, T1, T2, and T2*. In this review (the first of 2 parts), we present the technical background for SWI. We discuss the concept of gradient-echo images and how we can measure local changes in susceptibility. Armed with this material, we introduce the steps required to transform the original magnitude and phase images into SWI data. The use of SWI filtered phase as a means to visualize and potentially quantify iron in the brain is presented. Advice for the correct interpretation of SWI data is discussed, and a set of recommended sequence parameters for different field strengths is given.
22. [simka08] Simka M, and Rybak Z: Hypothetical molecular mechanisms by which local iron overload facilitates the development of venous leg ulcers and multiple sclerosis lesions. Med Hypotheses. 2008 Aug;71(2):293-7. Epub 2008 Apr 8. PMID 18400414, doi:10.1016/j.mehy.2008.02.009. PDF
    Department of Angiology, Wodzislawska 78, 43-200 Pszczyna, Poland.
    Abstract

    This paper presents a hypothetical model of role for iron in the development of venous leg ulcers and multiple sclerosis. Elevated concentrations of iron were found in the skin affected by venous hypertension and also in the areas of brain with multiple sclerosis lesions. Individuals with hemochromatosis gene (HFE) mutations: C282Y and H63D, which result in a less efficient transport of iron by macrophages, are characterized by an increased risk for venous leg ulcer and multiple sclerosis. Multiple sclerosis is a T cell-mediated disease, and T cells probably participate in the development of venous ulcers. This deleterious role of ferric ions could be related to the regulation of T cell proliferation and apoptosis. Under normal conditions excessive accumulation of T cells cannot take place, because nitric oxide and interferon-gamma drive these cells toward apoptosis. However, in tissues with a high concentration of iron, T lymphocytes proliferate instead of undergoing apoptosis. This is possible due to the internalization of the INF-gammaR2 chain of the interferon-gamma receptor, the downregulation of inducible nitric oxide synthase expression in macrophages and the inactivation of the active site of caspases. Yet, it should be emphasized that this hypothesis does not claim for the increased concentration of iron as a direct causal factor for the development of venous ulcerations or multiple sclerosis, but rather, iron is a factor that modulates and exaggerates the autoimmune process. Iron chelators, administered systemically or locally, should potentially exhibit therapeutic and prophylactic activity against venous leg ulcers and multiple sclerosis.
23. [talbert08] Talbert DG: Raised venous pressure as a factor in multiple sclerosis. Med Hypotheses. 2008 ;70(6):1112-7. Epub 2008 Feb 20. PMID 18079069, doi:10.1016/j.mehy.2007.10.009. PDF
    Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, Du Cane Road, London W12 ONN, United Kingdom.
    Abstract

    It is hypothesised that the inflammatory condition seen in MS and the progressive myelopathy that is being successfully halted by obliteration of dural arteriovenous fistulas (DAVFs), may actually be two sides of the same coin. Excessive venous hypertension can stretch vein walls sufficiently to separate the tight junctions between endothelial cells forming the blood-brain-barrier (BBB). Colloids, etc., but not necessarily erythrocytes, could then pass through the exposed porous basement membranes. The resulting changes in osmotic pressure, etc. would disrupt the axon and dendrite internal transport systems, leading to their disintegration. The normal inflammatory processes which would follow, might be indistinguishable from those associated with autoimmune disease. Ascending progressive myelopathy and disablement are associated with an intracranial DAVF when its outflow enters the spinal venous system and descends past the cervical region. This can be arrested, and some degree of recovery produced, if the DAVF can be successfully eliminated or blocked. However, if the DAVF outflow is entirely into the spine, intracranial venous pressure may be normal and so there is nothing to alert the clinician to the presence of an intracranial DAVF. It is suggested that where spinal MS has been diagnosed from clinical observations, patients should be referred for angiological investigation to search for DAVFs within the head to identify any treatable subjects.
24. [ge08] Ge Y, Zohrabian VM, and Grossman RI: Seven-Tesla magnetic resonance imaging: new vision of microvascular abnormalities in multiple sclerosis. Arch Neurol. 2008 Jun;65(6):812-6. Type: Case Reports. PMID 18541803, doi:10.1001/archneur.65.6.812. Full article, PDF
    Department of Radiology, Center for Biomedical Imaging, New York University School of Medicine, 650 First Ave, Room 615, New York, NY 10016, USA.
    Abstract

    BACKGROUND: Although the role of vascular pathology in multiple sclerosis (MS) lesions was suggested long ago, the derivation of these lesions from the vasculature has been difficult to assess in vivo. Ultrahigh-field (eg, 7-T) magnetic resonance imaging (MRI) has become a tool for assessing vascular involvement in MS lesions owing to markedly increased image resolution and susceptibility contrast of venous blood. OBJECTIVE: To describe the perivenous association of MS lesions on high-resolution and high-contrast 7-T susceptibility-sensitive MRI. DESIGN: Case study. SETTING: University hospital. PATIENTS: Two women with clinically definite relapsing-remitting MS. RESULTS: We demonstrated markedly enhanced detection of unique microvascular involvement associated with most of the visualized MS lesions with abnormal signals on and around the venous wall on 7-T compared with 3-T MRI. CONCLUSIONS: These findings, which have never been shown on conventional fields of MRI, not only allow for direct evidence of vascular pathogenesis in MS in vivo but also have important implications for monitoring lesion activity and therapeutic response.
25. [zamboni08a] Menegatti E, and Zamboni P: Doppler haemodynamics of cerebral venous return. Curr Neurovasc Res. 2008 Nov;5(4):260-5. Type: Review. PMID 18991660. PDF
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
    Abstract

    Physiologic functioning of the cerebrovenous system is indispensable for maintaining normal brain function. However, in contrast to the cerebroarterial system, the cerebral venous return is not routinely investigated. Combined high-resolution echo-colour-Doppler (ECD) and transcranial colour coded Doppler sonography (TCCS) represents an ideal method to investigate the haemodynamics of cerebral venous return. TCCS-ECD is noninvasive, repeatable, cost-effective and permits to investigate the cerebral venous outflow in its dependence upon changes in posture and the alternating pressure gradients of the thoracic pump. Several authors reported normal parameters concerning related aspects of cerebral venous return. However, there is no ECD-TCCS standardization of what can be considered a normal venous return. The authors have summarized the current knowledge of the Doppler haemodynamics of the cerebrovenous system and propose a list of reproducible clinical parameters for its sonographic evaluation. In future, the development of this diagnostic technique could be of singular interest in iron-related inflammatory and neurodegenerative disorders like multiple sclerosis.
26. [keyser08a] De Keyser J, Steen C, Mostert JP, and Koch MW: Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance. J Cereb Blood Flow Metab. 2008 Oct;28(10):1645-51. Epub 2008 Jul 02. Type: Review. PMID 18594554, doi:10.1038/jcbfm.2008.72. Article
    Department of Neurology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
    Abstract

    Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.
27. [zamboni07] Zamboni P, Menegatti E, Bartolomei I, Galeotti R, Malagoni AM, Tacconi G, and Salvi F: Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res. 2007 Nov;4(4):252-8. PMID 18045150. PDF
    Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
    Abstract

    In multiple sclerosis (MS) plaques are known to be venocentric; in addition, MS lesions and peripheral venous disorders share a number of key features. To date, however, despite the anatomical relationship between MS lesions and the venous system, no information on the intracranial venous haemodynamics of MS is available. Eighty-nine consecutive MS patients (58 relapsing-remitting, 31 secondary progressive) matched with 60 controls underwent transcranial color-coded duplex sonography (TCCS). We assessed, in supine as well as in sitting positions, the direction of flow at the activation of the thoracic pump in the deep middle cerebral veins (dMCVs), and in the transverse sinus (TS). In the dMCVs, we also measured peak systolic velocity (PSV), peak diastolic velocity (PDV), as well as the resistance index (RI). Reflux/bidirectional flow rate was significantly higher in the MS population determining also significant differences in PDV, characterized by negative values (16.2+/-1 cm/sec in controls vs. -1.3 +/-2.6 cm/sec in MS, respectively, p<0.0001). Consequently, RI was dramatically increased in the MS group, affecting impedance of cerebral venous drainage (0.48+/-0.04 in controls vs. 1.1 +/-0.08 in MS, respectively p<0.0001). Therefore, the detection of reflux directed toward the subcortical grey matter was significantly associated to highest disability scores (p < 0.0001). Our study of MS patients demonstrated significant haemodynamic alterations detected in veins anatomically related to plaque disposition. Our findings should contribute towards understanding the role of altered venous flow and tissue drainage in the MS inflammatory chain, as well as in the neurodegenerative process.
28. [zamboni06] Zamboni P: The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med. 2006 Nov;99(11):589-93. Type: Review. PMID 17082306, doi:10.1258/jrsm.99.11.589. Full article, PDF
    Vascular Diseases Center, University of Ferrara, 44100 Ferrara, Italy.

Publikationen (MRI, 1988 – 2006)

See a brief history of the early venous vascular observations in MS on ms-mri.com for a textual summary.

1. [schelling04] Schelling F: Multiple Sclerosis: The Image and its Message. The Meaning of the Classic Lesion Forms. ms-info.net. 04.05.2004. Full article, PDF
2. [law04] Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, and Grossman RI: Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology. 2004 Jun;231(3):645-52. PMID 15163806, doi:10.1148/radiol.2313030996. Article, PDF
   Departments of Radiology and Neurology, New York University Medical Center, MRI Department, Schwartz Building, Basement HCC, 530 First Avenue, New York, NY 10016, USA.
   Abstract

   PURPOSE: To prospectively determine hemodynamic changes in the normal-appearing white matter (NAWM) of patients with relapsing-remitting multiple sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced perfusion magnetic resonance (MR) imaging. MATERIALS AND METHODS: Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, fluid-attenuated inversion recovery, and T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years). Absolute cerebral blood volume (CBV), absolute cerebral blood flow (CBF), and mean transit time (MTT) (referenced to an arterial input function by using an automated method) were determined in periventricular, intermediate, and subcortical regions of NAWM at the level of the lateral ventricles. Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients. Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of brain regions in terms of each perfusion measure. RESULTS: Each region of NAWM in patients with RR-MS had significantly decreased CBF (P <.005) and prolonged MTT (P <.001) compared with the corresponding region in control patients. No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined. In control patients, periventricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS. CONCLUSION: The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls.
3. [prineas04] Barnett MH, and Prineas JW: Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458-68. Type: Case Reports. PMID 15048884, doi:10.1002/ana.20016. Article$, PDF
   Institute of Clinical Neurosciences, Department of Medicine, University of Sydney, Australia.
   Abstract

   The study describes the clinical and pathological findings in 12 patients with relapsing and remitting multiple sclerosis, who died during or shortly after the onset of a relapse. Pathological changes not previously associated with the formation of new symptomatic lesions were observed in seven cases, namely, extensive oligodendrocyte apoptosis and microglial activation in myelinated tissue containing few or no lymphocytes or myelin phagocytes. No current laboratory model of multiple sclerosis, in particular, experimental allergic encephalomyelitis, is known with these features, which raises the possibility of some novel process underlying new lesion formation in multiple sclerosis.
4. [minagar03] Minagar A, and Alexander JS: Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003 Dec;9(6):540-9. Type: Review. PMID 14664465. PDF
   Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
   Abstract

   The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (CEC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. Collectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the 'interior milieu' of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal CNS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/ chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in CEC. Exposure of endothelium to proinflammatory cytokines (IFN-gamma, TNF-alpha and IL-1beta) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial 'microparticles' (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated CEC in the pathogenesis of BBB failure in MS.
5. [bakshi02] Bakshi R, Benedict RH, Bermel RA, Caruthers SD, Puli SR, Tjoa CW, Fabiano AJ, and Jacobs L: T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study. Arch Neurol. 2002 Jan;59(1):62-8. PMID 11790232. Full article, PDF
   Department of Neurology, University at Buffalo, State University of New York, USA. rbakshi@buffalo.edu
   Abstract

   CONTEXT: While gray matter T2 hypointensity in multiple sclerosis (MS) has been associated with physical disability and clinical course, previous studies have relied on visual magnetic resonance imaging (MRI) assessments. OBJECTIVE: To quantitatively determine if T2 hypointensity is associated with conventional MRI and clinical findings in MS. DESIGN: Case-control study. SETTING: University-affiliated community-based hospital. SUBJECTS: Sixty patients with MS and 50 controls. MAIN OUTCOME MEASURES: T2 intensities of the substantia nigra, red nucleus, thalamus, putamen, globus pallidus, and caudate; third ventricular width; total brain T1 (hypointense) and T2 (hyperintense) lesion volumes; Expanded Disability Status Scale (physical disability) score; and disease course. RESULTS: Deep gray matter T2 hypointensity was present in patients with MS in all structures (P<.005) except for the substantia nigra. T2 hypointensity was associated with third ventricle enlargement and higher T2 but not T1 plaque load. The regression model predicting third ventricle width included caudate T2 hypointensity (P =.006). The model predicting T2 lesion load included globus pallidus T2 hypointensity (P =.001). Caudate T2 hypointensity was the only variable associated with disability score in regression modeling (P =.03). All T2 hypointensities differentiated the secondary progressive from the relapsing-remitting clinical courses. The final model (P<.001) predicting clinical course retained T2 hypointensity of the thalamus, caudate, and putamen but not MRI plaques or atrophy. CONCLUSIONS: Gray matter T2 hypointensity in MS is associated with brain atrophy and is a stronger predictor of disability and clinical course than are conventional MRI findings. While longitudinal studies are warranted, these results suggest that pathologic iron deposition is a surrogate marker of the destructive disease process.
6. [tan00] Tan IL, van Schijndel RA, Pouwels PJ, van Walderveen MA, Reichenbach JR, Manoliu RA, and Barkhof F: MR venography of multiple sclerosis. AJNR Am J Neuroradiol. 2000 Jun-Jul ;21(6):1039-42. PMID 10871010. Full article, PDF
   Department of Radiology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
   Abstract

   BACKGROUND AND PURPOSE: The distribution of multiple sclerosis (MS) lesions in the brain follows a specific pattern, with most lesions in the periventricular regions and in the deep white matter; histopathologic studies have shown a perivenous distribution. The aim of this study was to illustrate these distribution patterns in vivo using high-resolution MR venography. METHODS: Seventeen MS patients underwent MR imaging at 1.5 T. Venographic studies were obtained with a 3D gradient-echo technique. MS lesions were identified on T2-weighted images, and their shape, orientation, and location were compared with the venous anatomy on the venograms. RESULTS: The use of contrast material facilitated the visualization of small veins and increased the number of veins seen. A total of 95 MS lesions could be identified on both the T2-weighted series and the venograms; a central vein was visible in all 43 periventricular lesions and in all but one of the 52 focal deep white matter lesions. The typical ovoid shape and orientation of the long axis of the MS lesions correlated well with the course of these veins. CONCLUSION: With MR venography, the perivenous distribution of MS lesions in the brain can be visualized in vivo. The venous anatomy defines the typical form and orientation of these lesions.
7. [engell99] Engell T, Sellebjerg F, and Jensen C: Changes in the retinal veins in acute optic neuritis. Acta Neurol Scand. 1999 Aug;100(2):81-3. PMID 10442446.
   Department of Ophthalmology, Sønderborg Hospital, Denmark.
   Abstract

   OBJECTIVE: To investigate patients with acute optic neuritis (ON) for changes of the retinal veins. MATERIAL AND METHODS: Seventy-six patients with acute ON were extensively neuro-ophthalmologically examined. RESULTS: Multiple sclerosis (MS) was found in 41 patients of whom 1 had periphlebitis retinae (PR) and 2 had venous sheathing (VS). Probable MS was found in 15 patients without prior symptoms of MS. One had PR and VS, and 2 had VS. Twenty patients had mono-symptomatic ON, none had retinal changes. CONCLUSION: Changes of the retinal veins should alert the clinician to a probable diagnosis of MS. ON appears frequently as the initial symptom of MS. Our observation of VS in these patients suggest that clinically silent retinal disease activity had occurred prior to the ON.
8. [juurlink98] Juurlink BH: The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated? Med Hypotheses. 1998 Oct;51(4):299-303. PMID 9824835. PDF
   Department of Anatomy & Cell Biology, Cameco Multiple Sclerosis & Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
   Abstract

   A mechanism is proposed that may explain the factors that initiate a multiple sclerosis (MS) lesion. It is based upon the following two hypotheses: (i) there is a lower stimulus threshold for upregulating the mechanisms that result in leukocyte infiltration in individuals predisposed to developing MS; (ii) the MS lesion is initiated as a reduction in blood flow to a localized region of white matter. This reduction in blood flow leads to: (a) degenerative white matter changes affecting oligodendrocytes; (b) upregulation of chemokines in the endothelial cells and/or glial cells; and (c) upregulation of cell adhesion molecules on endothelial cells. Signals from the hypoxemic and hypoglycemic glial cells, likely involving myelin molecules and cytokines, result in an inflammatory immune response that results in rampant demyelination. Evidence supporting the proposed mechanism is presented, as well as suggestions on how to test the validity of the proposal.
9. [levine97] LeVine SM: Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 1997 Jun;760(1-2):298-303. PMID 9237552. PDF
   Department of Physiology and the Smith Mental Retardation Research Center, University of Kansas Medical Center, Kansas City 66160, USA.
   Abstract

   Iron may contribute to the pathogenesis of neurological diseases by promoting oxidative damage. The localization of iron in multiple sclerosis (MS) and Alzheimer's disease (AD) brains was investigated to further the understanding of its pathogenic role in these disease states. Earlier studies, utilizing a standard Perls' stain, yielded conflicting reports regarding the distribution of iron deposits in MS brains, and a previous study on AD brains utilized a diaminobenzidine (DAB) enhanced version of this stain. In the present study, a modified version of the DAB-enhanced stain was used; it utilizes sodium borohydride, proteinase K, Triton X-100 and xylenes to increase the accessibility of tissue iron to histochemical reagents. This modified method can reveal iron deposits that are missed by the Perls' or DAB-enhanced Perls' stains. In addition to its normal deposition in oligodendrocytes and myelin, iron was detected in reactive microglia, ameboid microglia and macrophages in MS brains. In AD brains, three types of plaques were stained: dense core, clear core and amorphous plaques. Punctate staining was also observed in neurons in the corticies of AD brains. The structure accounting for punctate labeling may be damaged mitochondria, lipofuscin or amyloid deposits. Dense core plaques, clear plaques and punctate labeling were not detected in the previous AD study which utilized only the DAB-enhanced Perls' stain. The labeling of these additional structures illustrates the benefit of the modified method. In summary, the localization of iron deposition in MS and AD brains indicates potential sites where iron could promote oxidative damage in these disease states.
10. [birch96] Birch MK, Barbosa S, Blumhardt LD, O'Brien C, and Harding SP: Retinal venous sheathing and the blood-retinal barrier in multiple sclerosis. Arch Ophthalmol. 1996 Jan;114(1):34-9. PMID 8540848. PDF
    St Paul's Eye Unit, Royal Liverpool England University Hospital.
    Abstract

    OBJECTIVE: To assess the temporal relations among retinal appearance, disruption of the blood-retinal barrier, clinical subgroup, disease course, and disruption of the blood-brain barrier in multiple sclerosis. DESIGN: A 6-month prospective study involving monthly clinical ocular examinations, color fundus photography, fundus fluorescein angiograms, and magnetic resonance brain scans with gadolinium-diethylenetriamine-pentaacetic acid (Gd-DPTA) enhancement. SETTING: University-based ophthalmology and neurology departments. PATIENTS: Twenty-three patients with relapsing-remitting, primary-progressive, or secondary-progressive multiple sclerosis. RESULTS: Retinal venous sheathing was seen in six patients. The appearances observed included focal venous sheathing, diffuse venous sheathing, sheathing centered on sites of arteriovenous crossover, and focal perivenous hemorrhage. Arteriolar sheathing was also observed in one patient. Venous leakage on fundus fluorescein angiogram was detected in three patients, all of whom also had sheathing. The following three patterns of disruption of the blood-retinal barrier were seen on fundus fluorescein angiogram: focal leakage, extensive leakage, and very late wall staining. In one patient, the leakage was transitory. No correlations were observed between ophthalmologic features and multiple sclerosis clinical subgroup, disease course, or the number of new (Gd-DTPA-enhancing) lesions on magnetic resonance imaging. CONCLUSIONS: Disruption of the blood-retinal barrier, like the more frequent disruption of the blood-brain barrier seen on magnetic resonance imaging, is often unrelated to clinical neurologic relapses and occurs with apparently similar frequency in different patients independent of clinical disease course.
11. [kermode90] Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, Rudge P, and McDonald WI: Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain. 1990 Oct;113 ( Pt 5):1477-89. Type: Case Reports. PMID 2245307. PDF
    Multiple Sclerosis NMR Research Group, Institute of Neurology, London, UK.
    Abstract

    From an extensive serial magnetic resonance imaging (MRI) study in multiple sclerosis (MS) we have identified 4 cases in which disruption of the blood-brain barrier, as detected by gadolinium-DTPA enhancement, preceded other MRI abnormalities and in 1 case clinical evidence of the new lesion. This supports the view that a defect in the blood-brain barrier, and therefore inflammation, is an early and possibly crucial event in the pathogenesis of the new lesion in MS. These cases showed a marked discrepancy between MRI abnormality and symptoms. The mechanisms contributing to this disparity are discussed, and it is concluded that far from being surprising it is to be expected.
12. [oger88] Oger J, Kastrukoff LF, Li DK, and Paty DW: Multiple sclerosis: in relapsing patients, immune functions vary with disease activity as assessed by MRI. Neurology. 1988 Nov;38(11):1739-44. PMID 3185908.
    University of British Columbia, Department of Medicine, Vancouver, Canada.
    Abstract

    We have serially studied immunoglobulin G secretion in vitro, natural killer cell function, and concanavalin A-induced suppression in a group of seven patients with relapsing-remitting multiple sclerosis. In two patients, the development of a large clinically asymptomatic MRI lesion was accompanied by reductions in natural killer cell function, immunoglobulin G secretion in vitro (after pokeweed mitogen stimulation), and concanavalin A-induced suppression without parallel change in lymphocyte markers. We did not see this type of change in matched controls nor in stable multiple sclerosis studied serially. When clinical attacks appeared, there was no significant change in immune function. We conclude that changes in immune function correlate well with the activity of the disease as recognized by MRI. We suspect that decreased natural killer cell function, immunoglobulin G secretion in vitro, and concanavalin A-induced suppression are secondary to the large lesions recognized by MRI.

Publikationen (1850 – 1988)

See a brief history of the early venous vascular observations in MS on ms-mri.com for a textual summary.

1. [adams88] Adams CW: Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1988 Feb;51(2):260-5. PMID 3346691. Article, PDF
   Division of Histopathology, United Medical School of Guy's Hospital, University of London, UK.
   Abstract

   Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.
2. [nicolson88] Nicolson M, McLaughlin C: Social constructionism and medical sociology: a study of the vascular theory of multiple sclerosis. Sociology of Health & Illness Vol. 10 No. 3, pp. 234–261 1988, published online: 28 Jun 2008. ISSN 0141-9889, doi:10.1111/j.1467-9566.1988.tb00008.x. Article, PDF
3. [adams87] Adams CW, Abdulla YH, Torres EM, and Poston RN: Periventricular lesions in multiple sclerosis: their perivenous origin and relationship to granular ependymitis. Neuropathol Appl Neurobiol. 1987 Mar-Apr ;13(2):141-52. PMID 3614542. PDF
   Abstract

   The periventricular region was studied in the brains of 129 cases of multiple sclerosis, with the purpose of establishing the mechanism and order of events in the development of the periventricular plaque, and deciding whether there is any relationship between granular ependymitis and such plaques. Periventricular plaques were found in 82.2% of cases. Observation and computerized morphology showed that the early stage of the periventricular plaque is the formation of a lesion around a subependymal vein and that adjacent lesions later coalesce. These plaques do not appear to arise from the ependyma, which is against any role for the CSF in their initial development. Chronic or burnt-out periventricular lesions often show overlying granular ependymitis (10.9% of cases) and subependymal gliosis (17.8%), presumably as a result of the long-continued low-grade inflammatory process. This process, which is not specific for multiple sclerosis, is sometimes associated with transfer of IgG and C3, as shown with peroxidase methods, across the subependymal vein wall and the ependymal epithelium. Increased permeability of the inflamed ependyma constitutes a possible abnormal entry route from plaque to CSF or, in reverse, from CSF to brain.
4. [lightman87] Lightman S, McDonald WI, Bird AC, Francis DA, Hoskins A, Batchelor JR, and Halliday AM: Retinal venous sheathing in optic neuritis. Its significance for the pathogenesis of multiple sclerosis. Brain. 1987 Apr;110 (Pt 2):405-14. PMID 3567529. Article$
   Abstract

   A systematic study of the frequency of retinal vascular abnormalities and cells in the media has been made in 50 patients presenting with acute optic neuritis. Abnormalities were found in 14 (fluorescein leakage in 10, perivenous sheathing in 6, cells in the vitreous in 6 and in the anterior chamber in 4; in 2 the cells in the media were seen without vascular changes). After a mean follow up of 3.5 years multiple sclerosis (MS) had developed in 8/14 patients with vascular abnormalities and/or evidence of inflammation and in 5/32 without; the difference is significant (P less than 0.02). The occurrence of perivenular abnormalities in a region free of myelin and oligodendrocytes provides evidence that the vascular changes in MS can occur independently of contiguous demyelination, and may be the primary event in the formation of a new lesion.
5. [schelling86] Schelling F: Damaging venous reflux into the skull or spine: relevance to multiple sclerosis. Med Hypotheses. 1986 Oct;21(2):141-8. PMID 3641027. PDF
   Abstract

   Unequal propagation of central venous excess pressure into the different cerebral and spinal venous drainage systems is the rule rather than the exception. The intensity of the forces thus to be exerted on vulnerable cerebrospinal structures by the resulting pressure-gradients in the craniovertebral space is unknown. There is a need to consider the various conditions which may cause individual proneness to heavier reflux into particular cerebral as well as epi- and subdural spinal venous compartments. An attempt is made to indicate eventual consequences of excessive retrograde dilatation especially of internal cerebral veins. The importance of elucidating the neuropathological and clinical implications of undue reflux into the skull or spine is deduced from the probability of relations between localized backflow into the craniovertebral space and unexplicated cerebrospinal diseases. In this regard the features of multiple sclerosis are discussed.
6. [adams85] Adams CW, Poston RN, Buk SJ, Sidhu YS, and Vipond H: Inflammatory vasculitis in multiple sclerosis. J Neurol Sci. 1985 Jul;69(3):269-83. PMID 4031947. PDF
   Abstract

   Fifty-two plaque or lesion areas were examined from 25 cases of multiple sclerosis. Twenty-four of these showed acute features, whereas the rest were more chronic in nature. The acute lesions showed lymphocytic infiltration (79%), fibrinous exudation (63%), lymphocytic meningitis (50%) and venulitis (58%). Of the chronic lesions, there were only 21% with lymphocytic infiltration, 11% with fibrinous exudates, none with meningitis, 29% with organising endovenulitis, 36% with fibrosed vein walls. The finding of a fibrinous inflammatory exudate in the acute lesion is a new observation in multiple sclerosis. Likewise, the observation of an inflammatory infiltrate confined to the vein wall (and often present at a distance from the plaque) has not been previously recorded in the disease. The chronic lesion, by contrast, showed relatively little fibrin, but there was considerable reparative thickening of the walls of the involved veins. The evidence provides new humoral and cellular evidence of an inflammatory process in multiple sclerosis which precedes or is not directly associated with the demyelinating process.
7. [walton84] Walton JC, and Kaufmann JC: Iron deposits and multiple sclerosis. Arch Pathol Lab Med. 1984 Sep;108(9):755-6. PMID 6547829.
   Abstract

   A recent publication described autopsy samples from five brains in which positive staining for iron was observed as surrounding demyelinated plaques. Because this has not been previously reported, autopsy material from 13 patients who were being followed up at the Multiple Sclerosis (MS) Clinic, University Hospital, The University of Western Ontario, London, Ontario, was reviewed. A total of 32 paraffin-embedded blocks containing demyelinated plaques of varying age were sectioned and stained using a standard acid ferrocyanide technique (Peris' test) for iron. Microscopic examination failed to detect the presence of significant positive staining either within or surrounding the areas of demyelination. Positive histochemical staining for iron identifies hemosiderin, the presence of which suggests either iron overload or remote hemorrhage. Support for these two processes in the pathogenesis of MS could not be provided from our material.
8. [adams75] Adams CW: The onset and progression of the lesion in multiple sclerosis. J Neurol Sci. 1975 Jun;25(2):165-82. PMID 1151432.
   Abstract

   The active established plaque in multiple sclerosis is characterized by hypercellularity at its edge and lipid phagocytosis (gitter cells). The hyperactive early plaque shows cells throughout the lesion. Active plaques seems to extend at their edges; proteolysis of myelin basic protein is perhaps an important factor in the myelin breakdown at the rim of these lesions. The hyperactive early plaque usually shows infiltration with monocytes, lymphocytes and plasma cells around its central vein. The phagocytic element is presumably a response to myelin breakdown but the significance of the lymphocytes in these lesions in uncertain. Perivenular infiltrates that are predominantly composed of lymphocytes are seen around veins and venules in the vicinity of established lesions in some patients who died during an acute episode...
9. [fog65] Fog T: The topography of plaques in multiple sclerosis with special reference to cerebral plaques. Acta Neurol Scand Suppl. 1965 ;15:1-161. Type: Case Reports. PMID 5213727.
10. [schlesinger39] Schlesinger B: The venous drainage of the brain, with special reference to the galenic system. Brain, 62:274, 1939. PDF
    Department of Human Anatomy, Oxford.
    Abstract

    On the basis of experiments on dogs, Bedford reported (1937) that a collateral circulation becomes rapidly established after occlusion of the great vein of Galen {Vena magna cerebri). He concluded, therefore, that the hydrocephalus which was occasionally found by Dandy and Blackfan (1914) and by Gulecke (1930), in dogs in which the vein had been blocked experimentally, was not directly due to the occlusion of the vein. In a subsequent series of experiments, Bedford (1934) occluded the great vein of Galen in monkeys. These animals likewise failed to show hydrocephalus after a survival period of six weeks, but no evidence was found of the manner in which the collateral circulation had developed in the choroidal plexus and the basal ganglia. Schwartz and Fink (1925-26), who injected the great vein of Galen in human brains, were unable to reach positive conclusions regarding the collaterals of the vein and the venous drainage of the basal ganglia, and they suggested that these investigations required to be further extended. A study of the venous system is also of importance for the question of the localization and pathogenesis of certain infections and other pathological conditions which have been described in the monkey and in Man, and are known to have a definite topographical relationship to the venous channels of the grey and white matter. The present paper comprises a report of an investigation, based on the examination of normal and experimental material, with the object of elucidating these details of the circulation.
11. [putnam37b] Putnam T: Evidences of vascular occlusion in multiple sclerosis and encephalomyelitis. Arch Neurol Psychiatry 1937;37(6):1298-1321. PDF$
    Neurological Unit, Boston City Hospital, and the Departments of Neuropathology and Surgery, Harvard Medical School.
    Introduction

    Recent experimental work¹ has made it seem probable that the lesions of multiple sclerosis and also those of the forms of "disseminated encephalomyelitis" which seem to represent a more acute stage of the same process² are produced by a local circulatory disturbance, apparently of the nature of an obstruction on the venous side. According to this point of view, there must be a primary change in the contents of the vessels of the central nervous system, or possibly of the intimal lining, which leads to thrombosis of venules. This produces local passive congestion and a mild degenerative process which affects myelin sheaths more than other structures. The myelin degenerates and is phagocytosed. The "inflammatory" phenomena would then be regarded as secondary or symptomatic and the gliosis as reparative or reactive. This hypothesis obviously must remain largely a speculation as long as it rests on the results of experimentation …
12. [putnam37a] Putnam T and Adler A: Vascular architecture of the lesions of multiple sclerosis. Arch Neurol Psychiat, 38:1, 1937. PDF$
    Neurological Unit, Boston City Hospital, and the Departments of Neuropathology and Surgery, Harvard Medical School.
    Introduction

    A relationship between the location of the lesions of multiple sclerosis and the veins of the nervous system was pointed out by Rindfleisch.¹ The majority of those who have dealt with the subject have agreed that small lesions usually surround small veins and that larger plaques probably arise by coalescence. A similar relationship between lesions and veins in cases of "post-infectious encephalomyelitis" has recently been pointed out by Finley.² In other papers of this series the probable cause for such a relationship has been traced. Veins in the neighborhood of sclerotic plaques are often found to be engorged, tortuous, surrounded by blood pigment, thrombosed or obstructed. Thrombosis of veins in the central nervous system invariably produces lesions of the same general type as those seen in "encephalomyelitis" and multiple sclerosis. Presumably, therefore, the vascular abnormality is primary to the parenchymal lesions.³ It is the purpose of the …
13. [putnam35] Putnam T: "Encephalitis" and sclerotic plaques produced by venular obstruction. Arch Neurol Psychiatry. 1935;33(5):929-940. PDF$, PDF
    Neurological Unit, Boston City Hospital, and the Departments of Neuropathology and Surgery, Harvard Medical School.
    Introduction

    In previous papers it has been shown that a series of histologic pictures resembling those of "postinfectious encephalomyelitis" may be produced in animals by a variety of agents, such as minute doses of tetanus toxin, carbon monoxide poisoning and certain types of embolism.¹ The pathologic alterations ranged, sometimes in a single specimen, from mild perivascular infiltrations with glia and occasional lymphocytic cells through areas of damage to and loss of perivascular myelin to areas of softening and destruction of the axis-cylinders. In one instance, more than a year after the original injection of tetanus toxin, lesions were found which closely simulated those of multiple sclerosis,² with plaques of loss of myelin, but with almost complete preservation of the axiscylinders and with local gliosis. Multiple sclerosis has been observed as a sequel of "postinfectious encephalomyelitis,"³ and the hypothesis that all of these conditions represent variants of the same …
14. [dawson16] Dawson JW: The histology of disseminated sclerosis. Trans Roy Soc Edinb, 50: 517, 1916.
15. [rindfleisch72] Rindfleisch E: A Manual of Pathological Histology. London, New Sydenham Society, 1872, Vol. 2, pp. 344–351.
16. [charcot68] Charcot JM: Histologie de la sclérose en plaque. Gazette Hosp Paris 41:554-566.
17. [rindfleisch63] Rindfleisch E: Histologisches Detail zu der grauen Degeneration von Gehirn und Rückenmark (Zugleich ein Beitrag zu der Lehre von der Entstehung und Verwandlung der Zelle). Arch Path Anat Physiol Klin Med, 26:474,1863.

Publikationen in Vorbereitung

1. [prep_lee10a] Lee BB et al.: Embryological Background of Truncular Venous Malformation in the Extracranial Venous Pathways as the Cause of Chronic Cerebro-Spinal Venous Insufficiency.
   Dr. Byung-Boong Lee of Georgetown University in Washington DC
2. [prep_gabbiani09] Gabbiani G, Coen M, Mascoli F, Zamboni P. Manuscript in preparation.
3. [prep_ctevd09] Buffalo Neuroimaging Analysis Center (BNAC), New York State University (SUNY), Buffalo: Combined Transcranial and Extracranial Venous Doppler evaluation in multiple sclerosis and related diseases (CTEVD study). CTEVD press release, TV news, WBFO Public Radio, Buffalo News, CTEVD Study Enrollment, Newsletter Vol 1 Issue 1, 4 Feb 2010 (PDF), Press release Feb 9, 2010
   Description

   Das Ziel ist die Resultate von Prof. Zamboni zu überprüfen. Die Studie wird von Prof. Robert Zivadinov geleitet. Die Studie wird 1600 Erwachsene und 100 Kinder umfassen. Diese Personen teilen sich auf folgende Gruppen auf: 1100 Patienten mit möglicher oder gesicherter MS, 300 alters- und geschlechtsbestimmte Kontrollpersonen und 300 Patienten mit anderen Autoimmunerkrankungen und neurodegenerativen Erkrankungen. Die Studie hat bereits begonnen und wird sich über zwei Jahre erstrecken. Erste Zwischenresultate werden auf Anfang Februar erwartet und die Publikation der endgültigen Resultate ist auf 2011 vorgesehen.

4. [prep_haacke09a] Haacke EM, Garbern J, Miaob Y, Habiba C, and Liua M: Iron stores and Cerebral Veins in MS Studied by Susceptibility Weighted Imaging (SWI). To be submitted. PDF.
   Wayne State University, USA and Dalian Medical University, China.
5. [prep_ubc09] University of British Columbia (UBC), Canada, announced 15 Dec 2009. The Globe and Mail, CTV News, Facebook

Kritische Publikationen

1. [khan10a] Khan O, Filippi M, Freedman M, Barkhof F, Dore-Duffy P, Lassman H, Trapp B, Bar-Or A, Zak I, Siegel MJ, Lisak R: Point of View: Chronic cerebrospinal venous insufficiency and multiple sclerosis. Annals of Neurology, 2010. doi:10.1002/ana.22001. PDF$
   Abstract

   A chronic state of impaired venous drainage from the central nervous system, termed as chronic cerebrospinal venous insufficiency (CCSVI), is claimed to be a pathologic phenomenon exclusively seen in multiple sclerosis (MS). This has invigorated the causal debate of MS and generated immense interest in the patient and scientific communities. A potential shift in the treatment paradigm of MS involving endovascular balloon angioplasty or venous stent placement has been proposed as well as conducted in small patient series. In some cases, it may have resulted in serious injury. In this Point of View, we discuss the recent investigations that led to the description of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCVSI has been recognized by the scientific bodies engaged in MS research. Several scientific endeavors examining the presence of CCSVI in MS are being undertaken. At present, invasive and potentially dangerous endovascular procedures as a therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.
   Embry A: An Open Letter to the Authors of Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis (Khan et al, 2010, Annals of Neurology). PDF

   Open letter reply
2. [ana10a] Experimental multiple sclerosis vascular shunting procedure halted at Stanford. Ann Neurol. 2010 Feb;67(1):A13-A15. PMID 20186848, doi:10.1002/ana.21969. PDF

Verwandte Publikationen

Neue MRI-Technologie

1. [eddleman09] Eddleman CS, Jeong HJ, Hurley MC, Zuehlsdorff S, Dabus G, Getch CG, Batjer HH, Bendok BR, and Carroll TJ: 4D radial acquisition contrast-enhanced MR angiography and intracranial arteriovenous malformations: quickly approaching digital subtraction angiography. Stroke. 2009 Aug;40(8):2749-53. Epub 2009 May 28. PMID 19478223, doi:10.1161/STROKEAHA.108.546663. Abstract (Article$)
   Department of Neurological Surgery Feinberg School of Medicine, Northwestern University, 676 North St Clair Ste 2210, Chicago, IL 60611, USA.
   Abstract

   BACKGROUND AND PURPOSE: The current gold standard for imaging intracranial AVMs involves catheter-based techniques, namely cerebral digital subtraction angiography (DSA). However, DSA presents some procedural risks to the patient. Unfortunately, AVM patients usually undergo multiple DSA exams throughout their diagnostic and therapeutic course, significantly increasing their procedural risk exposure. As such, high-quality noninvasive imaging is desired. We hypothesize that 4D radial acquisition contrast-enhanced MRA approximates the vascular architecture and hemodynamics of AVMs compared to conventional angiography. METHODS: Thirteen consecutive AVM patients were assessed by 4D radial acquisition contrast-enhanced MRA and DSA. The 4D rCE-MRA images were independently assessed regarding the location, nidal size, Spetzler-Martin grade, and identification of arterial feeders, drainage pattern, and any other vascular anomalies. RESULTS: 4D rCE-MRA correctly depicted the size, venous drainage pattern, and prominent arterial feeders in all cases. Spetzler-Martin grade was correctly determined between reviewers and between the different imaging modalities in all cases except 1. The nidus size was in good correlation between the reviewers, where r=0.99, P<0.000001. There was very good agreement between reviewers regarding the individual scans (kappa=0.63 to 1), whereas the agreement between the DSA and 4D rCE-MRA images was also good (kappa=0.61 to 0.85). CONCLUSIONS: We have developed a 4D radial acquisition contrast-enhanced MRA sequence capable of imaging intracranial AVMs approximating that of DSA. Image analysis demonstrates equivalency in terms of grading AVMs using the Spetzler-Martin grading scale. This 4D rCE-MRA sequence has the potential to avoid some applications of DSA, thus saving patients from potential procedural risks.
2. [spuentrup09] Spuentrup E, Wiethoff AJ, Parsons EC, Spangenberg P, and Stracke CP: High spatial resolution magnetic resonance imaging of experimental cerebral venous thrombosis with a blood pool contrast agent. Eur J Radiol. 2009 Apr. PMID 19394183, doi:10.1016/j.ejrad.2009.03.061. Abstract (Article$)
   Department of Radiology, University Hospital, University of Cologne, Cologne, Germany; Department of Diagnostic Radiology, University Hospital, RWTH Aachen University, Aachen, Germany.
   Abstract

   PURPOSE: The purpose of this study was to investigate the feasibility of clot visualization in small sinus and cortical veins with contrast enhanced MRA in a cerebral venous thrombosis animal model using a blood pool contrast agent, Gadofosveset, and high spatial resolution imaging. MATERIAL AND METHODS: For induction of cerebral venous thrombosis a recently developed combined interventional and microsurgical model was used. Cerebral sinus and cortical vein thrombosis was induced in six pigs. Two further pigs died during the procedure. Standard structural, time-of-flight- and phase contrast-angiograms were followed by fast time resolved high resolution 3D MRA (4D MRA) and subsequent high spatial resolution 3D MRA in the equilibrium phase with and without addition of parallel imaging. Visualization of the clots using the different sequences was subjectively compared and contrast-to-noise ratio (CNR) was assessed. RESULTS: In the remaining six animals the procedure and MR-imaging protocol including administration of Gadofosveset was successfully completed. The 3D high resolution MRA in the equilibrium phase without the addition of parallel imaging was superior to all the other applied MR measurement techniques in terms of visualization of the clots. Only applying this sequence bridging vein thromboses were also seen as a small filling defect with a high CNR of >18. CONCLUSION: Only the non-accelerated high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset allows for high-contrast visualization of very small clots in the cerebral sinus and cortical veins. STATEMENT CLINICAL IMPACT: Detection of cortical vein thrombosis is of high clinical impact. Conventional MRI sequences often fail to visualize the clot. We could demonstrate that, in contrast to conventional sequences, with high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset very small clots in the cerebral sinus and cortical veins could be successfully visualized. We think that with the presented approach cortical vein thrombosis might also be sufficiently visualized in patients.
3. [willinek08] Willinek WA, Hadizadeh DR, von Falkenhausen M, Urbach H, Hoogeveen R, Schild HH, and Gieseke J: 4D time-resolved MR angiography with keyhole (4D-TRAK): more than 60 times accelerated MRA using a combination of CENTRA, keyhole, and SENSE at 3.0T. J Magn Reson Imaging. 2008 Jun;27(6):1455-60. PMID 18504736, doi:10.1002/jmri.21354.Abstract (Article$)
   Department of Radiology, University of Bonn, Bonn, Germany.
   Abstract

   PURPOSE: To present a new 4D method that is designed to provide high spatial resolution MR angiograms at subsecond temporal resolution by combining different techniques of view sharing with parallel imaging at 3.0T. MATERIALS AND METHODS: In the keyhole-based method, a central elliptical cylinder in k-space is repeated n times (keyhole) with a random acquisition (CENTRA), and followed by the readout of the periphery of k-space. 4D-MR angiography with CENTRA keyhole (4D-TRAK) was combined with parallel imaging (SENSE) and partial Fourier imaging. In total, a speed-up factor of 66.5 (6.25 [CENTRA keyhole] x 8 [SENSE] x 1.33 [partial Fourier imaging]) was achieved yielding a temporal resolution of 608 ms and a spatial resolution of (1.1 x 1.4 x 1.1) mm(3) with whole-brain coverage 4D-TRAK was applied to five patients and compared with digital subtraction angiography (DSA). RESULTS: 4D-TRAK was successfully completed with an acceleration factor of 66.5 in all five patients. Sharp images were acquired without any artifacts possibly created by the transition of the central cylinder and the reference dataset. MRA findings were concordant with DSA. CONCLUSION: 4D time-resolved MRA with keyhole (4D-TRAK) is feasible using a combination of CENTRA, keyhole, and SENSE at 3.0T and allows for more than 60 times accelerated MRA with high spatial resolution.

Andere venöse Publikationen

1. [chung10a] Chung CP, Chao AC, Hsu HY, Lin SJ, and Hu HH: Decreased jugular venous distensibility in migraine. Ultrasound Med Biol. 2010 Jan;36(1):11-6. Epub 2009 Nov 8. PMID 19900748, doi:10.1016/j.ultrasmedbio.2009.08.007.
   Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
   Abstract

   It has been demonstrated that internal jugular vein (IJV) compression aggravates headache intensity in patients of migraine. We hypothesized that patients with migraine may have veins that are less distensible; consequently, these veins are more likely to develop and transmit venous hypertension caused by the increased venous blood volume during IJV compression. We used ultrasonography to measure the extent of venodilatation and distensibility of IJV in response to increased transmural pressure, which was produced by a Valsalva maneuver. The extent of venodilatation were compared between 23 migraine patients (5 men, 18 women; mean age: 40.22+/-12.71 years, range: 27-7 years) and 23 age- and gender-matched normal individuals (5 men, 18 women; mean age: 40.23+/-12.04 years, range: 27-7 years). In the result, the venodilatation of IJV in response to each level of Valsalva pressure in patients with migraine was significantly less than that in normal individuals. Our results suggest that patients with migraine have less compliant IJVs, which makes them susceptible to cerebral venous hypertension. Further studies are needed to elucidate the clinical implications of decreased venous distensibility in migraine patients. (E-mail: hhhu@vghtpe.gov.tw).
2. [zamboni08b] Zamboni P, Lanzara S, Mascoli F, Caggiati A, and Liboni A: Inflammation in venous disease. Int Angiol. 2008 Oct;27(5):361-9. Type: Review. PMID 18974697. PDF
   Department of Surgery, Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
   Abstract

   Chronic venous disease (CVD), mainly due to venous reflux or, sometimes, to venous outflow obstruction, produces a microcirculatory overload leading to the impairment of venous drainage. Venous drainage depends primarily on a major hemodynamic parameter called trans-mural pressure (TMP). TMP is increased in patients affected by CVD, leading to impaired tissue drainage, and, consequently, facilitating the beginning of the inflammatory cascade. Increased TMP determines red blood cell extravasation and either dermal hemosiderin deposits or iron laden-phagocytes. Iron deposits are readily visible in the legs of all patients affected by severe CVD. Local iron overload could generate free radicals or activate a proteolytic hyperactivity of metalloproteinases (MMPs) and/or downregulate tissue inhibitors of MMPs. These negative effects are particularly evident in carriers of the common HFE gene's mutations C282Y and H63D, because intracellular iron deposits of mutated macrophages have less stability than those of the wild type, inducing a significant oxidative stress. It has been demonstrated that such genetic variants increase the risk of ulcers and advance the age of ulcer onset, respectively. The iron-dependent vision of inflammation in CVD paves the way to new therapeutic strategies including the deliberate induction of iron deficiency as a treatment modality for non-healing and/or recurrent venous leg ulcers. The inflammatory cascade in CVD shares several aspects with that activated in the course of multiple sclerosis, an inflammatory and neurodegenerative disease of unknown origin in which the impairment of cerebral venous outflow mechanisms has been recently demonstrated.
3. [doepp08] Doepp F: Die zerebrale venöse Hämodynamik: Neue Aspekte zur Physiologie und Pathophysiologie unter besonderer Berücksichtigung dopplersonographischer Methoden. Habilitationsschrift, Klinik für Neurologie, Medizinische Fakultät der Charité-Universitätsmedizin Berlin, April 2008. PDF
4. [schreiber05a] Schreiber SJ, Doepp F, Klingebiel R, and Valdueza JM: Internal jugular vein valve incompetence and intracranial venous anatomy in transient global amnesia. J Neurol Neurosurg Psychiatry. 2005 Apr;76(4):509-13. PMID 15774436, doi:10.1136/jnnp.2004.043844. Article.
   Department of Neurology, University Hospital Charité, Schumannstrasse 20/21, 10117 Berlin, Germany.
   Abstract

   BACKGROUND: Recently a causal relation between internal jugular vein valve incompetence (IJVVI) and transient global amnesia (TGA) has been suggested. IJVVI is postulated to provoke a transient mesiotemporal ischaemia by venous congestion. This mechanism requires a patent venous pathway from the affected IJV through the transverse sinus, confluens, straight sinus (SS), vein of Galen into the basal vein of Rosenthal and the internal cerebral veins. OBJECTIVE: To study IJVVI in TGA patients in relation to the intracranial venous anatomy. METHODS: IJVVI was defined if a repeated Valsalva manoeuvre (VM) led to a retrograde jugular flow detected by extracranial duplex ultrasound. Non-contrast venous MR angiography (MRA) was performed to analyse intracranial drainage patterns of the SS in relation to the side of the IJVVI. SS drainage was differentiated into three groups: predominantly right, left, and bilateral drainage. Ultrasound studies were performed in 25 TGA patients and 85 age matched controls. Twenty patients underwent venous MRA. RESULTS: Sixty eight per cent of patients and 33% of controls showed unilateral or bilateral IJVVI (p = 0.0025). In 36% of patients a TGA preceding VM was reported. Drainage pattern of SS and side of IJVVI corresponded in five of eight patients (63%) with VM and four of 12 patients without VM (33%, p = 0.0994). CONCLUSION: Our study confirms the significantly higher prevalence of IJVVI in TGA patients. However, no specific IJVVI related intracranial venous drainage patterns could be found to further support the hypothesis of a direct causal relation between IJVVI and TGA.
5. [sander00a] Sander D, Winbeck K, Etgen T, Knapp R, Klingelhöfer J, and Conrad B: Disturbance of venous flow patterns in patients with transient global amnesia. Lancet. 2000 Dec;356(9246):1982-4. PMID 11130530, doi:10.1016/S0140-6736(00)03313-4.
   Abstract

   Transient global amnesia (TGA) is an inability to form new memories. The pathophysiology and cause of TGA have not been defined. We examined the changes of internal jugular venous flow patterns in 21 patients with TGA and 21 age-matched and sex-matched controls using duplex ultrasonography during two Valsalva manoeuvres (blocking venous return through the superior vena cava). During both manoeuvres a retrograde flow component was seen significantly more frequently in the TGA group than in the controls. Ten patients reported Valsalva-like activities preceding TGA. In these patients a retrograde flow component took place more frequently than in those who did not report preceding Valsalva-like activities. Our results lend support to the hypothesis that TGA may be attributable to venous congestion, and consequent venous ischaemia to bilateral diencephalic or hippocampal structures.

Allgemein

1. [prineas09] Henderson AP, Barnett MH, Parratt JD, and Prineas JW: Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol. 2009 Dec;66(6):739-53. PMID 20035511, doi:10.1002/ana.21800. Abstract, PDF$
   Institute of Clinical Neuroscience, Department of Medicine, University of Sydney, Sydney, Australia.
   Abstract

   OBJECTIVE: CD4 T-cell-dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis (MS). However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions. METHODS: Twenty-six active lesions from 11 patients with early MS were serially sectioned and immunostained for T and B cells, plasma cells, ramified microglia, macrophages, monocytes, and CD209-positive dendritic cells. Cell counts were compared in prephagocytic, phagocytic, and immediately postphagocytic areas. RESULTS: Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells, and immunoglobulin G (IgG)-positive plasma cells. Lesions in 2 exceptionally early cases contained relatively few T and B cells, and no IgG-positive plasma cells. INTERPRETATION: Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.
2. [bartholomaeus09] Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, Klinkert WE, Flügel-Koch C, Issekutz TB, Wekerle H, and Flügel A: Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009 Nov;462(7269):94-8. Epub 2009 Oct 14. PMID 19829296, doi:10.1038/nature08478. Abstract (Full$), Nature News (Full$)
   Max Planck Institute for Neurobiology, 82152 Martinsried, Germany.
   Abstract

   The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.

Konferenz-Poster

1. [pos_zamboni09d] Menegatti E, Galeotti R, Genova V, Tessari M, Bartolomei I, Zuolo M, Salvi F, and Zamboni P: Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis. Onset symptom and clinical course in relation to the hemodynamic pattern. European Charcot Foundation Symposium 2009. 12–14 Nov. 2009, Lisbon, Portugal. [ecfs09]. Poster (PDF), FB: Poster
   Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
   Abstract

   Venography and transcranial and extracranial Color-Doppler high-resolution examination (TCCS-ECD) permitted us to detect 5 different malformative patterns of the venous vessels (annulus, septum/valve malformation, twisting, membranous obstruction, agenesis/hypoplasia) and 4 major hemodynamic patterns of extracranial-extravertebral venous outflow. The aim of this work were to correlate pattern of CCSVI with clinical findings such as the MS onset symptom and the subsequent clinical course.
2. [pos_zamboni09c] Bartolomei I, Salvi F, Galeotti R, Malagoni AM, Alcanterini M, Menegatti E, and Zamboni P: Coulour Doppler in CCSVI-Multiple Sclerosis: Diagnostic Accuracy and Reproducibility. European Charcot Foundation Symposium 2009. 12–14 Nov. 2009, Lisbon, Portugal. [ecfs09]. FB: Poster
   Vascular Diseases Center, University of Ferrara, Ferrara, Italy.
3. [pos_zamboni09b] Zamboni P, Galeotti R, Weinstock-Guttman B, Cutter G, Menegatti E, Malagoni A, Hojnacki D, Cox J, Kennedy C, Bartolomei I, Salvi F, and Zivadinov R: Endovascular treatment for chronic cerebrospinal venous insufficiency in multiple sclerosis. A longitudinal pilot study. Study presented at the European Multiple Sclerosis Congress ECTRIMS Düsseldorf, 9–12 Sep 2009 [ectrims09]. Abstract
   Ferrara, IT; Buffalo, Birmingham, US; Bologna, IT
   Abstract

   Objective: To evaluate safety of minimally invasive endovascular treatment (EVT) for chronic cerebrospinal venous insufficiency (CCSVI) associated to multiple sclerosis (MS) using MRI, clinical and haemodynamic outcome measures.
   Background: CCSVI is a vascular picture characterized by multiple strictures at the level of the main extracranial cerebrospinal venous outflow routes including the internal jugular and the azygous venous systems. It is strongly associated to MS (JNNP 2009 Apr;80(4):392-9).
   Design/Methods: We designed an open-label, MRI-blinded, two-center, randomized, EVT intervention parallel-group, 12 month study (EVTMS) following an initial cross-sectional (CVIMS) study. Sixteen relapsing-remitting (RR) MS patients, 8 from Bologna, Italy and 8 from Buffalo, NY were enrolled in CVIMS. All 16 patients who completed the CVIMS study and presented severe hemodynamic venous anomalies accepted participation in the EVT intervention prospective study (EVTMS). Half of the cohort (early intervention group, 4 from Buffalo and 4 from Italy) were randomly selected to have the EVT procedure (in Italy) at 3 months and half (delayed control intervention group, late group) at 6 months. The EVT procedure consists of selective venography complemented by balloon dilatation when significant stenosies are detected. All patients will be prospectively evaluated at 3, 6, 9 and 12 months with sonography, MRI, and clinical examinations, or in case of MS relapse only with sonography and clinical examinations.
   Outcome measures: Safety, and preliminary efficacy will be monitored using MRI (T2 and Gd lesions measures), Doppler haemodynamic parameters of CCSVI and clinical measures (relapse rate, EDSS, MS functional composite). In addition, a variety of vascular and other MRI measures (including susceptibility-weighted imaging and CSF flow) assessments will be performed and compared to the 1-year outcome in all cohort as well as in between the 2 groups (early and delayed EVT intervention).
   Preliminary Results: Mean age at baseline was 36.1±7.3 yrs, mean disease duration 7.5 ±1.9 yrs and median EDSS 2.5. Mean number of gadolinium (Gd) active lesions at baseline was 0.38±1.5 and mean number of T2 lesions 27.1±10.5. Median of Doppler parameters of CCSVI was 4 (2-5). Mean follow up at the time of abstract presentation will be 11 months.
   Conclusion/Relevance: This study should provide valuable data on safety, tolerability and preliminary efficacy of EVT for CCSVI associated to MS.
4. [pos_zamboni09a] Zamboni P, Menegatti E, Weinstock-Guttman B, Cox J, Schirda C, Malagoni A, Hojnacki D, Kennedy C, Carl E, Dwyer M, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, and Zivadinov R: Chronic cerebrospinal venous insufficiency is related to inverted and decreased cerebrospinal fluid flow and greater brain atrophy in patients with multiple sclerosis. Study presented at the European Multiple Sclerosis Congress ECTRIMS Düsseldorf, 9–12 September 2009 [ectrims09]. Abstract
   Ferrara, IT; Buffalo, US; Bologna, IT
   Abstract

   Objective: To investigate the cerebral Doppler venous outflow haemodynamics (VH) in multiple sclerosis (MS) patients vs healthy controls (HC) and to correlate VH parameters with MRI measures of disease severity. Background: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular picture characterized by stenosies affecting the main extracranial venous outflow pathways. This picture is strongly and constantly associated to MS and determines significant alterations of five specific VH criteria (JNNP doi:10.1136/jnnp.2008.157164). CCSVI diagnosis needs to fulfill at least 2 out of 5 VH criteria. VH in CCSVI is characterized by blocked outflow and a high rate of cerebral venous reflux, but the relationship with MRI disease outcome has never been investigated.
   Methods: Sixteen (16) consecutive relapsing-remitting MS patients (mean age 36.1±7.3 yrs, mean disease duration 7.5 ±1.9 yrs and median EDSS 2.5) and 8 age- and sex-matched HC were scanned on a GE 3T scanner. CSF flow and velocity measures, as well as lesion volume (LV), atrophy and perfusion MRI outcomes were assessed. VH was obtained in MS and HC by means of the detection of the 5 above mentioned criteria.
   Results: All MS patients and none of the HC presented severe CCSVI. Particularly, HC presented 1/40 pathologic VH criteria, whereas MS patients 61/80 (median 0 vs 4, p< 0.0001). MS patients showed a higher antegrade and retrograde peak velocities and higher antegrade and retrograde CSF flow than HC. The net CSF flow was inverted and significantly lower in MS patients than in HC (p=0.038). Both in correlation and regression analyses the number of VH criteria was highly related to decreased mean net CSF flow (r=0.8, p<0.0001, R2=0.6, p<0.0001, respectively). In addition the number of pathologic VH criteria was related significantly to greater whole brain atrophy(r= -0.5, p=0.05), and there was a trend for increased gray matter atrophy (r=0.46, p=0.079). Finally, the relationship with LV and perfusion measures did not reach statistical significance.
   Conclusion: Inverted direction and decreased CSF flow in MS suggest the activation of patho-physiological mechanisms in CCSVI in response to impaired venous drainage of brain tissue. In addition, the relationship between brain atrophy and VH measures on one side, and the strong correlation between VH and net CSF flow on the other, clearly suggest a pivotal role of CCSVI in MS pathogenesis.

Präsentationen

1. [pres_zivadinov10a] Zivadinov R: CCSVI and MRI Outcomes in MS. CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
2. [pres_al-omari10a] Al-Omari M, Rousan L: CCSVI: Evidence from Jordanian experience. CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
3. [pres_haacke10a] Haacke EM: Is the Basic Etiology of Multiple Sclerosis Vascular in Origin? CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
4. [pres_dake10a] Dake MD: Locations and etiologies of extracranial venous lesions in MS. CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
5. [pres_simka10a] Simka M: Preliminary results of preoperative diagnostics and endovascular treatment for CCSVI. CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
6. [pres_haacke09] Haacke EM: Iron and Chronic Cerebral Spinal Vascular Insufficiency (CCSVI). 1 October, 2009, MRA Club. ms-mri.com. PDF
7. [pres_simka09] Simka M: Chronic cerebrospinal venous insufficiency and multiple sclerosis: theoretical and practical issues. XVI World Congress of the Union Internationale de Phlébologie, Monaco, 31 Aug – 4 Sep 2009 [uip09]. Slides, Slides (PPT), Slides (PDF)
8. [pres_cernuda09] Cernuda E, Calleja S: Insuficiencia venosa cerebroespinal crónica en pacientes con esclerosis múltiple. Sesiones de Neurología, Oviedo, Hospital Universitario Central De Asturias (HUCA), España, 3 de abril de 2009. PDF, Scribd (PDF, PPT), Neurobsesion Blog, 6 abril, Neurobsesion Blog, 2 abril
9. [pres_zamboni07] Zamboni P: Cerebro spinal venous outflow impairment and multiple sclerosis: a new challenge? London, Charing Cross Symposium 14–17 April 2007 Slides (PDF)

Konferenzen, Meetings and Workshops

1. [ws_hamilton10_2] Chronic Cerebral Spinal Venous Insufficiency (CCSVI) and Multiple Sclerosis (MS) Workshop. Sunday, February 7, 2010, Chair - Dr. Ian Rodger, St. Joseph’s Healthcare Hamilton, Canada. Program [pres_haacke10a] [pres_dake10a] [pres_simka10a] [pres_zivadinov10a] [pres_al-omari10a]
2. [ecfs09] European Charcot Foundation Symposium 2009. 12–14 Nov. 2009, Lisbon, Portugal. Link [pos_zamboni09c] [pos_zamboni09d]
3. [ectrims09] 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). 9–12 Sept. 2009, Düsseldorf, Germany. Link, Conference program. [pos_zamboni09a] [pos_zamboni09b]
4. [bologna09] Venous Function And Multiple Sclerosis. Fondazione Hilarescere, Bologna, 8 Sept. 2009. Program (PDF), Scientific Committee (Doc), Press release (Doc) (Deutsche Übersetzung der Pressemeldung), Short notes (Doc), Unofficial minutes of the conference by an attendee (PDF) (Deutsche Übersetzung des inoffiziellen Protokolls), CCSVI and Multiple Sclerosis (Youtube), Abstract: B. Weinstock-Guttman (PDF), Abstract: B.B.Lee (PDF), Abstract: A. Ferlini (PDF)
5. [uip09] XVI World Congress of the Union Internationale de Phlébologie. Monaco, 31 Aug. – 4 Sept. 2009.> Link, Conference program, p. 22. [pres_simka09] [lee09a]
6. [cx09] CX Charing Cross – 31st International Symposium: Vascular and Endovascular Controversies Update. Imperial College, London, UK. 4–7 April 2009. Link, Conference program, p. 8. [zamboni09c] [zamboni09f], video

Weitere Unterlagen

1. [rowland09] Rowland LP: The legacy of Tracy J. Putnam and H. Houston Merritt: Modern Neurology in the United States. 2009, Oxford University Press (New York). ISBN-10: 0195379527, ISBN-13: 9780195379525. Open library, Amazon
   Reviews

   1. [lisak09] Lisak RP: The legacy of Tracy J. Putnam and H. Houston Merritt: Modern Neurology in the United States. Journal of the Neurological Sciences - 15 May 2009 Vol. 280, Issue 1, Page 133 doi:10.1016/j.jns.2009.01.004. Article$
   2. [kaminski09] Kaminski HJ: The legacy of Tracy J. Putnam and H. Houston Merritt: Modern Neurology in the United States. N Engl J Med 2009 360: 941-942 Article$
2. [simkaop09] Simka M: CCSVI 1st OP in Poland. Stent OP 19.10.2009. Youtube
3. [ms-mri09] Haacke EM: MRI protocol, parameters and case studies. 2009. ms-mri.com. Potential SWI/MRV/FQ protocol, Scanning Procedure (PDF), MS Protocol for MS study for 3T (PDF), SIEMENS MAGNETOM Verio Syngo MR B15V (PDF), Important notes (PDF), Case studies: Case 0, Case 1
4. [doppler09] Simka M: The many sonographic faces of the chronic cerebrospinal venous insufficiency: How to perform doppler examination in a multiple sclerosis patient. 2009. PDF (2MB), Doc (7MB)
5. [spin09] SPIN: A powerful software for MRI DICOM data post-processing.MR Center Wayne State University. SPIN (Signal Processing in NMR) supports SWI processing. SPIN software with SWI (Windows, free)
6. [cxnews09] Endovascular Treatment for Multiple Sclerosis. May 2009 in Vascular News ed. 80, pp. 392–399. Article (JPG)
7. [aerztezeitung08] Meißner T: Jugularvenenthrombose - da kann auch eine maligne Erkrankung die Ursache sein. Ärzte Zeitung (Deutschland), 29.09.2008 Article
8. [deistung08] Deistung A, Reichenbach J et al.: Informatics in Radiology: GUIBOLD: a graphical user interface for image reconstruction and data analysis in susceptibility-weighted MR imaging. Radiographics 28 (2008), no. 3, 639–651. Full article, PDF Susceptibility Weighted Imaging (SWI), Medical Physics Group, Department of Diagnostic and Interventional Radiology, Jena University Hospital. GUIBOLD Software (free)
9. [haacke06] Haacke EM: Susceptibility Weighted Imaging: Opening new doors to clinical applications of magnetic resonance imaging. Brochure, 5th Edition (2006). SWI mrimaging.com, PDF, SPIN software (Windows, free) [spin09]
10. [sciencenewsletter35] : Multiple Sclerosis laid to blood that clots too easily. Science News Letter for May 18, 1935. Article

Kritik ausserhalb wissenschaftlicher Publikationen

1. [blog_rose10a] Rose C: Zamboni and the Occult Art of “CCSVI”. Blog Panaceia or Hygeia. Blog posting 10.02.2010
   Colin Rose MD PhD, Cardiologist, Associate Professor of Medicine, McGill University
2. [blog_rose09a] Rose C: The Zamboni Myth: Why “CCSVI” is Surreal. Blog Panaceia or Hygeia. Blog posting 24.11.2009, Deutsche Übersetzung
   Colin Rose MD PhD, Cardiologist, Associate Professor of Medicine, McGill University

Interessenskonflikte in der Medizin

1. [lo10a] Lo B: Serving two masters – conflicts of interest in academic medicine. N Engl J Med. 2010 Feb;362(8):669-71. PMID 20181969, doi:10.1056/NEJMp1000213. PDF. Deutsche Übersetzung
   University of California, San Francisco, San Francisco, USA.
2. [jelinek09] Jelinek G and Neale S: The influence of the pharmaceutical industry in medicine. Journal of Law and Medicine, Volume 17, Number 2, October 2009, 216. Abstract, PDF
   Departement of Medicine, University of Melbourne, Australia
   Abstract

   Pharmaceutical companies are known to be amongst the most profitable companies in the world. Proceedings of legal cases and published research provide insights into the nature of the influence of drug companies into research and publication practices relating to the drugs they manufacture, marketing disguised as ‘education’ and their influence on doctors who prescribe their drugs. The influence of drug companies extends further to sponsorship of opinion leaders promoting their drugs and groups producing clinical guidelines. More rigorous regulation of the relationship between the industry and medicine is required.
3. [hinchliffe05] Hinchliffe D, Amess D, Austin J, Bradley K, Burns S, Calton P, Dowd J, Owen J, McDonagh S, Naysmith D, and Taylor R: The influence of the pharmaceutical industry. House of Commons Health Committee, Fourth Report of Session 2004–05, Volume I. PDF
   House of Commons, Parliament of the United Kingdom

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