Hypothèse d'une SEP veineuse | CCSVI | IVCC

New publications

• [ferlini10a] Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, Salvi F, Gemmati D, Liboni A, and Zamboni P: Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis. BMC Med Genet. 2010 Apr;11(1):64. Epub 2010 Apr 28. PMID 20426824, doi:10.1186/1471-2350-11-64. Article, PDF.
  Abstract

  Background
  Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance.
  Methods
  In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate.
  Results
  In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype.
  Conclusions
  The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.
• [qiu10a] Qiu J: Venous abnormalities and multiple sclerosis: another breakthrough claim? Lancet Neurol. 2010 May;9(5):464-5. PMID 20398855, doi:10.1016/S1474-4422(10)70098-3.
• [beal10a] Beal E: Vascular angioplasty for ms? Nat Rev Neurol. 2010 Apr;6(4):184. PMID 20383884. Article$.
• [rynor10a] Rynor B: Canadian trials to examine "liberation procedure" for multiple sclerosis. CMAJ. 2010 May:. PMID 20439450, doi:10.1503/cmaj.109-3251. PDF. See [trial_rodger10a] [trial_knox10a]

Announced studies

• [trial_zamboni10a] Zamboni P: Randomised controlled CCSVI treatment trial. Source (medpage interview at 2:15)
  Italy
  Abstract

  IRB: June 2010
  Start: Summer 2010
• [trial_dake10a] Dake M: CCSVI Study. Stanford University. Source (Video interview). Needs funding.
  Stanford University
  Abstract

  Start: 2010
• [trial_sinan10a] Sinan T, Al Khashan S, Safar H, Almuzaini AA, Bin naki AM, Al bader M, Bahzad M: CCSVI study Kuwait. ccsvikuwait.com. Study description, Introduction.
  Mubarak Hospital and other Hospitals of Kuwait
  Abstract

  AIM & OBJECTIVE:
  

  In Kuwait the MS patient is increasing and it is estimated about 2000-3000 patients. This program started in March. 2010, it is multidisciplinary approach, vascular diagnostic lab. doctor, vascular surgeon, and vascular intervention radiology, radiologist and neurologist.

  Our objective to diagnose MS patient with Chronic cerebrospinal venous insufficiency (CCSVI) and to evaluate them with Duplex scanning and magnetic resonance venography and to evaluate clinical and or radiological improvement of these cases after treating them with angioplasty with or without stent of the diseased affected part of the internal jugular vein.

  This method is a new application of a standard procedure that may be helpful in relieving some of the symptoms of MS patients with CCSVI and it was advocated in Italy, Poland and USA. In Kuwait we would like as usual to lead the way in the Gulf state and Arabian countries to study and assess the feasibility of such a new method of possible clinical improvement of some or all of the symptoms of MS patients which may help improve quality and functions of the patients and whether or not reach and meet our expectation, therefore we will do a pilot study of 100 patients and evaluate clinical improvement by a neurologist at 1, 3, 6, and 12 months. Colour Duplex scan at 1, 3, 6, 9, and 12 months intervals. MRV at 6 and 12 months intervals. MRI brain at 3, 6, and 12 months intervals. If the initial results of the study fulfilling our objectives then we will do more cases and continue the study for 1 year to include total 500 cases at least.

  SAMPLE SIZE:
  100 - 500 MS patients from all hospital.

• [trial_hubbard10a] Hubbard D: The fMRI BOLD Response in MS, Support for the CCSVI Hypothesis. Hubbard Foundation for fMRI Research. Grant Request (PDF)
  Hubbard Foundation for fMRI Research.
  Abstract

  Lay Summary
  The pathogenesis of MS remains unknown. The well-known inflammatory changes may not be causative and may not correlate with clinical symptoms or disability. A new theory of the cause of MS, known as CCSVI, has been proposed by Dr. Zamboni in Italy. According to this theory, inadequate drainage from neurons leads to leakage of iron-containing and immune cells across the blood-brain barrier, exposing neurons and myelin-producing cells to inflammation. In the past year, he found in MS patients narrowing of neck veins using ultrasound and reported clinical improvement by removing the obstructions in the internal jugular veins with percutaneous transluminal angioplasty. Dr. Haacke at Wayne State in Detroit and Dr. Zivadinov at the University of Buffalo have confirmed these findings using MRI venography. While promising, these methods do not address the drainage of blood from cerebral cortex directly. We present new data on a method to test cerebral cortex drainage, using functional MRI that measures cortex blood flow specifically. If our preliminary findings are confirmed, venous drainage from cortex is dramatically altered in MS patients, recognizable at the single subject level, further supporting the CCSVI hypothesis and promising a clinical test for this abnormality whether it is secondary to neck vein obstruction or delay in smaller veins in the brain.

  Scientific Abstract
  Chronic cerebrospinal venous insufficiency has been proposed by Zamboni and Haacke as the proximate cause of multiple sclerosis (MS). They have proposed using ultrasound and MRI venograms to study the large veins in the neck and head. We have shown in MS patients that functional MRI can demonstrate delayed venous recovery of the hemodynamic response to stimulation of frontal lobe function, providing direct evidence of venous insufficiency in the cerebral cortex and a potential index for evaluating potential treatments.

  Background and Significance
  Chronic cerebrospinal venous insufficiency (CCSVI) is the theory that the autoimmune neurodegeneration of MS may be triggered by narrowing of and restricted flow in the veins of the head and neck leading to venous hypertension and insufficiency. The theory has been recently reinvigorated by Zamboni who has conducted clinical studies showing cerebral and spinal outflow stenoses in a large group of MS patients. He proposes the resultant venous hypertension may damage the vessel wall further causing local proximal iron depositions as well as the long recognized inflammatory changes and demyelination. He has gone further proposing that interventional percutaneous transluminal angioplasty or stenting of the stenotic veins may be a treatment option for MS patients.

• [trial_tornatore10a] Tornatore C, Neville R: CCSVI treatment study. Georgetown University Hospital. Source
  Georgetown University Hospital, USA
  Abstract

  2 year study

Comparison by Charity Intelligence Canada of the Canadian studies [trial_rodger10a] and [trial_knox10a] which are seeking funding: PDF document.

Note: Kuwait offers angioplasty for CCSVI to all Kuwaitis affected by MS through the public health system. Source: CTV.

Related studies

These studies are related to venous MS, e.g. they describe perfusion measurements in the brain.

• [ge06a] Ge Y, Law M, Johnson G, Herbert J, Babb JS, Mannon LJ, and Grossman RI: Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am J Neuroradiol. 2005 Jun-Jul ;26(6):1539-47. PMID 15956527.
  Department of Radiology, New York University School of Medicine, NY 10016, USA.
  Abstract

  BACKGROUND AND PURPOSE: Perfusion measurement in multiple sclerosis (MS) may cast light on the disease pathogenesis and lesion development since vascular pathology is frequently demonstrated in the disease. This study was performed to investigate the perfusion characteristics in MS lesions using dynamic susceptibility contrast MR imaging (DSC-MRI) to better understand the hemodynamic changes in MS. METHODS: Seventeen patients with relapsing-remitting MS were studied with DSC-MRI. Perfusion measurements included cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT), were obtained in enhancing, non-enhancing lesions covered by DSC-MRI and contralateral normal appearing white matter (NAWM) in patients as well as normal white matter in seventeen control subjects. RESULTS: DSC-MRI data demonstrated reduced perfusion with significantly prolonged MTT (P < 0.001) in lesions and NAWM in patients compared with normal white matter in controls. Compared to contralateral NAWM, enhancing lesions demonstrate increased CBF (P = 0.007) and CBV (P < 0.0001), indicating inflammation-mediated vasodilatation. A K means cluster analysis was performed and identifies approximately 63.8% of non-enhancing lesions (Class 1) with significantly decreased perfusion (P < or = 0.0001) when compared with contralateral NAWM. In contrast, the remainder 36.2% non-enhancing lesions (Class 2) show increased CBV (P = 0.02) in a similar fashion to enhancing lesions and can be observed on quantitative color-coded maps even without blood-brain barrier breakdown. CONCLUSION: DSC-MRI measurements demonstrate potential for investigating hemodynamic abnormalities that are associated with inflammatory activity, lesion reactivity and vascular compromise in MS lesions. Non-enhancing lesions showed both low and high perfusion suggesting microvascular abnormalities with hemodynamic impairment and inflammatory reactivity that cannot be seen on conventional MRI.
• [inglese08a] Inglese M, Adhya S, Johnson G, Babb JS, Miles L, Jaggi H, Herbert J, and Grossman RI: Perfusion magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis. J Cereb Blood Flow Metab. 2008 Jan;28(1):164-71. Epub 2007 May 02. PMID 17473851, doi:10.1038/sj.jcbfm.9600504.
  Department of Radiology, Hospital for Joint Disease, New York University School of Medicine, New York, New York 10016, USA.
  Abstract

  Although cognitive impairment is common in multiple sclerosis (MS), its pathophysiology is still poorly understood. Abnormalities of cerebral blood flow (CBF) have long been acknowledged in MS and advances in perfusion magnetic resonance imaging (MRI) allow for their assessment in vivo. We investigated the relationship between regional perfusion changes and neuropsychological (NP) dysfunctions in patients with relapsing-remitting and primary-progressive MS. Absolute CBF, cerebral blood volume (CBV) and mean transit time were measured in 32 MS patients and 11 healthy controls using dynamic susceptibility contrast-enhanced T2(*)-weighted MRI. A comprehensive NP test battery was administered to all patients. A mixed model analysis of covariance was performed for group comparisons in terms of perfusion measures in normal-appearing white matter (NAWM) and deep gray matter (GM). Pearson's correlations were used to describe the association of perfusion metrics with NP Z-scores. CBF and CBV values were significantly decreased in both NAWM and deep GM in MS patients compared with controls (P=0.01). In all patients, deep GM CBF was significantly associated with Rey Complex Figure Test (RCFT)-Copy (r=0.5; P=0.001) and deep GM CBV and NAWM CBV were significantly associated with Color-Word Interference Inhibition Switching test (D-KEFSIS) (r=0.4; P=0.008 and r=0.4; P=0.02). However, the only associations that remained significant after Bonferroni correction were between deep GM CBF and RCFT-Copy (P=0.006), and deep GM CBV and D-KEFSIS (P=0.04). Our results suggest a role for tissue perfusion impairment in NP dysfunction in MS. Large-scale studies are needed to characterize better this association.
• [inglese07a] Inglese M, Park SJ, Johnson G, Babb JS, Miles L, Jaggi H, Herbert J, and Grossman RI: Deep gray matter perfusion in multiple sclerosis: dynamic susceptibility contrast perfusion magnetic resonance imaging at 3 T. Arch Neurol. 2007 Feb;64(2):196-202. PMID 17296835, doi:10.1001/archneur.64.2.196.
  Departments of Radiology and Neurology, Hospital for Joint Disease, New York University School of Medicine, 650 First Avenue, New York, NY 10016, USA.
  Abstract

  OBJECTIVES: To assess the presence of perfusion abnormalities in the deep gray matter of patients with relapsing-remitting and primary progressive multiple sclerosis (MS) in comparison with healthy controls and to investigate the impact of perfusion impairment on clinical disability and fatigue. DESIGN: Survey. SETTING: Research-oriented hospital. Patients Twenty-two patients with MS and 11 age- and sex-matched healthy volunteers. Intervention Absolute cerebral blood flow, cerebral blood volume, and mean transit time were measured in the thalamus, putamen, and caudate nuclei. MAIN OUTCOME MEASURES: Decrease of cerebral blood flow in the deep gray matter of patients with MS and correlation between perfusion impairment and the severity of fatigue. RESULTS: The cerebral blood flow value averaged over the thalamus, putamen, and caudate nuclei was significantly lower in patients with primary progressive MS (P<.001) and in patients with relapsing-remitting MS (P = .01) compared with controls, and there was a trend for patients with primary progressive MS to have lower average cerebral blood flow than patients with relapsing-remitting MS (P = .06). With respect to cerebral blood volume, there was a significant difference between patients with primary progressive MS and controls (P<.001) and between the 2 groups of patients (P = .03) but not between patients with relapsing-remitting MS and controls (P>.30). The fatigue score was significantly correlated with cerebral blood flow (r = 0.4; P<.001) and cerebral blood volume (r = 0.5; P = .004). CONCLUSION: The decrease of tissue perfusion in the deep gray matter of patients with MS is associated with the severity of fatigue.</div>
• [simon05a] Simon J: Ischemia and multiple sclerosis: perfusion MR imaging provides insight into an underexplored pathophysiology. AJNR Am J Neuroradiol. 2005 Jun-Jul ;26(6):1306-8. PMID 15956486.
• [ge05a] Ge Y, Law M, Johnson G, Herbert J, Babb JS, Mannon LJ, and Grossman RI: Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am J Neuroradiol. 2005 Jun-Jul ;26(6):1539-47. PMID 15956527.
  Department of Radiology, New York University School of Medicine, NY 10016, USA.
  Abstract

  BACKGROUND AND PURPOSE: Perfusion measurement in multiple sclerosis (MS) may cast light on the disease pathogenesis and lesion development since vascular pathology is frequently demonstrated in the disease. This study was performed to investigate the perfusion characteristics in MS lesions using dynamic susceptibility contrast MR imaging (DSC-MRI) to better understand the hemodynamic changes in MS. METHODS: Seventeen patients with relapsing-remitting MS were studied with DSC-MRI. Perfusion measurements included cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT), were obtained in enhancing, non-enhancing lesions covered by DSC-MRI and contralateral normal appearing white matter (NAWM) in patients as well as normal white matter in seventeen control subjects. RESULTS: DSC-MRI data demonstrated reduced perfusion with significantly prolonged MTT (P < 0.001) in lesions and NAWM in patients compared with normal white matter in controls. Compared to contralateral NAWM, enhancing lesions demonstrate increased CBF (P = 0.007) and CBV (P < 0.0001), indicating inflammation-mediated vasodilatation. A K means cluster analysis was performed and identifies approximately 63.8% of non-enhancing lesions (Class 1) with significantly decreased perfusion (P < or = 0.0001) when compared with contralateral NAWM. In contrast, the remainder 36.2% non-enhancing lesions (Class 2) show increased CBV (P = 0.02) in a similar fashion to enhancing lesions and can be observed on quantitative color-coded maps even without blood-brain barrier breakdown. CONCLUSION: DSC-MRI measurements demonstrate potential for investigating hemodynamic abnormalities that are associated with inflammatory activity, lesion reactivity and vascular compromise in MS lesions. Non-enhancing lesions showed both low and high perfusion suggesting microvascular abnormalities with hemodynamic impairment and inflammatory reactivity that cannot be seen on conventional MRI.
• [wuerfel04a] Wuerfel J, Bellmann-Strobl J, Brunecker P, Aktas O, McFarland H, Villringer A, and Zipp F: Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain. 2004 Jan;127(Pt 1):111-9. Epub 2003 21. PMID 14570816, doi:10.1093/brain/awh007.
  Institute of Neuroimmunology, Charité, Berlin, Germany.
  Abstract

  New MRI techniques such as the analysis of magnetization transfer or diffusion have provided evidence for subtle progressive alterations in tissue integrity prior to focal leakage of the blood-brain barrier (BBB) as part of plaque formation in multiple sclerosis. Since inflammation is capable of modulating the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. 20 patients with definite relapsing-remitting multiple sclerosis were analysed with regard to cerebral blood volume, cerebral blood flow, mean transit time and apparent diffusion coefficient (ADC), as well as conventional MRI parameters, on monthly follow-up scans. Among 89 gadolinium-enhancing lesions, we selected 18 that developed during the study and met strict inclusion criteria. In these, changes of perfusion parameters were detectable not only prior to the BBB breakdown, but also prior to increases in the ADC. Our data indicate that inflammation is accompanied by altered local perfusion, which can be detected prior to permeability of the BBB.
• [swank83a] Swank RL, Roth JG, and Woody DC: Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis. Neurol Res. 1983 ;5(1):37-59. PMID 6140655.
  Abstract

  Regional cerebral blood flow (rCBF) was determined in 77 normal females and 53 normal males of different ages and in 26 men and 45 women with multiple sclerosis by the inhalation of radioactive Xe133 method. In the normal subjects the CBF was relatively high in the teens and fell, at first rapidly and then slowly in both sexes with age. During adult life the flow in females was significantly higher than in males. The delivery of packed red cells (RCD) was determined by multiplying the CBF by the percentage concentration of red cells (HCT). The RCD for both sexes was nearly the same. In the patients with multiple sclerosis there occurred a progressive generalized decrease in CBF and in RCD with age which was significantly greater than observed in normal subjects. The rate of decrease in CBF and RCD correlated directly with the rate of progress of the disease.
• [lassmann03a] Lassmann H: Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci. 2003 Feb;206(2):187-91. Type: Review. PMID 12559509.
  Division of Neuroimmunology, Brain Research Institute, University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
  Abstract

  Recent data suggest that the mechanisms of demyelination and tissue damage in multiple sclerosis (MS) are heterogenous. In this review, evidence is discussed, which show that in a subset of multiple sclerosis patients the central nervous system (CNS) lesions show profound similarities to tissue alterations found in acute white matter stroke, thus suggesting that a hypoxia-like metabolic injury is a pathogenetic component in a subset of inflammatory brain lesions. Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis.
• [arhart10a] Arhart RW: A possible haemodynamic mechanism for Amyotrophic Lateral Sclerosis. Med Hypotheses. 2010 Apr:. PMID 20400230, doi:10.1016/j.mehy.2010.03.017.
  2117 Belaire Drive, Salt Lake City, UT 84109, USA.
  Abstract

  The hypothesis proposed in this article is that a haemodynamic mechanism may cause Amyotrophic Lateral Sclerosis (ALS). The hypothesis is synthesized from three separate streams of medical research: (1) multiple sclerosis (MS) research; (2) ALS research; (3) atherosclerosis research. Each research stream was reviewed as prerequisite for proposing the hypothesis. A vascular mechanism for MS was first advanced in the medical literature 130years ago. Seventy years ago researchers knew that the plaques aligned along a central vein, and the wall of that central vein was damaged and leaky. Twenty-five years ago the refluxing blood mechanism was proposed. Zamboni imaged the veins of MS patients in 2007 and saw stenoses, twistings, and membrane blockages in the jugular, azygous, and vertebral veins, and refluxing venous blood upstream of the constrictions. The refluxing blood damages the blood-brain-barrier (BBB) of the veins. Leakage of blood components into the central nervous system then causes the plaques in the brains of MS people. Zamboni dilated the venous constrictions endovascularly, and the MS symptoms and brain plaques diminished dramatically. ALS research has recently revealed that this disease is started by blood-spinal cord-barrier (BSCB) damage. The ALS mutant mouse shows BSCB damage and down regulation of tight junction proteins Occludin and ZO-1 before motor neuron harm. Samplings of ALS patients' spinal cords show downregulation of mRNA for tight junction proteins compared to controls. Atherosclerosis research provides the mechanism for how the refluxing blood breaks the tight junctions between the endothelial cells of the veins. Atherosclerosis research on blood flow effects shows that normal pulsatile laminar blood flow is necessary for maintenance of the tight junctions between endothelial cells. Abnormal flow conditions, such as turbulent, stopped, or reversed flow, cause downregulation of tight junction proteins Occludin and ZO-1. Blood flow (haemodynamic) effects explain the BBB damage in MS and may explain the BSCB damage in ALS. The hypothesis: ALS is caused by constrictions in veins draining the spinal cord and brain, which cause venous reflux, which downregulates tight junction proteins Occludin and ZO-1, which leads to breaks in the tight junctions between endothelial cells in the veins, which leads to leakage of toxic blood components into CNS tissue. The consequences of the hypothesis are discussed. If a venous constriction can be reached endovascularly it can be dilated, and such dilation may constitute cure of ALS.