Publications for Venous Multiple Sclerosis

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)

[phillips10a] Phillips LA: This Way In: CCSVI and Multiple Sclerosis. Neurology Now. Jul/Aug 2010;6(4):9-11. doi:10.1097/01.NNN.0000387765.20876.4c. Article
[alexander10a] Alexander JS, Zivadinov R, Maghzi AH, Ganta VC, Harris MK, and Minagar A: Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms. Pathophysiology. 2010 Jul:. PMID 20663648, doi:10.1016/j.pathophys.2010.04.002.
Department of Cellular and Molecular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.

Abstract
Multiple sclerosis (MS) is believed to be an immune-mediated neurodegenerative disorder of the human central nervous system which usually affects younger adults with certain genetic backgrounds. The causes and cure for MS remain elusive. Based on the recent advances in our understanding of the pathogenic mechanisms of MS, it appears to represents a heterogeneous group of disorders with dissimilar pathophysiology and neuropathology. Currently, there is no unifying hypothesis to explain the pathogenesis of this complex disease. The three prevailing concepts on the pathogenesis of MS include viral, immunological, and vascular hypotheses. This review presents MS as a neuroinflammatory disease with a significant vascular component and examines the existing evidence for the role of cerebral endothelial cell dysfunction in the pathogenesis of this progressive central nervous system (CNS) inflammatory disorder.
[habib10a] Habib CA, Zheng W, Haacke EM, Webb S, Nichol H: Visualizing Iron Deposition in Multiple Sclerosis Cadaver Brains. In: Siu KKW, publisher. 6TH INTERNATIONAL CONFERENCE ON MEDICAL APPLICATIONS OF SYNCHROTRON RADIATION. Melbourne (Australia): AIP; 2010. p. 78-83. Article$
Department Of Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA

Abstract
Aim: To visualize and validate iron deposition in two cases of multiple sclerosis using rapid scanning X-Ray Fluorescence (RS-XRF) and Susceptibility Weighted Imaging (SWI). Material and Methods: Two (2) coronal cadaver brain slices from patients clinically diagnosed with multiple sclerosis underwent magnetic resonance imaging (MRI), specifically SWI to image iron content. To confirm the presence of iron deposits and the absence of zinc-rich myelin in lesions, iron and zinc were mapped using RS-XRF. Results: MS lesions were visualized using FLAIR and correlated with the absence of zinc by XRF. XRF and SWI showed that in the first MS case, there were large iron deposits proximal to the draining vein of the caudate nucleus as well as iron deposits associated with blood vessels throughout the globus pallidus. Less iron was seen in association with lesions than in the basal ganglia. The presence of larger amounts of iron correlated reasonably well between RS-XRF and SWI. In the second case, the basal ganglia appeared normal and acute perivascular iron deposition was absent. Conclusion: Perivascular iron deposition is seen in some but not all MS cases, giving credence to the use of SWI to assess iron involvement in MS pathology in vivo.
[sclafani10a] Sclafani SJ (Commentary by Dake MD and Katzen BT): Chronic Cerebrospinal Venous Insufficiency: A new paradigm and therapy for multiple sclerosis. Encovascular Today. July 2010:41-6. Article. PDF
Radiology, Surgery and Emergency Medicine, State University of New York Downstate Medical Center in Brooklyn, New York.
[stanbrook10a] Stanbrook MB, and Hébert PC: Access to treatment for multiple sclerosis must be based on science, not hope. CMAJ. 2010 Jun:. PMID 20584927, doi:10.1503/cmaj.100835, PDF.
[wiehl10a] Wiehl M: Venöse Insuffizienz im Gehirn bei MS entdeckt. Ärzte Zeitung für Neurologen/Psychiater, 23. Juni 2010. Article.
Abstract
MS-Patienten haben offenbar einen abnormen venösen Blutfluss im Gehirn. Darauf deuten moderne bildgebende Verfahren. Ob die Störungen Auswirkungen der MS sind oder den MS-Verlauf beeinflussen, ist noch unklar.
[laino10a] Laino C: New Theory on CCSVI and MS Needs Further Study, Experts Say. Neurology Today. 2010 6;10(12):28-29. doi:10.1097/01.NT.0000383489.93815.43. Article
Info
News From the Aan Annual Meeting
[rynor10a] Rynor B: Canadian trials to examine "liberation procedure" for multiple sclerosis. CMAJ. 2010 May:. PMID 20439450, doi:10.1503/cmaj.109-3251. PDF. [trial_knox10a] [trial_rodger10a]
[beal10a] Beal E: Vascular angioplasty for ms? Nat Rev Neurol. 2010 Apr;6(4):184. PMID 20383884. Article$.
[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.
[zamboni10c] Zamboni P: Chronic cerebrospinal venous insufficiency. Int Angiol. 2010 Apr;29(2):91-2. PMID 20351663. PDF , Article$.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy
[embry10a] Embry AF: Integrating CCSVI and CNS autoimmunity in a disease model for MS. Int Angiol. 2010 Apr;29(2):93-4. PMID 20351664. PDF , Article$
Direct-MS, Calgary, AL, Canada
[lee10a] Lee AB, Laredo J, and Neville R: Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency. Int Angiol. 2010 Apr;29(2):95-108. PMID 20351665. PDF , Article$.
Department of Vascular Surgery, Georgetown University Hospital, Washington DC, USA.

Abstract
The truncular venous malformation (VM) represents an embryologically defective vein where developmental arrest has occurred during the vascular trunk formation period in the 'later stage' of the embryonic development. A relatively simple truncular VM lesion such as a venous web at the hepatic venous outlet causes portal hypertension giving a profound damage/impact to the liver. A similar condition involving the head and neck venous system may cause chronic cerebro-spinal venous insufficiency (CCSVI) and may be involved in the development or exacerbation of multiple sclerosis.
[simka10b] Simka M, Kostecki J, Zaniewski M, Majewski E, and Hartel M: Extracranial Doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis. Int Angiol. 2010 Apr;29(2):109-14. PMID 20351666. PDF , Article$
Department of Angiology, Private Healthcare Institution SANA, Pszczyna, Poland

Abstract
AIM: The aim of this open-label study was to assess extracranial Doppler criteria of chronic cerebrospinal venous insufficiency in multiple sclerosis patients. METHODS: Seventy patients were assessed: 49 with relapsing-remitting, 5 with primary progressive and 16 with secondary progressive multiple sclerosis. The patients were aged 15-58 years and they suffered from multiple sclerosis for 0.5-40 years. Sonographic signs of abnormal venous outflow were detected in 64 patients (91.4%). RESULTS: We found at least two of four extracranial criteria in 63 patients (90.0%), confirming that multiple sclerosis is stronghly associated with chronic cerebrospinal venous insufficiency. Additional transcranial investigations may increase the rate of patients found positive in our survey. Reflux in internal jugular and/or vertebral veins was present in 31 cases (42.8%), stenosis of internal jugular veins in 61 cases (87.1%), not detectable flow in internal jugular and/or vertebral veins in 37 cases (52.9%) and negative difference in cross-sectional area of the internal jugular vein assessed in the supine vs. sitting position in 28 cases (40.0%). Flow abnormalities in the vertebral veins were found in 8 patients (11.4%). Pathologic structures (membranaceous or netlike septa, or inverted valves) in the junction of internal jugular vein with brachiocephalic vein were found in 41 patients (58.6%), in 15 patients (21.4%) on one side only and in 26 patients (37.1%) bilaterally. CONCLUSION: Multiple sclerosis is highly correlated with chronic cerebrospinal venous insufficiency. These abnormalities in the extracranial veins draining the central nervous system can exist in various combinations. The most common pathology in our patients was the presence of an inverted valve or another pathologic structure (like membranaceous or netlike septum) in the area of junction of the IJV with the brachiocephalic vein.
[al-omari10a] Al-Omari MH, and Rousan LA: Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol. 2010 Apr;29(2):115-20. PMID 20351667. PDF , Article$.
Radiology Department, King Abdullah University Hospital, Jordan University of Science and Technology, Jordan.

Abstract
AIM: The aim of this study is to compare the hemodynamics and the morphology of the internal jugular veins using Colour-Doppler and B-mode sonongraphy in multiple sclerosis patients (MS) and in controls. METHODS: The internal jugular veins of 25 MS patients and 25 controls were examined using colour Doppler and B-mode ultrasound in sitting and supine positions, recording the changes in hemodynamics and the presence or absence of morphological changes. The presence of at least two of the extracranial Zamboni criteria in the same individual was considered positive for evidence of chronic cerebrospinal venous insufficiency (CCSVI). RESULTS: According to the described criteria, 92% of the MS patients showed abnormal findings and 84% of them showed evidence of CCSVI, however; only 24% of controls showed abnormal findings, but none of them showed evidence of CCSVI (OR=7.25, 95% CI 2.92-18.01, P<0.0001). CONCLUSION: Hemodynamic abnormalities and morphological changes involving the internal jugular vein are strongly associated with MS. These findings can be demonstrated by a non-invasive, cost effective Doppler ultrasound criteria.
[menegatti10a] Menegatti E, Genova V, Tessari M, Malagoni AM, Bartolomei I, Zuolo M, Galeotti R, Salvi F, and Zamboni P: The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. Int Angiol. 2010 Apr;29(2):121-6. PMID 20351668. PDF , Article$.
Vascular Diseases Centre, University of Ferrara, Italy

Abstract
AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome described in multiple sclerosis (MS) patients, characterized by stenosis of the main extracranial veins with hampered cerebral venous outflow. In the original description echo-colour Doppler demonstrated to be an ideal non invasive tool for screening CCSVI patients, but the reproducibility was not assessed. Aim of this study is to assess the variability coefficient between trained and in not trained echo-colour Doppler operators. METHODS: Thirty-six (36) subjects, matched for age and gender, were subset in 3 groups (group A, 12 healthy controls, HC; group B, 12 multiple sclerosis patients, MS; group C, 12 patients with other neurological disease, OND) underwent echo-colour Doppler screening for CCSVI according to an original protocol previously described. The inter observer variability rate was assessed by comparing respectively trained vs not trained operators, and trained vs trained operators, by using the same echo-colour Doppler equipment. In addition, by scanning 15 subjects after one month from the first session, intra observer coefficient was also assessed in trained operator. RESULTS: The inter observer variability rate between trained and not trained echo-colour Doppler operators, were not completely satisfactory (K coefficient 0.47 95% CI 0.27-0.68). To the contrary the inter observer agreement between trained operators was much more reliable (K coefficient 0.80 95% CI 0.59-1.01). Finally, the intra observer variability rate in trained operators was 0.93, (95% CI 0.80-1.06) confirming a highly satisfactory agreement. CONCLUSION: Echo-colour Doppler is a powerful, non-invasive and reproducible tool for screening CCSVI-MS but it needs special training.
[hojnacki10a] Hojnacki D, Zamboni P, Lopez-Soriano A, Galleotti R, Menegatti E, Weinstock-Guttman B, Schirda C, Magnano C, Malagoni AM, Kennedy C, Bartolomei I, Salvi F, and Zivadinov R: Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls. Int Angiol. 2010 Apr;29(2):127-39. PMID 20351669. PDF , Article$.
The Jacobs Neurological Institute, State University of New York, Buffalo, NY, USA

Abstract
AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of primary veins outside the skull that restrict normal outflow of blood from the brain. CCSVI was recently described as highly prevalent in patients with multiple sclerosis (MS), and can be non-invasively diagnosed by Doppler sonography (DS) and invasively by selective venography (SV). The aim of this paper was to investigate the value of neck magnetic resonance venography (MRV) for the diagnosis of CCSVI compared to DS and SV in patients with MS and in healthy controls (HC). METHODS: Ten MS patients and 7 HC underwent DS, 2D-Time-Of-Flight venography (TOF) and 3D-Time Resolved Imaging of Contrast Kinetics angiography (TRICKS). MS patients also underwent SV. The internal jugular veins (IJVs) and the vertebral veins (VVs) were assessed by both MRV sequences, and the findings were validated against SV and DS. SV has been considered the diagnostic gold standard for MS patients. RESULTS: All MS patients and none of the HC presented CCSVI, according to the DS criteria. This was confirmed by SV. For CCSVI diagnosis, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, whereas the figures were 40%, 85%, 58%, 80% and 50% for 3D-TRICKS, and 30%, 85%, 52%, 75% and 46% for 2D-TOF in the IJVs. In MS patients, compared to SV, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, 75%, 95%, 94% and 100%, whereas the figures were 31%, 100%, 45%, 100% and 26% for 3D-TRICKS and 25%, 100%, 40%, 100% and 25% for 2D-TOF in the IJVs. CONCLUSION: The use of MRV for diagnosis of CCSVI in MS patients has limited value, and the findings should be interpreted with caution and confirmed by other imaging techniques such as DS and SV.
[zamboni10b] Zamboni P, Menegatti E, Weinstock-Guttman B, Schirda C, Cox JL, Malagoni AM, Hojnacki D, Kennedy C, Carl E, Dwyer MG, Bergsland N, Galeotti R, Hussein S, Bartolomei I, Salvi F, Ramanathan M, and Zivadinov R: CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study. Int Angiol. 2010 Apr;29(2):140-8. PMID 20351670. PDF , Article$.
Vascular Diseases Center, University of Ferrara-Bellaria Neurosciences, Ferrara and Bologna, Italy

Abstract
AIM: We previously reported unexpectedly robust associations between vascular haemodynamic (VH) anomalies in the principal extracranial cerebral veins, causing chronic cerebrospinal venous insufficiency (CCSVI), and multiple sclerosis (MS). Aim of this study was to investigate the relationship between the VH changes and MRI measures of MS disease severity in a cross sectional survey. METHODS: The number of anomalous VH criteria were measured using an echo-color Doppler, whereas CSF flow, atrophy and lesion measures were obtained from quantitative magnetic resonance imaging (MRI) analysis in sixteen consecutive relapsing-remitting MS patients, (mean age: 36.1+/-SD 7.3 years, disease duration: 7.5+/-1.9 years and median EDSS: 2.5) and in 8 healthy controls (HC) with similar age and sex distributions. RESULTS: All 16 MS patients investigated and none of the HCs met the VH criteria for CCSVI (P<0.0001). MS patients showed significantly lower net CSF flow compared to the HC (P=0.038) that was associated with number of anomalous VH criteria present (r=0.79, P<0.001). Moreover, increases in the number of anomalous VH criteria present were negatively associated with lower whole brain volume (Spearman R=-0.5, P=0.05). CONCLUSION: VH changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.
[haacke10a] Haacke EM, Garbern J, Miao Y, Habib C, and Liu M: Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol. 2010 Apr;29(2):149-57. PMID 20351671. PDF , Article$.
Department of Radiology, Wayne State University, Detroit, MI, USA; Department of Radiology, the First Affiliated Hospital, Dalian Medical University, Dalian, China

Abstract
AIM: In this paper, we seek to determine whether the iron deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus of patients with multiple sclerosis is greater than the iron content measured in normal subjects (individuals unaffected by multiple sclerosis). As increased iron content may result from increased venous pressure, such information would add credence to the concept of Zamboni et al (1) that MS is caused by chronic cerebrospinal venous insufficiency. METHODS: Fourteen MS patients were recruited for this study with a mean age of 38 years ranging from 19 to 66 year-old. A velocity compensated 3D gradient echo sequence was used to generate SW images with a high sensitivity to iron content. We evaluated iron in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron content region and a low iron content region. The measured values were compared to previously established baseline iron content in these structures as a function of age. RESULTS: Twelve of fourteen patients had an increase in iron above normal levels and with a particular pattern of iron deposition in the medial venous drainage system that was associated with the confluence of the veins draining that structure. CONCLUSION: Iron may serve as a biomarker of venous vascular damage in multiple sclerosis. The backward iron accumulation pattern seen in the basal ganglia and thalamus of most MS patients is consistent with the hypothesis of venous hypertension.
[zivadinov10a] Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Weinstock-Guttman B, Menegatti E, Heininen-Brown M, Magnano C, Malagoni AM, Wack DS, Hojnacki D, Kennedy C, Carl E, Bergsland N, Hussein S, Poloni G, Bartolomei I, Salvi F, and Zamboni P: Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study. Int Angiol. 2010 Apr;29(2):158-75. PMID 20351672. PDF , Article$.
Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA

Abstract
AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular phenomenon recently described in multiple sclerosis (MS) that is characterized by stenoses affecting the main extracranial venous outflow pathways and by a high rate of cerebral venous reflux that may lead to increased iron deposition in the brain. Aim of this study was to investigate the relationship between CCSVI and iron deposition in the brain of MS patients by correlating venous hemodynamic (VH) parameters and iron concentration in deep-gray matter structures and lesions, as measured by susceptibility-weighted imaging (SWI), and to preliminarily define the relationship between iron measures and clinical and other magnetic resonance imaging (MRI) outcomes. METHODS: Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched healthy controls (HC) were scanned on a GE 3T scanner, using SWI. RESULTS: All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC. In MS patients, the higher iron concentration in the pulvinar nucleus of the thalamus, thalamus, globus pallidus, and hippocampus was related to a higher number of VH criteria (P<0.05). There was also a significant association between a higher number of VH criteria and higher iron concentration of overlapping T2 (r=-0.64, P=0.007) and T1 (r=-0.56, P=0.023) phase lesions. Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume. CONCLUSION: The findings from this pilot study suggest that CCSVI may be an important mechanism related to iron deposition in the brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a modest-to-strong predictor of disability progression, lesion volume accumulation and atrophy development in patients with MS.
[malagoni10a] Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, and Zamboni P: Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study. Int Angiol. 2010 Apr;29(2):176-82. PMID 20351673. PDF , Article$.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy

Abstract
AIM: Chronic fatigue (CF) severely affects patients with multiple sclerosis (MS), but its pathogenesis remains elusive and the effectiveness of available treatments is modest. We aimed to evaluate the effect on CF of the balloon dilatation of stenosing lesions affecting the main extracranial veins configuring the chronic cerebrospinal venous insufficiency (CCSVI), a condition strongly associated with MS. METHODS: Thirty-one MS consecutive patients (16 males, age 46.2+/-9.4 years) with associated CCSVI and CF underwent the endovascular procedure. Fatigue was assessed using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) at baseline (T0) and one (T1), six (T6) and twelve (T12) months after the procedure. In ambulatory patients (N.=28), mobility was evaluated using the 6-min walking test at T0 and T1. RESULTS: and MFIS scores significantly improved from preoperative values, and the positive trend was maintained at one year (FSS: T0=5.1+/-1.0 to T12=3.5+/-1.8, P<0.001; MFIS-total score: T0=34.9+/-14.8 to T12=22.5+/-13.7, P<0.001; MFIS-Physical subscale: T0=21.2+/-8.0 to T12=13.5+/-9.7 P<0.001; MFIS-Cognitive subscale: T0=9.2+/-9.5 to T12=6.0+/-6.3, P=0.03; MFIS-Psychosocial subscale: T0=4.5+/-2.1 to T12=2.5+/-2.1, P<0.001). Six-min walking distance (6MWD) at T1 improved significantly (332+/-190m to 378+/-200m, P=0.0002). In addition, an inverted correlation between 6MWD and MFIS-physical subscale variations was found in the subgroup of patients (N.=8) with no lower limb motor impairment (r=-0.74, P=0.035). CONCLUSION: The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI.
[bartolomei10a] Bartolomei I, Salvi F, Galeotti R, Salviato E, Alcanterini M, Menegatti E, Mascalchi M, and Zamboni P: Hemodynamic patterns of chronic cerebrospinal venous insufficiency in multiple sclerosis. Correlation with symptoms at onset and clinical course. Int Angiol. 2010 Apr;29(2):183-8. PMID 20351674. PDF , Article$.
Center for Rare and Neuroimmunitary Diseases, Department of Neurological Science, Bellaria Hospital, Bologna, Italy

Abstract
AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS). CCSVI is detected by transcranial and extracranial color-Doppler high-resolution examination (TCCS-ECD) and venography that permit to identify five types of venous malformations and four major (A-D) hemodynamic patterns of anomalous extracranial-extravertebral venous outflow. We investigated possible correlation between such hemodynamic patterns and both the symptoms at onset and clinical course in patients with MS and CCSVI. METHODS: TCCS-ECD, selective venography and clinical records of 65 patients affected by definite MS and CCSVI were reviewed. RESULTS: The four hemodynamic patterns of CCSVI were unevenly (P<0.0001) distributed with respect to the types of clinical presentation and course. In particular the Type A or B patterns were common in patients with onset of optic neuritis, but rare in patients presenting with spinal cord symptoms who typically showed a type D pattern. As well, the type A or type B hemodynamic were more common in patients with relapsing remitting course than in patients with secondary progressive course and rare in patients with primary progressive course. The C hemodynamic pattern was not observed in patients with primary progressive course who showed a remarkable prevalence of the type D pattern. CONCLUSION: The distribution of venous malformations and the resulting hemodynamic pattern show correlation with symptoms at onset and clinical course in patients with MS and CCSVI.
[plasmati10a] Plasmati R, Pastorelli F, Fini N, Salvi F, Galeotti R, and Zamboni P: Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis. Int Angiol. 2010 Apr;29(2):189-92. PMID 20351675. PDF , Article$.
Department of Neurology, Bellaria Hospital, Bologna, Italy2 Vascular Diseases Centre, University of Ferrara, Italy

Abstract
The pyramidal pathway is frequently affected early on in multiple sclerosis (MS) and impaired motor performance is a major cause of disability. Pyramidal tract function can be assessed using transcranial magnetic stimulation (TMS). TMS supports the diagnosis of MS, detecting corticospinal tract involvement and monitoring its course with or without treatment. It has been never investigated whether any relationship exists between the TMS outcome measure and minimally invasive treatment of multiple severe extracranial stenosis, affecting the principal ce rebrospinal venous segments in MS patients. We report the clinical and transcranial magnetic stimulation follow-up of a patient during a relapse in relapsing-remitting MS. She underwent percutaneous balloon angioplasty of the associated chronic cerebrospinal venous insufficiency (CCSVI), due to membranous obstruction of the proximal azygous vein, with severe stenosis of the left internal jugular vein. Treatment of the associated CCSVI made a parallel improvement in both clinical and neurophysiological parameters, allowing us to avoid high dose steroid therapy. The relationship between the clinical and neurophysiological course on the one hand, and haemodynamic correction of the associated CCSVI on the other, calls for further exploration on a wider number of patients. The impact of CCSVI on the different neuro-physiological parameters has not been fully estimated, but the intriguing case here reported suggests that it may be greater than previously assumed. The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.
[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.
[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.
[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]. 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.

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.
Source: Fondazione Hilarescere

Comment
CCSVI wird unter den venösen Missbildungen klassifiziert.

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.
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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
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⁹⁸ = [zamboni09b]
[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.
[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.

Comment
Diese Studie beschreibt als erste eine vaskuläre Behandlung von CCSVI bei MS-Patienten.

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.
[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.
[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$
[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.
[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.
[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.
[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.
[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.
[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: [zamboni09g], Deutsche Übersetzung
[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.
[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.
[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$
[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.

Comment
Dies ist zur Zeit die Hauptpublikation über CCSVI.

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.
[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.

Comment
Eisenablagerungen könnten einen Zusammenhang mit MS haben. Diese Studie beschreibt die MRI SWI Methode zum Messen von Eisenablagerungen im Gehirn.

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.
[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.
[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.
[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.
[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.
[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.
[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.
[zuolo08a] Zuolo M: Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis: An Experimental Study. Disseration 2007-2008, Supervisor: Zamboni P, University of Ferrara. PDF
University of Ferrara - School of Medicine Department of Surgical, Anesthesiological and Radiological Sciences General Surgery

Summary
Background: The extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have never been investigated.

Aim: To assess whether anomalies in intracerebral venous circulation in MS can affect the disease's clinical development and whether venous stenoses are the cause or consequence of SM.

Type of study: experimental case-control study with correlation between clinical data and instrumental findings

Setting: Vascular Disease Center, University of Ferrara.

Methods: 65 patients affected by CDMS, and 235 controls composed 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) respectively, blindly underwent combined transcranial and extracranial Color-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of abnormal venous outflow. According to TCCS-ECD screening, patients and HAV-C further underwent selective venography of the azygos and jugular venous system with venous pressure measurement.

Results: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29-65, p<0.0001). Subsequently, venography showed in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the main cerebrospinal venous segments; it shows a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of stenosis and collateral circulation distribution. Moreover, relapsing-remitting (SM-RR) and secondary progressive (SM-SP) courses were associated to CCSVI patterns significantly different from those of the primary progressive kind (p<0.0001). Finally, the pressure gradient measured in the venous stenoses was slightly but significantly higher.

Conclusions: CDMS is strongly associated with CCSVI, a picture never described so far, characterized by abnormal venous hemodynamics determined by extracranial multiple venous stenoses of unknown origin. The location of the venous obstructions plays a key role in determining the clinical course of the disease.
[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.
[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.
[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.
[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.

Comment
Das ist die erste Publikation von Prof. Zamboni. Er stellt die Hypothese von schädlichen Eisenablagerungen und MS auf und zeigt Parallelen zu CVI in den Beinen.

Kritische Publikationen

[sundstroem10a] Sundström P, Wåhlin A, Ambarki K, Birgander R, Eklund A, Malm J: Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study. Annals of Neurology. 2010;68(2):255-259. doi:10.1002/ana.22132. Article$. PDF.
Department of Clinical Neuroscience, Umeå, Sweden

Abstract
The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing-remitting multiple sclerosis cases and 20 healthy controls with phase-contrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrast-enhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis.

Comment Dr. Sclafani
It is regretful that Drs. Doepp and co-authors’ attempt to reproduce Professor Zamboni’s discovery of a link between multiple sclerosis and disturbance of the outflow veins of the brain and spine has been unsuccessful. It is particularly unfortunate that the authors’ misunderstanding of Dr. Zamboni’s publications about this subject have led to their conclusions that “No cerebrocervical venous congestion in patients with multiple sclerosis" exists

The authors mis-state several of the criteria for a positive ultrasound examination. They state that reflux must be present in both internal jugular veins or both vertebral veins. This is not accurate. Reflux in any one of these veins was considered a positive criteria by Zamboni.

It appears to me that Dr Doepp and colleagues have tried to elicit reflux by testing for incompetent valves in the lower jugular vein. Incompetent valves result in reversal of blood flow from the heart back up into the jugular veins. They used the Valsalva maneurer, a technique to increase pressure in the chest that reverses blood flow. However, Zamboni explicitly states that one should assess flow “never in (by) a forced condition such as the Valsalva manoeuvre.”

That the authors’ attempts were unsuccessful is not surprising. The ultrasound examination used by Zamboni is a simple one but the description of the technique has not been fully elaborated in his papers. Thus performance of the ultrasound by some investigators is often at variance and this may lead to differences of results. At my own institution, we were surprised that non-invasive testing by ultrasound did not correlate with the very obvious obstructive phenomena seen on catheter venography, which remains the Gold Standard of assessing veins. We also had difficulty identifying CCSVI on ultrasound, initially using the Valsalva maneuver during out testing. In fact we were able to find an obstruction in only one patient of twenty. It was only after being shown how to correctly perform this simple screening test by the Zamboni team during a visit to Ferrara, that we have become facile in detecting these abnormalities. It is clear that there is a learning curve to the use of this technique.

Nor does this paper refute the concept of CCSVI. Doppler ultrasound is only a screening test for CCSVI. When Doppler shows signs of CCSVI, the gold standard test of catheter venography is indicated to detect the sites of potential obstruction. Doppler is not the definitive test of CCSVI because it cannot assess the azygous vein, an important contributor to cerebrspinal venous outflow resistance. Catheter venographies routinely show evidence of outflow obstructions. Sluggish flow, reversal of flow, extensive collateral veins, strictures, duplications, reversed valves, thickened incompletely opening valves and misplaced valves are among the many abnormalities seen in MS patients that we never see in patients without MS.

The paper by Sundstrom and coauthors similarly rejected the CCSVI hypothesis by performing MR venograms and flow quantification in the neck. MR venography is suboptimal as a screening test because it underestimates and overestimates stenoses quite regularly. One can see from their illustrations two MRV images. It is noteworthy that neither image shows the portion of the jugular vein where lesions causing flow resistance are usually found: behind the clavicle as the vessel enters the chest. Both images show considerable collateral vasculature suggestive of CCSVI. Moreover the image on the right on page 258 purports to show a stenosis with an arrow. It is well known that most of the narrowings referred to by the white arrow are a common transient, non-stenotic narrowing caused by a true narrowing below the clavicle. Catheter venography shows abnormalities that cannot be detected by MRV.

I was struck by the rapidity of publication of both articles. Surprising! Both papers were accepted within six weeks. I have never had such rapid decision, editing and publication of any of my more than 120 publications.

This debate is going to be a challenging one. One side wants randomized prospective trials to prove efficacy. However while many proceduralists have noted sometimes impressive gains for patients, these proceduralists need to evaluate nuances of techniques before consensus can be built regarding the best approach to therapy. Only then can intelligent, carefully designed randomized prospective trials begin. Some who commonly perform randomized trials will try to reduce the work of those who will try to develop the best practices because they are not randomized. However, in my view this is a necessary initial step toward the final trials.

Source: This Is MS, 11 Aug 2010
[wiehl10b] Wiehl M, Müller: Multiple Sklerose durch venöse Störung? Daran gibt es immer mehr Zweifel. Ärzte Zeitung online. 3 Aug 2010. Artikel
Abstract
MS-Patienten haben einen abnormen venösen Blutfluss im Gehirn - darauf weisen Studien mit modernen bildgebenden Verfahren bei MS-Patienten. Deutsche Forscher zweifeln jedoch an den Ergebnissen. Unklar ist auch, ob die vermuteten venösen Störungen Folge oder Ursache einer MS sind.
[doepp10a] Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ: No cerebro-cervical venous congestion in patients with multiple sclerosis. Annals of Neurology. 2010. doi:10.1002/ana.22085. Article$
Department of Neurology, University Hospital Charité, Humboldt University, Berlin, Germany; Barts and The London Queen Mary School of Medicine & Dentistry, London, UK

Abstract
Objective:
Multiple sclerosis (MS) is characterized by demyelination centered around cerebral veins. Recent studies suggested this topographic pattern may be caused by venous congestion, a condition termed chronic cerebro-spinal venous insufficiency (CCSVI). Published sonographic criteria of CCSVI include reflux in the deep cerebral veins and/or the internal jugular and vertebral veins (IJVs and VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage.

Methods:
We performed an extended extra- and transcranial color-coded sonography study including analysis of extracranial venous blood volume flow (BVF), cross-sectional areas, IJV flow analysis during valsalva manoever (VM) as well as CCSVI criteria. 56 MS patients and 20 controls were studied.

Results:
Except for one patient, blood flow direction in the IJVs and VVs was normal in all subjects. In none of the subjects was IJV stenosis detected. IJV and VV BVF in both groups were equal in the supine body position. The decrease of total jugular BVF upon turning into the upright position was less pronounced in patients (173±235 vs 362±150 ml/min, p<0.001), leading to higher BVF in the latter position (318 ml/min±242 vs 123±109 ml/min; p<0.001). No differences between groups were seen in intracranial veins and during VM. None of the subjects investigated in this study fulfilled more than one criterion for CCSVI.

Interpretation:
Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation.
Conflicts of interest
- K.S. [K Schmierer] has received research support and honoraria from Biogen Idec and has received research support from Schering and EMD Serono. [Neurology]
- The Charité University in Berlin and sanofi-aventis sign an innovative research cooperation agreement [Bloomberg, sanofi-aventis (PDF)]
Comment Dr. Sclafani
It is regretful that Drs. Doepp and co-authors’ attempt to reproduce Professor Zamboni’s discovery of a link between multiple sclerosis and disturbance of the outflow veins of the brain and spine has been unsuccessful. It is particularly unfortunate that the authors’ misunderstanding of Dr. Zamboni’s publications about this subject have led to their conclusions that “No cerebrocervical venous congestion in patients with multiple sclerosis" exists

The authors mis-state several of the criteria for a positive ultrasound examination. They state that reflux must be present in both internal jugular veins or both vertebral veins. This is not accurate. Reflux in any one of these veins was considered a positive criteria by Zamboni.

It appears to me that Dr Doepp and colleagues have tried to elicit reflux by testing for incompetent valves in the lower jugular vein. Incompetent valves result in reversal of blood flow from the heart back up into the jugular veins. They used the Valsalva maneurer, a technique to increase pressure in the chest that reverses blood flow. However, Zamboni explicitly states that one should assess flow “never in (by) a forced condition such as the Valsalva manoeuvre.”

That the authors’ attempts were unsuccessful is not surprising. The ultrasound examination used by Zamboni is a simple one but the description of the technique has not been fully elaborated in his papers. Thus performance of the ultrasound by some investigators is often at variance and this may lead to differences of results. At my own institution, we were surprised that non-invasive testing by ultrasound did not correlate with the very obvious obstructive phenomena seen on catheter venography, which remains the Gold Standard of assessing veins. We also had difficulty identifying CCSVI on ultrasound, initially using the Valsalva maneuver during out testing. In fact we were able to find an obstruction in only one patient of twenty. It was only after being shown how to correctly perform this simple screening test by the Zamboni team during a visit to Ferrara, that we have become facile in detecting these abnormalities. It is clear that there is a learning curve to the use of this technique.

Nor does this paper refute the concept of CCSVI. Doppler ultrasound is only a screening test for CCSVI. When Doppler shows signs of CCSVI, the gold standard test of catheter venography is indicated to detect the sites of potential obstruction. Doppler is not the definitive test of CCSVI because it cannot assess the azygous vein, an important contributor to cerebrspinal venous outflow resistance. Catheter venographies routinely show evidence of outflow obstructions. Sluggish flow, reversal of flow, extensive collateral veins, strictures, duplications, reversed valves, thickened incompletely opening valves and misplaced valves are among the many abnormalities seen in MS patients that we never see in patients without MS.

The paper by Sundstrom and coauthors similarly rejected the CCSVI hypothesis by performing MR venograms and flow quantification in the neck. MR venography is suboptimal as a screening test because it underestimates and overestimates stenoses quite regularly. One can see from their illustrations two MRV images. It is noteworthy that neither image shows the portion of the jugular vein where lesions causing flow resistance are usually found: behind the clavicle as the vessel enters the chest. Both images show considerable collateral vasculature suggestive of CCSVI. Moreover the image on the right on page 258 purports to show a stenosis with an arrow. It is well known that most of the narrowings referred to by the white arrow are a common transient, non-stenotic narrowing caused by a true narrowing below the clavicle. Catheter venography shows abnormalities that cannot be detected by MRV.

I was struck by the rapidity of publication of both articles. Surprising! Both papers were accepted within six weeks. I have never had such rapid decision, editing and publication of any of my more than 120 publications.

This debate is going to be a challenging one. One side wants randomized prospective trials to prove efficacy. However while many proceduralists have noted sometimes impressive gains for patients, these proceduralists need to evaluate nuances of techniques before consensus can be built regarding the best approach to therapy. Only then can intelligent, carefully designed randomized prospective trials begin. Some who commonly perform randomized trials will try to reduce the work of those who will try to develop the best practices because they are not randomized. However, in my view this is a necessary initial step toward the final trials.

Source: This Is MS, 11 Aug 2010
[krogias10a] Krogias C, Schröder A, Wiendl H, Hohlfeld R, and Gold R: "Chronic cerebrospinal venous insufficiency" and multiple sclerosis : Critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt. 2010 Apr PMID 20386873, doi:10.1007/s00115-010-2972-1. Article$.
Neurologische Klinik, St. Josef-Hospital, Ruhr-Universität Bochum, Gudrunstrasse 56, 44791, Bochum, Deutschland, christos.krogias@rub.de.

Abstract
Currently, the hypothesis that altered venous hemodynamics might play a causative role in the pathogenesis of multiple sclerosis (MS) is being controversially discussed. This new "venous hypothesis" postulates that obstructions of the cervical venous system cause an increased pressure of the intracranial venous system and that in turn intracranial congestion disintegrates the blood-brain barrier initiating the inflammatory process in MS.The "venous hypothesis" is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the "chronic cerebrospinal venous insufficiency (CCSVI)" cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive "therapeutic" approaches, especially if they are performed outside of clinical trials.

Zusammenfassung
Über die Hypothese eines möglichen ursächlichen Zusammenhangs von Störungen der zerebralen venösen Hämodynamik und der Entstehung der Multiplen Sklerose (MS) wird aktuell kontrovers diskutiert. Die neue „venöse Hypothese“ postuliert, dass Abflussstörungen des zervikalen Venensystems eine Stauung und Druckerhöhung des intrakraniellen Venensystems mit nachfolgender Entzündungsreaktion bedingen. Diese Hypothese wird unter drei Gesichtspunkten analysiert und bewertet: (1) Validität der publizierten Befunde, (2) Plausibilität im Licht derzeitig akzeptierter Pathogenesemodelle der MS und (3) Kompatibilität mit ersten eigenen Untersuchungen.
Die Autoren kommen zu der Schlussfolgerung, dass die „venöse Hypothese“ als ausschließliche Ursache die MS keinesfalls erklären kann. Lediglich 20% unseres unselektierten MS-Kollektivs erfüllten zwei der neu aufgestellten neurosonologischen Kriterien einer „chronischen zerebrospinalen venösen Insuffizienz“. Die pathogenetische Relevanz dieser subtilen Veränderungen der venösen Flussverhältnisse ist derzeit völlig offen. Ebenfalls ist unklar, inwieweit diese Veränderungen Grund oder Folge der MS sind. Keinesfalls lassen sich damit nach derzeitigem Erkenntnisstand invasive „therapeutische“ Maßnahmen rechtfertigen, insbesondere nicht außerhalb kontrollierter Studienprotokolle.
Conflicts of Interest
- Dr. Gold, lecture and consulting fees from Biogen Idec, Bayer–Schering, Merck Serono, and Teva–Sanofi-Aventis and grant support from Biogen Idec and Teva. [NEJM]
- Dr. Hohlfeld, receiving consulting, advisory, or lecture fees from Bayer, Biogen Idec, Novartis, Sanofi Aventis, and Teva and grant support from Novartis. [NEJM]
- Dr. Wiendl has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and TEVA. [Drug Des Devel Ther. 2010]
[khan10a] Khan O, Filippi M, Freedman MS, Barkhof F, Dore-Duffy P, Lassmann H, Trapp B, Bar-Or A, Zak I, Siegel MJ, and Lisak R: Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol. 2010 Mar;67(3):286-90. PMID 20373339, doi:10.1002/ana.22001, Abstract, PDF$.
Multiple Sclerosis Center, Department of Neurology, Wayne State University School of Medicine, 4201 St Antoine, Detroit, MI 48323, USA.

Abstract
A chronic state of impaired venous drainage from the central nervous system, termed 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 therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.
Financial interests
- Dr Khan has received research support from the National MS Society (NMSS), the National Institutes of Health (NIH), Teva Neuroscience, Genzyme Corporation, Biogen Idec, Novartis Pharmaceuticals, and Acorda Therapeutics; consultancy and speaking honoraria from Teva Neuroscience, Biogen Idec, Novartis Pharmaceuticals, and Bayer Healthcare.
- Dr Lisak has received research support from the NMSS, NIH, Teva Neuroscience, and Questcor; consultancy and speaking honoraria from Teva Neuroscience and Bayer Healthcare.
- Dr Barkhof has received research support from the Dutch MS Research Foundation and Merck-Serono; consultancy and speaking honoraria from EMD Merck-Serono, Bayer-Schering Pharma, Biogen-Idec, UBC, Sanofi-Aventis, Novo-Nordisk.
- Dr Trapp has received research support from the NIH, NMSS, Canadian MS Society, Ohio Third Frontier, Vertex, and EMD Merck-Serono; consultancy and speaking honoraria from Teva Neuroscience, Biogen Idec and Pfizer.
- Dr. Bar-Or has received research support from the MS Society of Canada (MSSC) and the MSSC Research Foundation, The Canadian Institutes of Health Research, the FRSQ, Bayhill Therapeutics, Biogen Idec, Bio MS, Genentech, and Teva Neuroscience; consultancy and speaking honoraria from Biogen Idec, Eli Lilly, Genentech, MerckSerono, Novartis, Roche and Teva Neuroscience.
- Dr Dore-Duffy has received research support from the NMSS and the NIH.
- Dr Filippi has received research support from Bayer-Schering Pharma, Biogen-Dompé AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla (FISM), and Fondazione Mariani; consultancy and speaking honoraria from Bayer Schering Pharma, Biogen-Dompé AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd.
- Dr Freedman has received research support from the Canadian MS Society, EMD Merck-Serono, Genzyme, and Bayer Schering Pharma; consultancy and speaking honoraria from Teva Neuroscience, Bayer Healthcare, and EMD Merck-Serono.
- Drs Siegel, Lassmann, and Zak have nothing to disclose.
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
[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

Publikationen (MRI, 1988 – 2006)

You can find textual summeries on:

ms-mri.com: A brief history of the early venous vascular observations in MS
msrc.co.uk: The venous connection to MS- a timeline

[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
[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.
[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.
[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

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.
[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.
[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.
[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.
[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.
[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.
[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.
[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)

You can find textual summeries on:

ms-mri.com: A brief history of the early venous vascular observations in MS
msrc.co.uk: The venous connection to MS- a timeline

[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.
[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
[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.
[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.
[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.
[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.
[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.
[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...
[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.
[zimmerman50a] Zimmerman HM, and Netsky MG: The pathology of multiple sclerosis. Res Publ Assoc Res Nerv Ment Dis. 1950 ;28:271-312. PMID 15413018.
[dow42a] Dow RS, Berglund G: Vascular pattern of lesions of multiple sclerosis. Arch Neurol Psychiatry. 1942;47(1):1-18. Article$
Institut Bunge, Antwerp, Belgium, and the Department of Anatomy, University of Oregon Medical School, Portland, Ore.

Introduction
The theory of a relation between the cerebrovascular system and the lesions of multiple sclerosis has been advanced by many workers. The first of many to assign a primary role to vascularlesions was Rindfleisch.¹ Ribbert² early maintained that the demyelinated areas were related to a primary disseminated thrombosis. He described a congested central vessel in all the sclerotic patches. In two small patches cut in serial section he found white blood cells in the lumen of the vessel, partly adherent to the vessel wall and partly filling the vessel as an embolus. He stated that these changes in the vessel were multiple thrombi and expressed the belief that they had an important causative role in multiple sclerosis. The most recent adherents to the idea that vascular lesions play a primary role in the pathogenesis of the lesions of multiple sclerosis have been Putnam and his collaborators.³
[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.
[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 …
[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 …
[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 …
[dawson16] Dawson JW: The histology of disseminated sclerosis. Trans Roy Soc Edinb, 50: 517, 1916.
[rindfleisch72] Rindfleisch E: A Manual of Pathological Histology. London, New Sydenham Society, 1872, Vol. 2, pp. 344–351.
[charcot68] Charcot JM: Histologie de la sclérose en plaque. Gazette Hosp Paris 41:554-566.
[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.
Info

Rindfleisch in Zürich wies 1863 erstmals auf die pathologischen Veränderungen an den Gefässen hin ("ihre Wandung ist durch eine Anhäufung von Kernen und Zellen in der Adventitia enorm verdickt") und nahm ätiologisch "häufig wiederkehrende oder langanhaltende mit Hyperämie verbundene Reizzustände der gesammten Centralorgane" als Primärereignis und die Parenchymveränderungen als Sekundärphänomen an: "Die Neuroglia macht in Fortsetzung der formativen Reizung von den Gefässwänden auf die Nachbarschaft eine Reihe von Metamorphosen durch. Dieser Prozess trägt durchaus den Stempel des Kümmerlichen."

Zitiert aus Kapitel 1 Historische Übersicht, Seite 17, Jürg Kesselring, Ludwing Kappos et. al, Multiple Sklerose, aus der Reihe Psychiatrie, Neurologie, Klinische Psychologie, Grundlagen - Methoden - Ergebnisse, T. Brandt et al. (Hrsg.), Verlag W. Kohlhammer, 4. Auflage, 2005

Publikationen in Vorbereitung und klinische Studien

[trial_mcdonald10a] McDonald S: Double-blinded study for assessing CCSVI and its treatment. Source

Info
With health officials clamouring for more scientific research before green-lighting the new liberation treatment for multiple sclerosis (MS), local supporter and cardiovascular-thoracic surgeon Sandy McDonald is stepping up to provide it.

“I’m working with colleagues to design a double-blinded study for assessing CCSVI and its treatment,” he said, anticipating a more extensive test group than the preliminary trials first published by pioneering Italian vascular surgeon Paolo Zamboni.

“We have two neurologists, three vascular surgeons and interventional radiologists interested in being involved.”

In the process of gaining Institutional Review Board approval, McDonald said the trial is moving forward as quickly as possible, but “we have a lot of hurdles to get past before we get there.”
Source: simcoe.com
[trial_siddiqui10a] Siddiqui A, Levy E and Hopkins LN: Prospective Randomized Endovascular therapy in Multiple Sclerosis (PREMiSe). University at Buffalo Neurosurgery (UBNS). Source: UB, prweb.com, CTV
University at Buffalo Neurosurgery (UBNS)

Info
Researchers at the University at Buffalo, led by the Department of Neurosurgery, will embark on a landmark prospective randomized double-blinded study to test the safety and efficacy of interventional endovascular therapy—dubbed “liberation treatment”—on MS symptoms and progression.

(Vocus/PRWEB ) June 29, 2010 -- Recently, chronic cerebrospinal venous insufficiency (CCSVI) has been strongly associated with multiple sclerosis (MS). In a series of original studies, Dr. Paolo Zamboni of the University of Ferrara, Italy demonstrated blockage of major venous outflow from the brain and spinal cord in patients with MS. Researchers from many institutions, including the University at Buffalo, have confirmed the association.

It is hypothesized that the narrowing in the large veins in the neck and chest might cause improper drainage of blood from the brain, resulting in eventual injury to brain tissue. It is thought that angioplasty—a treatment commonly used by cardiologists and other endovascular surgeons to treat atherosclerosis—may remedy the blockages. Dr. Zamboni has further conducted preliminary studies suggesting the efficacy of venous angioplasty (“liberation procedure”) in the amelioration of MS symptoms.

Now, researchers at the University of Buffalo will launch PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) to determine if endovascular intervention via balloon angioplasty to correct the blockages improves MS symptoms or progression. PREMiSe is believed to be the first IRB-approved prospective randomized double-blinded study of balloon angioplasty for MS being performed in a rigorous fashion in the US with significant safeguards in place to ensure careful determination of risks and benefits.

The study is being led by principal investigator Dr. Adnan Siddiqui along with co-principal investigators Dr. Elad Levy and Dr. L.N. Hopkins of the University at Buffalo Department of Neurosurgery. Additional independent researchers from University at Buffalo will participate in the evaluation and follow-up of study patients. An independent Data Safety Monitoring Board (DSMB) will ensure the safety and effectiveness of the study on an ongoing basis.

In the first phase of the study, ten MS patients from the United States and Canada exhibiting venous insufficiency will undergo minimally invasive venous angioplasties to determine if the procedure can be performed safely. The procedures, scheduled for June 29 and 30, 2010, will be performed by Drs. Siddiqui and Levy at Kaleida Health’s Millard Fillmore Gates Hospital in Buffalo, New York.

The second phase of the study will randomize 20 MS patients to undergo either venous angioplasty or a “sham angioplasty” (i.e. a catheter will be inserted but there will be no inflation of the balloon). The treatment will be blinded in such a way that neither the patient undergoing the procedure nor the clinicians evaluating the patient will be aware which procedure was performed.

If results suggest an appropriate safety profile and preliminary effectiveness, then researchers will approach the University at Buffalo Institutional Review Board (IRB) for an extension of the protocol to study a larger number of patients in order to convincingly prove or disprove a causal relationship between CCSVI and MS.

If angioplasty is proven effective at improving MS symptoms, the resultant implications for the future of MS treatment could be monumental. The physicians conducting PREMiSe are cautious but optimistic that initial findings will be promising.

Source: prweb.com
[prep_epidem10a] Italian MS Foundation (FISM): Epidemiological study to confirm and extend Dr. Zamboni’s findings by evaluating the prevalence of CCSVI in healthy controls, MS and other neurodegenerative diseases. Source: msif.org
Italian MS Foundation (FISM)

Info
FISM is promoting an epidemiological study to confirm and extend Dr. Zamboni’s findings by evaluating the prevalence of CCSVI in healthy controls, MS and other neurodegenerative diseases, other inflammatory diseases of the central nervous system and other systemic autoimmune diseases. This study plans to enroll 1690 subjects and will involve15 clinical centres. … studies are likely to start in the second half of 2010.
Source: msif.org
[trial_zivadinov10a] Zivadinov R: Controlled Randomized EndovaScular Therapy (CRET) study for CCSVI. Sources: mastersofms.com, BNAC newsletter.
Buffalo Neuroimaging Analysis Center (BNAC), University of Buffalo, The State University of New York

Info
Our group in Buffalo is undertaking a larger placebo-controlled trial (PTA versus a “fake” treatment) in 30 RRMS patients. This study will compare many of the standard outcomes in MS but will also include important quality of life measures such as pain, fatigue, and mobility. This study will soon begin enrolling patients at the University of Buffalo. This will be a 6-month study that will evaluate the safety and preliminary efficacy of therapeutic angioplasty, and will include 30 patients with MS.
[trial_cihr10a] Canadian Institute for Health Research (CIHR): Randomized, blinded clinical trial on the effect of this therapeutic approach (CCSVI). CTV Winnipeg
Canadian Institute for Health Research (CIHR)

Info
The Canadian Institute for Health Research wants scientists to submit grant proposals to study whether treating vein abnormalities in multiple sclerosis patients helps relieve their symptoms.

CIHR President Dr. Alain Beaudet told the parliamentary Subcommittee on Neurological Disease in Ottawa Tuesday that his agency, which is the major federal agency responsible for funding health research in Canada, wants scientists to submit proposals for such research.

"What I'm asking is for Canadian researchers to propose a protocol for a proper randomized, blinded clinical trial on the effect of this therapeutic approach," he said.

The study would look at whether balloon angioplasty to open up blocked neck and chest veins relieves MS symptoms any better than patients given a sham treatment or no treatment.

"I urge researchers interested in better understanding the linkages between MS and CCSVI to apply to CIHR," Beaudet said, noting the deadline for grant proposals is August.

"Research into clinical treatment of MS has to be accelerated."

The U.S. and Canadian MS Societies announced last week the awarding of $2.4 million in research grants to study a vein condition dubbed CCSVI, or chronic cerebrospinal venous insufficiency. Those studies will focus on the prevalence of CCSVI in MS patients, not on treatment.
Source: CTV Winnipeg
[trial_wolinsky10a] Wolinsky J: CCSVI and its relationship to MS. University of Texas Health Science Center at Houston, USA. Info.
University of Texas Health Science Center at Houston, USA.

Abstract
replicating the ultrasound methods used by Dr. Zamboni to investigate the association of CCSVI with major clinical types of MS and in non-MS control groups. The team is also testing whether other imaging methods can confirm the ultrasound findings, while identifying the most reliable technique to screen for CCSVI.
Term/Amount: 7/1/10-6/30/12; $574,958

Project Details: Recent preliminary studies have suggested that a phenomenon called Chronic Cerebrospinal Venous Insufficiency (CCSVI), a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy. This pilot study warrants a subsequent larger and better controlled study to definitively evaluate the possible impact of CCSVI on the disease process in MS.
Dr. Wolinsky has assembled an expert team to increase our understanding of CCSVI. Using a comprehensive approach, this team will first attempt to replicate the ultrasound methods used by Dr. Zamboni in 100 people with all major clinical types of MS, compared with 175 people in various non-MS control groups. Then, they are seeking to determine whether the findings are validated by noninvasive imaging techniques, such as an MRI machine using a powerful magnet. The team includes experts in MS, as well as experts from other fields such as vascular disease and venous imaging.
Validating a reliable diagnostic approach and demonstrating that CCSVI is specific to MS and contributes to disease activity would be necessary first steps before controlled therapeutic trials may be attempted.
[trial_knox10a] Traboulsee A, Knox K, Li DKB, Machan L, Rauscher A, MacKay A, Illes J, Voll C, Wiebe S, Szkup P, Kelly M: Investigation into Venous Insufficiency in Multiple Sclerosis. MS clinic in Saskatoon, Saskatchewan, Canada. [rynor10a] Charity Intelligence Canada Report (PDF). The StarPhoenix. The Globe and Mail, CTV News, Funding granted for studies to see if blocked veins cause MS, Facebook. Info. Fact Sheet (PDF). UBC page.
University of British Columbia MS Clinic, UBC Faculty of Medicine, MS clinic in Saskatoon, University of Saskatchewan, Canada

Abstract

studying the prevalence of CCSVI in people with MS and controls without MS, using catheter venography, ultrasound, and magnetic resonance venography. Unique to this study is the inclusion of family members, such as identical twins of MS patients who have not developed MS, in control groups. They also hope to verify the usefulness of techniques that would make it easier to screen for CCSVI.

Timing: 7/1/10/-6/30/12 Amount: C$200,000 over two years

Project Details: This team is taking a comprehensive approach to study the prevalence of venous insufficiency in 200 people with MS and controls without MS, using catheter venography, Doppler ultrasound such as what was originally used to identify CCSVI, and magnetic resonance studies of the veins (MR venography). A unique aspect of this program is that they are including family members – including identical twins of MS patients who have not developed MS -- as control groups to gain further insight into CCSVI. The team hopes to verify the usefulness of non-invasive techniques that would make it easier to detect venous insufficiency, should this and other research suggest that future therapeutic trials are warranted.
Recruitment: A total of 200 participants including eligible persons with MS and their family members who are registered with the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Recruitment number is approximate and is subject to change.
[trial_torres10a] Torres C, Cameron IG, Hogan MJ, Schweitzer ME, Lum C, Bussière ME, Chakraborty S, Freedman MS: Chronic Cerebrospinal Venous Insufficiency in relation to Multiple Sclerosis. The Ottawa Hospital, University of Ottawa, Ontario, Canada. Info. Fact Sheet (PDF).
The Ottawa Hospital, University of Ottawa, Ontario, Canada

Abstract
employing powerful MRI technology to explore vein anatomy and assessing for iron deposits in the brains of people with MS and in age-matched healthy volunteers. These studies work towards mapping out normal variations in brain vein anatomy and providing insight into CCSVI in MS.
Timing: 7/1/10-6/30/12 Amount: C$102,866 over 2 years

Project Details: This team is employing “3 Tesla” MRI technology that is twice as powerful as a standard MRI magnet to explore differences in the anatomy of veins in the neck, chest and spine and to assess for iron deposits in the brain. They are comparing findings in 50 people who have MS with those in 50 age-matched healthy volunteers. They are also using Doppler ultrasound techniques that were used by originators of the CCSVI hypothesis, and seeking verification that there is a relationship between blocked veins and areas of iron deposition in the brain by measuring levels of iron in the brain in those with and without vein blockages. The questions the team is focused on include: How frequent are the vein blockages and abnormalities in people who do not have MS? How frequently do they occur in people with MS? Can the team detect brain iron pooling in patients with blocked veins?
These studies should lead to a better understanding of normal variations in the anatomy of the veins that drain the brain, and the potential role of venous insufficiency in MS.
Recruitment: A total of 100 participants including participants with MS and healthy individuals. Participants will be recruited through The Ottawa Hospital MS Clinic Research Unit. Recruitment number is approximate and is subject to change.
[trial_fox10a] Fox RJ: A Multi-Modal Assessment of Chronic Cerebrospinal Venous Insufficiency. Dr. Robert Fox Cleveland Clinic, Cleveland, USA. Info.
Dr. Robert Fox Cleveland Clinic, Cleveland, USA.

Abstract
studying people with MS or who are at risk for MS (CIS) and comparison groups including healthy volunteers and people with brain atrophy (shrinkage) from Alzheimer’s disease. This team is using the ultrasound techniques originally used by Dr. Zamboni, as well as magnetic resonance studies of the veins (MR venography), MRI scans of the brain, and clinical measures to determine MS activity and atrophy. They are also examining neck and spinal cord tissue from MS patients at autopsy to provide a tissue-based evaluation of CCSVI and its possible relationship to MS.
Term/Amount: 7/1/10-6/30/12; $571,261

Project Details: Recent preliminary studies have suggested that a phenomenon called Chronic Cerebrospinal Venous Insufficiency (CCSVI), a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy. This pilot study warrants a subsequent larger and better controlled studies to definitively evaluate the possible impact of CCSVI on the disease process in MS.
Dr. Fox and his team are seeking to reproduce these findings in 90 people with different forms of MS and 80 controls without MS. His team is conducting the same tests that were done in the original studies (ultrasound tests of the veins in the neck), an MRI test that looks specifically at veins, and neurological examinations. Most of these MS patients have been followed for the past 10 years in a longitudinal study using quantitative clinical and imaging measures, which will provide an opportunity to compare CCSVI findings to MS disease evolution. To distinguish whether vein abnormalities are from atrophy (brain tissue volume loss) and not specifically MS, they also are comparing the MS group to people with atrophy from Alzheimer's disease. Finally, they are examining the neck and spinal cord veins obtained via autopsy from people with MS and non-MS controls.
Data from these studies will shed light on the meaning of Dr. Zamboni’s original reports and how CCSVI relates to disease activity in MS.
[trial_field10a] Field A: Study of CCSVI in MS using quantitative time-resolved 3D MRV. University of Wisconsin School of Medicine and Public Health, Madison, USA. Info.
University of Wisconsin School of Medicine and Public Health, Madison, USA.

Abstract
using magnetic resonance (MRI) scans to generate detailed images of the head and neck veins in people with early and later MS, healthy volunteers, and controls with other neurological conditions. This team is also using the ultrasound techniques originally used by Dr. Zamboni. If they obtain similar results as those published by Dr. Zamboni, it would represent a powerful confirmation of the CCSVI hypothesis and help lead the way toward trials of appropriate treatment.
Term/Amount: 7/1/10-6/30/12; $593,261

Project Details: Recent preliminary studies have suggested that a phenomenon called Chronic Cerebrospinal Venous Insufficiency (CCSVI), a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy. This pilot study warrants a subsequent larger and better controlled study to definitively evaluate the possible impact of CCSVI on the disease process in MS.
Dr. Field’s team is using alternative imaging methods, in addition to the ultrasound method used in Dr. Zamboni’s original reports, to conduct a controlled study of the CCSVI hypothesis in people with MS. This study uses an MRI scanner to generate highly detailed images of the head and neck veins in 112 people with early and later MS, 56 controls without MS, and 56 people with other neurological conditions. The team is also measuring the rate at which blood flows in the veins. Dr. Field’s collaborates have years of experience in bioengineering, radiology, and medical physics.
If this technique obtains similar results as the ultrasound method originally used, it would represent a powerful confirmation of the CCSVI hypothesis and help lead the way toward trials of appropriate treatment targeting abnormal veins.
[trial_costello10a] Costello F, Goyal M, Frayne R, Mah JK, Davenport J, Scott J: Determining the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS). Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. Info. Fact Sheet (PDF).
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta.

Abstract
examining a cross-section of people with MS compared to other neurological diseases and healthy volunteers. The team is seeking linkages between vein abnormalities and different aspects of MS activity and tissue damage to gain insight into the significance of differences in vein drainage and their implications for the future treatment of MS.
Timing: 7/1/10-6/30/12 Amount: C$199,994.18 for 2 years

Details: This controlled study will carefully compare vein drainage between a cross-section of 120 people with MS with that seen in 60 healthy controls. In those MS patients who exhibit signs of abnormalities of vein drainage, the investigators will explore whether the sites and severity of vein abnormalities correlate with common markers of MS disease activity, seeking linkages between any venous abnormalities observed and many different aspects and measures of MS activity and tissue damage.
The team is using ultrasound as originally used by Dr. Zamboni, and magnetic resonance studies of the veins (MR venography) to further explore the prevalence of venous insufficiency. The technologists and radiologists who interpret all scans will be blinded as to the clinical status of the participants.
This study should help quickly determine whether there are significant differences in venous drainage in people with MS, and their implications for the future treatment of MS.
Recruitment: A total of 180 participants including adults and children with MS and healthy participants. Participants with MS will be recruited from the Calgary MS Clinic at Foothills Medical Centre. Recruitment number is approximate and is subject to change.
[trial_banwell10a] Banwell B, Macgowan c, Laughlin S, Shroff M, Sled J, Yeung R, Benseler S, Traubici J, Moharir M, Arnold D, Narayanan S, Bar-Or A,Marrie RA: Cerebral Venous Hemodynamics in Pediatric Multiple Sclerosis. The Hospital for Sick Children, Toronto, Ontario, Canada. Info. Fact Sheet (PDF)
The Hospital for Sick Children, Toronto, Ontario, Canada

Abstract
studying vein abnormalities in children and teenagers who have MS, and healthy controls of the same age. The team is seeking to determine whether the veins are abnormal at an early age among pediatric MS patients. These findings will add additional depth to studies of CCSVI in adult MS.
Timing: 7/1/10/-6/30/12 Amount: C$196,579.14 for 2 years

Project Details: Recent preliminary studies have suggested that a phenomenon called Chronic Cerebrospinal Venous Insufficiency (CCSVI), a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy. This pilot study warrants a subsequent larger and better controlled studies to definitively evaluate the possible impact of CCSVI on the disease process in MS.
Dr. Banwell, a noted expert in pediatric MS, has assembled a team to study CCSVI in pediatric MS patients – a population where the disease process is at a very early stage, and where advanced age and other health conditions that might affect blood flow do not exist. They are determining whether CCSVI occurs in children with MS using non-invasive MRI measures of vein anatomy and novel measures of venous flow and are comparing the results to children without MS. The team also is using “hemodynamic” (blood flow) tests to investigate a hypothesis that might explain how blood flow problems could lead to myelin damage, through the accumulation of excess iron.
Determining whether the veins and vein flow are abnormal very early in the MS process in pediatric MS will add additional depth to studies of CCSVI in adult MS.
Recruitment: A total of 60 participants that includes healthy children and adolescents and pediatric MS participants. Participants with MS will be within 5 years of their first MS attack and recruited from the Pediatric MS Clinic atSickKids . Recruitment number is approximate and is subject to change.
[trial_zamboni10b] 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_tornatore10a] Tornatore C, Neville R: CCSVI treatment study. Georgetown University Hospital. Source
Georgetown University Hospital, USA

Abstract
2 year study
[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_mehta10a] Mehta M: Liberation Study - 500 person. clinicaltrials.gov: NCT01089686. Study to evaluate treating chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients. v-aware Vol. 2, Issue 1, March 2010, p18: Announcement. Some info.

The Vascular Group, PLLC, Albany NY, USA.

Description

Primary Outcome Measures:

Incidence of major adverse events [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
The evaluation of safety will be defined as the incidence of major adverse events at 30 days following the index procedure. The evaluation of feasibility and efficacy will be determined by those patients that do not have more than 50 percent restenosis within the 30 day time frame.

Secondary Outcome Measures:

Mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Secondary endpoints will be evaluated with all subjects based upon mortality, incidence of all secondary interventions and incidence of all major adverse events for a period of 2 years.

Estimated Enrollment:	500
Study Start Date:	April 2010
Estimated Study Completion Date:	April 2012
Estimated Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Intervention Details:

Procedure: Angioplasty
To identify the presence of CCSVI, all patients will undergo a clinical evaluation by a neurologist, a duplex ultrasound of central extracranial venous system, an MRV, and a venogram. The decision to enroll patient in percutaneous angioplasty for CCSVI will be made at the time of venogram, in select patients that have greater than or equal to 50 percent stenosis of the extracranial central veins including the internal jugular veins and the azygos vein. Extracranial venous ultrasound will be performed at 3, 6, 12, 18, and 24 months following the procedure or if clinical symptoms recur. MRV and venograms will be performed at 12months and 24 months or if clinical symptoms recur.

[trial_rodger10a] Rodger I, Haacke EM: St. Joe's MS study - 100 person and 100 controls. St. Joseph's Healthcare, Canada. [rynor10a] The Hamilton Spectator. Requested Grant (PDF). Charity Intelligence Canada Report (PDF). Needs funding. Donate. See also [ws_hamilton10_2]
St. Joseph's Health Care, McMaster University and Hamilton General Hospital, Canada
[trial_zamboni10a] Zamboni P, Galeotti R, Weinstock-Guttman B, Cutter G, Menegatti E, Malagoni AM, Bartolomei I, Cox JL, Salvi F, and Zivadinov R: Endovascular Treatment for Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis: A Longitudinal, Magnetic Resonance Imaging, Blinded Pilot Study. - 16 person. J Vasc Surg. 2010 Mar;51(3):794. doi:10.1016/j.jvs.2009.11.022. Abstract, PDF
University of Ferrara, Ferrara, Italy; NY State University in Buffalo, Buffalo, NY
Comment
Schedule:
1. Conclusion: October 2010
2. Publication: Fall 2011
Abstract
Among abstracts from the 2010 American venous forum annual meeting.

Background: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by stenoses of the internal jugular veins or the azygous vein, or both. It has been recently reported that this condition contributes to severe dis-regulation of the physiologic mechanisms of cerebral venous outflow in patients with multiple sclerosis (MS). Endovascular treatment (EVT) was demonstrated to be a safe and effective CCSVI treatment, but only in an unblinded clinical evaluation.

Methods: We designed an open-label, magnetic resonance imaging (MRI)-blinded, two-center, randomized, EVT intervention parallel-group, 12-month study (EVTMS) after an initial cross-sectional (CVIMS) study. CIVMS enrolled 16 relapsing-remitting MS patients (8 from Ferrara, Italy and 8 from Buffalo, NY). All 16 patients who completed the CVIMS study and presented severe Doppler venous hemodynamic (VH) anomalies accepted participation in the EVT intervention prospective study (EVTMS). Half of the cohort, the early intervention group (4 from Buffalo and 4 from Italy), was randomly selected to have the EVT procedure in Italy at 3 months, whereas 6 patients comprised the delayed control intervention group (late group) at 6 months; 2 patients were followed-up without any EVT. The EVT procedure consists of selective venography complemented by balloon dilatation when significant stenoses are detected. All patients will be prospectively evaluated at 3, 6, 9, and 12 months with ultrasound imaging, MRI, and clinical examinations.

Results: For the CVIMS cross-sectional study, mean age at baseline was 36.1 ± 7.3 years, mean disease duration was 7.5 ±1.9 years, and median Expanded Disability Status Scale (EDSS) was 2.5. The mean number of gadolinium-active lesions at baseline was 0.38 ± 1.5. The mean number of T2 lesions was 27.1 ± 10.5. Median of VH of CCSVI was 4 (range, 2-5). The six MS patients investigated and none of the HCs met the VH criteria for CCSVI (P < .0001). MS patients showed significantly lower net cerebrospinal fluid flow compared with the HC (P = 0.038), which was associated with the number of anomalous VH criteria present (r = 0.79, P < .001; Fig, A) and confirmed by the strong relationship with the venous hemodynamic insufficiency severity score (r = 0.77, P < .0007). Moreover, increases in the number of anomalous VH criteria present were negatively associated with lower whole brain volume (Spearman R = –0.5; P = 0.05; Fig B). The 1-year blinded EVTMS longitudinal study will be concluded next October and results analysis completed within the Fall.

Conclusions: CCSVI is associated with abnormal cerebrospinal fluid flow dynamics and decreased brain volume. Finally, the EVTMS study should provide valuable data on preliminary efficacy of EVT for CCSVI associated with MS.

Fig. A, Net cerebrospinal fluid (CSF) flow was lower in patients with multiple sclerosis and was associated with the number of venous hemodynamic (VH) criteria present. B, Increases in the number of anomalous VH criteria present were negatively associated with lower normalized brain volume.
[prep_gabbiani09] Gabbiani G, Coen M, Mascoli F, Zamboni P. Manuscript in preparation.
[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). - 1700 person. 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.
Schedule:
1. Preliminary results, first 500 patients: April 2010
2. Publication: Fall 2011
[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.

Critical publications on established paradigms

[behan10a] Behan PO: Futility of the autoimmune orthodoxy in multiple sclerosis research. Expert Rev Neurother. 2010 Jul;10(7):1023-5. PMID 20586684, doi:10.1586/ern.10.69. PDF.
Division of Clinical Neuroscience, Faculty of Medicine, University of Glasgow, UK and School of Life Sciences, Glasgow Caledonian University, Glasgow, UK.
[raftery10a] Raftery J: Multiple sclerosis risk sharing scheme: a costly failure. BMJ. 2010 ;340:c1672. doi:10.1136/bmj.c1672, PMID 20522654, PDF.
Wessex Institute, School of Medicine, University of Southampton
[mccabe10a] McCabe C, Chilcott J, Claxton K, Tappenden P, Cooper C, Roberts J, Cooper N, and Abrams K: Continuing the multiple sclerosis risk sharing scheme is unjustified. BMJ. 2010 ;340:c1786. doi:10.1136/bmj.c1786, PMID 20522655, PDF.
Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds
[charlton08a] Charlton BG: Zombie science: a sinister consequence of evaluating scientific theories purely on the basis of enlightened self-interest. Med Hypotheses. 2008 Sep;71(3):327-9. Epub 2008 Jul 7. PMID 18603380, doi:10.1016/j.mehy.2008.05.018, PDF.
Abstract
Although the classical ideal is that scientific theories are evaluated by a careful teasing-out of their internal logic and external implications, and checking whether these deductions and predictions are in-line-with old and new observations; the fact that so many vague, dumb or incoherent scientific theories are apparently believed by so many scientists for so many years is suggestive that this ideal does not necessarily reflect real world practice. In the real world it looks more like most scientists are quite willing to pursue wrong ideas for so long as they are rewarded with a better chance of achieving more grants, publications and status. The classic account has it that bogus theories should readily be demolished by sceptical (or jealous) competitor scientists. However, in practice even the most conclusive 'hatchet jobs' may fail to kill, or even weaken, phoney hypotheses when they are backed-up with sufficient economic muscle in the form of lavish and sustained funding. And when a branch of science based on phoney theories serves a useful but non-scientific purpose, it may be kept-going indefinitely by continuous transfusions of cash from those whose interests it serves. If this happens, real science expires and a 'zombie science' evolves. Zombie science is science that is dead but will not lie down. It keeps twitching and lumbering around so that (from a distance, and with your eyes half-closed) zombie science looks much like the real thing. But in fact the zombie has no life of its own; it is animated and moved only by the incessant pumping of funds. If zombie science is not scientifically-useable--what is its function? In a nutshell, zombie science is supported because it is useful propaganda to be deployed in arenas such as political rhetoric, public administration, management, public relations, marketing and the mass media generally. It persuades, it constructs taboos, it buttresses some kind of rhetorical attempt to shape mass opinion. Indeed, zombie science often comes across in the mass media as being more plausible than real science; and it is precisely the superficial face-plausibility which is the sole and sufficient purpose of zombie science.

Konferenz-Poster

[pos_magnano10a] Magnano C, Schirda C, Weinstock-Guttman B, Hojnacki D, Bergsland N, Kennedy C, Reuther J, Brooks C, Dwyer MG, Zivadinov R: Cine Cerebrospinal Fluid Imaging in Multiple Sclerosis. A Case-Control Study. [P03.133] AAN Annual Meeting 2010. Toronto, 14 Apr 2010 [aan10a]. Abstract.
Buffalo, NY

Abstract
OBJECTIVE: To investigate the cerebrospinal fluid (CSF) dynamics in Sylvius aqueduct in multiple sclerosis (MS) patients versus healthy controls (HC) and to define correlates with other specific disease metrics. BACKGROUND: CSF velocity and flow dynamics, as measured by MRI in MS patients, may be impaired and associated with higher disease activity. DESIGN/METHODS: Fifty eight (58) consecutive MS patients (41 RR and 17 SP) with mean age 45.3 yrs, mean disease duration 13 yrs and median EDSS 4.0 and 22 age- and sex-matched HC were scanned on a GE 3T scanner. A two-dimensional, phase-contrast gradient-echo MR acquisition using peripheral cardiac gating, with in-plane resolution 0.39x.039mm2 and 32 phases, corresponding to a full cardiac cycle, was collected on one 4mm thick slice positioned perpendicular to the Sylvius aqueduct. In addition to CSF measures, we calculated T2, T1- and contrast enhancing (CE) lesion volume (LV), global, tissue-specific and central brain atrophy measures. RESULTS: All CSF flow and velocity measures were significantly altered in the patients with MS, compared to HC. Net CSF flow in the aqueduct, which physiologically is towards 4^th ventricle, was significantly lower in MS patients than in HC (3.8 vs. 8.4, p=0.011). There were no CSF dynamics differences between RR and SP MS patients. In MS patients, lower net CSF flow was significantly related to a higher number of relapses in the previous year (r=-0.28, p=0.029) and longer disease duration (r=-0.25, p=0.048). The lower CSF flow was related to central atrophy, as measured by the enlargement of the lateral ventricle volume and third ventricle width (r=0.3, p<0.02). CONCLUSIONS/RELEVANCE: This study shows that CSF flow is significantly altered in MS patients, compared to HC. Altered CSF dynamics may play an important role in the pathophysiology of MS disease process and warrants further investigation.
Category - MS and Related Diseases - Clinical Science
Wednesday, April 14, 2010 7:30 AM
Poster Session III: Multiple Sclerosis and Related Diseases: MRI/Technique (7:30 AM-12:00 PM)
[pos_zivadinov10a] Zivadinov R, Marr K, Ramanathan M, Zamboni P, Benedict RRHB, Cutter G, Kennedy C, Elfadil M, Hojnacki D, Munschauer F, Reuther J, Brooks C, Hunt K, Andrews M, Weinstock-Guttman B: Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD Study). Description of the Design and Interim Results of an Epidemiological Study of the Prevalence of Chronic Cerebrospinal Venous Insufficiency in MS and Related Diseases. [P06.144] AAN Annual Meeting 2010. Toronto, 15 Apr 2010 [aan10a]. Abstract.
Buffalo, NY; Ferrara, Italy; Birmingham, AL

Abstract
OBJECTIVE: To ascertain the prevalence of chronic cerebrospinal venous insufficiency (CCSVI) in a large cohort of patients with multiple sclerosis (MS), patients with other neurological diseases (OND) and in normal controls (NC), by using specific proposed Doppler criteria (Zamboni et al, JNNP, 2009). BACKGROUND: CCSVI is a complex vascular condition characterized by anomalies of the main extracranial cerebrospinal (CS) venous routes that interfere with the normal CS venous outflow. This condition was previously associated with clinically definite MS. DESIGN/METHODS: Cross-sectional study that will enroll consecutive 1700 subjects at one MS center including: 1000 adult patients with possible and definite MS (50 clinically isolated syndrome, 50 radiologically isolated syndrome, 500 relapsing-remitting, 300 secondary-progressive, 50 primary-progressive MS and 50 neuromyelitis optica). A comparative group will include 300 OND patients and 300 adult age- and sex-matched NC. Fifty pediatric patients (<18 yrs) with acquired demyelinating diseases (MS and acute disseminated encephalomyelitis) and 50 pediatric NC will be assessed. All participants will undergo clinical examination and a Doppler scan of the head and neck. All MS patients and a subcohort of NC and OND will undergo an MRI of the brain. A consecutive subgroup (MS, NC and OND) will have also an MRI of the veins of the neck to corroborate the Doppler diagnosis of CCSVI. The Doppler, and MRI evaluators are blinded to the subject status. The prevalence and severity of venous hemodynamic abnormalities identified in the different groups will be analyzed. Data will be unblinded at three predetermined time-points based on the number of subjects enrolled: at 500, 1000 and 1700 subjects respectively. RESULTS: As of 1 Nov 2009, 473 subjects signed informed consent. The initial interim analysis following the first 500 subjects is scheduled for December 2009. CONCLUSIONS/RELEVANCE: The interim results of the first 500 enrolled subjects will be presented.
Category - MS and Related Diseases - Clinical Science
Thursday, April 15, 2010 3:00 PM
Poster Session VI: Multiple Sclerosis and Related Diseases: Clinical Trials (3:00 PM-7:30 PM)
[pos_zamboni10a] Zamboni P, Menegatti E, Weinstock-Guttman B, Dwyer MG, Schirda C, Malagoni AM, Hojnacki D, Kennedy C, Carl E, Bergsland N, Magnano C, Bartolomei I, Salvi F, Zivadinov R : Hypoperfusion of Brain Parenchyma Is Strongly Associated with the Severity of Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis. [P03.128] AAN Annual Meeting 2010. Toronto, 14 Apr 2010 [aan10a]. Abstract.
Buffalo, NY; Ferrara, Italy; Bologna, Italy; Cesena (FC), Italy

Abstract
OBJECTIVE: To investigate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and cerebral perfusion in patients with multiple sclerosis (MS). BACKGROUND: CCSVI is a vascular condition described in MS patients, characterized by stenoses of the main extracranial veins with hampered cerebral venous outflow. We hypothesized that the impaired venous outflow contributes to hypoperfusion of brain parenchyma. DESIGN/METHODS: Sixteen consecutive relapsing-remitting MS patients (mean age 36.1yrs, mean disease duration 7.5yrs and median EDSS 2.5) and 8 age- and sex-matched normal controls (NC), were scanned on a GE 3T scanner using dynamic susceptibility contrast enhanced perfusion-weighted imaging (PWI). Cerebral blood flow (CBF), blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM), normal appearing (NA) GM, NAWM, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra. Diagnosis of CCSVI was established based on the venous hemodynamic (VH) Doppler criteria (Zamboni, JNNP, 2009) and the severity was based on fulfilled VH criteria (score 0-5) and VH insufficiency severity score (VHISS) (score 0-16). RESULTS: All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4, median VHISS=9) and none of the NC. There was a significant association between VH criteria and VHISS, and CBF, CBV and MTT in all examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for lower CBF and higher VHISS in the GM, WM, NAGM and NAWM (r= -0.70 to -0.72, p<0.002), and in the thalamus, caudate, putamen, hippocampus, nucleus accumbens (r= -0.6 to -0.72, p<0.008). The correlation coefficients for CBV and MTT were in a range between r= -0.5 to -0.65. No relationship was observed for NC. CONCLUSIONS/RELEVANCE: This study demonstrates that severity of CCSVI is directly associated with hypoperfusion of the brain parenchyma in MS. Supported by: Hillarescere Foundation and Buffalo Neuroimaging Analysis Center.
Category - MS and Related Diseases - Clinical Science
Wednesday, April 14, 2010 7:30 AM
Poster Session III: Multiple Sclerosis and Related Diseases: MRI/Technique (7:30 AM-12:00 PM)
[pos_dwyer10a] Dwyer MG, Zamboni P, Haacke EM, Menegatti E, Weinstock-Guttman B, Schirda C, Malagoni AM, Hojnacki D, Kennedy C, Carl E, Bergsland N, Hussein S, Heininen-Brown M, Bartolomei I, Salvi F, Zivadinov R: Chronic Cerebrospinal Venous Insufficiency and Iron Deposition on Susceptibility-Weighted Imaging in Patients with Multiple Sclerosis. [P03.126] AAN Annual Meeting 2010. Toronto, 14 Apr 2010 [aan10a]. Abstract.
Buffalo, NY; Ferrara, Italy; Detroit, MI

Abstract
OBJECTIVE: To investigate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and iron deposition in the brain of multiple sclerosis (MS) patients by correlating venous hemodynamic (VH) parameters and iron concentration in deep-gray matter (DGM) structures and lesions, as measured by susceptibility-weighted imaging (SWI). To preliminarily define the relationship between iron measures and disability outcomes. BACKGROUND: CCSVI is a vascular picture recently described in MS patients that is characterized by stenoses affecting the main extracranial venous outflow pathways and by a high rate of cerebral venous reflux that may lead to increased iron deposition in the brain. DESIGN/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 normal controls (NC) were scanned on a GE 3T scanner, by using SWI. Iron concentration was measured in the following DGM structures: thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra. Iron concentration was also measured in T2, T1, SWI phase and SWI magnitude lesions. Diagnosis of the CCSVI was established based on the previously published VH Doppler criteria (Zamboni, JNNP, 2009). RESULTS: All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4, median VHISS=9) and none of the NC. There was a significant association between higher number of VH criteria and higher iron concentration in T2 (r=0.64, p=0.007) and T1 (r=0.56, p=0.023) lesion volumes. The only DGM structure that correlated significantly with VH criteria was globus pallidus (r=0.58, p=0.019). No relationship was observed for NC. Higher iron concentration in DGM structures was predictive of higher disability status (EDSS) in almost all examined regions. The highest correlations were detected for thalamus (r=0.79, p<0.0001) and red nucleus (r=0.7, p=0.005). CONCLUSIONS/RELEVANCE: The findings from this pilot study suggest that CCSVI may be an important mechanism leading to iron deposition in brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a strong predictor of disability progression in patients with MS. Supported by: Hillarescere Foundation and Buffalo Neuroimaging Analysis Center.
Category - MS and Related Diseases - Clinical Science
Wednesday, April 14, 2010 7:30 AM
Poster Session III: Multiple Sclerosis and Related Diseases: MRI/Technique (7:30 AM-12:00 PM)
[pos_schirda10a] Schirda C, Zamboni P, Magnano C, Lindzen E, Wack D, Weinstock-Guttman B, Ramasamy D, Carl E, Hojnacki D, Kennedy C, Dwyer MG, Bergsland N, Cox JL, Salvi F, Zivadinov R: Objective Quantification of Cerebrospinal Fluid (CSF) Flow Rate in Cerebral Aqueduct in Patients with Multiple Sclerosis. [IN7-2.006] AAN Annual Meeting 2010. Toronto, 14 Apr 2010 [aan10a]. Abstract.
Buffalo, NY; Ferrara, Italy

Abstract
OBJECTIVE: To develop an objective MRI technique for quantifying the cerebrospinal fluid (CSF) flow in Sylvius aqueduct. To apply this technique in a pilot study in multiple sclerosis (MS) patients versus normal controls (NC) and provide further correlates with other MRI specific disease metrics. BACKGROUND: Non-invasive MRI investigation of the CSF dynamics in MS has not been previously reported. DESIGN/METHODS: For consistency and objective quantification of the antegrade (towards 4^th ventricle), retrograde (towards 3^rd ventricle) and net CSF flow rates, a semi-automated program was developed. The CSF flow quantification technique was validated on a tube phantom, using a power injector which provided a controlled flow rate. 2 NC and 2 MS patients were scanned and rescanned within a week, to test reproducibility. Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched NC were scanned on a GE 3T scanner using a two-dimensional phase-contrast gradient-echo MR technique with high spatial-temporal resolution (in-plane resolution 0.39x.039mm² and 32 phases, corresponding to a full cardiac cycle) on one 4mm thick slice positioned perpendicular to the Sylvius aqueduct. In addition to CSF flow measures, lesion volume (LV) and atrophy MRI outcomes were calculated. RESULTS: Net CSF flow scan-rescan reproducibility was 10.9%. Net CSF flow rate (stroke volume) was significantly lower in MS patients than in NC (p=0.038). In MS patients, T1-LV was strongly correlated with CSF retrograde (r=0.71, p=0.002) and antegrade flow rates (r=-0.64, p=0.008). T2-LV was also related to CSF flow rate (0.58, p=0.019). Lower net CSF flow rate was related to gray matter (r=-0.63, p=0.009), whole brain and cortical atrophy (p<0.037). CONCLUSIONS/RELEVANCE: CSF flow rate in the Sylvius aqueduct is significantly lower in MS patients than in NC. In MS patients, robust correlations between higher LVs, and advanced atrophy, and altered flow rate measures were found.
Category - MS and Related Diseases - Clinical Science
Wednesday, April 14, 2010 3:30 PM
Poster Session: Integrated Neuroscience: Multiple Sclerosis Imaging (3:30 PM-4:30 PM)
[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.
[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.
[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.
[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

[webcast_calgary10a] Zivadinov R and Weinstock-Guttman B: Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis. Direct-MS, Coast Plaza Hotel Calgary, Alberta Canada. April 30, 2010. Webcast. Q&A Session
Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA
[pres_zamboni10b] Zamboni P: Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis: A Paradigm Shift in the Physiology of Cerebral Venous Return. Invited Speaker Session, AAN Annual Meeting 2010. Toronto, 14 Apr 2010, 5.30pm - 5.50pm [aan10a]. Program (PDF) p67
[pres_poloni10a] Poloni GU, Zamboni P, Haacke EM, Bastianello S, Dwyer MG, Bergsland N, Schirda C, Wack D, Magnano C, Weinstock-Guttman B, Salvi F, Hojnacki D, Zivadinov R: Quantitative Venous Vasculature Assessment on Susceptibility-Weighted Imaging Reflects Presence of Severe Chronic Venous Insufficiency in the Brain Parenchyma of Multiple Sclerosis Patients. A Case-Control Study. [IN7-1.003] AAN Annual Meeting 2010. Toronto, 14 Apr 2010 [aan10a]. Abstract.
Buffalo, NY; Ferrara, Italy; Detroit, MI; Pavia, Italy

Abstract
OBJECTIVE: To develop an objective method for quantifying venous vasculature in brain parenchyma on susceptibility-weighted imaging (SWI). To apply this technique in multiple sclerosis (MS) patients and in healthy controls (HC). BACKGROUND: SWI is a MRI application that can directly image cerebral veins by exploiting venous blood oxygenation. DESIGN/METHODS: Sixty-two (62) MS patients (44 relapsing-remitting and 18 secondary-progressive) and 33 age- and sex-matched HC were imaged on a 3T GE scanner using pre-contrast SWI. A subset of MS patients (50) and HC (7) obtained SWI-post gadolinium contrast sequence (0.1 mMol/Kg Gd-DTPA with 10 min delay). In-house developed segmentation algorithm, based on a 3D multi-scale line filter, was applied for vein segmentation. Absolute volumetric measurement for total vein vasculature was performed in milliliters (ml) and the relative venous intracranial fraction (VIF) was obtained to correct for head size and amount of brain atrophy. The size of individual veins was measured in mm and 4 groups were created according to their mean diameter: <0.3mm, 0.3-0.6mm, 0.6-0.9mm and >0.9 mm. Voxel brain average distance-from-vein maps was also calculated with higher distance indicating fewer veins. RESULTS: A significantly lower absolute venous volume was detected in MS patients compared to HC, both in pre-contrast (67.5 vs. 82.7ml, -18.3%, p<0.001) and post-contrast (70.4 vs. 87.1ml, -19.1%, p<0.011) images. The VIF was significantly lower in MS patients (p<0.001). The highest mean diameter difference was found for the smallest veins (<0.3 mm), both on pre- (p<0.001) and post-contrast (p<0.018) images. The distance-from-veins was also significantly higher in MS patients (p<0.001). CONCLUSIONS/RELEVANCE: We developed and validateda quantitative vein segmentation method that showed altered visibility of venous vasculature on SWI pre- and post-contrast images in MS patients. These findings suggest severely compromised brain venous system in MS patients.
Category - MS and Related Diseases - Clinical Science
Wednesday, April 14, 2010 2:30 PM
Platform Session: Integrated Neuroscience: Multiple Sclerosis Imaging (2:00 PM-3:30 PM)
[pres_dake10b] Dake MD: Stenting jugular veins for MS. Society of Interventional Radiology 35th Annual Scientific Meeting March 13–18 2010; Tampa, FL, USA [conf_sir10a] Annoucement. Frontiers of IR, Frontiers of IR webcast (From 45' 30'', slide 356 to 1h04', slide 436). Youtube part 1, part 2.
[pres_zamboni10a] Zamboni P: CCSVI: Implications in Multiple Sclerosis. CCSVI and MS Workshop, Feb 7 2010, St. Joseph’s Healthcare Hamilton [ws_hamilton10_2] PDF
[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
[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
[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
[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
[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
[pres_haacke09] Haacke EM: Iron and Chronic Cerebral Spinal Vascular Insufficiency (CCSVI). 1 October, 2009, MRA Club. ms-mri.com. PDF
[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)
[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
[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

[ectrims10] 26th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). 13–16 Oct. 2010, Gothenburg, Sweden. Link, CCSVI symposia
[ws_glasgow10a] CCSVI conference at Glasgow. Glasgow in November 2010. Source
Essential Health Clinic

Abstract
We have started preparations for a CCSVI conference at Glasgow in November 2010. This will bring together all the leading people in the world of CCSVI.
[suny10a] Sclafani SJA: Symposium On Proposed Endovascular Treatment Of Chronic Cerebrospinal Venous Insufficiency. July 26 2010, SUNY Downstate Medical Center, New York. Medicalnewstoday, press release. Youtube playlist.
Departments of Radiology and Neurology at SUNY Downstate Medical Center

Abstract
The Departments of Radiology and Neurology at SUNY Downstate Medical Center will hold a symposium on CCSVI (chronic cerebrospinal venous insufficiency) on Monday, July 26 from 9:00 am to 4:00 pm, in the Alumni Auditorium, 395 Lenox Road, Brooklyn, New York 11203.

CCSVI is a syndrome in which blood flow from the brain is compromised. While CCSVI is a disease state that by itself often requires intervention, it has been proposed that the syndrome promotes the development of multiple sclerosis (MS). Speakers from the United States, Bulgaria, Italy, and Kuwait will present a thorough review of CCSVI, including the proposed relationship between CCSVI and MS.

Salvatore J. A. Sclafani, MD, professor and chair of radiology at SUNY Downstate, has organized the symposium and will provide an overview of CCSVI for interventional radiologists.

While this free symposium is directed at physicians and other healthcare providers, members of the general public are invited and there will be a presentation on patient activism.

Source: Ron Najman, SUNY Downstate Medical Center

[conf_ismrm10a] International Society for Magnetic Resonance in Medicine: Susceptibility Weighted Imaging Study Group. ISMRM-ESMRMB Joint Annual Meeting 2010, Stockholm, 1–7 May. Program 4 May 2010

Abstract

Program:

18:15	Introduction Juergen Reichenbach, Ph.D., Professor, Universitätsklinikum Jena, Germany
18:30	An Overview of the State of the Art Now in SWI Juergen Reichenbach, Ph.D., Professor, Universitätsklinikum Jena, Germany
18:45	Iron Associated with MS Lesions, Thalamus & the Basal Ganglia with SWI Mark Haacke, Ph.D., Director, The MRI Institute for Biomedical Research, Detroit, MI, USA
19:00	Correlating SWI Iron Measurements with MS Disease Progression & CCSVI Robert Zivadinov, M.D., Ph.D., Director, Buffalo Neuroimaging Analysis Center, Buffalo, NY, USA
19:15	The Role of CCSVI in Multiple Sclerosis Paolo Zamboni, M.D., Director, Vascular Diseases Center, ITALY
19:30	Phase Image and Iron Content - A Word of Caution Dmitriy A. Yablonsky, PhD, Professor, Mallinckrodt Institute of Radiology, USA
19:45	Panel Discussion
20:00	Closing Remarks
20:15	Adjourn

[ws_sardinia10a] Zamboni P, Galeotti R and Savli F: First Regional Workshop "CCSVI and Multiple Sclerosis". Sardinia S.M. Transcript (PDF). Youtube 14 parts (engl sub).
Sardinia, Italy
[webcast_aan10] Zamboni P, Zivadinov R, Common A, Miller A: Live web forum about CCSVI and MS. Hosted by MS Society and the American Academy of Neurology. 14 Apr [aan10a]. Online viewer, transcript. Siehe vollen Artikel. Zivadinov slides.
Panel
The panel will consist of the following speakers:
- Dr. Paolo Zamboni, Director, Vascular Diseases Center, University of Ferrara, Italy
- Dr. Robert Zivadinov, Associate Professor of Neurology at the University at Buffalo, State University of New York
- Dr. Andrew Common, Radiologist in Chief at St. Michaels Hospital, University of Toronto, Ontario, CA
- Dr. Aaron Miller, Professor of Neurology and Director of the MS Center at Mount Sinai, New York, member of the AAN Board of Directors, Chief Medical Officer of the National MS Society
Quelle: nationalmssociety.org
Summary
1. There is a definite correlation of CCSVI and MS. When tested with venography (the gold standard) there are problems found in the veins of 90-100% of all MS patients.

When tested by doppler alone, the number falls to 65% in all MS patients, although PPMS patients show higher correlation in the BNAC study

2. Both Dr. Zamboni and Dr. Zivadinov believe that MS patients who are not responding to their current medicines, or are progressing rapidly, deserve to have a "compassionate treatment"--meaning, they should be treated outside of a clinical trial by an appropriate caregiver--meaning, an interventional radiologist or vascular surgeon.

Dr. Zivadinov believes we need to separate the research side of CCSVI studies (which need to be scientifically rigorous and double blind studies) with PATIENTS' RIGHTS...meaning, if you have a venous problem now, you have the right to get it treated by a vascular doctor.

3. Both Dr. Zs would like patients to stay at home, bring the research to their local caregivers for possible treatment. They recommend staying on the DMDs patients are on.

4. The fibrin cuff is a marker of venous hypertension. It is also found in the lesions in MS brains. Iron deposition encircles the veins of MS patients...this is also found in chronic venous disease. There is a large correlation between venous disease found in other parts of the body, and venous disease in the MS brain. Dr. Zamboni invites the doctors to study this.

Also, the change in cerebrospinal fluid levels in MS brains and how that relates to venous congestion is a HUGE new area of research.

5. The neurologists and NMSS know that we are watching, and that we understand what is at stake. Dr. Zivadinov calls it the "elephant in the room." It is because of all of you, that they know they cannot sweep this research into the corner--as they did with Dr. Schelling 30 years ago. This is out there, and we understand it.

Here are the notes:

Points made by Dr. Zamboni-

1. BNAC's numbers are different because they did not use gold standard venography-

2. CCSVI is a truncular venous malformation, as determined by vascular specialists across the globe, published research

3. MRV does not see azygos vein, why venography is essential

4. doppler is good, non-invasive test

5. Please refer to published science

Dr. Z is going over all of his papers...the numbers as verified by his research.

-a genetics study will be released and published next month-showing correlation between CCSVI and MS locus

We have established a strong connection of CCSVI and MS with research and data...now talking about iron depsiton and chronic venous disease and how this initiates the immune system. He invites experts to study this. The fibrin cuff encircles the vein, the marker of venous hypertension

Reduction of CSF flow suggests less reabsorption due to increased venous pressure in the brain. The CSF flow is modified, it is the mirror of MS disease, majority of data comes from CSF flow examination. CSF flow dynamics are changed by CCSVI. Complement cascade is reactivated, overloads the CNS. NEW SPECTACULAR FINDING! Needs more research by neuroimmunologists...invites colleagues to investigate

Zivadinov is up...the elephant in the room...there is ENORMOUS attention in the work...this brings millions of people together, not just a handful of scientists. THis is new, because of this attention, we must put MORE attention on this.

The tension is high because of the urgency in this research. What is usually ethical might be in conflict with patients' rights...we need to balance this.

THis is important for the community of MS -Work on CCSVI must continue under scientific and public scrutiny. CCSVI expands our understanding of MS. THis might not be applicable to all MS patients. We need blinded, traditional studies. Diagnosis and treatment should be provided by care givers and studies by researchers should be separated.

CTEVD study was blinded 64% of MS patients showing def. CCSVI...using ultrasound doppler and some MRV to establish prevalence. No venography

500 subjects tested thru 12/09. Phase 2 needs funding. Data coming...

primary progressive 70%,, SPMS 70% RRMS 64% CCSVI

We need ethical oversight...IRB approvals may not be sufficient. Wants to create a monitoring task force. He believes there is no risk in testing and treating, but invites oversight. He questions open-label treatment without IRB. Need transparency of funding. We need to begin putting together scientists to discuss this, thanks AAN

Zivadinov continues: Intraluminal ultrasounds, new technology- venograpahy is still gold standard. From patient case reports and rigorous studies, we need to use MRI and clinical outcomes in blinded control fashion to show if treatment modifies. We can't ignore symptom relief--we care about the quality of life in treatments. Most dream again, sleep again, less fatigue, headache...this was unexpected. But clearly, science will further confirm.

Dr. Common- IRV speaks on venous procedures-has not performed any CCSVI intervention, but is familiar with treatments. Many patients have contacted him. He has followed the research. (My question is, why did they get him to speak, and not someone who has studied this????)

Veins are redundant...blood can still flow around blockage. Stenoses caused by trauma, tumor, sheer stress in high flow states..

MRV is time consuming and expensive, not ideal for small vessels. Dye damages kidneys, radiation is dangerous....venography is invasive, wire insertion...dangerous...dye, perforation with wire... risks of venous intervention is small, safer the arterial system. Veins show large amount of recoil, which is why stenosis can occur. Stent-hold elastic structure open, need anti-coagulation therapy, risk of bleeding. Stents expensive, risk of migration

Are there benefits to treating? Benefit relating to CNS plaques? Recommends only a clinical trial setting with experienced radiologists and neurologists work together.

Questions: Wayne State Dr. Lisak- head of neurology (begins questioning rather aggressively by making a speech, not asking a question- this doctor also co-authored the Annals of Neurology hit piece on CCSVI)

You are incorrect, Dr. Zamboni...red blood cell escavation is not a hallmark of MS lesions- Your pathology doesn't match MS. Iron is normal in aging. There is a disconnect with your research and MS pathology. This is my comment, not a question.

Dr. Zamboni: (a bit ticked off, rightly so)

Your comment may permit YOU to explain to me...what is the origin of fibrin in the blood? Venous hypertension as in pulminary hypertension creates the hallmark fibrin cuffs. The iron in MS brains is found around the veins, in a circular pattern...very, very different than the location of iron in the brains of other neurological diseases!!

CCSVI in Multiple Sclerosis Avis Favaro- can you give us results in lay-person language?

Zivadinov- SWI study...attempt to look at correlation at amount of iron in structures of brain--iron does store in other diseases and normal people. I would like to understand the venous structure and neurodegenerative disease. Iron builds in different structures of the brain...there are certain pathways where iron is building in MS...in thalamus and around venous area of pulvinar nucleus of thalamus, thanks to new technology. We need to understand this buildup with disability in MS.

Dr. Miller-

This is highly technical information...iron deposition is giving us lots to explore. There are many explanations for this (for you in the audience) cause and effect...iron may be a consequence of disease process...

Johanna on Facebook-

Is this a possible cure? Stay on our drugs?

Dr. Miller- no reason to get off drugs. Procedure only in controlled trial. No reason to discontinue DMDs.

Zivadinov- No reason for patients to stop therapy. DMDs have advantages until something else is determined.

Zamboni- I agree completely. Continue and wait for new evidence. Concern regarding ...

Kelley Crew CBC

What do you say to traveling patients?

Zivadinov- do not do it until we know this is helpful.

We do not have data to prove this is useful. We need efficacy studies. BUT we should respect patients' needs and rights. The caregivers must decided this with patients. It is outside the researchers' realm.

Cheryl from New York-

Anything outside of surgery to help veins?

Dr. Cooke -interventional procedure is all I am aware of to help venous narrowings. The interventions are not difficult, but we recommend a follow-up with a neurologist.

CBC radio-

Placebo affect as high as 50% for this?

Dr. Miller- High placebo response in almost any subjective symptoms...we can't measure fatigue- these tend to be the most responsive to any new treatment. Placebo response is lower in neuro changes, strength, spasms. MRI is a sensitive measure of therapy. We need properly controlled trial...you need a sham control.

Kim online-

Are there certain symptoms we may have with CCSVI?

Zivadinov-we are testing vitamin D, smoking, in gathering our research in risk to MS. Symptoms are relevent...certain symptoms may affect certain blockage...as in optic neuritis and jugular vein connection. These are "regional pathways" which show a connection

Clinical Neurology News-

How many patients are undergoing outside research studies? Where?

Dr. Miller- We don't have any idea. Among the MS community there is interest, there is no registry yet.

Dr. Zivadinov- important point. We recommend doctors get IRB approved and connect with team researchers.

Dr. Zamboni we are preparing a registry, a good tool. We reduce malpractice risk.

Don from US-

How many trials or tests until this in mainstream in US?

Dr. Miller- NMSS is reviewing research applications. Hard to say when the answer will come

Medscape Neurology-

Did Dr. Dake...WSJ story cause you to rethink?

Dr. Cooke- I've spoken to Dr. Dake regarding his 35 interventions, his complications, migration and blood thinning. He was asked to stop...not sure what grounds. Don't know why he stopped. Dr. Zamboni states we should not use stents.

Dr. Zamboni- stent may give the opportunity to keep veins open

Extending time...due to interest

Wheelchair Kamikazee asks a question-

What about things we know about MS that CCSVI does not seem to explain: women, EBV

Dr. Zivadinov. Excellent point. Key points of our study. Venous disease in general female 2;1 ration, jugular size smaller in women, EBV link is being studied.

press: how do you account for healthy people with CCSVI?

Dr. Zivadinov- I want to understand how this affects other neurological diseases. Our healthy controls included hashimotos, APS and FAMILIAL healthy controls (FINALLY he says this...These are NOT really healthy controls. Children of MS patients may show CCSVI)

Maybe if you are living in Buffalo, you do not get enough vitamin D, or if you're smoking, we want to learn more...

Dr. Miller- why is there so much discrepancy between Dr. Zivadinov and Dr. Zamboni? What is the implication? We need more controlled date from other centers.

Edward online-

What can MS community do to accelerate CCSVI research-

Dr. Miller-MS research communites and societies are actively involved and engaged. You need to get involved in pushing for more research $$$ Appropriate amounts of money need to be raised.

7000 questions were sent to them....sorry they couldn't get to it all. The session will be posted on NMSS shortly, with an official transcript.

Source: http://www.facebook.com/note.php?note_id=385357152210&comments
[aan10a] American Academy of Neurology: AAN Annual Meeting 2010. Toronto, 10–17 Apr 2010. Program (PDF), Abstracts Zamboni, Zivadinov. [pres_poloni10a] [pres_zamboni10b] [pos_magnano10a] [pos_zivadinov10a] [pos_zamboni10a] [pos_dwyer10a] [pos_schirda10a] [webcast_aan10]
[conf_sir10a] Society of Interventional Radiology: SIR Annual Scientific Meeting 2010. 35th Annual Scientific Meeting March 13–18; Tampa, FL, USA. Medical advances, new discoveries (PDF). Program. Frontiers of IR, Frontiers of IR webcast (From 45' 30'', slide 356 to 1h04', slide 436).
Presentation: Dake MD [pres_dake10b]

Info
On March 14, Matthew S. Johnson, M.D., FSIR, professor of radiology and surgery Indiana University School of Medicine, Indianapolis, Leads the discussion on “Frontiers of IR,” highlighting current cutting-edge news from animal research to clinical studies to innovative practice initiatives (including molecular medicine, nanotechnology, stenting jugular veins for multiple sclerosis).
[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] [pres_zamboni10a]
[ecfs09] European Charcot Foundation Symposium 2009. 12–14 Nov. 2009, Lisbon, Portugal. Link [pos_zamboni09c] [pos_zamboni09d]
[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]
[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)
Comment
Dies ist die erste grössere Konferenz über CCSVI, wo eine Information über CCSVI stattfand.
[uip09] XVI World Congress of the Union Internationale de Phlébologie. Monaco, 31 Aug. – 4 Sept. 2009.> Link, Conference program, p. 22. [pres_simka09] [lee09a]
[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] [zamboni09g], video

Weitere Unterlagen

[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$
[simkaop09] Simka M: CCSVI 1st OP in Poland. Stent OP 19.10.2009. Youtube
[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
Comment
Dies ist die Website von Prof. Haacke, dem Miterfinder von MRI SWI und Spezialisten in Angiographie. Die Website enthält ein von Prof. Haacke vorgeschlagenes MRI Protokoll zum Untersuchen von venösen Anomalien.
[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). Site Article.
Comment
Dieses Dokument beschreibt wie Dr. Simka die Ultraschalluntersuchung durchführt.
Outline
The structure of the document:
1. Stenosis or occlusion of the internal jugular vein
2. Reflux in the internal jugular or vertebral veins
3. No detectable flow in the internal jugular or vertebral veins
4. No position-dependent change in diameter of the internal jugular vein
5. Reflux in the deep cerebral veins
[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)
[cxnews09] Endovascular Treatment for Multiple Sclerosis. May 2009 in Vascular News ed. 80, pp. 392–399. Article (JPG)
[aerztezeitung08] Meißner T: Jugularvenenthrombose - da kann auch eine maligne Erkrankung die Ursache sein. Ärzte Zeitung (Deutschland), 29.09.2008 Article
[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)
[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]
[sciencenewsletter35] : Multiple Sclerosis laid to blood that clots too easily. Science News Letter for May 18, 1935. Article

Kritik ausserhalb wissenschaftlicher Publikationen

[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
[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

Über Forschung und andere generelle Themen

People interested in CCSVI follow research closely. This section lists books or articles which explain research. It's essential knowledge.

[evans10a] Evans I, Thornton H, Chalmers I: Testing Treatments Better Research for Better Healthcare. Pinter & Martin; 2010. Website, ISBN 978-1-905177-35-6. PDF, PDF (es), amazon.com.
Description
How do we know whether a particular drug, therapy or operation really works, and how well? How reliable is the evidence? Are clinical trials truly unbiased? And is current research focused on the real needs of patients? Such timely and pressing questions are raised and addressed in this probing enquiry into modern clinical research, with far-reaching implications for daily medical pactice and patient care.

Aimed at both patients and professionals, Testing Treatments builds a lively and thought provoking argument for better, more reliable, more relevant research, with unbiased or ‘fair’ trials, and explains how patients can work with doctors to achieve this vital goal.

Reviews.

Info
This book explains how evidence in medicine for reliable decisions can be created as fast as possible. Relevant for CCSVI. A must-read!
[goldacre09a] Goldacre B: Bad science. Fourth Estate; 2009. ISBN 978-0007284870, amazon.com
Description
Guardian columnist Dr Ben Goldacre takes us on a hilarious, invigorating and informative journey through the bad science we're fed by the worst of the hacks and the quacks! When Dr Ben Goldacre saw someone on daytime TV dipping her feet in an 'Aqua Detox' footbath, releasing her toxins into the water and turning it brown, he thought he'd try the same at home. 'Like some kind of Johnny Ball cum Witchfinder General', using his girlfriend's Barbie doll, he gently passed an electrical current through the warm salt water. It turned brown. In his words: 'before my very eyes, the world's first Detox Barbie was sat, with her feet in a pool of brown sludge, purged of a weekend's immorality.' Dr Ben Goldacre is the author of the 'Bad Science' column in the Guardian and his book is about all the 'bad science' we are constantly bombarded with in the media and in advertising. At a time when science is used to prove everything and nothing, everyone has their own 'bad science' moments -- from the useless pie-chart on the back of cereal packets to the use of the word 'visibly' in cosmetics ads.This book will help people to quantify their instincts -- that a lot of the so-called 'science' which appears in the media and in advertising is just wrong or misleading. Satirical and amusing -- and unafraid to expose the ridiculous -- it provides the reader with the facts they need to differentiate the good from the bad. Full of spleen, this is a hilarious, invigorating and informative journey through the world of 'bad science'.

Info
This book explains research with bad examples. It's written in an entertaining way. Highly recommended!
[moerman02a] Moerman D: Meaning, medicine, and the "placebo effect". Cambridge University Press; 2002. ISBN 978-0521806305, amazon.com
Description
Traditionally, the effectiveness of medical treatments is attributed to specific elements, such as drugs or surgical procedures. However, many other factors can significantly effect the outcome. Drugs with nationally advertised names can work better than the same drug without the name. Inert drugs (placebos, dummies) often have dramatic effects on some patients and effects can vary greatly among different European countries where the "same" medical condition is understood differently. Daniel Moerman traverses a complex subject area in this detailed examination of medical variables. Since 1993, Cambridge Studies in Medical Anthropology has offered researchers and instructors monographs and edited collections of leading scholarship in one of the most lively and popular subfields of cultural and social anthropology. Beginning in 2002, the CSMA series presents theme booksworks that synthesize emerging scholarship from relatively new subfields or that reinterpret the literature of older ones. Designed as course material for advanced undergraduates, graduate students, and for professionals in related areas (physicians, nurses, public health workers, and medical sociologists), these theme books will demonstrate how work in medical anthropology is carried out and convey the importance of a given topic for a wide variety of readers. About 160 pages in length, the theme books are not simply staid reviews of the literature. They are, instead, new ways of conceptualizing topics in medical anthropology that take advantage of current research and the growing edges of the field.

Info
This book explores the placebo effect. Recommended.

Example extract 'angina pectoris', p57ff
The logic of this theory of rusty pipes has had a long history. Several indirect revascularization techniques which involved rerouting various arteries were developed in the 1930s by Beck and in the 1940s by Vineburg (Meade 1961:480:515). Although Beck's procedure attained modest popularity, the first widely used surgical approach to angina was the bilateral internal mammary artery ligation (BIMAL). The internal mammary (or thoracic) arteries arise from the subclavian artery high in the chest and descend just inside the front wall of the chest, ultimately supplying blood throughout the chest and viscera. Following anatomical research by Fieschi, an Italian surgeon, which indicated connections between various ramifications of these arteries and the coronary circulation, several other Italian surgeons developed a procedure in which the arteries were ligated (tied off) below the point where these branches presumably diverged to the heart in order to enhance this flow and supplement the blood supply. The operation was first performed in the United States by Robert Glover and J. Roderick Kitchell in the late 1950s (Glover 1957 PMID 13475193; Kitchell, Glover and Kyle 1958 PMID 13497954). It was quite simple, and since the arteries were not deep in the body, could be performed under local anesthesia. The physicians reported symptomatic improvement (ranging from slight to total) in 68% of their first sample of fifty patients, in a two- to six-month follow-up. The operation quickly gained some popularity.

"The problem is that no one else believed that there was any real connection between these arteries and the heart! So, shortly after these reports appeared, two different surgical teams at two American medical centers - one from Kansas City under the direction of E. Grey Dimond (Dimond, Kittle, and Crockett 1960 PMID 13816818) and the other in Seattle under Leonard Cobb (Cobb et al. 1959 PMID 13657350) - did double blind trials of the procedure. In each case, the surgeon learned only while in the operating room which patients were to have the complete operation and which were to receive "sham surgery". Those patients receive the complete operation, but the arteries were not ligated. In both studies, the patients were followed for at least six month after the surgery by cardiologists who were unaware of which patients had received the ligations and which had not. In one of the studies (Seattle) the patients were told that the operation was experimental, but they were not informed that some of them would get the sham surgery. In the Kansas City study, it is not clear from the publication just what the patients were told; it does say that the patients did not know which procedure they had received (suggesting that they knew there were two possibilities). This seems not to have made any difference anyway. In both studies, most of the patients were much better after surgery regardless of whether they had the full operation or the sham surgery. Table 5.1 indicates the outcomes of the two studies and shows the combined outcome.

In both cases, patients experienced significant subjective improvement; that is, they reported that they had substantially less pain than before the surgery. This was true regardless of whether or not they had the full procedure (67% substantial improvement) or the shame procedure (82% substantial improvement). In the Seattle study, "need for nitroglycerine was uniformly decreased". In the Kansas city study, the average number of nitroglycerine tablets taken per week dropped 34% in patients with the full operation and 42% in patients with the sham operation. In both studies, patients were, on average, able to exercise longer before an angina attack. In neither study were there substantial changes in electrocardiogram readings, although one Seattle patient with striking abnormalities before surgery had none afterwards. He received the sham surgery.

It is hard to know how to account for substantial improvement in these patients. Whatever the truth may be about the alleged connection between the internal mammary arteries and the coronary arteries (it doesn't show up anywhere in my Gray's Anatomy!), it doesn't really matter; in these two studies, the patients with the sham procedure did as well (maybe even a bit better) than those with the complete procedure. But for people willing to trust their surgeons and doctors, this is a pretty compelling operation. The notion that your heart is starved for blood makes pretty good sense. And the notion that we can, by shutting off the flow of blood down one pipe, enhance the flow into another pipe - sort of like what happens in the bathroom sink when you turn off the sower - makes very good sense. One patient in Kansas City study, when asked if he felt better, said, "Yes. Practically immediately I felt better. I felt I could take a deep breath … I figure I'm about 95 percent better. I was taking five nitros a day before surgery. In the first five weeks following, I have taken a total of twelve." This patient's arteries were not ligated (Dimond, Kittle, and Crockett 1960:484 PMID 13816818). But he did have two scars on his chest, and he had an explanation that made sense (unless he was an aficionado of Gray's Anatomy). He had all the elements of meaning which he needed."

Interessenskonflikte in der Medizin

[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.
[jelinek09] Jelinek GA, and Neate SL: The influence of the pharmaceutical industry in medicine. J Law Med. 2009 Oct;17(2):216-23. PMID 19998591. Abstract, PDF, Deutsche Übersetzung (PDF)
Department of Medicine, University of Melbourne, St Vincent's Health, Fitzroy, Victoria, 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.

About Prof. Jelinek
My mother died of MS in 1981. Towards the end of her life, she was totally incapacitated, unable to feed or care for herself. I was diagnosed with MS in 1999. I was determined that this was not going to be my fate. Fortunately, my career as a Professor in Emergency Medicine and background as Editor-in-Chief of a major medical journal gave me the tools to sort through the medical literature on MS, giving appropriate weight to the various pieces of evidence I found. [Source]
[lo09a] Lo B, Institute of Medicine (U.S.): Conflict of interest in medical research, education, and practice. Washington D.C.: National Academies Press; 2009. Book (Online)

Description
Collaborations of physicians and researchers with industry can provide valuable benefits to society, particularly in the translation of basic scientific discoveries to new therapies and products. Recent reports and news stories have, however, documented disturbing examples of relationships and practices that put at risk the integrity of medical research, the objectivity of professional education, the quality of patient care, the soundness of clinical practice guidelines, and the public's trust in medicine.

Conflict of Interest in Medical Research, Education, and Practice provides a comprehensive look at conflict of interest in medicine. It offers principles to inform the design of policies to identify, limit, and manage conflicts of interest without damaging constructive collaboration with industry. It calls for both short-term actions and long-term commitments by institutions and individuals, including leaders of academic medical centers, professional societies, patient advocacy groups, government agencies, and drug, device, and pharmaceutical companies. Failure of the medical community to take convincing action on conflicts of interest invites additional legislative or regulatory measures that may be overly broad or unduly burdensome.

Conflict of Interest in Medical Research, Education, and Practice makes several recommendations for strengthening conflict of interest policies and curbing relationships that create risks with little benefit. The book will serve as an invaluable resource for individuals and organizations committed to high ethical standards in all realms of medicine.

Definition: Conflicts of interest are defined as circumstances that create a risk that professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest.
[klemperer09a] Klemperer D: Interessenkonflikte und Beeinflussung. [Conflict of interest and adaptation] Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen. 2009;103(3):133-135. PMID 19554886, PDF
Hochschule Regensburg, Fakultät Sozialwissenschaften, Regensburg, D
[rothman09a] Rothman DJ, McDonald WJ, Berkowitz CD, Chimonas SC, DeAngelis CD, Hale RW, Nissen SE, Osborn JE, Scully JH, Thomson GE, and Wofsy D: Professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. JAMA. 2009 Apr;301(13):1367-72. PMID 19336712, doi:10.1001/jama.2009.407.
Institute on Medicine as a Profession, Columbia College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA.

Abstract
Professional medical associations (PMAs) play an essential role in defining and advancing health care standards. Their conferences, continuing medical education courses, practice guidelines, definitions of ethical norms, and public advocacy positions carry great weight with physicians and the public. Because many PMAs receive extensive funding from pharmaceutical and device companies, it is crucial that their guidelines manage both real and perceived conflict of interests. Any threat to the integrity of PMAs must be thoroughly and effectively resolved. Current PMA policies, however, are not uniform and often lack stringency. To address this situation, the authors first identified and analyzed conflicts of interest that may affect the activities, leadership, and members of PMAs. The authors then went on to formulate guidelines, both short-term and long-term, to prevent the appearance or reality of undue industry influence. The recommendations are rigorous and would require many PMAs to transform their mode of operation and perhaps, to forgo valuable activities. To maintain integrity, sacrifice may be required. Nevertheless, these changes are in the best interest of the PMAs, the profession, their members, and the larger society.
[finzen07a] Finzen A, Fritze J: Behindert Sponsoring den Erkenntnisprozess in der Medizin? [For and against: does sponsoring impede the growth of knowledge in medicine?] Psychiatr Prax. 2007 Mai;34(4):162-164. PMID 17520527, doi:10.1055/s-2006-951952, Article, PDF
Basel; Köln
[moynihan08a] Moynihan R: Key opinion leaders: independent experts or drug representatives in disguise? BMJ. 2008 Jun;336(7658):1402-3. PMID 18566074, doi:10.1136/bmj.39575.675787.651, Article.
University of Newcastle, Newcastle, New South Wales, Australia.
[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
[angell00a] Angell M: Is academic medicine for sale? N Engl J Med. 2000 May;342(20):1516-8. Type: Comment. PMID 10816191, PDF.

Ähnliche Publikationen können gefunden werden mit PubMed Suchen 'Conflict of Interest' or 'Drug Industry'. Oder Healthy Skepticism Library.

Acknowledgements

We would like to thank Fondazione Hilarescere for funding the research and providing the publications for free.

Missing publications?

Do you know a publication that is missing above? If so, you can send us an email or write a comment.

Venöse Multiple Sklerose | CCSVI

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Interessenskonflikte in der Medizin

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