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J Cereb Blood Flow Metab. 2009 Sep 2. [Epub ahead of print] Links Anomalous venous blood flow and iron deposition in multiple sclerosis.Singh AV, Zamboni P. Department of Physics, European School of Molecular Medicine (SEMM), IFOM-IEO Campus, Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), University of Milan, Milan, Italy.

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.

ReviewInflammation in venous disease. Int Angiol. 2008 Oct; 27(5):361-9.
[Int Angiol. 2008]
The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci. 2009 Jul 15; 282(1-2):21-7. Epub 2009 Jan 13.
[J Neurol Sci. 2009]
ReviewOxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich’s ataxia. J Neurol Sci. 2005 Jun 15; 233(1-2):145-62.
[J Neurol Sci. 2005]
Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res. 2007 Nov; 4(4):252-8.
[Curr Neurovasc Res. 2007]
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J Neurol Sci. 2009 Jul 15;282(1-2):21-7. Epub 2009 Jan 13. Links
The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis.Zamboni P, Menegatti E, Galeotti R, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy.

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.

PMID: 19144359 [PubMed – indexed for MEDLINE]

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J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):392-9. Epub 2008 Dec 5.  Links

Comment in:
J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):358.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy.

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.

PMID: 19060024 [PubMed – indexed for MEDLINE]
PMCID: PMC2647682

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1: Curr Neurovasc Res. 2007 Nov;4(4):252-8. Links
Intracranial venous haemodynamics in multiple sclerosis.Zamboni P, Menegatti E, Bartolomei I, Galeotti R, Malagoni AM, Tacconi G, Salvi F.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy.

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.

PMID: 18045150 [PubMed – indexed for MEDLINE]

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Cited by 1 PubMed Central article
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F. J Neurol Neurosurg Psychiatry. 2009 Apr; 80(4):392-9. Epub 2008 Dec 5.
[J Neurol Neurosurg Psychiatry. 2009]

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 J Neurol Sci. 2009 Jul 15;282(1-2):21-7. Epub 2009 Jan 13. Links
The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis.Zamboni P, Menegatti E, Galeotti R, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F.
Vascular Diseases Center, University of Ferrara, Ferrara, Italy.

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.

PMID: 19144359 [PubMed – indexed for MEDLINE]

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Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009 Apr; 80(4):392-9. Epub 2008 Dec 5.
[J Neurol Neurosurg Psychiatry. 2009]
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