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When MS patients diagnosed with CCSVI in the Zamboni's studies underwent [[catheter]]ization of the azygous and IJV veins, the authors claimed that such veins were stenosed in around 90% of the cases. Nevertheless this part of the study was not blinded. Further studies are currently underway. <ref name=pmid20373339/><ref name="pmid19060024"/> A vascular component in MS had been cited previously.<ref>{{Cite journal |author=Simka M |title=Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis |journal=Curr Neurovasc Res |volume=6 |issue=2 |pages=132–9 |date=May 2009|pmid=19442163 |doi= |url=}}</ref>
When MS patients diagnosed with CCSVI in the Zamboni's studies underwent [[catheter]]ization of the azygous and IJV veins, the authors claimed that such veins were stenosed in around 90% of the cases. Nevertheless this part of the study was not blinded. Further studies are currently underway. <ref name=pmid20373339/><ref name="pmid19060024"/> A vascular component in MS had been cited previously.<ref>{{Cite journal |author=Simka M |title=Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis |journal=Curr Neurovasc Res |volume=6 |issue=2 |pages=132–9 |date=May 2009|pmid=19442163 |doi= |url=}}</ref>


It has been theorized by Zamboni and colleagues that the malformed blood vessels caused increased deposition of iron in the brain, which in turn triggers [[autoimmunity]] and degeneration of the nerve's [[Myelin|myelin sheath]].<ref name=pmid20373339/><ref name="pmid19724286"/> Nevertheless iron deposition occurs in different neurological diseases such as [[Alzheimer's disease]] or [[Parkinson's disease]] but CCSVI was not seen in their control group with neurological problems.<ref name=pmid20373339/><ref name="pmid19060024"/>
Zamboni and colleagues theorized that the malformed blood vessels caused increased deposition of iron in the brain, which in turn triggers [[autoimmunity]] and degeneration of the nerve's [[Myelin|myelin sheath]].<ref name=pmid20373339/><ref name="pmid19724286"/> Nevertheless iron deposition occurs in different neurological diseases such as [[Alzheimer's disease]] or [[Parkinson's disease]] but CCSVI was not seen in their control group with neurological problems.<ref name=pmid20373339/><ref name="pmid19060024"/>

A small genetic study looked at fifteen MS patients who also had CCSVI. It found 234 specific [[copy number variation]]s in the [[HLA locus]]. Of these, [[GRB2]], [[HSPA1L]] and [[HSPA1A]] were found to be specifically connected to both MS and [[angiogenesis]], [[TAF11]] was connected to both MS and artery passage, and [[HLA-DQA2]] was suggestive of having an implication for angiogenesis as it interacts with [[CD4]].<ref>{{cite journal |title=Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis |author=Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, Salvi F, Gemmati D, Liboni A, Zamboni P |journal=BMC Med Genet |year=2010 11: 64 |date=2010 April 28 |pmid=20426824 |pmc=2880319 |doi=10.1186/1471-2350-11-64}} (primary source)</ref>


==Proposed consequences==
==Proposed consequences==

Revision as of 20:03, 22 July 2010

Chronic cerebrospinal venous insufficiency controversy
SpecialtyCardiology Edit this on Wikidata

Chronic cerebro-spinal venous insufficiency (CCSVI) is a syndrome, classified by the International Union of Phlebology as a truncular malformation , in which the flow of blood in the veins draining the central nervous system (CNS) is compromised. It has been proposed to promote the development of multiple sclerosis.

The reported blood flow compromises involve both reduced and intermittently reversed (reflux) flow velocities in the cerebral veins, altering the blood-brain barrier, and are reportedly associated with stenosis of the jugular and azygos veins. Such a vascular picture was described by Paolo Zamboni in 2008, who also reported an association of CCSVI with multiple sclerosis (MS). The hypothesis has generated optimism among people with MS regarding effective treatment options. Research efforts are underway to clarify the CCSVI hypothesis.

History

Paolo Zamboni described CCSVI in 2008.

This syndrome was described in 2008 by Paolo Zamboni, one of the main defenders of its relationship with multiple sclerosis. CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.[1][2] It was soon followed by small open-label study which reported a positive effect of angioplasty in MS patients with CCSVI by the same research group.[1][3] The first international symposium took place in 2009, at Bologna, Italy.[4] Venous stenosis due to developmental abnormalities was established as the primary cause of CCSVI by the International Union of Phlebology.[5] In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.[6][7][8]

Pathophysiology

Most of the venous problems in MS patients have been reported to be truncular venous malformations, including azygous stenosis, jugular defective valves and jugular veins aneurysms. Innominate vein and superior vena cava have also been reported to contribute to CCSVI.[9]

When MS patients diagnosed with CCSVI in the Zamboni's studies underwent catheterization of the azygous and IJV veins, the authors claimed that such veins were stenosed in around 90% of the cases. Nevertheless this part of the study was not blinded. Further studies are currently underway. [1][2] A vascular component in MS had been cited previously.[10]

Zamboni and colleagues theorized that the malformed blood vessels caused increased deposition of iron in the brain, which in turn triggers autoimmunity and degeneration of the nerve's myelin sheath.[1][11] Nevertheless iron deposition occurs in different neurological diseases such as Alzheimer's disease or Parkinson's disease but CCSVI was not seen in their control group with neurological problems.[1][2]

A small genetic study looked at fifteen MS patients who also had CCSVI. It found 234 specific copy number variations in the HLA locus. Of these, GRB2, HSPA1L and HSPA1A were found to be specifically connected to both MS and angiogenesis, TAF11 was connected to both MS and artery passage, and HLA-DQA2 was suggestive of having an implication for angiogenesis as it interacts with CD4.[12]

Proposed consequences

Proposed consequences of this theories include: intracranial hypoxia, delayed perfusion, reduced drainage of the catabolites and increased transmural pressure,[13] and iron deposits around the cerebral veins.[11][14]

It has been proposed that CCSVI can produce multiple sclerosis and that the fatigue that MS patients suffer could be a direct consequence of CCSVI, rather than a consequence of the lesions.[15]

Diagnosis

Computer-enhanced transcranial doppler.

CCSVI was first found using specialized extracranial and transcranial doppler sonography.[1][2] Five parameters of venous drainage have been proposed to be characteristic of the syndrome, although having two of them is enough for diagnosis of CCSVI:[1][2][16]

  • reflux in the internal jugular and vertebral veins,
  • reflux in the deep cerebral veins,
  • high-resolution B-mode evidence of stenosis of the internal jugular,
  • flow in the internal jugular or vertebral veins that could not be detected with Doppler, and
  • reverted postural control of the main cerebral venous outflow pathways.

Use of Magnetic resonance venography for the diagnosis of CCSVI in MS patients has limited value, and has been proposed to be used only in combination with other techniques.[17]

While the initial article on CCSVI claimed that abnormal venous function parameters were not seen on healthy people others have noted that this is not the case.[1] In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did.[1][2] Such outstanding results have raised suspicions on a possible spectrum bias, which originates on a diagnostic test not being used under clinically significant conditions.[1]

The original results have been replicated in a second study,[6] but others have found CCSVI to only occur in 20% of MS patients,[7] and still others found that none of the studied subjects fulfilled the criteria for CCSVI.[8]

Treatment

Diagram of a balloon catheter.

There has been a small pilot study which used balloon angioplasty to treat MS patients who had been diagnosed of CCSVI and had their cerebral veins stenosed.[3] This study reported a clinical benefit, especially in those patients with the relapsing-remitting MS.[1][3] In the follow-up of these patients (up to 18 months) there was a very high rate of re-stenosis (around 50%).[1][3] Improvements in this study are hard to interpret due to the lack of a control group and blindness among the evaluators, small treated sample, and use of approved therapies for the disease among patients.[1]

The high re-stenosing rates led the authors of the pilot study to propose that the use of stents might be a more feasible treatment,[1][3] while they said at a later date that stents should not be used.[18] Rare but serious adverse events have been reported when using stents.[19] Some US hospitals have banned the surgical procedure outside of clinical trials until more evidence to support its use is available.[19][20]

Research directions

The Multiple Sclerosis Society of Canada has committed to funding further experimental trials on the hypothesis, though the head of the organization noted that the results "merit serious and robust studies" but also "pleaded with patients to not do anything drastic until the theory is tested and proven".[21]

There are further ongoing studies aiming to clarify if there is a relationship between MS and CCSVI using similar methods to Zamboni's initial study. A large ongoing study at Buffalo Neuroimaging Analysis Center has had preliminary results partially conflicting with those of Zamboni: while 62% of MS patients had CCSVI this was also true for 26% of healthy controls and 45% of participants with other neurological disorders.[18] On the other hand VU University Medical Center in Amsterdam has claimed in a press release that they have found no differences between the veins of healthy people and MS patients in a preliminary group of participants. The study is planned to continue with the support of the MS Research Foundation.[22]

Reception

The hypothesis has generated optimism from people with MS for more effective treatment options. It has been received with caution or skepticism by a number of experts, who find it relies on limited data to support either some or all of the following claims: (a) that the syndrome actually exists; (b) that it could be causative of (or a co-factor in) multiple sclerosis; (c) that vascular treatments for the syndrome would prevent or reduce the incidence of multiple sclerosis.[23]

The neurology community and many MS organizations such as the National Multiple Sclerosis Society of the USA recommend not to use the proposed treatment until its effectiveness is confirmed by controlled studies.[1][19][24][25]

Media coverage of the theory has been perceived by some in the scientific community to be out of proportion with exaggerated claims which have led to excessive expectations in people with MS. Conversely, by others, it is a theory that is 'long overdue'.

See also

References

  1. ^ a b c d e f g h i j k l m n o Khan O, Filippi M, Freedman MS; et al. (March 2010). "Chronic cerebrospinal venous insufficiency and multiple sclerosis". Ann. Neurol. 67 (3): 286–90. doi:10.1002/ana.22001. PMID 20373339. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e f Zamboni P, Galeotti R, Menegatti E; et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e Zamboni P, Galeotti R, Menegatti E; et al. (December 2009). "A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency". J. Vasc. Surg. 50 (6): 1348–58.e1–3. doi:10.1016/j.jvs.2009.07.096. PMID 19958985. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ Rossini, F (2009-09-08). "Venous Function And Multiple Sclerosis" (doc). Fondazione Hilarescere. Retrieved 2009-12-03.
  5. ^ Lee BB, Bergan J, Gloviczki P; et al. (December 2009). "Diagnosis and treatment of venous malformations Consensus Document of the International Union of Phlebology (IUP)-2009". Int Angiol. 28 (6): 434–51. PMID 20087280. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b Al-Omari MH, Rousan LA (April 2010). "Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis". Int Angiol. 29 (2): 115–20. PMID 20351667.
  7. ^ a b Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R (April 2010). "["Chronic cerebrospinal venous insufficiency" and multiple sclerosis : Critical analysis and first observation in an unselected cohort of MS patients.]". Nervenarzt. doi:10.1007/s00115-010-2972-1. PMID 20386873.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Doepp F, Paul F, Valdueza J.M, Schmierer K, Schreiber S.J (11 June 2010). "No cerebro-cervical venous congestion in patients with multiple sclerosis". Annals of Neurology. doi:10.1002/ana.22085.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Lee AB, Laredo J, Neville R (April 2010). "Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency" (PDF). Int Angiol. 29 (2): 95–108. PMID 20351665.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Simka M (May 2009). "Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis". Curr Neurovasc Res. 6 (2): 132–9. PMID 19442163.
  11. ^ a b Singh AV, Zamboni P (December 2009). "Anomalous venous blood flow and iron deposition in multiple sclerosis". J. Cereb. Blood Flow Metab. 29 (12): 1867–78. doi:10.1038/jcbfm.2009.180. PMID 19724286.
  12. ^ Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, Salvi F, Gemmati D, Liboni A, Zamboni P (2010 April 28). "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. doi:10.1186/1471-2350-11-64. PMC 2880319. PMID 20426824. {{cite journal}}: Check date values in: |year= and |date= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) (primary source)
  13. ^ Franceschi C (April 2009). "The unsolved puzzle of multiple sclerosis and venous function". J Neurol Neurosurg Psychiatr. 80 (4): 358. doi:10.1136/jnnp.2008.168179. PMID 19289474.
  14. ^ Zamboni P (November 2006). "The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis". J R Soc Med. 99 (11): 589–93. doi:10.1258/jrsm.99.11.589. PMC 1633548. PMID 17082306.
  15. ^ Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P (2010 Apr). "Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study". Int Angiol. 29 (2): 176–82. PMID 20351673. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link) (primary source)
  16. ^ Simka M, Kostecki J, Zaniewski M, Majewski E, Hartel M (April 2010). "Extracranial Doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis". Int Angiol. 29 (2): 109–14. PMID 20351666.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Hojnacki D, Zamboni P, Lopez-Soriano A; et al. (April 2010). "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. 29 (2): 127–39. PMID 20351669. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  18. ^ a b Laino, Charlene (2010-06-17). "New Theory on CCSVI and MS Needs Further Study, Experts Say". Neurology Today. Retrieved 2010-06-17.
  19. ^ a b c "Experimental multiple sclerosis vascular shunting procedure halted at Stanford". Ann. Neurol. 67 (1): A13–5. January 2010. doi:10.1002/ana.21969. PMID 20186848.
  20. ^ Siri Agrell (29 April 2010). "Legal fears thwart doctor's bid for 'liberation' from MS pain". The Globe and Mail. Retrieved 2010-06-26.
  21. ^ Picard, A (2009-11-23). "MS group to fund research into 'liberation procedure'". The Globe and Mail. Retrieved 2009-12-29.
  22. ^ "Nieuwe theorie oorzaak multiple sclerose niet bevestigd". Amsterdam: VU Medical Center. 2010-06-17. Retrieved 2010-06-17. {{cite news}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  23. ^ Murray, Terry (5 May 2010). "Zamboni's MS theory on thin ice". The Medical Post. 46 (8): 1, 6–7.
  24. ^ Susan Jeffrey (2009-12-03). "Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May Provide Benefit in MS". Medscape. Retrieved 2010-01-27.
  25. ^ Qiu J (2010). "Venous abnormalities and multiple sclerosis: another breakthrough claim?". Lancet Neurol. 9 (5): 464–5. doi:10.1016/S1474-4422(10)70098-3. PMID 20398855. {{cite journal}}: Unknown parameter |month= ignored (help)

External links

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