Chronic cerebrospinal venous insufficiency

From Self-sufficiency
Jump to: navigation, search
Chronic cerebrospinal venous insufficiency
Classification and external resources
File:Venenwinkel.png
Veins of the neck. Please note v.jugularis interna (that is stenosed or have a malformed valve that leads to CCSVI) and smaller veins that provide collateral circulation (they are visible in patients with CCSVI on the MRV investigation)
ICD-10 I87.8
MeSH D014689

Chronic cerebro-spinal venous insufficiency (CCSVI) is a proposed syndrome, in which the flow of blood in the veins draining the central nervous system is compromised leading to multiple sclerosis (MS).[1][2] This hypothesis was first put forth by Paolo Zamboni in 2008.[3][4] An endovascular intervention for the syndrome has been proposed however further research is required to determine if the benefits out weight the risks of the procedure.

The hypothesis has generated optimism among people with MS but has received skepticism by the majority of medical community as the procedure may lead to serious complications while its benefit has not been proven.[5][6] Zamboni's research was neither blinded nor controlled[5] and a later study found similar distribution of venous reflux in both patients with multiple sclerosis and normal controls.[7] Another study failed to replicate the abnormalities found by Zamboni.[8] Research efforts are underway to clarify the CCSVI hypothesis.

Consequences

Proposed consequences of these theories include: intracranial hypoxia, delayed perfusion, reduced drainage of the catabolites and increased transmural pressure,[9] and iron deposits around the cerebral veins.[10][11]

Multiple sclerosis has been proposed as the main outcome of CCSVI. Additionally, fatigue that MS patients suffer could be a direct consequence of CCSVI, rather than a consequence of the lesions.[12] A vascular component in MS had been cited previously.[13][14]

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.[15]

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.[3][16]

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.[10][16] 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.[3][16]

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.[17]

Diagnosis

File:Doppler ultrasound analyzer of blood velocity.jpg
Computer-enhanced transcranial doppler.

CCSVI was first found using specialized extracranial and transcranial doppler sonography.[3][16] Five ultrasound criteria of venous drainage have been proposed to be characteristic of the syndrome, although having two of them is enough for diagnosis of CCSVI:[3][16][18]

  • reflux in the internal jugular and vertebral veins,
  • reflux in the deep cerebral veins,
  • high-resolution B-mode ultrasound evidence of stenosis of the internal jugular vein,
  • absence of flow in the internal jugular or vertebral veins on Doppler ultrasound, 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.[19]

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.[16] In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did.[3][16] Such outstanding results have raised suspicions on a possible spectrum bias, which originates on a diagnostic test not being used under clinically significant conditions.[16]

Conflicting results

Several studies have further studied the relationship between CCSVI and MS with conflicting results. Studies have found CCSVI to only occur in 20% of MS patients,[20] that none of the studied subjects fulfilled the criteria for CCSVI,[8] or that there were no differences between patients and controls.[7] A study found that 92% of the MS patients showed abnormal findings and 84% of them showed evidence of CCSVI, but only 24% of controls showed abnormal findings and none of them showed evidence of CCSVI.[21]

Treatment

Balloon angioplasty has been proposed as a treatment option for MS.[16] Further trials however are required to determine if the benefits of the procedure outweigh its risks.[16] As a form of treatment, outside the trial setting, these procedures are not currently recommended.[1]

History

File:Paolo Zamboni.jpg
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. According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis;[3][16] a more detailed evidence of a correlation between the place and type of venous malformations imaged and the reported symptoms of multiple sclerosis in the same patients was published in 2010.[4]

The first international symposium took place in 2009, at Bologna, Italy.[22] Venous stenosis due to developmental abnormalities was established as the primary cause of CCSVI by the International Union of Phlebology.[23]

In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.[7][8][20][21]

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.[24]

The neurological 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,[5][6][16][25] while interventional radiologists in USA and Canada support its use with caution:

At present, SIR (Society of Interventional Radiology) considers the published literature to be inconclusive on whether CCSVI is a clinically important factor in the development and/or progression of MS, and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS. ... use of any treatment (antiinflammatory, immunomodulatory, interventional, or other) in patients with MS should be based on an individualized assessment of the patient’s disease status, his/her tolerance of previous therapies, the particular treatment’s scientific plausibility, and the strength and methodologic quality of its supporting clinical evidence. When conclusive evidence is lacking, SIR believes that these often difficult decisions are best made by individual patients, their families, and their physicians.[26]

Media coverage of the theory has been perceived by some in the scientific community as out of proportion, with exaggerated claims that have led to excessive expectations in people with MS. This has been partially attributed to some of the same investigators of the theory.[5]

Research

File:Balloon-catherter.png
Diagram of a balloon catheter
File:Stent4 fcm.jpg
Stents for peripheral vessels

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,[16] while they said at a later date that stents should not be used.[27] Rare but serious adverse events have been reported when using stents. In 2009 a patient with a family history of hemorrhagic stroke had stents inserted into both her internal jugular veins and a few days later died of a haemorrhagic stroke that might have been provoked by the anticoagulant medication (warfarin) prescribed after stenting.[6] Another patient had to have open-heart surgery to remove a jugular-vein stent that had come loose and entered the right ventricle.[5][6] Some US hospitals have banned the surgical procedure outside of clinical trials until more evidence to support its use is available.[6][28]

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.[27] 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.[29]

Debate has been heated regarding funding of CCSVI research in Canada. In 2009, the Multiple Sclerosis Society committed to funding research on the connection between CCSVI and MS,[30] although later in 2010 it has come under criticism for actually opposing clinical trials of CCSVI therapy.[31] The MS Society of Canada has since announced 1 million Canadian dollars towards such a clinical trial "when a therapeutic trial is warranted and approved".[32] At a political level there have been contradictory positions, with some provinces funding trials, others stating that since therapy is unproven they should wait,[33][34] and others urging for a pan-Canadian trial.[35] Canadian Institutes of Health Research, the federal agency responsible for funding health research, has recommended that Canada Health not fund a pan-Canadian trial of liberation therapy yet because "There is an overwhelming lack of scientific evidence on the safety and efficacy of the procedure, or even that there is any link between blocked veins and MS." It has suggested a scientific expert working group made up of the principal investigators for the seven MS Society-sponsored studies.[36] The health minister accepted the CIHR recommendation and has said that Canada will not fund a clinical trial at this time.[37] Debate was further fueled by a report in the media that a former researcher at Saskatchewan, proposed investigating a link between blood flow in the brain and MS in 1998.[38][39] The Society of Interventional Radiology (USA), together with the Canadian Interventional Radiology Association in August 2010 issued a positon statement where it supports clinical research on the safety and efficacy of interventional MS therapies.[26]

See also

References

Cite error: Invalid <references> tag; parameter "group" is allowed only.

Use <references />, or <references group="..." />

de:Chronische Cerebro-Spinale Venöse Insuffizienz es:Insuficiencia venosa cerebroespinal crónica it:Insufficienza venosa cronica cerebrospinale nl:Chronische cerebro-spinale veneuze insufficiëntie no:CCSVI pl:Przewlekła mózgowo-rdzeniowa niewydolność żylna ru:Хроническая цереброспинальная венозная недостаточность

fi:CCSVI
  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 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 Freely accessible. PMID 19060024. 
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Experimental multiple sclerosis vascular shunting procedure halted at Stanford". Ann. Neurol. 67 (1): A13–5. January 2010. doi:10.1002/ana.21969. PMID 20186848. 
  7. ↑ 7.0 7.1 7.2 Peter Sundström, A. W. �H. (2010). "Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study". Annals of Neurology. 68 (2): 255–259.  replacement character in |first= at position 7 (help) edit
  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  9. ↑ 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. 
  10. ↑ 10.0 10.1 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. 
  11. ↑ 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 Freely accessible. PMID 17082306. 
  12. ↑ 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.  Check date values in: |date= (help) (primary source)
  13. ↑ 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. doi:10.2174/156720209788185605. PMID 19442163. 
  14. ↑ Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis, PMID 20350978
  15. ↑ 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. 
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 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. 
  17. ↑ Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, Salvi F, Gemmati D, Liboni A, Zamboni P (2010-04-28). "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. 11: 64. doi:10.1186/1471-2350-11-64. PMC 2880319 Freely accessible. PMID 20426824.  Check date values in: |year= (help) (primary source)
  18. ↑ 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. 
  19. ↑ 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. 
  20. ↑ 20.0 20.1 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. 81 (6): 740–6. doi:10.1007/s00115-010-2972-1. PMID 20386873. 
  21. ↑ 21.0 21.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  22. ↑ Rossini, F (2009-09-08). "Venous Function And Multiple Sclerosis" (doc). Fondazione Hilarescere. Retrieved 2009-12-03. 
  23. ↑ 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. 
  24. ↑ Murray, Terry (5 May 2010). "Zamboni's MS theory on thin ice". The Medical Post. 46 (8): 1, 6–7. 
  25. ↑ Susan Jeffrey (2009-12-03). "Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May Provide Benefit in MS". Medscape. Retrieved 2010-01-27. 
  26. ↑ 26.0 26.1 Vedantham, S; Benenati, JF; Kundu, S; Black, CM; Murphy, KJ; Cardella, JF (2010). "Interventional endovascular management of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association". Journal of vascular and interventional radiology : JVIR. 21 (9): 1335–7. doi:10.1016/j.jvir.2010.07.004. PMID 20800776. 
  27. ↑ 27.0 27.1 Laino, Charlene (17 June 2010). "New Theory on CCSVI and MS Needs Further Study, Experts Say". Neurology Today. Retrieved 2010-06-17. 
  28. ↑ Siri Agrell (29 April 2010). "Legal fears thwart doctor's bid for 'liberation' from MS pain". The Globe and Mail. Retrieved 2010-06-26. 
  29. ↑ "Nieuwe theorie oorzaak multiple sclerose niet bevestigd [New theory about cause MS not confirmed]" (Press release). Amsterdam: VU Medical Center. 17 June 2010. http://www.vumc.nl/zorg/nieuws/4259655/. Retrieved 2010-06-17. 
  30. ↑ Picard, A (23 November 2009). "MS group to fund research into 'liberation procedure'". The Globe and Mail. Retrieved 2010-09-05. 
  31. ↑ "MS Society's stand sparks resignation". The Telegram. 1 September 2010. Retrieved 2010-09-05. 
  32. ↑ "MS Society sets aside $1M in case CCSVI patient trial developed and approved". CBC News. 16 September 2010. Retrieved 2010-09-18. 
  33. ↑ Breakenridge R (4 August 2010). "Premiers jump the gun on MS treatment". Calgary Herald. 
  34. ↑ "Premiers to debate MS treatment". CBC News. 2 August 2010. 
  35. ↑ "MS therapy trial urged by Manitoba minister". CBC News. Canadian Press. 16 August 2010. 
  36. ↑ http://www.cihr-irsc.gc.ca/e/42382.html
  37. ↑ http://www.cbc.ca/canada/newfoundland-labrador/story/2010/09/01/ms-ccsvi-liberation-aglukkaq.html
  38. ↑ Juurlink B. H. The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated? PMID 9824835
  39. ↑ "Start MS trials now, says ex-U of S prof". The StarPhoenix. 28 August 2010. Retrieved 2010-09-05. 
Retrieved from "http://ssf.f15ijp.com/wiki/index.php?title=Chronic_cerebrospinal_venous_insufficiency&oldid=39238"