Chronic cerebrospinal venous insufficiency
Encyclopedia
Chronic cerebrospinal venous insufficiency (CCSVI or CCVI) is a term developed by Italian
researcher Paolo Zamboni
in 2008 to describe compromised flow of blood
in the vein
s draining the central nervous system
. Zamboni hypothesized that it played a role in the cause of multiple sclerosis
(MS).
Zamboni also devised a procedure (Zamboni liberation procedure or Zamboni liberation therapy) involving angioplasty
(or stenting) of certain veins in an attempt to improve blood flow.
Within the medical community, both the procedure and CCSVI itself have been met with skepticism. Zamboni's first published research was neither blinded nor did it have a comparison group
. Research on CCSVI has been fast tracked
but have been unable to confirm whether CCSVI has a role in causing MS. The "liberation procedure" has been criticized for possibly resulting in serious complications and deaths while its benefits have not been proven. This has raised serious objections to the hypothesis
of CCSVI originating multiple sclerosis. Additional research efforts investigating the CCSVI hypothesis are underway.
, delayed perfusion
, reduced drainage of catabolites, increased transmural pressure
, and iron
deposits around the cerebral veins
. Multiple sclerosis
has been proposed as the main outcome of CCSVI.
and IJV veins
are stenotic in around 90% of the cases. Zamboni theorized that malformed blood vessels cause increased deposition of iron in the brain, which in turn triggers autoimmunity
and degeneration of the nerve's myelin sheath
. 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. In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did. Such outstanding results have raised suspicions on a possible spectrum bias
, which originates on a diagnostic test not being used under clinically significant conditions.
In 2010 and 2011 further studies of the relationship between CCSVI and MS have had variable results.
As of September 2010 there were a growing number of papers that raise serious questions about its (CCSVI) validity", although evidence had been "both for and against the controversial hypothesis". It has been agreed that it is urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS, while existing data does not support CCSVI as the cause of MS. A randomised controlled study of 499 patients confirmed twice as big prevalence of CCSVI in MS patients in comparison with healthy controls, but this prevalence was also increased, to a lesser extent, in patients with other neurological diseases. If there is a relationship between CCSVI and MS it is expected to be a complex one.
s. The innominate vein and superior vena cava
have also been reported to contribute to CCSVI. A vascular
component in MS had been cited previously.
Several characteristics of venous diseases make it difficult to include MS in such group. In its current form, CCSVI cannot explain some of the epidemiological
findings in MS. These include risk factors such as epstein-barr infection, parental ancestry, the day of birth and geographic location. MS is also more common in women, while venous diseases are more common in men. Venous pathology is commonly associated to hypertension
, infarcts, edema
and transient ischemia
, and occur more often with age, however they are hardly ever seen in MS and the disease is rare to appear after age 50. Finally, an organ-specific immune response is not seen in any other kind of venous disease.
study and criticism as other researchers found normal ferritin
levels in the cerebrospinal fluid
of MS patients. Additionally iron deposition occurs in different neurological diseases such as Alzheimer's disease
or Parkinson's disease
that are not associated with CCSVI. Evidence linking CCSVI and iron deposition is lacking, and dysregulation of iron metabolism
in MS is more complex than simply iron accumulation in the brain tissue.
focus. 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
. A study in 268 MS patients and 155 controls reported more than twice higher frequency of CCSVI in the MS group vs the controls group and also higher in the progressive MS group vs in the non-progressive MS group. This study found no relationship between CCSVI and HLA DRB1*1501
, a genetic variation that has been consistently linked to MS.
CCSVI was first found using specialized extracranial and transcranial
doppler sonography. 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:
It is still not clear whether magnetic resonance venography
, venous angiography, or Doppler sonography should be considered as the gold standard for the diagnosis of CCSVI. Use of magnetic resonance venography for the diagnosis of CCSVI in MS patients has been proposed by some to have limited value, and to be used only in combination with other techniques. Others have stated that magnetic resonance venography has advantages over doppler since results are more operator-independent.
and stent
ing have been proposed as a treatment option for CCSVI in MS. As a form of treatment, outside the trial setting, these procedures are not currently recommended. The proposed treatment has been termed "liberation procedure" though the name has been criticized for suggesting unrealistic results. As of 2011, angioplasty treatment for CCSVI is in phase III trials.
Angioplasty in a preliminary study by Zamboni improved symptoms in MS. High re-stenosing rates led authors of Zamboni's pilot study to propose that the use of stent
s might be a better treatment than balloons angioplasty, while later they stated that stents should not be used.
Further trials however are required to determine if the benefits, if any, of the procedure outweigh its risks. 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, The Society of Interventional Radiology in USA and Canada considers that published literature on the effectiveness of CCSVI intervention is inconclusive and support decisions made by patients, families and physicians to perform angioplasty in such cases. The Cardiovascular and Interventional Radiological Society of Europe
(CIRSE) position is that procedures for CCSVI should not be offered outside well designed clinical trials as harm could be caused.
Kuwait has become the first country in the world where it is explicitly allowed by the medical authorities and paid by the state health system. The procedure is being performed privately in 40 countries. It is not available in Canada as of September 2010.
, stent migration into the heart and jugular vein thrombosis
. Two cases with severe adverse events have been reported in the scientific literature; a death due to a cerebral hemorrhage while on anticoagulant following a stent insertion, and a migration of a stent to the heart's ventricle. Some United States hospitals have banned the surgical procedure outside of clinical trials until more evidence to support its use is available.
In 2010 Stanford University
halted CCSVI treatments after two serious incidents. Dr Jeffrey Dunn, associate director of Stanford’s MS centre, called on other neurologists to speak out about the potential "dangers" of the unproven procedure: "If I can do anything to protect MS patients from the potentially devastating effects of false hopes or the risks of invasive and unproven treatment, I am happy to do so".
Two Canadians have died after undergoing CCSVI treatment abroad.
was able to produce similar lesions in dogs blocking their veins
The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. According to Zamboni, CCSVI had a high sensitivity and specificity
differentiating healthy individuals from those with multiple sclerosis
. Zamboni's results were criticized as his study was not blinded and they need to be verified by further studies. 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.
The first international symposium took place in 2009, at Bologna
. Venous stenosis
due to developmental abnormalities was established as the primary cause of CCSVI by the International Union of Phlebology of which Zamboni is a member.
Another international conference was held in Glasgow
on October 2010.
Social media coverage has been perceived by some as "hype", with exaggerated claims that have led to excessive expectations. This has been partially attributed to some of the same investigators of the theory. Social media have also been accused of creating a division between CCSVI supporters and those who say it does not work, while a positive effect of the important media coverage may be that it forces the world of medical research to be self-critical and give appropriate responses to the questions that globalization of the theory raises, specially among MS sufferers.
Many patients who have had the surgical procedure show their improvements on social media websites such as YouTube. Such stories are anecdotal evidence
of efficacy. It has been pointed out that those who have had a positive result are more prone to post their case than those who had little or no improvement, and the reported improvements in patients' condition can be attributed to the placebo
effect. Patients' reasons for not publishing negative results may include embarrassment about the money spent in the procedure without effect, or the negative reaction they expect from other people with MS. Caution has been recommended regarding patients' self-reports found on the web.
In 2009, the Multiple Sclerosis Society of Canada
committed to funding research on the connection between CCSVI and MS, although later in 2010 it has come under criticism for opposing clinical trials of CCSVI therapy. The MS Society of Canada in September 2010 reserved one million dollars toward CCSVI research "when a therapeutic trial is warranted and approved."
At a political level there have been contradictory positions, with some provinces funding trials, others stating that since therapy is unproven they should wait, and others urging for a pan-Canadian trial. Canadian Institutes of Health Research
, the federal agency responsible for funding health research, has recommended against funding 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. The health minister accepted the CIHR recommendation and has said that Canada will not fund a clinical trial at this time.
Debate was further fueled by a report in the media that a former researcher in Saskatchewan proposed investigating a link between blood flow to the brain and MS in 1998.
randomised
trial which should be monitored by an independent organization.
In June 2011, the Canadian federal government announced that they will fund clinical trials of Dr Zamboni's procedure to widen the veins after a panel of scientific experts unanimously agreed that there is enough evidence to warrant the trial.
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
researcher Paolo Zamboni
Paolo Zamboni
Paolo Zamboni is an Italian doctor and vascular surgeon who found in a preliminary study that in over 90% of the participants afflicted with Multiple sclerosis there were several problems in veins draining their brain, like stenosis or defective valves...
in 2008 to describe compromised flow of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
in the vein
Vein
In the circulatory system, veins are blood vessels that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart...
s draining the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Zamboni hypothesized that it played a role in the cause of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(MS).
Zamboni also devised a procedure (Zamboni liberation procedure or Zamboni liberation therapy) involving angioplasty
Angioplasty
Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel, the latter typically being a result of atherosclerosis. An empty and collapsed balloon on a guide wire, known as a balloon catheter, is passed into the narrowed locations and then inflated to a fixed size...
(or stenting) of certain veins in an attempt to improve blood flow.
Within the medical community, both the procedure and CCSVI itself have been met with skepticism. Zamboni's first published research was neither blinded nor did it have a comparison group
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...
. Research on CCSVI has been fast tracked
Fast Track
Fast Track is an informal English phrase meaning "the quickest and most direct route to achievement of a goal, as in competing for professional advancement".Fast Track may also refer to:* Fast Track, a FoxBusiness.com show hosted by Anna Gilligan...
but have been unable to confirm whether CCSVI has a role in causing MS. The "liberation procedure" has been criticized for possibly resulting in serious complications and deaths while its benefits have not been proven. This has raised serious objections to the hypothesis
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
of CCSVI originating multiple sclerosis. Additional research efforts investigating the CCSVI hypothesis are underway.
Consequences
Proposed consequences of CCSVI syndrome include intracranial hypoxiaHypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, delayed perfusion
Perfusion
In physiology, perfusion is the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue. The word is derived from the French verb "perfuser" meaning to "pour over or through."...
, reduced drainage of catabolites, increased transmural pressure
Transmural pressure
Transmural pressure is the difference in pressure between two sides of a wall or equivalent separator.*For body vasculature or other hollow organs, see Smooth muscle#Contraction and relaxation basics*For lungs, see Transpulmonary pressure...
, and iron
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
deposits around the cerebral veins
Cerebral veins
The cerebral veins are divisible into external and internal groups according to the outer surfaces or the inner parts of the hemispheres they drain into....
. Multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
has been proposed as the main outcome of CCSVI.
Pathophysiology
Zamboni and colleagues claimed that in MS patients diagnosed with CCSVI, the azygosAzygos
In anatomy, azygos, from the Greek άζυξ, refers to a structure that is unpaired. This is relatively unusual, as most elements of anatomy reflect bilateral symmetry. Another term for the same concept is impar....
and IJV veins
Internal jugular vein
The two internal jugular veins collect the blood from the brain, the superficial parts of the face, and the neck.-Path:On both sides and at the base of the brain, the inferior petrosal sinus and the sigmoid sinus join to form the internal jugular vein...
are stenotic in around 90% of the cases. Zamboni theorized that malformed blood vessels cause increased deposition of iron in the brain, which in turn triggers autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
and degeneration of the nerve's myelin sheath
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
. 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. In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did. Such outstanding results have raised suspicions on a possible spectrum bias
Spectrum bias
Initially identified in 1978, spectrum bias refers to the phenomenon that the performance of a diagnostic test may change between different clinical settings owing to changes in the patient case-mix thereby affecting the transferability of study results in clinical practice...
, which originates on a diagnostic test not being used under clinically significant conditions.
In 2010 and 2011 further studies of the relationship between CCSVI and MS have had variable results.
As of September 2010 there were a growing number of papers that raise serious questions about its (CCSVI) validity", although evidence had been "both for and against the controversial hypothesis". It has been agreed that it is urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS, while existing data does not support CCSVI as the cause of MS. A randomised controlled study of 499 patients confirmed twice as big prevalence of CCSVI in MS patients in comparison with healthy controls, but this prevalence was also increased, to a lesser extent, in patients with other neurological diseases. If there is a relationship between CCSVI and MS it is expected to be a complex one.
Venous malformations
Most of the venous problems in MS patients have been reported to be truncular venous malformations, including azygous stenosis, defective jugular valves and jugular vein aneurysmAneurysm
An aneurysm or aneurism is a localized, blood-filled balloon-like bulge in the wall of a blood vessel. Aneurysms can commonly occur in arteries at the base of the brain and an aortic aneurysm occurs in the main artery carrying blood from the left ventricle of the heart...
s. The innominate vein and superior vena cava
Superior vena cava
The superior vena cava is truly superior, a large diameter, yet short, vein that carries deoxygenated blood from the upper half of the body to the heart's right atrium...
have also been reported to contribute to CCSVI. A vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
component in MS had been cited previously.
Several characteristics of venous diseases make it difficult to include MS in such group. In its current form, CCSVI cannot explain some of the epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
findings in MS. These include risk factors such as epstein-barr infection, parental ancestry, the day of birth and geographic location. MS is also more common in women, while venous diseases are more common in men. Venous pathology is commonly associated to hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, infarcts, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and transient ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, and occur more often with age, however they are hardly ever seen in MS and the disease is rare to appear after age 50. Finally, an organ-specific immune response is not seen in any other kind of venous disease.
Iron deposits
Iron deposition as a cause of MS received support when a relation between venous pressure and iron depositions in MS patients was found in a neuroimagingNeuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
study and criticism as other researchers found normal ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...
levels in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
of MS patients. Additionally iron deposition occurs in different neurological diseases such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
or Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
that are not associated with CCSVI. Evidence linking CCSVI and iron deposition is lacking, and dysregulation of iron metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in MS is more complex than simply iron accumulation in the brain tissue.
Genetics
A small genetic study looked at fifteen MS patients who also had CCSVI. It found 234 specific copy number variations in the human leucocitar antigenHLA
-Biochemistry:*Human leukocyte antigen, a key part of the human immune system, or the paternity test based upon it*Hyaluronic Acid, an important molecule that plays a role throughout the body's skin and connective tissues.-Computing:...
focus. Of these, GRB2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, HSPA1L
HSPA1L
Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene.-Further reading:...
and HSPA1A
HSPA1A
Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....
were found to be specifically connected to both MS and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, TAF11
TAF11
Transcription initiation factor TFIID subunit 11 is a protein that in humans is encoded by the TAF11 gene.-Interactions:TAF11 has been shown to interact with TAF15, TAF13, TATA binding protein, GTF2F1, POLR2A and Transcription Factor II B....
was connected to both MS and artery passage, and HLA-DQA2
HLA-DQA2
HLA class II histocompatibility antigen, DQ alpha chain is a protein that in humans is encoded by the HLA-DQA2 gene. Also known as HLA-DXA or DAAP-381D23.2, it is part of the human leucocyte antigen system....
was suggestive of having an implication for angiogenesis as it interacts with CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
. A study in 268 MS patients and 155 controls reported more than twice higher frequency of CCSVI in the MS group vs the controls group and also higher in the progressive MS group vs in the non-progressive MS group. This study found no relationship between CCSVI and HLA DRB1*1501
HLA-DRB1
HLA class II histocompatibility antigen, DRB1-9 beta chain is a protein that in humans is encoded by the HLA-DRB1 gene. DRB1 encodes the most prevalent beta subunit of HLA-DR.- Function :...
, a genetic variation that has been consistently linked to MS.
Diagnosis
Transcranial doppler
Transcranial Doppler is a test that measures the velocity of blood flow through the brain's blood vessels. Used to help in the diagnosis of emboli, stenosis, vasospasm from a subarachnoid hemorrhage , and other problems, this relatively quick and inexpensive test is growing in popularity in the...
doppler sonography. Five ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
criteria of venous drainage have been proposed to be characteristic of the syndrome, although having two of them is enough for diagnosis of CCSVI:
- reflux in the internal jugular and vertebral veins,
- reflux in the deep cerebral veinsCerebral veinsThe cerebral veins are divisible into external and internal groups according to the outer surfaces or the inner parts of the hemispheres they drain into....
, - 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.
It is still not clear whether magnetic resonance venography
Magnetic Resonance Angiography
Magnetic resonance angiography is a group of techniques based on Magnetic Resonance Imaging to image blood vessels. Magnetic resonance angiography is used to generate images of the arteries in order to evaluate them for stenosis , occlusion or aneurysms...
, venous angiography, or Doppler sonography should be considered as the gold standard for the diagnosis of CCSVI. Use of magnetic resonance venography for the diagnosis of CCSVI in MS patients has been proposed by some to have limited value, and to be used only in combination with other techniques. Others have stated that magnetic resonance venography has advantages over doppler since results are more operator-independent.
Treatment
Balloon angioplastyAngioplasty
Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel, the latter typically being a result of atherosclerosis. An empty and collapsed balloon on a guide wire, known as a balloon catheter, is passed into the narrowed locations and then inflated to a fixed size...
and stent
Stent
In the technical vocabulary of medicine, a stent is an artificial 'tube' inserted into a natural passage/conduit in the body to prevent, or counteract, a disease-induced, localized flow constriction. The term may also refer to a tube used to temporarily hold such a natural conduit open to allow...
ing have been proposed as a treatment option for CCSVI in MS. As a form of treatment, outside the trial setting, these procedures are not currently recommended. The proposed treatment has been termed "liberation procedure" though the name has been criticized for suggesting unrealistic results. As of 2011, angioplasty treatment for CCSVI is in phase III trials.
Angioplasty in a preliminary study by Zamboni improved symptoms in MS. High re-stenosing rates led authors of Zamboni's pilot study to propose that the use of stent
Stent
In the technical vocabulary of medicine, a stent is an artificial 'tube' inserted into a natural passage/conduit in the body to prevent, or counteract, a disease-induced, localized flow constriction. The term may also refer to a tube used to temporarily hold such a natural conduit open to allow...
s might be a better treatment than balloons angioplasty, while later they stated that stents should not be used.
Further trials however are required to determine if the benefits, if any, of the procedure outweigh its risks. The neurological community and many MS organizations such as the National Multiple Sclerosis Society
National Multiple Sclerosis Society
The National Multiple Sclerosis Society, a United States-based non-profit organization, and its network of chapters nationwide promote research, educate, advocate on issues relating to multiple sclerosis, and organize a wide range of programs, including support for the newly diagnosed and those...
of the USA recommend not to use the proposed treatment until its effectiveness is confirmed by controlled studies, The Society of Interventional Radiology in USA and Canada considers that published literature on the effectiveness of CCSVI intervention is inconclusive and support decisions made by patients, families and physicians to perform angioplasty in such cases. The Cardiovascular and Interventional Radiological Society of Europe
Cardiovascular and Interventional Radiological Society of Europe
The Cardiovascular and Interventional Radiological Society of Europe is a professional body comprising interventional radiologists from Europe and overseas. The society has its headquarters in Vienna, Austria and was founded in 1985. It currently has approximately 4,200 members from around the...
(CIRSE) position is that procedures for CCSVI should not be offered outside well designed clinical trials as harm could be caused.
Kuwait has become the first country in the world where it is explicitly allowed by the medical authorities and paid by the state health system. The procedure is being performed privately in 40 countries. It is not available in Canada as of September 2010.
Adverse effects
While the procedure has been reported to be in general safe for MS patients, severe complications related to the angioplasty and stenting include intracranial hemorrhageIntracranial hemorrhage
An intracranial hemorrhage is a hemorrhage, or bleeding, within the skull.-Causes:Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks. It can result from physical trauma or nontraumatic causes such as a ruptured aneurysm...
, stent migration into the heart and jugular vein thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. Two cases with severe adverse events have been reported in the scientific literature; a death due to a cerebral hemorrhage while on anticoagulant following a stent insertion, and a migration of a stent to the heart's ventricle. Some United States hospitals have banned the surgical procedure outside of clinical trials until more evidence to support its use is available.
In 2010 Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...
halted CCSVI treatments after two serious incidents. Dr Jeffrey Dunn, associate director of Stanford’s MS centre, called on other neurologists to speak out about the potential "dangers" of the unproven procedure: "If I can do anything to protect MS patients from the potentially devastating effects of false hopes or the risks of invasive and unproven treatment, I am happy to do so".
Two Canadians have died after undergoing CCSVI treatment abroad.
History
Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins. Later, in 1935, Tracy PutnamTracy Putnam
Tracy Jackson Putnam was the co-discoverer, together with H. Houston Merritt, of Dilantin for controlling epilepsy.He graduated from Harvard College in 1915. Later from Harvard medical school in 1920. He worked by the Boston City Hospital and in the New York Neurological Institute at Columbia...
was able to produce similar lesions in dogs blocking their veins
The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. According to Zamboni, CCSVI had a high sensitivity and specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
differentiating healthy individuals from those with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Zamboni's results were criticized as his study was not blinded and they need to be verified by further studies. 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.
The first international symposium took place in 2009, at Bologna
Bologna
Bologna is the capital city of Emilia-Romagna, in the Po Valley of Northern Italy. The city lies between the Po River and the Apennine Mountains, more specifically, between the Reno River and the Savena River. Bologna is a lively and cosmopolitan Italian college city, with spectacular history,...
. Venous stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
due to developmental abnormalities was established as the primary cause of CCSVI by the International Union of Phlebology of which Zamboni is a member.
Another international conference was held in Glasgow
Glasgow
Glasgow is the largest city in Scotland and third most populous in the United Kingdom. The city is situated on the River Clyde in the country's west central lowlands...
on October 2010.
Society and culture
The hypothesis has generated optimism from people with MS for more effective treatment options.Media
CCSVI has received a lot of attention in all media, scientific literature and internet. People with MS often read extensively on the CCSVI theory and its development on internet sites, and a search for "liberation procedure" in Google yielded as of August 2010 more than 2.5 million hits. Internet has also been used to make commercial advertisement of places where stenting for CCSVI is performed.Social media coverage has been perceived by some as "hype", with exaggerated claims that have led to excessive expectations. This has been partially attributed to some of the same investigators of the theory. Social media have also been accused of creating a division between CCSVI supporters and those who say it does not work, while a positive effect of the important media coverage may be that it forces the world of medical research to be self-critical and give appropriate responses to the questions that globalization of the theory raises, specially among MS sufferers.
Many patients who have had the surgical procedure show their improvements on social media websites such as YouTube. Such stories are anecdotal evidence
Anecdotal evidence
The expression anecdotal evidence refers to evidence from anecdotes. Because of the small sample, there is a larger chance that it may be true but unreliable due to cherry-picked or otherwise unrepresentative of typical cases....
of efficacy. It has been pointed out that those who have had a positive result are more prone to post their case than those who had little or no improvement, and the reported improvements in patients' condition can be attributed to the placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
effect. Patients' reasons for not publishing negative results may include embarrassment about the money spent in the procedure without effect, or the negative reaction they expect from other people with MS. Caution has been recommended regarding patients' self-reports found on the web.
Research funding in Canada
Debate has been heated regarding funding of CCSVI research in Canada.In 2009, the Multiple Sclerosis Society of Canada
Multiple Sclerosis Society of Canada
Founded in 1948, the Multiple Sclerosis Society of Canada promotes multiple sclerosis research and provides education and services to people with MS and their families and caregivers...
committed to funding research on the connection between CCSVI and MS, although later in 2010 it has come under criticism for opposing clinical trials of CCSVI therapy. The MS Society of Canada in September 2010 reserved one million dollars toward CCSVI research "when a therapeutic trial is warranted and approved."
At a political level there have been contradictory positions, with some provinces funding trials, others stating that since therapy is unproven they should wait, and others urging for a pan-Canadian trial. Canadian Institutes of Health Research
Canadian Institutes of Health Research
Canadian Institutes of Health Research is the major federal agency responsible for funding health research in Canada. It is the successor to the Medical Research Council of Canada. It aims to create new health knowledge, and to translate that knowledge from the research setting into real world...
, the federal agency responsible for funding health research, has recommended against funding 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. The health minister accepted the CIHR recommendation and has said that Canada will not fund a clinical trial at this time.
Debate was further fueled by a report in the media that a former researcher in Saskatchewan proposed investigating a link between blood flow to the brain and MS in 1998.
Research directions
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 CCSVI was found in 62% of MS patients, it was also found in 26% of healthy controls and 45% of participants with other neurological disorders. The US and Canadian MS societies have launched seven studies aiming to clarify the relationship between MS and CCSVI. The CIRSE has stated that treatment research should begin by a small, placebo-controlled, prospectiveProspective
Prospective literally means "looking forward". It can also refer to an event that is likely or expected to happen in the future. For example, a prospective student is someone who is considering attending a school — typically a high school student who is seriously considering applying to a...
randomised
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
trial which should be monitored by an independent organization.
In June 2011, the Canadian federal government announced that they will fund clinical trials of Dr Zamboni's procedure to widen the veins after a panel of scientific experts unanimously agreed that there is enough evidence to warrant the trial.
See also
- Chronic venous insufficiencyChronic venous insufficiencyChronic venous insufficiency or CVI is a medical condition where the veins cannot pump enough oxygen-poor blood back to the heart. It is sometimes referred to as an "impaired musculovenous pump", this is due to damaged or "incompetent" valves as may occur after deep vein thrombosis or phlebitis...
- Pathophysiology of multiple sclerosis
- Vascular myelopathyVascular myelopathyVascular myelopathy refers to an abnormality of the spinal cord in regards to its blood supply. The blood supply is complicated and supplied by two major vessel groups: the posterior spinal arteries and the anterior spinal arteries—of which the Artery of Adamkiewicz is the largest...
Further reading
- Rhodes, Marie A. (Author), Haacke, Mark E. (Foreword), Moore, Elaine A. (Series Editor, McFarland Health Topics) "CCSVI as the Cause of Multiple Sclerosis: The Science Behind the Controversial Theory"