CHRONIC CEREBRO-SPINAL

VENOUS INSUFFICIENCY(CCSVI)

AMEDS CentrumPOLAND

www.ameds.co

CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY…………………………………..3

DIAGNOSIS AND TREATMENT………………..9

TREATMENT RELATED RISKS………………..16

TREATMENT RESULTS………………………...18

SUMMARY……………………………………….25 GLOSSARY………………………………………27

CONTENTS - slide

CCSVI stands for Chronic Cerebrospinal Venous Insufficiency and has been a vital issue in scientific discussions over the last few years.

Recently CCSVI was officially classified as belonging to a group of venous malformations (Congres Union Internationale de Phlebologie, Monte Carlo 2009), and has had its symptoms and methods of treatment described.

CCSVI procedure consists of different pathologies: constrictions, stenosis, mostly located near internal cervical veins (vena jugularis interna) and the azygos vein (vena azygos).

This disease has a positive correlation to multiple sclerosis patients.

CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY

Multiple sclerosis is a demyelinating disease of the central nervous system, characterized by multifocal damage to the nervous tissue and the ever-changing course. There are periods of remission and exacerbations (relapses) with progressive loss of neurons and deterioration of the central nervous system tissue.

In MS, damage to the myelin sheath surrounding the nerve cells occurs, making it impossible to properly transmit nerve impulses along the tracks in the brain and spinal cord. A characteristic feature of the disease is the dissemination of CNS lesions in time and space. There are several subtypes of multiple sclerosis. Primarily progressive form is characterized by a steady neurologic decline, while relapsing-remitting subtype involves unpredictable attacks (relapses) followed by periods of remissions. Initial relapsing-remitting form that begins to have neurologic decline without periods of remission is known as a secondary progressive subtype.

Multiple sclerosis was first described by Jean-Martin Charcot in 1868. The incidence depends on the geographic region and ranges from 2 to 150 per 100 000 population in different countries and specific populations. MS affects mostly young adults, with peak incidence between 20 and 40 years of age. Women tend to get sick more often than men.

Many theories have been proposed to determine the etiology of multiple sclerosis, but so far there is no one underlying cause of multiple sclerosis found. Theory of autoimmune etiology seems to be dominating, although viral, bacterial, and other unknown environmental factors may also play an important role in the development of disease.

Multiple sclerosis

Hypothesis assuming the relationship between vascularabnormalities and MS are known for many years.

First observations in the 19th century – in 1863, Rindfleisch noted cumulation of blood vessels in the center of MS plaques and Charcot observed vascular blockages in MS patients.

  In 1934 T. Putnam suggested a major role of compromised venous

drainage of the brain in forming MS lesions as well as inflammatory changes of the central nervous system.

In 1981 F. A. Schelling proposed venous refluxes as one of the causes of MS.

All those studies led to the introduction of endovascularprocedures in MS patients – called Liberation Treatment, as first proposed by professor Zamboni in 2009.

What is the relation between CCSVI and MS?

Professor Zamboni launched a study to define whether there is a link between CCSVI and MS. With the use of a Doppler

ultrasound, he examined the necks of MS patients and according to data included in his publication, over 80% of

patients with a RR (relapsing - remitting) type, more than 90%

patients with a SP (secondary - progressive) type, and 90% patients with PP (primary - progressive) type meet the criteria for

CCSVI diagnosis and liberation treatment (term proposed by prof. Zamboni). The majority of patients with MS evaluated by the team presented with stenosis, valve malformations and

refluxes.

Dr Paolo Zambonii Drawing on previous experiences with standard coronary angiography procedures, in which

balloons were used to restore patency of blocked coronary arteries and with the cooperation of experienced vascular surgeon Dr Galeotti, they proposed venous angioplasty as a method of CCSVI treatment in MS patients.

Prof. Zamboni’s open labeled angioplasty study involved 65 participants and showed significant improvement in neurologic outcome and patients’ quality of life.

It has opened doors for further research all over the world and the widespread use of endovascular treatment of CCSVI.

The subject still remains open and even controversial, especially the theory that the venous pathology could constitute the primary patomechanism of the autoimmune process.

CCSVI and MS – prof. Zamboni’s research

The real link between CCSVI and MS remains not fully understood; therefore it is crucial that further studies are carried out to determine the exact mechanism and the underlying association. Not every MS patient has his veins blocked, but this correlation is relatively more significant in MS patients group. Maybe endovascular treatment does not cure MS, however it definitely affects its course, improving the state of health and helping to relieve aggravating symptoms.

Even in studies that were not supportive for CCSVI theory, a link between CCSVI and MS duration and severity has been demonstrated. Indeed, there is no certainty around CCSVI and MS but we have proven efficacy and safety of venous angioplasty in treating MS patients. What is more, there are a number of ongoing studies and trials and there are positive statements, recommendations and guidelines from international associations. Vascular component does not play a major role in every case. Still, it is worth trying to restore patency. Improving flow even in insignificant stenosis often turns out to be beneficial in many respects and can really change a patient’s life.

Does every MS patient have CCSVI?

“The existence of CCSVI, its relation to MS and the legitimacy of

performing balloon angioplasty is the source of much controversy among and is dismissed by many neurologists. This state of affairs is the result of the unfamiliarity with CCSVI, the attachment to their theory of immuno-inflammatory disease, as well as the conviction that procedures using stents (which are rarely used) are dangerous. Reports presented at two international symposia devoted to CCSVI in Katowice and Bologna in March 2011 confirm the association of CCSVI with MS. As a result of venous re-canalization after angioplasty, it has been objectively confirmed that the levels of venous oxygen saturation do improve. The reports emphasized the positive influence balloon angioplasty has on the quality of life of patients, on their fatigue levels, bladder disorders, balance disorders, vision problems, sensory problems and, to a lesser degree, mobility issues. Improvement was also noted in cognitive abilities (memory, concentration, attention).”

Professor Jerzy Kotowicz, MD, PhD

The position of neurologists regarding CCSVI

Ultrasound (Doppler and transcranial) The basic method used in the diagnosis of

patients with chronic cerebro-spinal venous insufficiency (CCSVI) is a Doppler ultrasound. It is a safe and completely non-invasive diagnosis of the vascular system.

3D Doppler technology is used to determine the hemodynamic severity of venous insufficiency.

  There were five criteria introduced for the diagnosis

of CCSVI in the Doppler examination. Fulfilling two out of the five criteria confirms the diagnosis.

The following parameters are assessed during diagnosis: The presence of venous stenosis Circulatory disorders and reversed blood flow (reflux) Flow change in extra-cranial veins dependent on body

position The presence of valvular disease

DIAGNOSIS AND TREATMENT

MRI of the brain and neck has two main purposes:

The assessment of brain activity in the context of determining the presence and location of demyelinating lesions, as well as the possible presence of other abnormalities. Evaluation of venous outflow, in particular the jugular and azygos veins. The analysis includes: symmetry of venous outflow, width and patency of the veins, as

well as an assessment of any stenosis or vein modeling caused by adjacent anatomical structures. The examination of the venous system is made using modern techniques with the

use of a contrast agent (which allows for optimum picture clarity): Multi-phase MRI venography as well as a T1-weighted 3D GRE sequence of very high resolution, which guarantees very high quality images.

Magnetic Resonance Imaging (MRI)

The final step in the diagnostic process is a venography, which produces the

most reliable diagnosis of abnormalities in the venous system. It

consists of the administration of a contrast agent into the vein via

a catheter (inserted in either the femoral or subclavian vein). This allows the

most accurate visualization of vascular lesions. This procedure is invasive and therefore entails a risk of complications. Venography precedes any intra-vascular operations. The venography procedure

allows for an exact examination and imaging of the venous system, which provides an excellent

method of verifying and confirming the presence of any abnormalities detected by

Doppler or MRV.

Venography

Venous angioplasty, also known as balloon angioplasty, is the basic method of treatment applied to CCSVI patients.

Venous angioplasty is a procedure performed in order to widen the constricted

vein with the use of a special catheter placed in the vein via percutaneous

access (the catheter is introduced in the groin area, into the femoral vein). A

balloon is then inserted into the constricted vein and inflated with gas, which

enlarges the vessel and restores its patency.

Evidence showed that using cutting balloons may improve the effect of

treatment, decrease the risk of restenosis and reduce the intraoperative trauma

of healthy tissue. For best results balloon with cutting blades is used together

with standard balloon catheters during angioplasty. This technique can also be

beneficial in cases of hardened or calcified occlusion when standard balloons

alone may not be as effective in restoring patency.

In exceptional cases when the narrowing does not expand under the balloon

pressure, or a vein dissection occurs, the balloon angioplasty is supplemented

with the insertion of a stent.

Venous angioplasty

Stenting procedure may require the insertion of one or two stents, depending on whether the stenosis is unilateral or

bilateral.

However according to recent publications and recommendations in CCSVI management, insertion of stents is not recommended as a method of choice and should be used only when there is a

direct indication present.

Stents are difficult to deliver particularly in small and twisted vessels. One should be aware that a stent is a metallic foreign

object placed in the human body, carrying the risk of thrombosis, systemic reactions and restenosis (due to the intimal hyperplasia), not to mention stent migration or major

hemorrhages. Once it has been inserted it cannot be removed or repositioned.

What is more, patient after stent insertion requires prolonged time of receiving anticoagulants and antiplatelet agents, which are associated with various side effects and increase the risk of

bleeding.

Stents - Stenting

Approximately 2% of patients with implanted stents are prone to formation of clots in the place of their location within the vessels. Thrombus may be the cause of embolic complications including

pulmonary embolism and brain stroke.

The risk of forming clots is greatest during the first few months after placing the stent in the vein. For this reason it is recommended to

use antiplatelet drugs such as aspirin or clopidogrel, or other anticoagulants for a period of one month to one year after stent

implantation.

The period, during which patients are supposed to be on anticoagulants, depends on the type of surgery performed, as well as on the type of stent. Taking anticoagulants and antiplatelet agents is linked to a number of side effects and increases the risk of bleeding.

It is difficult to identify the direct cause of stent thrombosis, or to predict its occurrence. It is suspected that in some patients developing this serious problem is a result of the suboptimal

response to anticoagulants. Complex and unpredictable clinical course of stent thrombosis can contribute to many difficulties met in

treating this condition.

pregnancy

lack of patient's voluntary consent for the surgery

a relapse occurring (active demyelinating changes in the MRI)

Absolute contraindications for the CCSVI treatment include:

Angioplasty is a very safe procedure with low rate of complications (1-2%) and rather those of small significance. Most common complications (like small hematomas or swelling at the puncture site or fever) occur in very low percentage of patients. Nevertheless, this is an invasive procedure and as one of such kind may bring some more serious risks like thrombosis, pulmonary embolism or hemorrhage. Those happen extremely rare (and in most cases do not put patient in danger) but need to be pointed out.

Worldwide, there have been reports on major complications like cerebral hemorrhage (2 cases) and stent migration (2-3 cases) but it happened over 20 000 procedures done and involved only stent implantation cases.

Any method of medical treatment is an intrusion in the functioning of human organism and therefore may be producing, apart from the therapeutic result, also undesirable side effects. Surgical intervention is a unique form of intrusion. It involves tissue incision, removal of organs or their parts, anatomical structure alterations, etc. No matter how beneficial it could be for regaining one’s health, it incurs a certain risk of complications occurring either during or after the surgery.

TREATMENT RELATED RISKS

Complications, which may occur during the surgery, include: bleeding that leads to a significant loss of blood; pressure drop; disorder of blood supply to vital organs and blood clotting disturbances; accidental injury to anatomical organs and structures caused by their abnormal position or by inflammatory or neoplastic infiltration; heart action disorder (arrhythmia, cardiac infarction) and central nervous system disorder (apoplexy) in patients suffering from cardiovascular system diseases.

Complications which may occur after the surgery include: bleeding from the wound; intramural or internal hematoma; wound infection; intramural purulence; arteriovenous fistulas; pulmonary complications / atelectasis; inflammation; pleural exudates; thrombotic inflammation of veins; pulmonary embolism; dysuria; urinary tract infection; renal insufficiency; circulatory insufficiency; respiratory insufficiency; consciousness disorders (mainly in elderly persons); dissection (rupture) of the vein undergoing angioplasty; cardiac tamponade; perforation of a vessel.Apart from "surgical" complications, complications related to anesthetization, administered medications and to transfusion of blood and blood derivatives (post-transfusion reactions, viral infections) may also occur.

The risk of occurrence any of the complications listed above is usually very small, and depends on the type of surgical procedure carried out and on general condition of the patient. Most complications can be effectively cured, even if by means of another surgical procedure, and cases of fatal complications. are extremely rare.

The positive effects of treatment of MS patients are noticeable both in the objective assessment of the patients’ quality of life as per the MSIS-29 system, as well as in their own assessment.

AMEDS Centrum has treated more than 600 MS patients to 2011, from Poland and abroad, 38% of which have been men. Average age of patients was 46 years. The statistical patient has been diagnosed with MS 11 years ago. The majority of patients suffered from secondary progressive MS.

TREATMENT RESULTS

37%

39%

24%

MS type

Relapsing-remitting

Secondary progressive

Primary progressive

In two thirds of patients with multiple sclerosis, chronic fatigue is a typical accompanying symptom of the disease and always a big problem for the patient. The FSS scale helps in assessing fatigue levels. The scale is from 1 to 7, with higher scores reflecting higher fatigue levels (scores above 5.5 signify severe fatigue). Our patients have been observed to experience a marked improvement in the incidence of fatigue (a reduction of 35% on the FSS scale!) and a dramatic increase in strength and energy.

Fatigue Severity Scale (FSS)

The patients who underwent treatment report a significant improvement of their psychological state and physical condition. A reduction of points within MSIS-29 scale is noted after treatment.

Multiple Sclerosis Impact Scale 29 (MSIS-29) is a proven and reliable scale for measuring the quality of life in patients with MS. The patient answers 29 questions (20 regarding physical state, coordination and mobility and 9 about mental state). After the score is calculated we obtain a result on a scale of 0-100, where the higher the score, the worse the state of health of the patient.

Patients who have undergone treatment display a noticeable improvement in mental and physical health – shown below – with a corresponding reduction of points on the MSIS-29 scale.

Multiple Sclerosis Impact Scale 29 (MSIS-29)

A total of 47 patients suffering from Multiple Sclerosis (MS) with confirmed diagnosis of Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) who underwent endovascular treatment were included in the second study.

The improvement group was dominated by females (69% vs. 31% – males). Three out of four patients in the group with improvement were suffering from

Relapsing-Remitting type of MS.

However, it should be noted that CCSVI treatment is associated with positive results in people suffering from other types of MS as well.

The study also showed that young patients (age below 30) with short disease duration are probably benefiting the most from the treatment.

<30 years

30-40 years

40-50 years

>50 years

0102030405060708090

100

75%

36%

8% 22%

PREVALENCE OF IMPROVEMENT

IN RELATION TO AGE

<5 years

5-10 years

10-15 years

>15 years

0102030405060708090

100

63%

25%

13% 21%

PREVALENCE OF IMPROVEMENT IN

RELATION TO DISEASE DURATION

Characteristics of patients who have had positive results from CCSVI treatment indicate that most beneficial groups are:

females Relapsing-Remitting type of MS at young age with short disease duration with lower baseline EDSS.

After an endovascular surgery and following the discharge from hospital, patients will have to take anticoagulants on the daily basis, according to doctor's orders. How long the patient must remain under anticoagulant treatment depends on the type of surgical procedure and the type of stent used.

A recommended control test should be carried out after 3 and 6 months after the procedure. A control test should include: Doppler ultrasound, magnetic resonance, neurological examination and laboratory tests. Its objective is to test the flow in the previously treated veins.

All patients should undergo Doppler control every 6 months. In case of deterioration of neurological symptoms, a Doppler of the jugular veins should be done ASAP.

Patients should try not to overload physically during the first month after the procedure, but you can still do light exercises. At about four weeks after the procedure you can begin with moderate exercise (i.e. swimming) but it is advised to wait for 3 months with burdensome exercise like jogging, tennis or weightlifting in the gym.

Post-surgical recommendations

Slight elevation of the bed (head side) is recommended.

It is important for the patients to be well hydrated, they should drink at least 1.5 liters of fluid daily.

In order to maximize the benefits from the treatment rehabilitation is recommended strongly. Of course the best rehabilitation programs are the ones especially conceived for MS patients. In case of lack of access to this type of programs benefits can be drawn from swimming pool exercises, if such possibility exists or at least exercises to be performed at home developed for MS patients.

As it is the case with all types of conditions here also the appropriate diet is very important. There are several nutrition programs developed for MS patients, for instance low fat diet rich in vegetables. In light of recent research the most important seems to be to restrict animal fat and saturated fat in the diet. It is worth to use products rich in non-saturated fat (found mainly in fish), fruit and vegetables (rich in vitamins and antioxidants) and other diet components including vitamins E, D or beta-carotene. Of course that quitting smoking and giving up on alcoholic beverages is highly recommended.

We would like you to be aware of the fact that CCSVI treatment should not be perceived as a miracle drug curing multiple sclerosis once and for all. It can solely be treated as a complimentary therapy to other methods. The therapy is helpful in combating the condition and wonderfully complements the treatment methods applied so far, while its effectiveness depends in large degree from the attitude of the patient himself. The treatment brings the greatest benefits among persons who support it with regular physical activity (rehabilitation, physiotherapy), healthy lifestyle and adequate diet (balanced, rich in vitamins, non-saturated fats and omega-3 and omega-6 acids, drinking large amounts of water).

In the reality we are all still at the very beginning of the process of research and understanding of CCSVI and its correlation to MS. We know however – that independent of the temporary lack of results from the official clinical trials – the results achieved in many CCSVI treatment centers in the world and thousands of opinions of individual patients, readily available in the modern world of immediate communication (internet) – speak for themselves.

Up until now far more about 30 000 CCSVI procedures among patients with multiple sclerosis have been performed worldwide. According to reliable sources there have been only 3 cases of complications resulting in patient’s death. This means a mortality level of 1/7000, therefore much lower than with similar procedures performed for different reasons and considered statistically acceptable. It should be mentioned that the complications in all 3 cases were linked to some other underlying conditions.

Ultimately, it is the patient who takes the decision to undergo the treatment. Patients make that decision being aware that in a big majority of cases angioplasty procedure helps and brings a lot of positive changes such as the decrease of disease symptoms.

SUMMARY

improvement of blood circulation, greater warmth felt in the upper and lower limbs, reduced muscle spasticity and improvement of muscle

function, decreased limb tremors, full recovery from or significant decrease of fatigue, sight improvement, improvement of sphincter function (digestive and urinary

tract), increased endurance during physical effort, greater psychological strength and better mood, significant change in the overall quality of life.

Among the most common improvements reported by the patients are:

Angiograph – standard equipment of catheterization laboratory (Cat Lab). Modern radiologic device dedicated to vascular diagnostics and intravascular treatment.

Balloon Angioplasty – surgical widening of a narrowed blood vessel by means of a balloon catheter. Balloon Angioplasty is performed by incising the femoral vein in the groin and inserting a catheter (a narrow tube). Next, a balloon is passed through the catheter and into the narrowed location, and then inflated to a required size and kept in place for several minutes.

Balloon Catheter – thin, flexible tube with a balloon at its tips inserted into the vessel during angioplasty and used to restore patency of stenotic vessels.

CCSVI - Chronic Cerebro-Spinal Venous Insufficiency, a recently isolated disease which is a venous pathology (Congres Union Internationale de Phlebologie, Monte Carlo 2009), officially classified among vascular venous malformations. CCSVI is a malfunction caused by the narrowing of veins which collect blood from the brain and the spinal cord. The criteria for diagnosing CCSVI have been put forth by Prof. Paolo Zamboni.

GLOSSARY

Cutting balloon - is an angioplasty balloon catheter equipped with small blades attached to its surface. It is a new device developed for use in endovascular treatment of stenotic vessels. It acts by cutting the stenosis or occlusion when balloon is being inflated. Evidence showed that using cutting balloons may improve the effect of treatment, decrease the risk of restenosis and reduce intraoperative trauma of healthy tissue. For best results balloon with cutting blades is used together with standard balloon catheters during angioplasty. This technique can also be beneficial in cases of hardened or calcified occlusion when standard balloons alone may not be as effective in restoring patency.

Guidewire - very thin wire with a flexible tip inserted into the vessel during angioplasty before insertion of balloon catheter. Guidewire is passed to the blockage and then is used as a pathway to stenosis.

High-pressure balloon – these balloons are usually used during high pressure angioplasty since they are resistant to deformation at high pressure, allowing very effective dilatation of the narrowing.

Mitoxantrone - is an anti-neoplastic agent also used to treat multiple sclerosis (MS). It is not an absolute contraindication for the liberation procedure, however it may increase the risk of complications during and after surgery. There is a possibility of disqualification from the procedure, due to abnormal blood tests results (leucopenia, thrombocytopenia) as Mitoxantrone may affect the composition of the blood.

Restenosis – the recurrence of abnormal narrowing of a vessel (vein), which sometimes occurs after corrective surgery such as vascular Angioplasty.

Stent – a synthetic, elastic tube or a spiral, usually made of 316 LVM steel or a chromium-cobalt alloy, placed inside the vein to restore its patency. Stents implantation is used in angioplasty. Stents used in this procedure are not of the drug-eluting type. Once inserted into patient's body stents are irremovable.

Stenting –inserting one or more stents in the patient's venous vessels.

Valves – in cases of impaired blood flow through the valves the treatment might be performed. This treatment involves placement of the deflated angioplasty balloon in the exact area of venous valve and precise inflation in order to swing valve to the right position. In general one can benefit from this procedure but it is not always possible to proceed with and certainly not equally effective for all patients.

Venography (also called phlebography) – a procedure where a venogram of the veins is taken after a special dye (the so called contrast) and injected into the veins via a catheter inserted into the femoral vein in the groin, thus visualizing them as an X-ray image. This procedure makes it possible to assess the appearance of all venous vessels, exposing clogs and malformations.

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