Chronic cerebrospinal venous insufficiency (CCSVI), or the pathological restriction of venous vessel discharge from the CNS has been proposed by Zamboni, et al, as having a correlative relationship to Multiple Sclerosis. From a clinical perspective, it has been demonstrated that the narrowed jugular veins in an MS patient, once widened, do affect the presenting symptoms of MS and the overall health of the patient. It has also been noted that these same veins once treated, restenose after a time in the majority of cases. Why the veins restenose is speculative. One insight, developed through practical observation, suggests that there are gaps in the therapy protocol as it is currently practiced. In general, CCSVI therapy has focused on directly treating the venous system and the stenosed veins. Several other factors that would naturally affect vein recovery have received much less consideration. As to treatment for CCSVI, it should be noted that no meaningful aftercare protocol based on evidence has been considered by the main proponents of the ‘liberation’ therapy (neck venoplasty). In fact, in all of the clinics or hospitals examined for this study, patients weren’t required to stay in the clinical setting any longer than a few hours post-procedure in most cases. Even though it has been observed to be therapeutically useful by some of the main early practitioners of the ‘liberation’ therapy, follow-up, supportive care for recovering patients post-operatively has not seriously been considered to be part of the treatment protocol. To date, follow-up care has primarily centered on when vein re-imaging should be done post-venoplasty. The fact is, by that time, most patients have restenosed (or partially restenosed) and the follow-up Doppler testing is simply detecting restenosis and retrograde flow in veins that are very much deteriorated due to scarring left by the initial procedure. This article discusses a variable approach as to a combination of safe and effective interventional therapies that have been observed to result in enduring venous drainage of the CNS to offset the destructive effects of inflammation and neurodegeneration, and to regenerate disease damaged tissue.
As stated, it has been observed that a number of presenting symptoms of MS almost completely vanish as soon as the jugulars are widened and the flows equalize in most MS patients. Where a small number of MS patients have received no immediate benefit from the ‘liberation’ procedure, flows in subject samples have been shown not to have equalized post-procedure in these patients and therefore even a very small retrograde blood flow back to the CNS can offset the therapeutic benefits. Furthermore once the obstructed veins are further examined for hemodynamic obstruction and widened at the point of occlusion in those patients to allow full drainage, the presenting symptoms of MS retreat. This noted observation along with the large number of MS patients who have CCSVI establish a clear association of vein disease with MS, although it is clearly not the disease ‘trigger’.
MS as a General Disease Condition
Since keeping the jugular and azygos veins fully open is the key to reducing MS symptoms, it is of paramount importance to know what other post-procedure factors would create enduring effect in the venous drainage flow. All therapeutic modalities and interventions that could potentially affect the successful outcome of the ‘liberation’ therapy need to be included in the context of the treatment to establish which combination of therapies support the best long-term outcomes. Our own studies have so far shown that additional stem cell transplantation therapy done in a particular sequence immediately following the venoplasty, has led to increased luminal diameter and improved patency rates in the jugular veins. Since new clinical evidence also suggests there may be more than one primary cause in MS, and the need to create a multifaceted approach to therapeutically targeting MS as a general disease condition, it may not be appropriate to apply only ONE strategy. Based on the new histopathological discoveries outlined above, any advanced approach to treating MS obviously concerns itself with the reduction of the damage to the CNS, and to restore nerve function caused by neurodegeneration so as to prevent or delay onset and subsequent disability. By correlation, vascular pathology is part of this syndrome and cannot be ignored in isolation. The synthesis of therapies has demonstrated that patients treated through this protocol recover with:
- increased and faster neurologic improvement,
- enhanced angiogenesis and
- less pathological regression of the blood vessels,
- better and longer-term patency rates,
- less adverse metabolic reaction,
- much less risk of catastrophic iatrogenic injury to the veins leading to
- less intraluminal scarring and
- less risk of second, third and fourth procedures to open veins
Also, in this way, infused stem cells may work to heal ALL damage to the veins throughout the body, and may in fact serve to reduce or eliminate additional venous disorders and co-morbidities not yet fully associated with MS (May-Thurner Syndrome, among others).
Observational and statistical evidence from case studies into the sequential combination therapy that includes both venoplasty and stem cell transplantation has confirmed five beneficially therapeutic effects for MS:
1) Jugular Vein Dilation Otherwise Known as Liberation Therapy. The vein dilation or venoplasty therapy provides the appropriate drainage of the CNS that prevents a retrograde pressure exertion on the myelin sheath covering the CNS. Whatever triggers the autoimmune system to turn on in people predisposed to MS, this back-pressure needs to be resolved. In case after case, the typical symptoms of MS retreat in individuals where the veins are expanded and the flow pressures are equalized. Good case study observation and statistical analysis of disability scale quantifications for subject samples taken post-procedure eliminate the biases inherent in the system to permit this statement of confirmation. (Personal Note: Some of the conjecture that passed for ‘conclusions’ in the NL study are quite frankly fraught with inherent biases.)
2) Keeping the Neck Veins Open Long-term. Since keeping the jugular and azygos veins fully open is the key to reducing MS symptoms, it is of paramount importance to know what other post-procedure factors create enduring effect in the venous flow. For example, there is now good clinical and observational evidence to support the fact that stem cells (transplanted intravenously at the time of the venoplasty) reduce swelling, thrombin buildup, clotting and subsequent permanent intraluminal damage leading to scar tissue. As to what has already been established through clinical trials and subsequent therapeutic practice, it has been found that even in patients with severely malformed or abnormal jugular vein structure, the intravenous introduction of Mesenchymal stem cells (MSCs) post-operatively has served to repair injury attributable to venoplastic damage and desquamation of the endothelial and subendothelial cells of the interior venous lumen (tunica intima). Peak velocity, time average velocity vein area, and flow quantification have been assessed by means of echo colour Doppler at periodic intervals post-venoplasty. Significant hemodynamic improvement has been recorded at the level of the veins in the neck post-venoplasty. Moreover, this additional stem cell transplantation therapy has led to increased luminal diameter and improved patency rates demonstrating that the introduction of stem cells post-operatively significantly modifies the hemodynamics of the jugular veins more effectively than venoplasty alone.
3) Post Procedural Monitoring to Avoid Second and Third Procedures. Having followed up with patients who had restenosed (in the dilated jugular veins) within hours, days or weeks of their procedure, discontinuance of postoperative monitoring, or even the lack of access to medical care following surgery does not seem reasonable especially given that the site of the disease is subject to iatrogenic injury (injury occurring as a result of the procedure) as well as significant postoperative complications (thrombosis/restenosis). As with any surgical procedure, healing must take place. Veins are clearly more subject to damage through invasive therapy since they are much thinner-walled, smooth, longitudinal muscle layers displaying a wider variation in anatomical structure and fragility than corresponding arteries. From subject to subject, vein walls may be thinner or more fibrous. Additionally, reasons for the stenosis may be multifactorial, and may occur, or may have existed for a very long time in many different sites along one of several veins, complicating and compromising effective treatment. Where CCSVI exists, these veins are also subject to venous disease due to chronic increased venous pressure with respect to the internal hemodynamics. Once treated, the fact that the internal structure of the veins cannot be seen to directly observe the damage and changes that have occurred within the lumen due to a mechanical venoplastic procedure does not mean that it has nevertheless occurred, and a healing process within the vein(s) will take place over the next several months or longer, post-venoplasty.
This healing is no less complex or lengthy a process for an abnormal vein that has been significantly remodeled than it is for any other type of bodily injury. In fact, the short experience with neck venous angioplasty for CCSVI indicates that there is usually only one good chance to get it right; second procedures on the same vein due to restenosis can be very much more complicated due to inflammation and scar tissue. To avoid second procedures, the argument could be made that the patient aftercare protocol post-procedure is a form of ‘wound care’ where actions subsequent to the venoplasty must be consistent with supporting the critical initial phases of the healing process. Evidence suggests that this has been missed (or intentionally avoided) in any consideration of what the entire protocol spectrum for the ‘liberation’ treatment should be. By virtue of demonstrating CCSVI, a disease condition of the veins, subjects with MS are also at higher risk for complications due to invasive procedures. Therefore, any written protocol for the liberation therapy should certainly by definition include an ‘aftercare’ protocol similar to any other surgical intervention including monitoring post-procedure (observation and ability to image appropriately), position and movement control post-procedure, capacity and willingness to re-treat the affected veins if necessary, other therapeutic interventional strategies including stem cell transfusions directly to the venous site. The need to provide a defined aftercare protocol has been confirmed by the significant number of patients who have been tested within 24 hours of their venoplasty and have been found to have become thrombotic or restenosed at or proximal to the site of treatment. Yet up until now the clear need to monitor patients post-procedure to avoid risk of complications has not been a focus of either therapeutic practice or of the research, and at least therapeutically, has not been seen as necessary by the practitioners. This avoidance of post-procedure aftercare and lack of follow-up with MS patients just having undergone venoplasty is remarkably at odds with the evidence and consistent with the biases inherent in the current system of management of CCSVI.
4) Stem Cells Turn Off the Over-aggressive Immune System. Mesenchymal Stem cells or MSCs actively interfere with immune tolerance. Recent studies have identified and confirmed the biochemical responses within the CNS. The mechanisms involved in MSC-mediated effects provide important insight into the pathways responsible for the therapeutic benefit observed following MSC transfusion. Once transfused, MSCs turn off the over-aggressive immune system. This immunosuppressive effect of MSCs is stimulated by IFN-γ, a dimerized soluble cytokine and other inflammatory cytokines. In short, these combinations of cytokines induce MSCs to express inducible nitric oxide synthase (iNOS) and result in production of elevated levels of Nitric Oxide, which induce immunosuppression.
5) Stem Cells Natural Homing Characteristics to Locate and Repair Damaged Tissue. Mesenchymal Stem cells (MSCs) are known for their properties of immunomodulation, anti-apoptosis, angiogenesis, anti-scarring, homing through chemoattraction and support of growth and differentiation of stem and progenitor cells. These adherent stromal MSCs derived from bone marrow are extended in culture to generate differentiated progeny in response to a diversity of manipulative in vitro protocols (via chemical stimulation and/or use of growth factors). Once transfused in vivo, MSCs naturally localize to damaged tissue sites, and an environment is set up for regeneration and recovery of all tissue and neurons that have been damaged by disease. MSCs also secrete molecules that set up a favorable setting for tissue repair that avoids the formation of scar tissue. Where Glial scars and lesions had previously formed and where the glia actually produce factors that inhibit remyelination and axon repair, the MSCs overcome the natural inhibitors and optimize the environment for maximum regrowth potential. Immunological testing of lymphocytes and cytokines within the treated patient population has demonstrated the immediate immunomodulating results of MSCs within as early as 2-6 hours post-transplantation. The likelihood of both long-term neuroprotection and neuroregeneration by way of in vitro differentiation of MSCs into cells of the neuronal or glial lineage has been demonstrated in early clinical studies and observational case reports.
Regarding the ‘Liberation Therapy’ in Isolation of Additional Support Strategies
Current popular protocols for the ‘liberation’ procedure are not by themselves adequate to therapeutically benefit subject patients for symptomatic treatment outcomes for vascular and CSF mediated neurologic damage as they do not either acknowledge or guide us toward additional potentially safe and effective long-term treatment strategies. The large number of MS patients restenosing post-procedure has thus-far demonstrated a clear gap in the understanding of the CCSVI venous angioplasty therapy protocol. The CCSVI Clinic strategies account for MS as a general disease condition, sequencing the therapies for best effect:
The CCSVI Clinic Protocol Combination Repair and Regeneration Strategy
- Marrow-derived Adult Autologous Mesenchymal Stem Cells
- Stem Cells are infused into Jugular Veins and intrathecally into CSF
- Formation of Glial and Cell Scar Tissues are Inhibited
- Supports growth and differentiation of Stem and Progenitor Cells
Repair and Regeneration Strategy Benefits
- Permanent Remodeling and Intraluminal Repair of Diseased Veins (Angiogenesis, Anti-scarring)
- Stops new Neurogenerative Disease activity
- Blocks Neurite Outgrowth Inhibitors, increases Axonal sprouting
- Olig-1 Activation, increases OG Differentiation
- Increases Neuronal Survival and Regenesis
Typical responsive outcomes to this therapeutic protocol are being closely followed in 28 patients at this time. One of the most disabled patient’s (EDSS 8.0) improvements have been listed below. This patient has not had any motor function or sensation below the waist for 10 years. He is now able to walk short distances, 60 days after his therapies and is seeing improvements each day:
Common Clinical Symptoms of MS have diminished within 60 days
- Optic Neuritis (previously only 30% vision in right eye returned to 100%)
- General Weakness (return to normal, energy levels very high)
- Sensory (able to withstand hot and cold temperatures normally)
- Cognitive Dysfunction (previously significant, return to normal)
- Fatigue (Return to near-normal, some fatigue due to rapid neuronal and muscle tissue regrowth)
- Bladder Dysfunction (previously totally dysnergic, now near-normal)
- Bowel Dysfunction (previously neurogenic, now returned to normal)
- Cerebellar Dysfunction (still seen in walking gait, but improving rapidly)
- Spasticity (muscles contract and relax normally)
- Sexual Dysfunction (previously no desire or ability, now normal)
‘Liberation Therapy’ by itself is Not Adequate for Long-term Recovery
A just-released 2011 study commissioned by the Newfoundland/Labrador Provincial Government regarding the benefits of ‘liberation therapy’ in a population of 30 patients showed ‘no measurable, objective benefit’, one year post-therapy. However, most participants did self-report significant improvements in their physical and psychological well-being for the first 90 days post-procedure. This observation is completely consistent with what the patients contacting CCSVI Clinic are reporting since many have now had the CCSVI procedure done ‘somewhere else’ where neither an aftercare protocol nor supplementary interventional techniques were supported. To date, all patients seeking additional therapies for CCSVI have reported that their presenting symptoms returned, mostly within the first 6 months. However, a significant number also reported that the beneficial effects of their first therapy only lasted a few days or weeks. Indeed when these individuals were subsequently re-treated at CCSVI Clinic, their MRV imaging consistently showed IJV blockages or stenoses ≥ their previous DU or MRV images. Although the NL study conjectures that such benefits (alleviation of typical presenting MS symptoms) could be the result of the placebo effect, it is not possible to make that statement. Preliminary results from the CCSVI Clinic’s own studies show that when the venous drainage flow equalized, the presenting symptoms of MS disappeared. The NL Study did not image the veins pre and post-procedure at the appropriate intervals to make comparisons, so any statement beyond their single conclusion would be not only be highly speculative, it also clearly reflects the author’s inherent bias.
The hypothesis put forward by the CCSVI Clinic research group is the guiding principle of the CCSVI Clinic’s protocol. Therefore, as more patients treated through the Clinic continue to demonstrate clinical improvement above the median indicators, the research group is working towards confirming the observational data through the feedback analysis of patient case study evidence. This will allow a prospective cohort study currently approved through an IRB application to collect data on records made available through medical files prior to the therapy protocol, at the time of the procedure, and then by regular patient follow-up (case study data). Patient registry and supervision of data is through the hospital IRB Board. The study is exclusionary (based on EDSS scoring) and only patients diagnosed with MS will qualify for the study. All qualifying patients must participate. It should be noted that all patients freely self-select the CCSVI Clinic and are not pressured into any decisions. The Clinic does not actively recruit patients and intends to seek informed consent for participation at the time of application for treatment; if informed consent is given, all individual patient data will be entered into a dedicated and aggregated database for analysis that will be published later, compliant with all relevant security and personal privacy requirements (HIPAA). All medical procedures are in accordance with with the rules and regulations approved by the International Cellular Medicine Society (ICMS), the world-wide oversight body for therapeutic transplantation of stem cells. Particular biases will be disclosed. The researchers have no financial interests in CCSVI Clinic.