Marian Simka, MD PhD Katowice, Poland Chronic cerebrospinal venous insufficiency: State of the art and research challenges Marian Simka, MD PhD Katowice, Poland

Disclosures: received publication fees from Servier International received speaker fees from American Access Care is employed in the hospital, where the treatments for CCSVI are patient-paid

Multiple sclerosis is chronic and debilitating neurological disease that is commonly regarded as an autoimmune disorder However, a unifying hypothesis of such an autoimmunity has yet to be identified

The discovery of occlusions in the extracranial veins that drain the central nervous system, so called chronic cerebrospinal venous insufficiency CCSVI sheds a new light on this problem

Atrophy of small intracerebral veins in MS patients healthy control early MS advanced MS

Since CCSVI comprises the blood outflow from a vital organ, for many doctors it seems reasonable to unblock such an obstruction

Others, however, argue that such interventions should be accepted as a valid treatment option for MS only on condition that: ∎ an impact of venous insufficiency on MS was demonstrated ∎ the procedures to alleviate these vascular pathologies were proven technically feasible and safe ∎ the treatments were proven to result in clinical benefit

Rationale for the treatment for CCSVI At the moment no pharmacological agent for MS is effective in a long run Even if only a subgroup of MS patients would benefit from the treatments for CCSVI, such procedures could be a breakthrough in the MS management

Three main questions regarding hypothetical venous insufficiency in the cerebral and spinal territory should primarily be answered: Does chronic cerebrospinal venous insufficiency exist? If it does, is it exclusively associated with multiple sclerosis? If associated, does such a connection have an impact on neurological pathology?

Does chronic cerebrospinal venous insufficiency exist? Problems with definition of CCSVI: definition using ultrasonographic parameters definition using angiographic (phlebographic) parameters small but relevant differences between protocols and interpretations of the findings

normal abnormal

normal ?? abnormal ???

Published evidence: 13 different angiographic studies have shown 85-100% prevalence of venous lesions in MS patients

Does chronic cerebrospinal venous insufficiency exist? Yes at least, in terms of angiographic findings in MS patients

If CCSVI exists, is it exclusively associated with multiple sclerosis? CCSVI seems to be a clinical entity distinct from multiple sclerosis The majority of, but not all, MS patients, can demonstrate venous lesions Such vascular abnormalities can also be found in non-multiple sclerosis individuals, and also in healthy controls

CCSVI and Parkinson disease Atypical MRI outflow pattern found in >50% of Parkinson patients Haacke M et al.

If CCSVI exists, is it exclusively associated with multiple sclerosis? Sonographic signs of CCSVI commonly found in the patients suffering from: other neurodegenerative pathologies Parkinson disease migraine non-neurological autoimmune disorders

If CCSVI is associated with MS, does such a connection have an impact on neurological pathology? It is unlikely that CCSVI is secondary to pathological processes of nervous tissue CCSVI lesions are preferentially found in the left IJV (congenital deffect?)

If CCSVI is associated with MS, does such a connection have an impact on neurological pathology? It is unlikely that CCSVI is secondary to pathological processes of nervous tissue CCSVI lesions are free from inflammation in histological exams CONTROL MS

If CCSVI is associated with MS, does such a connection have an impact on neurological pathology? Hubbard et al. Normalization of fMRI BOLD after angioplasty in CCSVI patients

”Venous undershoot” in fMRI BOLD black - control red – MS patients before PTA blue – patients after PTA Hubbard et al. Normalization of fMRI BOLD after angioplasty in CCSVI patient

Hypothetical mechanisms by which venous insufficiency could influence MS-associated processes proinflammatory and toxic role for iron chronic brain hypoxia resulting from blockage of venous outflow disintegration of the blood-brain barrier caused by stagnant and refluxing flow pattern in cerebral venules

If CCSVI is associated with MS, does such a connection have an impact on neurological pathology? It has recently been suggested that CCSVI may change benign infection caused by hypothetical infections agent of MS into clinically overt neurological disease

Safety and feasibility of endovascular treatment for CCSVI

Papers on safety of endovascular procedures for CCSVI: (12 articles) Zamboni (Italy) J Vasc Surg 2009 - 65 pts Ludyga (Poland) Phlebology 2010 – 344 pts Mandato (USA) J Vasc Interv Radiol 2011 – 231 pts Petrov (Bulgaria) J Endovasc Ther 2011 - 461 pts Kostecki (Poland) Neuroendocrinol Lett 2011 – 36 pts Kipshidze (Georgia) Georg MedNews 2011 - 4 pts Lugli (Italy) Phlebology 2012 – 167 pts Beelen (Belgium) Phlebology 2012 – 67 pts Hubbard (USA) - J Vasc Interv Radiol 2012 – 259 pts Zamboni (Italy) - Eur J Vasc Endovasc Surg - 15 pts Simka (Poland)- Vasc Dis Manag 2012 – 340 pts Eisele (Argentina) – Fleb Linfol 2012 - 15 pts Total: 2004 pts No mortality, very low incidence of major complications (1-2%)

Safety of the treatment for CCSVI (a meta-analysis) The procedures are very safe if no stents are implanted The use of stents is associated with increased rate of complications (still, rarely serious) However, there is a high rate of restenosis after endovascular treatment (inadequate technique? elastic recoil? thrombosis/scarring? progression of CCSVI?)

compression of jugular vein by aberrant omohyoid muscle

Clinical efficacy of endovascular treatment for CCSVI

Clinical benefit from the treatment for CCSVI 10 open-label trials published, 1440 patients Zamboni ; J Vasc Surg. 2009 - 65 pts , 18 months follow-up – clinical improvement in relapsing-remitting patients, stop of progression in progressive MS Ludyga ; Przeg Flebol 2011 - 94 pts , 6 months follow-up – clinical improvement in majority of clinical domains, irrespective of clinical status before the treatment Kostecki ; Neuroendocrinol Lett 2011 – 36 pts, 6 months follow-up , temporary improvement, not statistically significant Lugli; Phlebology 2012 – 167 pts, 1 month follow-up , clinical improvement in 69% of patients Beelen; Phlebology 2012 – 67 pts, 3, 6, 12 months follow-up, temporary improvement, not statistically significant Hubbard - J Vasc Interv Radiol 2012 – 259 pts, 6 months follow-up – clinical improvement in majority of clinical domains, irrespective of clinical status before the treatment Simka; Vasc Dis Manag 2012 – 340 pts, 6 months follow-up –improvement of chronic fatigue Milic D; J Vasc Surg 2012 – 205 pts, 6 and 12 months follow-up, temporary improvement, not statistically significant Eisele G; Flebol Linfol 2012 – 15 pts, 1, 3 and 6 months follow-up, clinical improvement in majority of clinical domains except for EDSS Sekhar K; J Vasc Interv Radiol 2012 – 192 pts, 3 months follow-up, clinical improvement in majority of clinical domains, better results in relapsing-remitting patients

Clinical efficacy of the treatment for CCSVI (a meta-analysis) Chronic fatigue improves after the treatment in majority of MS patients Other symptoms that may improve include: headache, bladder control, balance problems, paresthesiae, cold extremities Impaired walking, weak legs, usually do not improve Some patients (10-20%) may deteriorate after the treatment for CCSVI

MRI efficacy of endovascular treatment for CCSVI Zamboni et al. Eur J Vasc Endovasc Surg 2011 15pts, a crossover study statistically significant improvement in terms of plaque load during 6 months follow-up

Clinical efficacy of endovascular treatment for CCSVI Randomized Control Trials with sham-surgery arm ongoing: USA (2 trials) Italy Australia planned: United Kingdom Canada

3rd Annual ISNVD Meeting 23-25 February 2013 Kraków, Poland  

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