PTCA treatment for MS: Techniques and Outcomes Nicholas Kipshidze, MD, PhD, FACC, FSCAI N.KIPSHIDZE CENTRAL UNIVERSITY HOSPITAL Tbilisi, Georgia NEW YORK CARDIOVASCULAR RESEARCH New York, NY

I have no real or apparent conflicts of interest to report. Nicholas N. Kipshidze, MD, PhD I have no real or apparent conflicts of interest to report.

Multiple Sclerosis (MS) Thank you! Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of unknown pathogenesis

Etiology of MS is unknown. MS is believed to be an autoimmune disease. Foreign (viral) agents make changes in immune system. Cell myelin becomes foreign for immune system, that causes demyelinisation, scars and sclerotic plaques are formatted.

Epidemiology Incidence of MS is 93 per100 000 of the world population. There are about 2.5 million patients suffering from MS in the world population. The mean age for the disease ranges between 20 and 50, thus MS can appear as in children as in elder population MS occurred twice as often in Caucasian population.  MS occurred twice as often in female population. 

Epidemiology on the world

DIAGNOSIS Clinical Neurological assessment. MRI. Electrophysiological tests (Evoked potentials). Cerebrospinal fluid test.    

Types of Multiple Sclerosis Relapsing-Remitting(RR) Primary-Progressive(PP) Secondary-Progressive(SP) Progressive-Relapsing(PR)

Hypoperfusion of brain parenchyma is associated Zamboni et al . BMC Medicine 2011, 9 :22 http://www.biomedcentral.com/1741-7015/9/22 RESEARCH ARTICLE Open Access Hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report Paolo Zamboni 1* , Erica Menegatti 1 , Bianca Weinstock-Guttman 2 , Michael G Dwyer 3 , Claudiu V Schirda 3 , Anna M Malagoni 1 , David Hojnacki 2 , Cheryl Kennedy 3 , Ellen Carl 3 , Niels Bergsland 3 , Christopher Magnano 3 , Ilaria Bartolomei 1 , Fabrizio Salvi 1 , Robert Zivadinov 2,3 Conclusions: This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.

Early Results of Venous Angioplasty in Multiple Sclerosis Marian Simka EuroMedic Vascular and Endovascular Surgrey Department Katowice Poland

RESULTS 357 diagnostic venographies in 331 patients(15 redo procedures) Pathology found in 97% of the cases

Results of the study Severity and localization of CCSVI lesions significantly modify clinical course of MS

No Cerebral or Cervical Venous Insufficiency in US Veterans with Multiple Sclerosis Ultrasonography of internal jugular veins, vertebral veins, and deep cerebral veins in 18 MS pts and 11 controls. It has been suggested that perivenous inflammation, a histopathological signature of multiple sclerosis (MS), may be initiated by cerebral venous hypertension or chronic cerebrospinal venous insufficiency (CCSVI) An equal number (n = 4) of patients and controls met the definition of CCSVI Study calls into question whether CCSVI plays a pathogenic role in MS Implications: This study and others refute the hypothesis that chronic cerebral venous insufficiency exists in patients with MS. Marder E, et al. Arch Neurol. 2011;68:1521-1525.

Worldwide, several centers are actively promoting and Cardiovasc Intervent Radiol (2011) 34:1-2 DOI 10.1007/s00270-010-0050-5 CIRSE COMMENTARY Cardiovascular and Interventional Radiological Society of Europe Commentary on the Treatment of Chronic Cerebrospinal Venous Insuf?ciency J. A. Reekers M. J. Lee A. M. Belli F. Barkhof Worldwide, several centers are actively promoting and performing balloon dilatation, with or without stenting, for CCSVI. Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in progress Therefore, the basis for this new treatment rests on anec- total evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population.

Venous angiography

Venous angiography and PTA

Problem 2 • Sizing of balloon or stent

Venous angiography

Problem 3 • We don’t have a durable therapy for venous s stenosis

Venous Angioplasty in Patients with Multiple + MODEL Eur J Vasc Endovasc Surg (2011) xx , 1 e 8 Venous Angioplasty in Patients with Multiple Sclerosis: Results of a Pilot Study P. Zamboni a, *, R. Galeotti b , B. Weinstock-Guttman c , C. Kennedy d , F. Salvi e , R. Zivadinov c,d a Vascular Diseases Centre, University of Ferrara, C.so Giovecca 203, 44100 Ferrara, Italy b Interventional Radiology Unit, University of Ferrara, Ferrara, Italy c The Jacobs Neurological Institute, University at Buffalo, Buffalo, NY, USA d Buffalo Neuroimaging Analysis Center, University at Buffalo, NY, USA e Bellaria Neurosciences, Bologna, Italy KEYWORDS Abstract Objectives: Chronic cerebrospinal venous insuf?ciency (CCSVI) is associated with Chronic cerebrospinal multiple sclerosis (MS). The objective of the study was to see if percutaneous transluminal venous insuf?ciency; angioplasty (PTA) of duplex-detected lesions, of the internal jugular and/or azygous veins, Multiple sclerosis; was safe, burdened by a signi?cant restenosis rate, and whether there was any evidence that Percutaneous treatment reduced MS disease activity. transluminal angioplasty Design : This was a case-control study. Materials : We studied 15 patients with relapsing e remitting MS and duplex-detected CCSVI. Methods: Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas seven had treatment with PTA after 6 months of medical therapy alone (de- F layed treatment group (DTG)). Results: No adverse events occurred. At 1 year, there was a restenosis rate of 27%. Overall, PTA was followed by a signi?cant improvement in functional score compared with baseline ( p < 0.02). The annualised relapse rate was 0.12% in the ITG compared with 0.66% in the DTG ( p Z NS). Magnetic resonance imaging (MRI) blindly demonstrates a trend for fewer T2 lesions in the ITG ( p Z 0.081), corresponding to a 10% decrease in the ITG compared with a 23% increase in the DTG over the ?rst 6 months of the study. Conclusions: This study further confirms the safety of PTA treatment in patients with CCSVI associated with MS. The results, despite the significant rate of restenosis, are encouraging and warrant a larger multicenter double-blinded, randomized study. ¦2011 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. * Corresponding author. Tel.: _ 39 0532236524; fax: _ 39 0532237443. E-mail address: zmp@unife.it (P. Zamboni). 1078-5884/$36 ¦ 2011 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. doi:10.1016/j.ejvs.2011.03.035 Please cite this article in press as: Zamboni P, et al., Venous Angioplasty in Patients with Multiple Sclerosis: Results of a Pilot Study, Eur J Vasc Endovasc Surg (2011), doi:10.1016/j.ejvs.2011.03.035

45 Patients with different types of MS: Study population 45 Patients with different types of MS: Relapsing-Remitting (RR) – 17 patients Secondary-Progressive (SP) – 8 patients Primary-Progressive (PP) – 20 patient

Methods Clinical neurologic assessment (Kurtzke Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC)). Magnetic Resonance Imaging (MRI). Percutaneous venous angiography.

Angiography and PTA Venous stenosis of different severity were found in all 45 patients with different types of MS after angiography. 23 patients of right-sided and 17 patients of left sided stenosis 5 patients bilateral stenosis Percutaneous Transluminal Balloon Angioplasty (PTA) was performed in 50 lesions.

Localization and severity of venous stenosis Types of MS Localization of stenosis Diameter stenosis (%) at baseline Diameter stenosis (%) after PTA MS-RR Right IJV 68 48 MS-SP Left IJV 63 33 76 MS-PP 72 28 65 35 38 79 32 61 55 70 34 67

Venous angiography and PTA

Evaluation of neurological dynamic According to clinical symptoms. According to MRI examination.

Neurological dynamics Patient Motoric dysfunction Sensor Mental changes Incoor-dinance Vision Muscle spasm Psychical changes Bladder and bowel dysfunction MS-RR   MS-SP MS-PP 0 = no disorder;  = no changes;  = improvement

and 4 months later after PTA MRI at baseline and 4 months later after PTA Patient 1

and 4 months later after PTA MRI at baseline and 4 months later after PTA Patient 1

and 4 months later after PTA MRI at baseline and 4 months later after PTA Patient 1

and 4 months later after PTA MRI at baseline and 4 months later after PTA Patient 2

and 4 months later after PTA MRI at baseline and 4 months later after PTA Patient 2

Conclusions: Chronic Cerebrospinal Venous Insufficiency can play a certain role in the development of MS. It is recommended to perform selective venous angiography for patients with MS to diagnose Chronic Cerebrospinal Venous Insufficiency. In case of venous insufficiency PTA may appear as an effective treatment strategy for the patients with various forms of MS. Future randomized studies are warranted to establish the efficacy of this new treatment for MS.