PRO BALLOON VENOPLASTY IS A PROMISING TECHNOLOGY FOR TREATMENT OF MS

Transcription

1 PRO BALLOON VENOPLASTY IS A PROMISING TECHNOLOGY FOR TREATMENT OF MS Manish Mehta MD MPH The Vascular Group The Institute for Vascular Health & Disease Albany Medical Center SVS 2012

2 DISCLOSURES Research, Clinical Trial, Consultant: WL Gore & Associates Medtronic Ave Trivascular Inc Aptus Endosystems Bolton Medical Cordis Endovascular EV3 Inc Abbott Vascular Harvest Technologies Lombard Medical Technologies Inc LeMaitre Vascular Inc Board Member VIVA Physicians Inc. President/ CEO Center for Vascular Awareness Inc. Founder/ CME V-Aware Journal

3 QUESTION IS CCSVI AN ENTITY AND A SUBSET OF MS?

4 CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY & MULTIPLE SCLEROSIS What do we know about Multiple Sclerosis? 2 Million affected worldwide Degenerative vs. autoimmunity: CD4 T-cell mediated Autoimmune reaction directed against myelin-related proteins Clinical manifestations: Motor, Somatosensory, Cognitive Differential diagnosis: Inflammatory, infectious, metabolic, neoplastic

5 WHAT WOULD DAN CLAIR SAY: It is difficult to conceptualize this concept There is no level 1 evidence suggesting Are CCSVI treatments reproducible? Primary endpoints in CCSVI study are difficult to assess We need a double blinded placebo controlled RCT

6 WHAT IS THE EVIDENCE FOR CCSVI? 2009: Paolo Zamboni (Vascular Surgeon) Established correlations between CCSVI and MS 65 MS patients: Internal Jugular/ Azygous vein PTA of >50% stenosis Zamboni etal. J Vasc Surg 2009;50:

7 WHAT IS THE EVIDENCE FOR CCSVI? 2009: Paolo Zamboni (Vascular Surgeon) Established correlations between CCSVI and MS 65 MS patients: Internal Jugular/ Azygous vein PTA of >50% stenosis Noted significant improvements in MS Functional Composite and MS 1yr. Zamboni etal. J Vasc Surg 2009;50:

8 WHAT IS THE EVIDENCE FOR CCSVI? 2010: Robert Zivadinov (Neurologist) Established correlations between CCSVI and MS CTEVD RCT (Combined Transcranial & Extracranial Venous Doppler) 500 patients with neurodegenerative disorders 280 MS patients vs. 161 healthy controls Zivadinov etal. Neurology 2011, Jul12;77(2):138-44

9 WHAT IS THE EVIDENCE FOR CCSVI? 2010: Robert Zivadinov (Neurologist) Established correlations between CCSVI and MS CTEVD RCT (Combined Transcranial & Extracranial Venous Doppler) 500 patients with neurodegenerative disorders 280 MS patients vs. 161 healthy controls Significantly higher MS patients exhibit extracranial central vein stenosis (56% vs. 22%) Zivadinov etal. Neurology 2011, Jul12;77(2):138-44

10 WHAT IS THE EVIDENCE FOR CCSVI? CCSVI & Iron Deposits on SW Imaging in Patients with MS: A pilot Case Controlled Study Aim: To investigate relationship between CCSVI & Iron Deposits in the brain of MS patients 16 RR-MS patients vs 8 age matched healthy controls (HC) Zamboni etal. Int. Angiology 2010 Apr;29(2):140-8 Zivadinov etal. Int. Angiology 2010 Apr;29(2):158-75

11 WHAT IS THE EVIDENCE FOR CCSVI? CCSVI & Iron Deposits on SW Imaging in Patients with MS: A pilot Case Controlled Study Aim: To investigate relationship between CCSVI & Iron Deposits in the brain of MS patients 16 RR-MS patients vs 8 age matched healthy controls (HC) All MS patients fulfilled diagnosis of CCSVI vs. None of the HC MS patients had higher CNS iron concentrations Significant association between CCSVI parameter and increased CNS iron concentration Zamboni etal. Int. Angiology 2010 Apr;29(2):140-8 Zivadinov etal. Int. Angiology 2010 Apr;29(2):158-75

12 WHAT IS THE EVIDENCE FOR CCSVI? Vascular aspects of multiple sclerosis Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction Endothelial dysfunction Global cerebral hypoperfusion, ischemic origin Pathophysiology might be a consequent of CCSVI secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals. D haeseleer et al. The Lancet Neurology, July 2011, 10(7):

13 WHAT IS THE EVIDENCE FOR CCSVI?

14 WHAT IS THE EVIDENCE FOR CCSVI?

15 WHAT IS THE EVIDENCE FOR CCSVI?

16 WHAT IS THE EVIDENCE FOR CCSVI? Study supported by National MS Society Cleveland Clinic Foundation Harvested & analyzed veins from 7 deceased MS patients vs. 6 non-ms MS patients: 7 abnormalities in 5 of 7 patients Non-MS controls: 1 abnormality in 6 patients Diaconu et al. European Committee for Treatment & Research in MS (ECTRIMS), October 2011

17 Diagnosis WHAT IS THE EVIDENCE FOR CCSVI? : 60 REPORTS ON CCSVI Confusion & Controversy! Ability to validate the spectrum of CCSVI Duplex, MRV, Venogram Treatment Feasible and relatively safe Although outcomes are poorly defined

18 WHAT IS THE EVIDENCE FOR CCSVI? : 60 REPORTS ON CCSVI Confusion & Controversy! < 25% of published studies: Evaluate evidence for or against CCSVI > 75% of published reports: Commentaries & interpretations

19 UTILITY OF CCSVI PTA FOR MS STUDY ALBANY VASCULAR GROUP EXPERIENCE 1. Prospective Evaluation Internal Jugular Venograms Healthy controls vs. MS patients 2. Prospective Evaluation Angioplasty only Standardized approach Int. Jugular & Azygous Vein Reflux & Stenosis > 50% Clinical Neurologic 1, 3, q 6 months Timed 25-Foot walk MSQOL 54 MFIS (Modified Fatigue Impact Scale)

20 UTILITY OF CCSVI PTA FOR MS STUDY ALBANY VASCULAR GROUP EXPERIENCE Prospective Evaluation Quantitative analysis of flow dynamics across IJV valves Venography Healthy volunteers vs. MS patients pre-pta vs. MS patients post PTA Quantitative analysis Time of flight from mid-ijv to superior vena cava Primary venous emptying time: >50% venous emptying from IJV

21 FLOW DYNAMICS ACROSS IJV VALVES ALBANY VASCULAR GROUP EXPERIENCE Healthy volunteers vs. MS patients pre-pta vs. MS patients post PTA 12 Healthy non-ms Internal Jugular veins evaluated via angiography 50 MS patients Internal Jugular veins evaluated via angiography Pre angioplasty and Post angioplasty for CCSVI Time of Flight & Primary Venous Emptying Time Recorded in all Healthy non-ms volunteers Recorded pre and post PTA in MS patients withccsvi

22 LIBERATION STUDY INTERNAL JUGULAR VEIN STENOSIS & REFLUX Healthy Non-MS Volunteer MS Patient with CCSVI Mehta et al. Presented SVS 2012

23 LIBERATION STUDY INTERNAL JUGULAR VEIN ANGIOPLASTY Mehta et al. Presented SVS 2012

24 LIBERATION STUDY INTERNAL JUGULAR VEIN POST-ANGIOPLASTY CCSVI: Pre-Angioplasty CCSVI: Post-Angioplasty Mehta et al. Presented SVS 2012

25 FLOW DYNAMICS ACROSS IJV VALVES ALBANY VASCULAR GROUP EXPERIENCE MS patients pre-pta vs. MS patients post PTA vs, Normal non-ms Patients TOF: Time of Flight PVET: Primary Venous Emptying Time We observed significant differences in TOF and PVET between MS patients with CCSVI and healthy controls. Furthermore, following IJV PTA the MS patients TOF and PVET improved and were similar to healthy controls Mehta et al. Presented SVS 2012

26 UTILITY OF CCSVI PTA FOR MS STUDY Prospective Evaluation Angioplasty only Standardized approach Int. Jugular & Azygous Vein Reflux & Stenosis > 50% Clinical Neurologic 1, 3, q 6 months Timed 25-Foot walk MSQOL 54 MFIS (Modified Fatigue Impact Scale)

27 CCSVI PTA FOLLOW-UP > 3 MONTHS TIMED 25-FOOT WALK N Pre- Procedure Post- Procedure P-value All MS Types

28 CCSVI PTA FOLLOW-UP > 3 MONTHS TIMED 25-FOOT WALK N Pre- Procedure Post- Procedure P-value All MS Types Relapsing Remitting

29 CCSVI PTA FOLLOW-UP > 3 MONTHS TIMED 25-FOOT WALK N Pre- Procedure Post- Procedure P-value All MS Types Relapsing Remitting Secondary Progressive

30 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS TIMED 25-FOOT WALK N Pre- Procedure Post- Procedure P-value All MS Types Relapsing Remitting Secondary Progressive Primary Progressive

31 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS QOL Physical Health Composite Score (Mean) Pre- Procedure Post- Procedure P-Value

32 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS QOL Physical Health Composite Score (Mean) MS QOL Mental Health Composite Score (Mean) Pre- Procedure Post- Procedure P-Value

33 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS QOL Physical Health Composite Score (Mean) MS QOL Mental Health Composite Score (Mean) Modified Fatigue Impact Score (Mean) Pre- Procedure Post- Procedure P-Value

34 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS Patients Reporting Improvement MS QOL Physical Health Composite Score (Mean) MS QOL Mental Health Composite Score (Mean) Modified Fatigue Impact Score (Mean) 84% 92% 82%

35 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS Symptoms Pre Procedure Loss of Balance 89% Lower Extremity Weakness 84% Bladder incontinence 71% Decreased Co-ordination 74% Vertigo 47%

36 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS Symptoms Pre Procedure Improved No Change Loss of Balance 89% 65% 35% Lower Extremity Weakness 84% 79% 21% Bladder incontinence 71% 67% 33% Decreased Co-ordination 74% 61% 39% Vertigo 47% 71% 29%

37 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS Symptoms Pre Procedure Fatigue 89% Heat Intolerance 68% Memory Loss 57% Depression 45%

38 CCSVI PTA MEAN FOLLOW-UP 4.5 MONTHS MS Symptoms Pre Procedure Improved No Change Fatigue 89% 79% 21% Heat Intolerance 68% 62% 38% Memory Loss 57% 71% 29% Depression 45% 74% 26%

39 WHAT IS THE EVIDENCE FOR CCSVI? : 60 REPORTS ON CCSVI Confusion & Controversy! < 25% of published studies: Evaluate evidence for or against CCSVI > 75% of published reports: Commentaries & interpretations

40 WHAT IS THE EVIDENCE FOR CCSVI? IS VENOUS ANGIOPLASTY HELPFUL? : 60 Reports on CCSVI < 25% evaluate evidence for or against CCSVI Studies by specialty Surgeons/ Interventionists: Favor CCSVI diagnosis & treatment Neurologist: Mixed results Smaller single center studies: Against diagnosis of CCSVI Larger RCT: Favor CCSVI diagnosis Collaboration among specialty: Favor CCSVI diagnosis & treatment

41 WHAT IS THE EVIDENCE FOR CCSVI? IS VENOUS ANGIOPLASTY HELPFUL? Preliminary data suggests that patients with MS have a significant association with CCSVI and increased CNS iron concentration. Furthermore, venous angioplasty is feasible, safe, and associated with significant clinical and QOL improvements

42 WHAT IS THE EVIDENCE FOR CCSVI? IS VENOUS ANGIOPLASTY HELPFUL? Today we have more questions than answers Need more DATA via collaboration among various specialties Need to define and validate the spectrum of CCSVI and its treatments Including Surgical Reconstructions

43 WHAT IS THE EVIDENCE FOR CCSVI? IS VENOUS ANGIOPLASTY HELPFUL? These findings need to be substantiated with ongoing studies (blinded RCTs, single and multicenter) that evaluate endovascular and surgical options before widespread use of interventional procedures for CCSVI