1 Trevor W Tucker, PhD Fluid Dynamics: The MS – CCSVI Missing Link? Presented At The NCS Conference “Les voix du progrès :: Voices of Progress” Sherbooke, PQ, Canada, September 2013

2 Background About Multiple Sclerosis (sic)  Autoimmune cells attack myelin insulation on neural axons  Attacks result in scleroses and nerve damage around fine cerebral veins  Symptoms and influences are many and varied About Chronic Cerebral Spinal Venous Insufficiency  Vein obstruction reduces cerebral blood flow The Scientific Controversy  Does MS cause CCSVI? Vis-versa? Or Neither? About Research Approaches Generally  Medical Research – Clinical Trials  Physics Research – “The Scientific Method” My Approach – Applying the Scientific Method  Specifically, applying the physics of Fluid Dynamics to cerebral blood flow

Applying The Scientific Method 3 What is the CCSVI – MS relationship? Have Internet, Will Google Experiments - Literature Reported Compare Experimental and Model Results Audience Participation Venous Reflux Venule Hypertension BBB Disruption T/B Cell Leakage Myelin Attack Venous Obstruction Fluid Dynamics Current Literature

4 The Physics of Fluid Dynamics Hypothesis: Travelling Pulses In a Tube Pressure SuperpositionStanding Pressure Wave Localized HypertensionOn Each and Every Pulse

5 One pulse period From Heart Toward Heart Compare Model and Experimental Results In a blocked tube the fluid flows back and forth - pushed by a pressure gradient Graphics from: a) Fendt (above) b) Haacke (MS- MRI.com, left) Pgrad Flow Pgrad Flow Back and forth flow in IJV occurs Increased venous flow occurs with increased pressure gradient (ie hypertension ) Hypertensive Flow Compare Right and Left IJV 9 5 Pgrad Flow

Sum Pressure of Direct and Reflux Pulses = Venule Hypertension Blocked Valve Venule End Distance From Blocked Valve (cm) Sum Venule Hypertension Direct Reflux

7 Pressure may become acute (hypertensive) at the drainage end of the capillary bed (ie the venules) Also from Schelling (2004): “MS lesions’ sizes and numbers increase in the blood’s “counter-flow direction”, consistent with hypertension increasing in that direction The distance from obstruction to venules and pulsatile wavelength determine if hypertension exists or not at the venules Blocked Valve Venule End Distance From Blocked Valve (cm) Hypertension & Lesions Standing Pressure Wave and Venule Hypertension Node

8 Capillary Bed Pressure Changes - IJV Unobstructed IJV Obstructed P out increases Blood Flow Decreases P in is constant Capillary Bed Venules Arterioles Cerebral Artery Internal Jugular Vein Blood Flow In Blood Flow Out Note Shelling’s Comment : “A striking widening of the venous passageways” Also note the Singh and Zamboni image showing primary and secondary vein stenosis Also note that if the primary stenosis is removed the secondary stenosis may disappear on its own (my “Eureka” moment) Venous Hypertension

9 Effects of Increased Venule Hypertension (from the Scientific Literature) Blood flow through the capillary bed is reduced by high pressure (hypertension) at the drainage (venule) end of the capillary bed Hence the amount of oxygen in the blood through the bed is reduced Hence the oxygen transferred into the brain is reduced Oxygen deficiency (hypoxia) in the brain:  Increases fatigue  decreases mental acuity (increases brain fog) The cells (oligodendrocyte cells) that repair the insulation around the nerve channels in the brain (the myelin) begin to die from lack of oxygen Hence, venous hypertension may cause myelin to deteriorate Observation: “Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions” (Henderson)

10 The Blood Brain Barrier The Blood Brain Barrier is a layer of (endothelial) cells around the capillaries and venules  Its purpose is to protect the brain from large cells and molecules in the blood Cells such as iron, auto-immune attack cells and bacteria  Allows small molecules (like oxygen, carbon dioxide) and nutrients like glucose to pass between the capillary bed’s blood and the brain If there is a disruption in the BBB then auto- immune attack cells and iron can make their way into the brain to attack deteriorating myelin

11 About Blood Brain Barrier Disruption (From the Scientific Literature) Acute systemic hypertension can cause BBB disruption  Any hypertension-induced BBB disruption would occur at the venule end of the cerebral capillary bed Venous reflux standing pressure wave may increase going into the venules causing local hypertension Localized venule hypertension may (and this may be the biggest hypothesis) also be sufficiently large to trigger a disruption in the Blood Brain Barrier With the failure of the blood-brain barrier, autoimmune attack cells may (certainly will?) enter the brain and may attack weakened or deteriorated myelin Observation: Blood Brain Barrier disruption has been widely observed in association with Multiple Sclerosis (Kermode, Gay, Simka)

12 Removing An Obstruction In A Cerebral Vein Increases blood flow through the capillaries Increases the transfer of oxygen, glucose and other nutrients into the brain (reduces hypoxia) This reduces chronic fatigue and brain fog May clear a secondary stenosis above a primary obstruction Doesn’t impact existing scleroses and iron deposits Disabilities from existing nerve damage remain However, may significantly improve quality of life

13 Does The Hypothesis Explain Other MS Risk Factors, Including: Twice as many female MS patients as male The Influence of geographic distribution The influence of vitamin D The influence of aging The influence of cigarette smoking The influence of previous viral infection The influence of genetics

14 Have Internet: Will Google

15 Impact of Hypoxia (Lack of Oxygen) On The BBB (From the Scientific Literature) Long term hypoxia reduces endothelial layer compliance (reduces venule elasticity) Hypoxia promotes adherence of autoimmune attack cells (leukocytes) to endothelial cells Hypoxia induces endothelial & oligodendrocyte cell death Hypoxia increases endothelial permeability (porosity) to larger molecules and cells Hypoxia promotes angiogenesis (growth of new vessels, like collaterals) to help restore the oxygen supply Hypoxia also induces fatigue and brain fog Observation - The above characteristics are all observed in the literature to be associated with MS

Predicted Results of a Reduction in Vein and Venule Compliance Less compliant (less elastic) veins have less capacity to expand to store blood pulses in the veins between the obstruction and the venules Hence, more blood and pressure is forced higher into the venules Hence reduced venous compliance:  Increases hypertension at the venules  Increases risk of Blood Brain Barrier disruption  Increases Multiple Sclerosis risk

Factors That Reduce Vein Compliance and/or Endothelial Continuity (From the Scientific Literature) Female (whose compliance is 50% less than males’) Vitamin D deficiency (and sunshine deficiency) Dietary influences such as coffee and gluten Cigarette smoking Previous Epstein Barr Virus infection Aging and genetics Observation: Such factors, through reducing vein compliance, increase venule hypertension, and hence the risk of BBB disruption, immune cell leakage, myelin attack and scleroses

18 Summary Gender Female veins are less compliant hence, more hypertension Sunshine/Vitamin D Vitamin D deficiency reduces vein compliance and increases hypertension Aging Reduces vein compliance And Increases hypertension Smoking Impairs endothelium, reduces vein compliance and increases hypertension Epstein-Barr Impairs endothelium Genetics Vein malformation & BBB susceptible to leukocyte passage IJV Venules Obstruction Causes venule hypertension Venule Hypertension Causes hypoxia Hypoxia Reduces vein compliance Increases leukocyte adhesion Increases endothelial permeability Increases endothelial cell death Promotes collateral vein growth

19 Progressing the Simple Fluid Dynamics Model Use Computation Fluid Dynamics (CFD) to Solve the Navier-Stokes equations  (Navier-Stokes is the fluid equivalent of Newton’s law) ma = f Measure with 4D MRI Enter Gravity, Compliance, Forces Solve Pressure Determine Venule Pressure - Is it Hypertensive? (Note: Commercial CFD Software Is Available)

20 CFD Is Currently Applied to Blood Flow

Recent Progress: A Symposium on CCSVI Computer Modeling: (Zamboni, Toro, Beggs et al) 21

My Observations Arising From The Hypothesis Venous reflux can result from many types of obstructions in many cerebral & spinal vein places Existence of CCSVI (venous reflux) does not ensure MS Existence of MS does not require CCSVI Existence and severity of MS is affected by:  Placement, number and sizes of venous obstructions  Properties of the endothelial layer (affected by diet, gender, pharmaceuticals, sunshine, smoking, etc.)  Immune system modulation via pharmaceuticals 22

Fluid Dynamics: The MS – CCSVI Missing Link? Do the results predicted by the fluid dynamics hypothesis match the characteristics of MS as reported in the scientific literature? Would this persuade a broad medical community? (I remain very optimistic, I have seen progress) Questions and Comments? 23