Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Investigating the root causes of multiple sclerosis using
systems analysis and dynamics, developing an integrated
treatment strategy
Thomas Ragnar Wood', Ulrik Sverdrup’, Kristin Vala Ragnarsdottir’, Harald U. Sverdrup*
‘Guy's Hospital and St Thomas’ Hospital, Great Maze Pond, London SE1 9RT, Great Britain *Physics
Engineering, LTH, Lund University, SE-221 00 Lund, Sweden, *Earth Sciences, University of Iceland, 101 IS-
Reykjavik, Iceland, “Chemical Engineering, Lund University, Box 124, SE-221 00 Lund, Sweden
Abstract
By applying the methods of systems analysis to the problem of what causes multiple sclerosis, we
have been able to show that it is a systemic illness, with multiple interacting causes and
mechanisms. The results were obtained by synthesizing state-of-the-art research on parts into a
whole systemic picture of the whole. These main components make up the illness system:
1. The root cause: A Permeable blood-brain barrier (BBB) and transmission of provocative
substances, antibodies and leucocytes into the brain. This may be caused by chronic cerebro-
spinal vascular insufficiency (CCSVI, and associated microclotting due to stagnant cerebro-
venous blood flow), latent infections that cause a Th1-dominated immune response and release
of matrix metalloproteases (MMPs) which can alter the BBB, or a general pro-inflammatory
state created due to dietary factors.
2. Triggers are antibodies to myelin and oligodendrocytes from
i. Infections by certain bacteria and viruses;
ii. Peripheral allergenic attacks
iii. Myelin and oligodendrocyte debris in the blood stream
3. Reinforcing loops:
a. Feedback system involving iron in the autocatalytic Fenton cycle and production of
oxidants, prominently peroxynitrite, reinforcing the increased permeability of the
BBB; keeping the BBB compromised
b. Autoimmune feedback loop involving immune system and myelin sheath breakdown,
leading to damages to the BBB, by oxidative denaturalization of the myelin surfaces.
c. Oxidative stresses, leading to scaring at damaged sites and impairment of the ability
to repair myelin sheaths, making the physical damage permanent
The partial mechanisms were linked together into one large integrated model leading to the disease.
Multiple sclerosis has no single cause, but a number of interacting of causes in a feedback system.
The model is capable of describing the untreated progress of the illness as it has been observed.
Multiple sclerosis is initiated by an opening of the blood-brain-barrier, combined with provocative
substances in the blood, which initiate a vicious cycle of oxidative stresses and immune attack. The
conceptual model was used to investigate the dynamics of the illness and understand its initiation
and subsequent illness progression qualitatively. With the model we can start to analyse how
treatment for multiple sclerosis must be approached in a multi-disciplinary way in order to be
successful. The conceptual model was developed into a systems dynamics model in the STELLA
environment. The simulation model is capable of reconstructing the basic outline of the illness, with
the onset at 25 years of age, and the transition to secondary progressive disease at 45-55 years of
age. This appears to confirm the validity of the fundamental features of our model.
Introduction
Multiple sclerosis (MS) is a chronic illness, characterised by immune attack on the myelin sheath
of white matter in the central nervous system. The patient initially experiences attacks of paraesthesia,
weakness, visual or bowel and bladder problems. These may initially resolve, but over time general
health decreases alongside permanent disabilities, which often leave MS sufferers wheelchair-bound.
Though rarely directly fatal, overall the life expectancy of MS patients is reduced by 5-10 years. On
autopsy and in MRI gadolinium contrasted scans, lesions in the grey and white matter can be seen,
where the nerve tissue of the brain has been destroyed. The atrophy is largely irreversible, but the
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
brain has a certain redundancy, and the critical functions can initially be compensated for. This will be
experienced as a remission. Multiple sclerosis is an ailment without a cure and generally poor
prognosis for the patient. Though some current treatments may reduce the severity of an attack,
nothing as yet can slow the overall progression of the disease. The illness strikes more women than
men, the ratio being close to 2:1 (Phadke 1987). We classify multiple sclerosis into 5 major types (El-
Moslimany and Lublin 2008, Andersen 2008, Polman and van Osten 2008):
Clinically isolated syndrome.
Relapsing-remitting multiple sclerosis
Secondary progressive multiple sclero:
Primary progressive multiple scleros
Progressive relapsing multiple sclerosis
Oo po
In most cases, MS affects both the brain and the spinal cord. However, in approximately 20% of the
cases it affects the spinal cord only. The general state-of-the-art picture of what multiple sclerosis
represents is described by Kesselring (2008), Andersen (2008) and Dean and Kurtzke (1971). Until
now multiple sclerosis has been an enigma - the visible symptoms are well described, but they are not
well understood.
Background and earlier work
Research into the cause of multiple sclerosis has gone on for decades, turning up few explanations
for the aetiology of the disease (e.g. Allen 1981, Barnett and Sutton 2006). The condition was first
properly described by Charcot (1868); however, it has probably existed as a disease since well before
that time. One of the possible reasons for the lack of significant progress was the focus on the
hypothesis that there was one single causal factor. Some recent efforts stand out as important
milestones on the road to discovering the root cause of multiple sclerosis:
I. The observation of constricted blood vessels for the return venous blood from the brain and
how this causes small lesions that allow blood and pathogenic material to leak into the
brain through the compromised blood-brain barrier (Zamboni et al., 2003, 2005, 2006,
2007, 2008, 2009a,b,c, 2010, Francesci 2009, Zamboni 2009, Khan et al., 2010, Lee et al.,
2009).
2. The discovery that multiple sclerosis is connected to accumulation of iron in the brain,
creating large internal oxidative stresses in the brain (Hooper et al., 1998, 2000, Szabo et
al., 2007, Szabo 2003, Gilun-Sherki et al., 2002).
3. The finding that multiple sclerosis not only affects white matter brain, but that it causes
grey-matter necrosis and that this is an initially inflammatory process, proportional to the
degree of micro-vascularisation of the grey-matter tissue.
Scope and objective
The objective of this study was to understand the different components influencing multiple
sclerosis; its initiation, first as attacks, and the mechanisms which potentiate the disease towards its
progressive phase. Finally, we use knowledge of the parts to derive an integrated model for MS that
explains the underlying causalities of the illness, as well as exploring possible treatment strategies that
can be derived from the systemic model.
Materials and methods
The basic methodology applied was systems analysis of existing data - where cause and effect
were systematically mapped in large system diagrams, recording causal chains in the systems and with
emphasis on finding important feedback loops that are present (Haraldsson and Sverdrup 2004, Ahn et
al., 2006a,b, Varkey et al., 2009). This we did in order to be able to investigate the behaviour of the
whole integrated system, but varying the main drivers and studying the responses in the main outputs.
This takes the expression of causal loop diagrams, which are powerful tools for problem solving in
complex systems. In this we work with defining the goal, identifying the gap between the present
status of the system and the goal, and developing a strategy for how the gap will be crossed. This
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
implies detecting the possibilities for changing the causal links, affect key driving factors, essential
triggers, and important self-sustained feedback loops in the system. Figure 1 shows how systems
analysis starts as simple mind-mapping, where a number of possible parameters or system parts are
just “thrown up” on a board. They are then sorted in order to find their place within the system, and
whether they are significant contributors to the overall picture. Some of the factors will have to be
disassembled into subsystems, and many factors may be eliminated as a part of the systems analysis
process. This is the first step towards establishing causal loop diagrams.
The different phases of a systems-thinking-based research process as was implemented here
has been shown on the right (Sverdrup et al. 2012). Figure 2 shows an outline of how the stakeholder
participation process is operated. A minimum number of 3 consecutive workshops, and often up to 5-
10 workshops, are required to achieve good results (Sverdrup et al. 2012).
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Figure 1. The systems analysis starts as simple mind-mapping, where a number of possible parameters
or system parts are evaluated (left). The process goes through four phases.
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Figure 2. Outline of how the stakeholder participation process is operated.
From 2009 to 2011, we conducted a large literature survey, reading and mapping the contents of about
700 scientific articles (Sverdrup et al. 2012). That study provided us with a large number of causal
loop diagrams and a systemic insight into MS as a system. The study, a 180 page booklet published as
a Lund University report, constitutes what the authors call a “knowledgebook” - the scientific notes,
methodology, description and activities log of our compilation as a part of the research process. For
those interested in our detail, we would refer to that report. The knowledge book is a living document,
and it steadily updated with everything new insight learned. The current article is drawn from this
compilation and has been significantly further reworked.
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Theory
The generally accepted hypothesis for multiple sclerosis is that it is caused by a permeable blood-
brain-barrier (BBB), which is instrumental in causing attacks of the immune system against the central
nervous system (CNS). We reviewed all of the proposed causal factors and assessed their validity. All
this was synthesised into one single holistic multiple sclerosis aetiology as is shown below. Based on
our systems analysis, an integrated picture of a systemic disease has emerged. Many components
appear to be interacting, and it becomes evident that there is no single cause of MS - there are many
causes, and they are connected in a system. The simple model we have derived, has four main
components:
1. Leakage across the blood-brain barrier. Pathogens, antigens and blood can pass into the brain,
leading to direct immune attack and iron deposition.
2. Infections which produce antibodies that cross-reaction with myelin in the CNS via molecular
mimicry
3. Oxidative stresses caused by iron deposition into the brain and immune-mediated CNS
inflammation. These both weaken the blood-brain barrier from within and keep it
compromised — this produces a reinforcing feedback loop
4. An autoimmune feedback loop that once triggered, becomes self-sustaining, driving white
matter scarring, oligodendrocyte necrosis and blood-brain barrier leakage.
Multiple sclerosis appears to be triggered when leaky vessels open a pathway for material
normally barred by the blood-brain barrier, to enter the CNS. This allows red and white blood cells, as
well as antibodies, to transgress the blood-brain barrier. Diagnostically, this is seen as iron
accumulation in the brain from red blood cell break-down, always in connection with lesions. Other
pathologies may also lead to iron deposits in the brain, but multiple sclerosis is only caused when
there are conditions that allow the oxidant cycles to start producing large amounts of oxidants.
Antibodies entering the central nerve system may “mark” the myelin sheath for immune system attack
as it has similar a localised molecular structure to the bacteria that the antibodies were intended for
(Tivana et al. 1999, Ebringer et al. 2003, 2008, 2010). Myelin fragments then trigger further responses
and an autoimmune feedback loop is established. The regenerative mechanisms strive to repair the
damage however, the accumulated iron leads to elevated levels of Fe™’, resulting in oxidative stress,
production of free-radicalr and reduction in the efficiency of the regenerative mechanism. Thus, re-
myelination is prevented and multiple sclerosis has developed. At least three mechanisms appear to be
associated with increasing permeability of the blood-brain barrier, any of which might trigger entry
into the MS cycle in a susceptible individual:
1. Latent infections, often with associated Th1-dominant immune response
2. A diet-related pro-inflammatory state, and direct effect of dietary breakdown products having
a direct effect on gut and BBB permeability
3. Chronic Cerebro-Spinal Venous Insufficiency (CCSVI)
Chronic and latent infections and associated molecular mimicry
Ebringer et al. (2005a,b, 2007), Gilden (2005), Grénning et al. (1993), Hughes et al. (2003), Panitch
(1994) and Bennet et al. (2008) showed that antibodies from certain bacteria are often associated with
multiple sclerosis. Ebringer and his colleagues among others, hypothesised that this could be one of
the triggering factors for the disease. Others have worked on the Epstein Barr Herpes virus, the human
herpes virus 6 and other viral components that have similar association patterns (Siegel 1997, Sola et
al., 1993, Vaughan et al., 1996). It seems like this antibody affiliation is a plausible hypothesis with
respect to epidemiological studies conducted in the Feerayar and Iceland concerning external
contagious agents in multiple sclerosis (Bray et al., 1992, Dean and Kurtzke 1971, Ebers et al., 1986,
Kurtzke 1983, 1993, Kurtzke and Hyllerstedt 1988, Kurtzke et al., 1979, Poses and Hibberd 1988,
Bennet et al., 2008).
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
The role of dairy products and gluten
According to our findings by far the most successful treatments for multiple sclerosis are specially
designed diets. The common denominator of most of these diets, are the avoidance of dairy products,
and to eliminate gluten. This is sometimes based on immunological reasoning, often from observed
effects of experimental diets over long times (Swank and Goodwin 2003).
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Figure 3. Causal loop diagram for the mechanisms causing a permeable brain-blood-barrier is
shown to the left. The emphasis of the diagram to the right is to show the triggering effect by different
types of infection from both bacteria and different types of viruses.
The elimination of dairy from the diet may in many cases lead to improvements that are orders of
magnitude larger than anything the traditional medicine can accomplish (Wills and Unsworth 2002,
Ventura et al. 1991, Volta et al. 2006, Volta and Georgio 2010). Research is needed to establish the
effect of food in general. Milk and gluten give rise to several constituents that may interfere with
different physiological mechanisms:
1. Small, dispersed fat particles are created through the homogenization process with ultrasonic
treatment, where the fat pearls in the milk are crushed to fragments by ultrasonic treatment. This
creates fat particle with sizes below membrane size of the gastrointestinal tract, and they can thus
pass into the bloodstream. Once in the blood-stream, they may get into the brain if the blood-brain
barrier has been compromised.
2. Milk proteins:
a. Casein is the protein of cheese, and it also contains bovine growth hormones. The proteins
may cause allergic reactions, and in the continuation lead to allergic or immune
mechanisms compromising the intestinal gut lining membranes.
b. Gluten. There is often a reaction to gluten similar in effect to that of milk protein, where
the intestinal tract may become inflamed and through that process become more
permeable, letting certain substances through (Volta and de Giorgio 2010).
c. Legume proteins have been suspected to be involved in protein mimicry. Many empirical
diets for multiple sclerosis eliminate these with good results.
d. Once an allergic reaction has been produced with release of histamines in significant
amounts, the immune system is stimulated to increased alert.
3. Lactose. Some people are lactose intolerant and cannot properly metabolize it. This may cause an
allergic reaction as the substance is not properly metabolized. The role of denaturalized sugars
remain unresearched
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
4. Bovine antibodies to proteins. Bovine antibodies to proteins are present to pre-vaccine the calf just
after birth, while it is lactating, before the own immune system of the calf can take over. Leaky
gastro-intestinal membranes, will let them into the bloodstream.
5. Bovine membrane cell particles may also enter the bloodstream, if the gastrointestinal barrier has
been compromised, also causing harmful antibodies.
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Figure 4. A causal loop diagram for the effect of milk on multiple sclerosis.
A simplified diagram has been made, based on an interpretation of the complex causal loop diagram.
For gluten and dairy products in Figures 4-5 and the whole system in Figure 12. The simplified
diagrams are shown in Figures 13-15. Our first approach to a proposal is shown above in details, and
below in generalized simplification: Dairy products lead to membrane penetrating mechanisms, and
alien particles can enter the blood stream. The penetration may be a full two step process: First the
membrane of the gastrointestinal tract towards the blood is compromised. As a result, alien particles
may enter the blood, causing immunological reactions. If the blood-brain barrier has been
compromised, they may pass further into the brain, and if the immunological reaction that triggered
are focused on constituents common to the blood vessel walls of the blood-brain barrier, this
membrane may also be compromised in a second step. This is supported by the fact that many
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
multiple sclerosis patients have been shown to have symptoms of a leaky gut (Samarkos and
Vaiopoulos 2005, Salvemini et al. 2006). This in turn opens the door for viral triggers and blood entry
to the brain, that results in oxidative stresses and peroxynitrite production, leading to the traditional
multiple sclerosis aetiology. Immune systems responses to membrane fragments and degenerated
tissue in the blood stream, may lead to initiation of autoimmune responses that leads to myelin
destruction. This represents a known multiple sclerosis initiation sequence.
B-casein (and milk in general) as a co-causative agent for multiple sclerosis
Incidence of multiple sclerosis largely follows worldwide trends in dairy intake, and cell-mediated
immunity against milk proteins is increased in multiple sclerosis patients (Lindeberg 2010).
Immunoglobulin domains of antibodies specific for myelin oligodendrocyte glycoprotein, as found in
patients with multiple sclerosis, have been found to cross-react with butyrophilin, a protein found in
cow’s milk (Guggenmos et a/. 2004). Butyrophilin is the major protein associated with fat droplets in
milk, and when injected into rodents, produces the multiple sclerosis-like experimental autoimmune
encephalitis (Winer ef al. 2001). This is one of the main processes by which it is thought that
molecular mimicry might have a role in the aetiology of multiple sclerosis. A study has also showed
that patients with multiple sclerosis have higher antibody responses to both myelin oligodendrocyte
glycoprotein and butyrophilin (Kennel De March et a/. 2003). Also implicated is the chief milk
protein, casein, and its breakdown proteins, particularly the B-caso-morphins (BCMs). B-casein is one
of the four most common casein variants, with B-caseins Al and A2 being the most prevalent. Caso-
morphins are inactive within the native protein, but released during digestion. Once, absorbed, these
proteins have been shown to have opioid-like activity within the central nerve system. BCM-7 is also
associated with a number of psychiatric disorders (including schizophrenia and autism), as well as
associated with generalised inflammatory processes and autoimmunity (ischemic heart
and diabetes) (Kamiski er a/. 2007). Although no studies appear to have looked at the link
between BCM-7 and multiple sclerosis, it could be implicated in a generalised inflammatory response,
leading to increased permeability of the brain-blood-barrier. BCM-7 has been shown to be a direct
releaser of histamine from peripheral leukocytes when injected into healthy volunteers (Kurek et al.
1992). Digestion of B-casein-al do cause production of B-caso-morfine, cause non-specific histamine
release, activates mast cell granulations which will release MMP, the opening substance for the
intercellular junctions in the blood-brain-barrier. Many authors have discussed the importance of
gluten for multiple sclerosis (Hadjivassiliou et al. 1996, 2004, 2006, 2008, 2010, Gobbi et al. 1992.
Volta et al. 2002, Lock et al. 2005, Volta et al. 2006, Cervio et al. 2007, Swank et al., 1952, 1983,
Swank and Pullen 1983, Swank and Dugan 1987, 1990, Swank 1950, 1961, 1970, 1991, Swank, and
Goodwin 2003, Swank and Hain 1952, MacDougall 1980, Shor et al. 2009, Hernandez-Lahoz et al.
2009, Ferro et al. 2008, Reichelt and Jensen 2004, Reynolds 1992). Several of these, but especially
Swank and his associates have through a large database, built up on thousands of patients from 1948
to 2010, of empirical experiences been able to demonstrate the importance of removing gluten from
the diet for multiple sclerosis patients.
The mechanisms of gluten
Up to 10% of the general population are suspected to have some degree of gluten intolerance (Sapone
et al., 2011). Unlike wheat allergy, there appears to be a spectrum of diseases that arise due to gluten
intake, but appear to not be due to immunological mechanisms. The symptoms may overlap with those
seen in celiac disease, but are wide-ranging and can even be purely neurological (Hadjivassiliou ef al.,
2010). The commonest manifestation is due to cerebellar involvement, leading to “gluten ataxia”.
However, patients may also present with mixed sensory-motor peripheral neuropathies or central
nervous system white matter encephalopathy. All of these patients tend to have antibodies to Tissue
Transglutaminase-6 (TGA) and gliding (AGA), but only a third have any evidence of enteropathy on
biopsy. Gluten encephalopathy is associated with white matter lesions on MRI that are suggestive of a
vascular aetiology. Initiating a gluten-free diet aides resolution of symptoms, but the lesions do not
regress. There are also cases of patients with celiac disease presenting a multiple sclerosis-like illness
and white-matter lesions identical to those seen in multiple sclerosis (Pengiran Tengah ef al. 2004).
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Gluten
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Figure 5. Causal loop diagram for the effect of gluten and dairy products on the blood brain barrier
and the creation of immuno-provocative substances.
One study showed no difference in the presence of antibodies associated with gluten sensitivity (AGA
and Anti-TG2) between healthy controls, patients with multiple sclerosis and others with white matter
lesions of unknown aetiology. However, TG6 is found exclusively in neural tissue, and autoantibodies
against this enzyme weren’t assayed for. There is also no direct correlation between gluten sensitivity
and prevalence of multiple sclerosis (Paul et a/. 2008), but some studies show an increased prevalence
of anti-gluten antibodies in multiple sclerosis (Fischer et al. 2008, Rudick et al. 2009, Lindeberg,
2010, Ranohoff and Lucinetti 2011). A causal loop diagram for the effect of gluten and dairy products
on the blood brain barrier and the creation of immuno-provocative substances is shown in Figures 7
and 8The substances interleukin-1$ and TNF-a are produced from omega-6. Grain has omega-6,
gluten and lektins. One substance that has been recently proven to induce a permeable BBB is wheat
lectin, and the ability of foreign proteins to permeate the blood-brain barrier has been shown to
increase with the consumption of wheat lectin (Lindeberg, 2010). Gluten, its derivatives and other
grain/legume-based lectins are indirectly associated with multiple sclerosis through “leaky gut
syndrome”. Gliadin binds to the chemokine receptor CXCR3, which has been shown to lead to zonulin
release and tight-junction dissolution in the gut wall. This will increase gut permeability to any
partially digested macromolecules, which may lead to chronic inflammatory or allergic responses
produced in response to any dietary component. After a gluten insult, those previously on a gluten-
free diet appear to have increased intestinal permeability (measured with a cellobiose/mannitol probe)
for at least a week afterwards (Hamilton ef a/., 1982). In fact, intestinal permeability associated with
gluten intake was significantly greater in those with celiac disease than healthy controls. This implies
that almost all humans are susceptible to a gluten-induced increase in gut permeability, but gluten
sensitivity may indeed be a protective immune reaction, due to increased expression of claudin 4, a
protein associated with regulating tight junctions in the intestinal mucosa (Sapone et a/. 2011). Gliadin
itself may also be transported across the intestinal mucosa by transferrin receptor CD71 or by an
apical-to-basal transcytosis process, stimulated by interferon-y (Rubio-Tapia and Murray, 2010). The
gliadin-TG complex, once in the serum, is thought to provoke an immunological response that may be
possible for some of the neurological symptoms associated with celiac disease and gluten intolerance.
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Gluten contains the protein gliadin that may act as a mimic for myelin proteins. There are clinical
treatment records and anecdotic information available showing that diet over long time does have a
positive effect on the venous valve insufficiency (CCSVI), however, this has not been subject to
scientific medical study yet. For a possible mechanism, a causal loop diagram was developed, this is
shown in Figure 5.
CCSVI; The breakthrough of Zamboni et al.
Dr. Paolo Zamboni, professor of angio-vascular medicine, at the University of Ferrara in Italy
(Zamboni et al., 2003, 2005, 2006a,b, 2007, 2008, 2009a,b,c,d,e, 2010, Francesci et al., 2009,
Zamboni 2009, Khan et al., 2010) was the first to fully understand the significance of the vascular
observations as far back as in the 1930’s (Putnam 1935, 1937, 1939) and again in the 1950’s: (Fog
1948, 1951, 1964, 1965, Macchi 1954, Swank and Hain 1952, Lewis and Swank 1953), and again in
the 1980’s (Schelling 1984, 1986, Swank et al. 1983). Dr. Zamboni and his research team suddenly
realized that the venous constrictions leading to blood vessel leaks and breaching of the blood-brain-
barrier could be the cause and not the result of multiple sclerosis. Zamboni et al. (2008, 2009) calls
this chronic cerebro-spinal venous insufficiency, abbreviated CCSVI. He and his team could show in
clinical experiments that the constrictions in vessels draining the brain and the spinal cord probably
were related to the development of multiple sclerosis. A number of studies have demonstrated that the
constrictions come before the multiple sclers (Bowman 1947, Adams 1988, 1989). We observe that
all the veins that drain the central nervous system, may suffer from chronic cerebro-spinal venous
insufficiency and this causes: The pair of internal jugular veins, the pair of vertebral veins,
obstructions in the brachiocephalic vein (part of the clava), normally by wall thickening or single
obstructive flaps, single filaments or obstructive wall membranes and the azygos system draining the
spinal cord.
100
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Age of the patient having multiple sclerosis
Figure 6. By combining the different data available we may create a plot of evolution of degree of
CCSVI over time in the life of the patient.
Relapsing-remitting multiple sclerosis normally evolves into secondary progressive MS with time.
Primary progressive MS is normally progressive from the onset. We may conclude that the types of
multiple sclerosis are clearly associated with the location, type and number of vascular obstructions.
However, CCSVI do increase with time as the veins age. Lee et al. (2009, 2010) explains how the
venous insufficiency is caused by defects that develop already at the foetal stage. The main defect is a
malformation of the backflush valves of the veins. The most frequent anomaly is that one of the flaps
in the valve is misplaced, and points in the wrong direction. This implies that the vascular
insufficiency arise from (Al-Omari and Rousan 2010, Simka 2011, Zamboni et al. 2011):
malformation of venous valves caused by inflammation of the functioning valves, leading to
malformation and subsequently malfunction of the venous wall, leading to compromised BBB and
possibly being able to provoke stenosis when the vascular inflammation is chronic. The progress of
stenosis and obstructions progress from what appear to be a very low incidence, linearly with time,
throughout the lifespan of the patient.
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Cerebral temperature
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+ nee
_ leficiency
+ +
Venous a
insufficiency +
~«
Valve surface _ Demyelination
specific" \g cascade
antigen ‘Antigens Oxidant
attached to Hemosiderin —— tS
venous valvi se ltposis - Se ) ‘4 asad
a ‘ Blood-brain-Barrier f
ermeabilit a
oy P y
Activated venlus
immune system _backflush
NS we
+» degeneration +7
Figure 7. A causal loop diagram, drawn from the interpretation of two provocative agents being
active, one that produces antigens specific for venous valves and vein walls and one active against
proteins similar to myelin. This would be consistent with the plot shown in Figure 3.
Malformed valve flap, pointing in the wrong direction
Normal valve flap Normal flow direction
Figure 8. Ultrasonic picture of a healthy jugular vein valve is shown to the left, to be compared to
the broken on the right. Sonogram of multiple sclerosis patient, 26 years old, picturing the right and
left internal jugular veins bottom backflush valves. Both are malformed, and block the blood from
draining the brain properly. In each valve, one flap, the lower, is normal and the upper is wrongly
placed. Pictures by the authors (Sverdrup et al 2012).
This implies that MS progress is independent of existing venous obstructions, and that it is not caused
by the neurological part of the multiple sclerosis, suggesting an external cause (environmental, diet
factor, something that remains fairly constant). From this we may correlate vascular insufficiency into
three basic types of multiple sclerosis each associated with specific types of vascular insufficiencies:
1. Relapsing-remitting multiple sclerosis; vascular insufficiency; (one internal jugular vein and
azygos vein, both internal jugular veins and azygos vein) vascular insufficiency. 65% of the cases
develop secondary progressive multiple sclerosis as vascular insufficiency progresses with age
and gets worse.
2. Secondary progressive multiple sclerosis vascular insufficiency; (one internal jugular vein and
azygos vein, both internal jugular veins and azygos vein, 2 internal jugular veins).
10
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
3. Primary progressive multiple sclerosis vascular insufficiency; (azygos vein and azygos tributary
veins) only oriented around the spinal cord and its associated blood supply. Jugulars and vertebral
veins are competent. The patient stays cognitively normal, but mobility is gradually lost.
4. Progressive relapsing multiple sclerosis vascular insufficiency; with complex and multiple
vascular insufficiency, affecting the brain, spinal cord and renal system (azygos vein and azygos
tributary veins and both internal jugular vein and both internal vertebral veins, Illiac vein, renal
vein). Quickly leads to central nerve system breakdown and demise.
Thus we can
multiple scleros
blish a relationship between the types of vascular insufficiency and different types of
, remitting relapsing, secondary progressive, primary progressive.
Vascular flow rates and their ramifications
Constriction in the blood vessels that drain the spinal cord and brain leads to reflux of blood, that in
turn cause minor leaks into the brain. The draining vessels are located far from the heart in the
vascular system, and thus have low pressure gradients to operate under, taking support also from the
pressure-variations caused by breathing (Zamboni 2010). Stenosis of the veins impedes blood flow,
implying that less blood can return from the brain. In a recent study Zamboni et al. (2010) compared
the venous status of 109 persons diagnosed with multiple sclerosis, and 177 persons determined to be
without the illness. Of those with multiple sclerosis, Zamboni’s team could find venous constrictions
in all of them (100%). In figure 8 from a multiple sclerosis patient, 26 years old, the right and left
internal jugular veins bottom backflush valves are malformed, and block the blood from draining the
brain. In each valve, one flap, the lower, is normal and the upper is wrongly placed. Their results show
that 97% of the patients have malformed valves, constricted veins or collapsed or missing jugular
veins. The interpretation of MRI scans, combined with Doppler ultrasound scans for checking actual
blood flow in the detected sections, are central to the diagnostics of multiple sclerosis (Zamboni et al.,
2009, 2010).
R_JUG SUPIN MID
Figure 9. Ultrasonic Doppler measurements on disturbed flow through the right jugular vein with
malformed backflush valves is shown. The measurements were made in erect and supine position,
when the jugular veins carry 70% of the total brain blood drainage. The right jugular vein has clear
backflushes, amounting to about 30% of normal flow. The scale of flow velocity (m/s). (Image by the
authors at the Essential Clinic, Glasgow).
Flow measurements and the ramifications of restricted blood flow through the brain
Flow through the veins draining the head can be assessed using ultrasound techniques in non-invasive
examinations. These examinations show that the blood flow can be significantly reduced. Figure 9
shows ultrasound Doppler measurements on flow through the left and right jugular vein with
malformed backflush valves and significant flow impediment (Sverdrup et al. 2012). The
measurements were made on a young man in erect position, when the vertebrate veins carry 70% of
the brain blood drainage as compared to the flow through the jugular veins in the supine position when
the situation is reversed (Weir 2010). Those with multiple sclerosis ed by vascular insufficiency,
show symptoms of oxygen deficiency to the brain, similar to altitude sickness. Dizziness, confusion,
problems with concentrations, lowered cognitive abilities, is all results of lack of oxygen supply to the
brain. Bastianello et al. (2011) analysed the clinical data of 710 multiple sclerosis patients attending
six centres carrying out liberation treatments. All patients had been submitted to venous Doppler
sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al.
11
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
(2009). CCSVI was diagnosed in 86% of the patients on the average, but the frequency varied greatly
between the treatment centres. It is possible that these malformed veins are the result of an immune
attack on the valves in the cerebral venous system, which causes chronic inflammation and wall
scarring. In a recent review of the role of venous reflux, Simka (2009) stated: "It is hypothesized that
pathological refluxing venous flow in the cerebral and spinal veins increases the expression of
adhesion molecules, particularly ICAM-1, by the cerebrovascular endothelium" (Simka 2011). Along
these lines, Ono et al. (1998) and Bergan et al. (2007, 2008) demonstrated, by occluding a major vein
in laboratory rats, that the number of leukocytes migrating across the vessel wall increased
progressively during occlusion. Multiple micro-haemorrhages occurred upstream of the occlusion
(creating holes in the of the blood-brain barrier; these are usually 20-30 jm in diameter, but some
breaches in the blood-brain-barrier are as large as 200 wm, real holes visible to the naked eye). "The
venular occlusion experiments showed that reduced flow can rapidly set in motion an inflammatory
cascade, including hallmarks like leukocyte adhesion to the endothelium, migration into the
interstitium, free radical production and parenchymal cell death that begins soon after occlusion..."
Antibody valve
surface adhesion
valve
- inflammation —.
Antibody to valve + + RS f
surface protein Nenous ae
molecular mimicry
f ‘. ‘
| ~ Immune 2 d \
response
Local pressure
we Stagnant blood shocks Oxidative stress,
in the small free radicals
Immune reaction vesvel * +
to alien substances : +
+
| Minor leaks R2
Lining in microvessels iron
: inflammation ———— * in the brain accumulation
+
Fs + x Ps
alien substances > . MY ood
in blood
Antibody gntey to
brain
production Stimulation of
+ RI histamines and MMP
Electromagnetic
radiation
Leaky gut qu,
problem
a”
Unsuitable _ +
diet
Figure 10. Causal loop diagram for the effect of vascular insufficiency. The emphasis of this diagram
is to show how the venous vessels become leaky and open a door through the blood-brain barrier.
Figure 10 shows a causal loop diagram for the effect of vascular insufficiency. Figure 3 shows some
of the mechanisms that actually open the blood-brain-barrier. Figure 4 shows the causal loop diagram
for the activation process for T-cells outside the central nervous system (CNS) and the role of
molecular mimicry initiated by viral and bacterial infections. Key is the MMP compound that opens
the tight joints in the blood-brain-barrier, histamine also can do that, it holds a key role not recognized
for what it does. Figure 11 shows how CCSVI may unbalance the system within a multiple
slerosisOsueceptible individual. The implications we have drawn from reading the literature is that
either bacteria and/or virus may deliver the triggering protein material, but that it a virus is needed to
incorporate it into a T-cell to be smuggled across the blood-brain barrier. Without CCSVI and
12
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
bleeding in the brain, the system consists only of balancing loops (B1-B9) and there is no way for a
runaway reaction. However, CCSVI introduce some new links, creating four new reinforcing loops in
the system (R1-R5), destabilizing it. The introduction of interferon treatment affect B8 and B9, but
also the reinforcing loop R5. The average incubation time for multiple sclerosis from initiation,
appears to be about 6 years after the triggering infection or incident (Dean and Kurtzke 1971).
However, Figure 3 actually tells another story, that the cause is there from the first year of life.
Activated § 4
Th1-cell
Allergenic thse — Antibodies
stimulus __ , T \ * Macrophage
from food ~“. 5 Fo OE B8 activation BY t
uper” BT a +
ames nan
Interferon x
\ ra B7 B-cell
Allergies from Viral IL-10 activation
external agents infection IL-4 " Fal
+ Myelin x BS -
So -* + ® protein B4 ‘, + +
Exposure ve BB mimicry N\ \
Ng mp Bacterial Ls ~ NSS Activated
infection oS
Th2-cell
Blood-Brain -Barrier
ccsvi ———__— + = permeability
a itric
BBB ae ate Sl 4
adhesion — R2 MMP R1 + NN
substance KR n A Blood
ns deposits in
awed ae Sie the brain
+> Thi-cell
Allergenic — ‘Antibodies
stimulus + sm Macroph
from food ~~ ae Sree we B9 +
Super® BI — BS activation
vi +
antigens +7 kh Fi
+ 4 j
+ Interferon RS 4 ) R3 a
Lowe 87 B-cell
Allergies from Viral I-10 activation
external agents infection
Myelin “hat\,
So 7 +> protein ®
Bapasere BB nines) be! ee od
XN Bacterial S,_ Mibaiiel
> — + Retvated
fecti
infection Th2-cell
+
Figure 11. On top, we show the Ty1-Ty2 immune system, without the presence of CCSVI, in a causal
loop diagram for the activation process for T-cells outside the central nervous system (CNS) and the
role of molecular mimicry initiated by viral and bacterial infections. Below, is the system with CCSVI
involved. It can be seen how CCSVI introduce some new links, creating four new reinforcing loops
in the system (RI-R5), destabilizing it. There are no balancing loos attached to two of them. Viral
and bacterial infection, may under some circumstances, incur molecular mimicry as well as antigens
that activate naive T-cells to become Tyl and Th2 cells.
Additional effects of chronic cerebro-spinal vascular insufficiency
In multiple sclerosis there are three different symptom layers put on top of each other:
1. Effects of oxygen deficiency in the brain and spinal cord
2. Effects of occasional local overheating and tissue damage
13
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
3. Nerve damage in the brain and spinal cord
Figure 13 summarizes the coupled effects of oxidants and oxidant stresses on nerve tissues, after
Gilun-Sherki (2004) and Foster (2006), and interpreted by the authors. Oxygen depravation has turned
out to be one of the main causes for several of the early symptoms in multiple sclerosis (Matute and
Perez-Cerda 2005, Trapp and Stys 2009, Juurlink 1997, Keyser et al 2008, Zamboni et al 2009).
Overheating of the brain seems to interact with both the immune attacks as well as the effects of
oxygen depravation (Gupta et al 2002, Lavinio et al., 2007, White et al 1996).
Oxidant stresses reworked into causal loop diagrams
After entry of iron to the brain, a production of free peroxynitrite starts after the local
reservoirs of antioxidants have been depleted. This affects the autoimmune cycles and the scarification
of damaged myelin tissues. It also starts a process, where the blood-brain barriers now becomes
punctured from the brain side and out towards the blood in the body. The blood-brain barrier has is
severely compromised through this process. Haider et al. (2011) confirms the presence of oxidized
DNA and oxidized lipids in the mitochondria of astrocytes and in particular oligodendrocytes in
multiple sclerosis patients, but not in controls. Oxidized DNA of oligodendrocytes correlated well
with active ongoing inflammation and active lesions. Inflammation is not one single phenomenon, but
there is a connection between inflammation, caused by microorganisms, and the subsequent immune
system attack against the lesions. This stands in a communicating system with the regeneration, where
attack and damage leads to activation of regenerative processes. According to a strictly
immunological explanation of multiple sclerosis, the inflammatory process is caused by T-cells, a type
of lymphocyte. Lymphocytes are cells that play an important role in the body's defences (Compston
and Coles 2002, 2008). In multiple sclerosis, T-cells gain entry into the brain via the blood-brain
barrier (Figures 4 and 7). Evidence from animal models also point to a role of B cells in addition to T-
cells in development of the disease. The T-cells recognize myelin as a foreign substance, it becomes
marked as alien by attached antibodies, and the immune systems attack it as were an invading
virus. This triggers the inflammatory processes, stimulating other immune cells and soluble factors
like cytokines and antibodies (Figure 9). Antibodies and potentially, denaturalization of the protein
surfaces by oxidants and metals, cause the sheath to appear as alien. Free radicals promote the
inflammation and retard the myelin sheath regeneration process. Several factors affect free radicals
and the oxidants that are their precursors. Vitamin A, C, E, K, and D are all oxidant scavengers. Both
NO and Fe”'/Fe™ are involved in generation of peroxides, superoxide, peroxynitrite and free radicals
(the Fenton reactions), all highly toxic to any living cells. In multiple sclerosis, oxygen deprivation is
not very pronounced, but rather local and occurs through localized blood vessel lesions, and the
damage associated with the iron accumulation. Free radicals are known to create blood vessel ulcers
(Simka and Rybak 2008), and most probably establish a reinforcing link, keeping the pathway
through the blood-brain barrier permanently or intermittently open, suggesting an explanation of the
remitting/permanent types of the illness. Blood deposited in the brain generates NO* upon
decomposition and leads to the deposits of iron in the brain. This is under reducing conditions
transformed to free iron ions (Fe~’). These auto-catalyse degeneration of vitamin C, catecholamines
and Vitamin E and may overcome the protection system against free radicals locally. When this
happens, the metabolites will contain superoxides, further aggravating damages (Coyle and
Puttefarcken 1993). The free radicals and Fe" in the brain interferes with the regenerative function of
the oligodendrocytes. It is also suspected that they may have a role in changing harmless antibodies to
a kind that initiate Th1 cell attack on the myelin sheaths of the brain.
Peroxynitrite and superoxide
Peroxynitrite is a very damaging oxidant, perhaps the most important in multiple sclerosis as well as
other illnesses of similar nature (Pacher et al. 2006). It is formed very rapidly from superoxide and NO
(Gilun-Sherki et al. 2002). NO is produced in the body at many sites, and serves as a signal substance
in many instances. It is thus always present and can do significant damage to membranes in the body.
Superoxide and hydrogen peroxide is regularly formed in mitochondria and during the normal
operation of many cells, normally these are neutralised by metal-superoxide dismutase and the
hydrogen peroxide by catalase. Nitric oxide (NO) in the system is important for this, as well as the
14
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
stimulus from excess Ca”*. Superoxide is not supposed to be forming in amounts that will allow it to
float freely around, but when the local superoxide dismutase capacity is overwhelmed, then
peroxynitrite will be the result. Peroxynitrite is destroyed in a first order reaction with respect to
glutathione peroxidase. And the oxidised glutathione peroxidase is regenerated at the cost of 2
glutathione (Stepien et al. 2000, Salvemini et al. 2006, Virag et al. 2003, Pacher et al. 2007, Szabo et
al. 2007, Szabo 2003, Toncev et al. 2002, Druclovic et al. 2001, Spitsin et al. 2001, 2000, Hooper et
al. 2000: Nelson et al. 2002), and selenium is required in the process. Low selenium status will thus
affect the antioxidant status of a person. Vitamin E and C form an important function as scavengers of
oxidants. They are not always catalytic like superoxide dismutase, glutathione peroxidase or katalase,
but still important. Thus, a potentially powerful detoxification mechanism is in place to take care of
oxidants in the body, and under normal conditions, this is very effective. However, through blood
vessel leaks, conditions arise where the antioxidants locally become exhausted, leaving residual free
radicals. In the micro-clotting that occurs in smaller and capillary blood vessels of those with multiple
sclerosis (Swank 1952, Lewis and Swank 1953, Fog 1951, 1964, 1965, Swank et al. 1983, Zamboni et
al. 2010), conditions will arise where peroxynitrite will be produced. The endogenous antioxidant
enzymes like katalase, glutathione peroxidase and super oxide dismutase then have supply restrictions
at the incidence site. Then peroxynitrite will cause increased permeability of the blood-brain barrier,
and keep it permeable as long as the conditions are such that the peroxynitrite cannot be cleared.
Figure 12. Causal loop diagram of the whole system with emphasis on the immune system. Here we
have put the diagrams together so that the multi-factorial aspects of multiple sclerosis development
can be viewed together. Such a large diagram is necessary as a part of the development, but
unreadable in any report, thus the Figures 13-15 were developed for communication and focusing
purposes.
The symptoms of multiple sclerosis arise partly from immune systems attack on the nerve system, but
as well from radical and peroxynitrite damage to tissues as well as damage resulting from oxygen
deficiency in the brain.
15
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Summarizing root causes of multiple sclerosis
In Figures 13-15 we show the causal loop diagram for the whole system of multiple sclerosis. Here we
have put the diagrams together so that the multi-factorial aspects of multiple sclerosis development
can be viewed together. We have simplified the large causal loop diagram (Figure 12) with all the
details, down to a simple diagram (Figure 14) showing the most important loops and their
interconnections. From this diagram, we can see the initiating functions, the compromising of the
blood-brain barrier, the starting of the oxidative stresses, interacting with the autoimmune reaction to
protein mimicry, promoting scarification and attacking the regenerative function. We can see that the
medical doctor treating a patient will see the symptoms of 3 ailments overlaid on each other:
1. The effect of oxygen deficiency in the brain and spine leading to depression, cognitive
deficiency and confusion
2. The effect of brain overheating leading to the classical symptoms of heat-stroke. Eventually,
this may lead to permanent tissue damage
3. The effect of damage to neural tissue in the brain and spine leading to immobility, failure of
inner organs, cognitive problems, impaired eyesight etc...
Multiple sclerosis has no simple cause-effect relationships that traditional methods will find. Multiple
lerosis is a whole system disease and must be seen as a system for any progress to be made. We can
see that there are three important reinforcing feedback loops in the multiple sclerosis system that must
be terminated in the treatment systemic process:
1. A feedback loop between minor vessel leaks and free radicals.
2. A feedback loop between immune system attacks, further production of iron and oxidants,
triggering autoimmune response
3. A feedback loop between wrongly triggered antibodies and myelin damage from leukocyte
attacks that produce more debris that further triggers attacks.
All feedback loops must be closed in order for treatment to be effective. The integrated systems
picture for multiple sclerosis with three different symptom group outputs is shown in Figure 16. This
causal loop diagram was instrumental in developing a treatment strategy for turning the illness off,
avoiding the internal self-reinitiating mechanisms. Figure 16 summarizes the treatment strategy as
superimposed on the systems diagram for multiple sclerosis.
The systems dynamics model
Based on an integrated conceptual model for multiple sclerosis, a computer model was developed. The
Integrated Multiple Sclerosis simulation model was validated against patient datasets. The numerical
simulations model is based on mapping the whole structure of the disease with systems analysis. The
causal loop diagrams form the basis of the design for the model. The model was programmed in the
modelling environment STELLA, and parameterized on literature data and patient data (Figure 15).
The conceptual model is expressed as causal loop diagrams, flow charts and inter-parameter
quantifications were used to create the model. Examples of model outputs are shown in Figure 16. The
model was used to simulate the progress of the disease with time for different potential treatments,
including state-of-the-art medical approaches. This development work is still going on. We may from
the modelling draw some important conclusions: The model seems to be able to predict the general
outline of the disease as it is observed, a relapsing remitting behaviour between the onset and when it
transforms into a progressive type. The remitting-relapsing multiple sclerosis with attacks are
reproduced. The use of a multi-component treatment strategy seems to be able to cause significant
improvements, if the underlying vascular problems can be improved. There is a shut-down sequence
that must be followed, if not, the feedback loops will restart the illness. The model stresses the
superiority of combined strategies, including diet, over single-component treatments. In the vascular
system, we generate the flow constrictions, that create pressure shocks in the system, reverse flows
and precipitations of minor clots in the fine vessels, that in turn leads to BBB permeability.
16
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Antioxidants
Minor lesions
in microvessels <q +
in the brain
‘Superoxide
\
r ’* h A gf lee
free radicals
~
Oligodendrocyte
Blood
entry to
he brain NO — 4
/ Fenton eB ae
+ reactions
— as
Blood = ay
decomposition
Vv PN,
Sheath soho
wom ee
® damage
Immune attacon signals
Antibody and modified
T-cell entry to the brain
SV * 7
‘at -_ R 1 a
Myelin-active Myelin
antibodies fragments
~~, ed
Figure 13. The effect of oxidants and oxidant stresses on nerve tissues, after Gilun-Sherki (2004) and
Foster (2006), and interpreted by the authors. Blue is the action of antioxidants, red is the actions of
iron and nitric oxide to create oxidative stresses, light green shows the actions of the immune system,
and black is the leakage through the blood-brain-barrier. Brown is the actions around the
oligodendrocytes that should carry out repairs on damaged nerves.
The dietary module, takes a certain diet and breaks it down to allergens, mimicry protein, different
fatty acids, oxidants, histamine, antioxidants and vitamins. The immune module, simulates the
activation of naive T-cells, and their conversion into Ty1, Ty2, and B cells, as well as carrying out the
attacks on myelin (Figure 9).
A new treatment designed
Here we use the insights gained by building the model for multiple sclerosis development and
progress to explore possible cure strategies. It can be seen that treatment must primarily do three
things above all else:
1. Eliminate the dominating root cause: investigate for any evidence of CCSVI and consider
liberation treatments if appropriate, though more studies are required.
2. Eliminate the pathogens and damaging constituents that may exploit the open passage into the
brain and keep it open and trigger the immune system.
3. Terminate the self-sustaining autoimmune carouse
a. The autoimmune cycle ruining the myelin sheaths, their destruction and prevention of
regeneration.
b. The oxidative stresses and oxidative attack on the blood vessel lining, keeping the
oxidative cycles going.
17
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
The strategy developed below has this aim, i.e. to stop the starting mechanisms, stop the self-
perpetuating processes and to make regeneration of damaged nerve tissue possible. the patient can
return to the same behaviour as before the onset of multiple sclerosis. He must most probably stay
away from those components of the diet that caused the illness forever, and failure to do so may
reintroduce the illness again.
Blood flow
insufficiency
“ —- > through the
ve = brain
Vascular - a
insufficiency ‘
. 1 Cooling
ro + Xs Insufficient
components Antibédies - onvgen
a \ Brain supply
7 \ overheating Gf
4 \
x J + Compromized 7 f
Gut RS bow brain RZ + % {
leak in
7 } Cellular
( ite eon
te ar = inflammation deficit
4 wi 4
\ Sotaan AS
% + cycle
Protein 7 N
mimic !
ve A ri + Py
® Molecular _: y Regenerative
+ precursors “& Immune omy Cognitive
in blood a ern
+
Infectous ‘Nerve a Nt
agents ‘damage re
.—
+
Body control
problems
Figure 14. The symptoms arise from both chronic cerebro-spinal vascular insufficiency leading to
compromised blood brain barrier, transfer of immune response-provoking substances and oxidant
precursors into the central nerve system that leads to neurological damage caused by autoimmune
tissue destruction and tissue damage from oxygen deficiencies and anoxic metabolism metabolites.
Black is the multiple sclerosis section, red is the brain heat damage section and turquoise is the
oxygen deficiency section.
Since there is a strong element of food allergy at the root of multiple sclerosis, that does not imply that
We suggest here several main lines of treatment in the strategy:
1. Stop triggers and provocative toxins:
a. Remove all gluten, dairy products and legumes from the diet.
b. Until proper blood flow has been restored;
i. Avoid going to high elevations, exhaustion that may bring down blood
oxygen concentrations
Avoid exercises that may increase the risk of overheating the brain.
iii. Avoid warm climates and any environments with temperatures above 27°C.
c. Stop provoking infections: Terminate any ongoing triggering infections in the upper
respiratory tract or sinuses by boosting the immune system with food containing
vitamins and minerals that support the immune system and/or take relevant vitamins —
and/or administer relevant antibiotic drugs.
2. Cut feedback loops:
a. Get treatment for any constricted blood vessels, invasive or other method, in order to
restore proper blood-flow for draining the brain and spinal cord of returning blood.
18
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
This implies invasive treatment to eliminate chronic cerebro-spinal vascular
insufficiency (CCSVI).
b. Elimination of free radicals through vitamin and antioxidant therapy in order to
prevent weakening of vessel walls, and disruption of antibody programming.
Strengthening the myelin sheath repair mechanisms with essential nutrients like
omega 3 for healing
c. Immuno-regulating medication to break off the vicious autoimmune circle acting on
oligodendrocytes and myelin sheaths, for example with interferon-B type short term
intensive treatment.
3. Rebuild damaged structures:
a. Strengthening of regenerative mechanisms (oligodendrocytes), through the necessary
resources demanded (e.g. omega 3 and?) as well as growth factors that can be included in
the diet.
b. Prevent further BBB opening substances by filling the BBB membranes with flavonoids
that prevent adsorption of foreign substances. The flavonoids from blueberries,
blackberries and blackcurrants are most effective.
4. Remove risk factors
a. Avoid all high histamine diets (Certain types of wine, fermented foods, old fish etc)
b. Avoid heavy metal exposure of any kind
c. Eliminate any unnecessary microwave radiation as it is suspected to be able to
compromise the blood-brain barrier and smaller venous blood vess
Other treatment is only supportive until this has been achieved. For further recovery, removal of
accumulated iron from the brain will be important, elimination of radicals through restoration of
vitamin status, supply of proteins and optimal fats, restoring the regenerative capability, and
elimination of trigger microorganisms in order to prevent relapses.
Discussions
Many articles focus on narrow aspects of multiple sclerosis and go in-depth on that, but seem to loose
the overall understanding. However, that does not lead to any systemic overview, and thus such a
methodology cannot find a cure. Only with people like Foster, Schelling, Simak, Zivadinov or
Zamboni was a more systemic approach possible. However, none of these distinguished scientists are
yet trained in systems analysis, they still haven’t learned those tools sufficiently well and thus do not
fully manage to build up a complete system where it can be said to constitute a model. For that, a
transdisciplinary systems approach and proper training over several years will be needed. Since
multiple sclerosis appears to be a multi-agent system, there will not be any single-cause type of
evidence available. From the derived causal loop diagrams, handbooks in nutritional therapy were
used to look for points of treatment entry to the system (Cordain 2006a,b,c, Cordain et al. 2002, 2003,
2005, Eaton et al. 2007, 2009, Ahn et al. 2006a,b).
19
Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Hyperthermia
symptoms
4 Hypoxia
: 7 mptoms
a
Blood vessel = + “b> Overheating
insufficiency _ Oxidant precursor
A food additives
Environmental Oxygen
deficiency
~~ Pd a / Antioxidants
Permeable + a a™
+ +
blood-brain a BRD, x
i Oxidative —~ Pood
+7 SS — stresses
Al \
‘
wil fh N
+ NO \
\ re Essential
Histamines 4p of immunologically _ -® components
4 os “ee i 7 wf
Fi
chemistry factors
Allergenes
Oligodendrocyte
~ > mediated myelin
Aan A 7 8 mann
+ t . Triggering ‘of R4
Unsuitable a > immune system <#—~ .
food wo
‘Myelin
7
> damage
Infections
Neurological and
immunological symptoms
Figure 15. Integrated systems picture for multiple sclerosis with three different symptom group
outputs. This causal loop diagram was instrumental in developing a treatment strategy for turning the
illness off, avoiding the internal self-reinitiating mechanisms. RI-R5 are reinforcing loops, B1-B4 are
balancing loops.
Hyperthermia
Behavior Symptoms Hypoxia
Vascular adjustment i symptoms Food
surgery ™, + / safety
ey ee regulations
Vaccinium N. -- +e mm
myrtillus c 4 » Overheating Consumer
avoidance
~~
Blood vessel _ Oxidant precursor
insufficiency cougar food additives =
#N deficiency | ‘
* N
<K pereate SS 5
Environmental
protection +
policies
Environmental
chemistry factors — Oe Ta —s, Protective
, Spe Fr Wcisnte a Prt
/ Tor barrier Shae 7
! op Hstamines a x
* ‘
m j
Lan ol ~~.
\ r Transmission z
of immunologically components
= oe ey,
Fi
regeneration Z
\
active substances
¢—w Antibodies 4+
Triggering’of
Prophylactic". immune Ne
a ihe x
aa Nain pe
Pam > camage --
diet
Behavioral Ly NS
caution
Antibiotic
treatment uel and
4 immunological
symptoms
Figure 16. A simplified causal loop diagram for MS, depicting the treatment strategies as well as the
superimposed symptom assemblies.
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Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
Figure 17. Overview of the STELLA model structure of the simplified model version.
“ger 2
Figure 18. Outputs from the computer simulation model developed by the authors. The outputs are
consistent with observed patient histories. The left diagram shows the evolution of attacks with time
(the zigzag curve with a hockey-stick shape, showing the transformations from relapsing remitting to
secondary progressive multiple sclerosis. Oxidant stress and antioxidant status are predicted. The
diagram to the right shows weight loss in different types of brain tissue as the illness progresses.
Conclusions
A firm conclusion of this study is that multiple sclerosis is a systemic illness, with multiple interacting
causes and mechanisms:
1. Chronic cerebro-spinal vascular insufficiency (CCSVI) that may lead to:
a. Permeable blood-brain barrier and transmission of antibodies, leucocytes and
unpermitted substances from the blood into the CNS, caused by malformed valves and
stenosis of the vein, leading to stagnant blood in the capillary vessels
b. Insufficient drainage of blood from the brain, causing less blood flow through the
brain and thus brain oxygen deficiency
c. Insufficient cooling of the brain, resulting in general nerve tissue damage
d. Leakage of blood into the CNS
2. Presence of protein mimicry in the bloodstream caused by:
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Oral presentation at the System Dynamics Society conference at St. Gallen, Switzerland, July 23-26th 2012
a. Infections from certain bacteria and viruses that leak through the BBB to trigger
immune response against nerve tissue
b. Leakage of pro-inflammatory substances in the bloodstream originating from food,
(gluten, dairy, legumes) into the central nerve system through the compromised brain-
blood barrier
3. Feedback system involving iron from blood decomposition, acting in the autocatalytic Fenton
cycle and causing production of oxidants
a. Reinforcing the increased permeability of the blood-brain barrier from the inside, as
well as causing general tissue damage
b. Oxidative damage to the oligodendrocytes and the myelin repair function
4. Feedback loop involving immune system activation, attacks on the myelin sheaths, and myelin
sheath breakdown, further triggered by more myelin debris
The symptoms of multiple sclerosis develop as a result of gradual destruction of the central nerve
system, through immune system action and the effects of oxygen depravation and reoccurring
deficient cooling of the brain. The treatment should be designed at targeting all causes listed above
simultaneously, stopping the triggers, such as the cause for blood vessel leaks and targeting the
triggering infections priming the immune system, as well as stopping self-propelling vicious circles,
(immune and autocatalytic oxidant stress cycles) as well trengthening the regeneration capability.
Multiple sclerosis is not a single cause illness, but a whole integrated system of causes and effects.
The systems overview is crucial for understanding the illness and for developing a treatment strategy
for it. Our results show that no single treatment will do, a series of measures are necessary to stop the
re-initiation of the inflammations, stop the precursors of free radicals, stop the autoimmune response,
repair the compromised blood-brain barrier, all at once. And they will have to come in the right order,
or the illness will self-reinitiate. Multiple sclerosis is a systemic illness, with multiple interacting
causes and mechanisms:
1. Leaky blood vessels leading to permeable blood-brain barrier and transmission of antibodies
and leucocytes into the brain
2. This triggers infections from certain bacteria and viruses
3. A feedback system evolves involving iron in the autocatalytic Fenton cycle and production of
oxidants, reinforcing the increased permeability of the blood-brain barrier
4. Immune feedback loop develops involving immune system and myelin sheath breakdown,
leading to brain side damages to the blood-brain barrier, driven by oxidative denaturalization
of the myelin surfaces.
The treatment is designed at targeting all 4 causes at once, stopping the triggers including the cause for
blood vessel leaks and targeting the triggering infections, as well as stopping autoimmune self-
propelling vicious circles, and as strengthening the regeneration capability. Figure 13, explains why
the whole sickness takes time to progress and move in discrete steps. A cure must start with
elimination of the initiators of the strongest causal factor. For multiple sclerosis this is leakage of
blood and immuno-active substances across the blood-brain barrier that starts iron deposits in the
brain. At intervals, the immune system will overcome the damage that is caused and initiated by blood
vessel leakage and infective triggers. However, since the drivers are persistent, they will re-initiate the
system, leading to the remitting-relapse type of illness. After some time, the damage will be so large
that the immune system capacity is overrun and the multiple sclerosis progress becomes persistent.
Our model is able to describe the evolution of multiple sclerosis in a patient, including the transitions
and the timing of these. The details of the illness in the vascular and immune system are well
modelled. The model is useful for investigating treatments for finding the cure for multiple sclerosis.
Modelling work is ongoing and we expect to be able to report more at a later point.
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