The Vein Lesion Relationship in MS

A normal blood-brain barrier is made up of healthy, tight blood vessels that keep blood cells and other harmful blood-borne substances from crossing through and damaging the brain. But as we age, vascular walls can become weakened or damaged for various reasons, including due to head or neck trauma. There is an intense new global research effort to determine the role of vascular injury in neurodegenerative diseases from MS to Alzheimer's. It turns out that vascular injury may be more prevalent than anyone thinks.

By Henry Broeska, Irvine California, May 22, 2019

NOTE: This was some of the original work of Alphonse (Franz) Schelling that guided our research forward from 2010. The first section of this article contains Schelling’s own narrative from a presentation he gave in Vienna in 2010 and in Rome in 2014. In early 2014 I spoke with Prof. Schelling to inform him of our hypothesis which prompted a question and answer thread on email. He was intrigued but concerned that the induced retrograde flow in the IJVs could be an effective delivery mechanism for a therapeutic agent. He confided that he had never considered stem cells as a potential treatment in the repair of damaged tissue due to the MS disease process. His own hypothesis, which he has championed for decades based on well-founded evidence, only accounted for a cause, not a cure. I sent him our data on the intravenous pressure gradients and he committed to follow our studies. I have now forwarded to him our published manuscript and that’s where the discussion has been left it for the moment.

In Professor Schelling's own words:

“I made observations which turned my attention to Multiple Sclerosis which were widenings like varicose veins in skulls which I found in the archives of the neurological hospital in Salzburg in 1982/83. Of the skulls showing abnormal widenings of the transition between the sigmoid sinus and internal jugular vein 80% had a diagnosis of MS. So I was forced to study the literature and I was amazed that nobody had noticed these SPECIFIC observations and specific kind of changes in the brain. THESE CHANGES WERE ALWAYS DEVELOPING AROUND VEINS NOT AROUND VENULES.”

Fig 1. 7T axial view image of MS brain demonstrating precise lesion correspondence to inner cerebral veins

The Vein-Relationship in Cerebral Multiple Sclerosis

“Whereas Carswell's lateral spinal patches, according to the condition's classical illustrations did not seem to be pervaded by any special structures, Charcot's specific brain plaque was (as the images immediately disclose), plowed through with conspicuous vascular channels. Knowledge of cerebral vascular anatomy enables us to identify these ramifying structures as relatively large veins draining the central parts of the cerebral hemispheres. This relationship appears unusual enough to merit a concrete, careful scrutiny.”

Charcot: First Indication of a Vein-Lesion Relationship

“A closer look at the drawing below is Charcot's first illustration of cerebral multiple sclerosis, reveals the following: The lesion is spread about the periventricular veins’ central course, i.e. the injurious process primarily involves the stronger vein segments. In addition, the peripheral lesion projections show a certain dependence on the course of major venous branches. The involved vein lengths themselves appear partly contoured by distinct, generally one-sided or at least eccentrical widenings of their perivascular spaces. As to the actual wall of the lesion veins, however, the illustration does not reveal anything unusual.”

Fig 2

“Curiously, it was not Charcot but Otto Buss of Göttingen who is credited with the discovery of a vein-relationship of the lesions of multiple sclerosis in general. What is thereby consistently referred to is a case report of Buss', presented in 1889, whose macroscopical lesion description seems at least compatible with a multiple sclerosisspecific affection of certain lateral and posterior sectors of the spinal cord. The observation that only the brain lesions preferentially harbor one larger or several medium-sized veins is also of interest. Yet neither as to the spinal cord nor to the brain did Buss provide a lesion specification which proves really distinctive of multiple sclerosis. In the given context, his report therefore deserves not to be paid further attention to.”

Dawson's Detailed Evidence

“The first written indication of an involvement of periventricular veins in the process of cerebral multiple sclerosis, as related by James Dawson, revealed the following: In the extensive areas of sclerosis immediately contiguous with the brain's ventricles, some large collecting veins running immediately underneath the ventricular lining, so-called subependymal veins, are directly outlined by zones of gelatinous tissue. The involved vein walls appear partly homogenized, lacking their normal structural differentiation, and are encompassed by distinctly widened perivenous spaces in which residues of minor hemorrhages are to be found. Nothing was mentioned as regards the significance of all these peculiar changes.”

Putnam: Remodeling Brain Lesions and their Veins

“Tracy J. Putnam and Alexandra Adler illustrated for the first time, in 1937, that cerebral plaques characteristically spread in a rather odd, specific relationship to large epiventricular veins and, further, to bizarrely altered affluents of these vessels. These researchers' most relevant observations are comprehensively summarized in Plate VII. Their three-dimensional reconstruction model of one particularly interesting, serially sectioned brain specimen demonstrated especially well the curious distensions and distortions of the involved veins.”

“I followed the development of MR imaging and at the same time I collected all the evidence on pathological observations in MS.”

WHATEVER I FOUND TO BE SPECIFIC OR DISTINCTIVE ABOUT MS WAS ALWAYS RELATED TO VEINS.”

Fig. 3. Sagittal view of Cranial Venous Drainage

“The blood of the brain being collected in the direction of the ventricles...in the brain stem (pons, medulla oblongata) it is the same but more difficult to demonstrate...

In EAE and ADEM we have just the OPPOSITE lesion development where we have VENULAR DAMAGE TO THE BRAIN WHICH IS TYPICAL FOR AGENTS THAT CIRCULATE IN THE BLOOD.

In MS it is the REVERSE - ALL THE LESIONS ARISE FROM THE LARGE COLLECTING VEINS (where they tend to stay) and further out from the centre they fluctuate. I was obliged to find a reason for his kind of lesion development and I could not imagine the veins inside the skull were producing the forces for these lesion developments.

So I realized that the main cause of MS must be trauma and this was the subject of my study in 1984. I wanted to understand why the venous damage in MS is related to competence of the internal jugular veins and valves and the confluence of the sinuses balancing the pressures in the left and right jugulars. Because if you have a blow on these large neck veins the blood cannot escape quickly enough in the direction of the heart.

THE BLOOD GOES AT HIGH VELOCITY BACK UP IN THE DIRECTION OF THE BRAIN (AGAINST THE FLOW OF NORMAL VENOUS BLOOD) which is dangerous for the inner drainage system because the excess pressure first arrives in the area of the inner cerebral veins then into the superficial veins which drain in into the cortical veins in the posterior (back) of the brain. So you must have engorgement of the entire brain surface here at the sagittal sinus before you have a filling of the cortical veins.

All of these veins are connected with multiple interconnections but the inner cerebral veins do not have interconnections so are at a far higher risk of compression.”

-Franz Schelling

Rationale for Research

What Schelling reveals through an abundance of clinical evidence is an expanded analysis, quite different than the usual indeterminate description of the pathogenesis of MS offered in the most recent literature. He cites historical evidence that dates back over a century as to disease morphology. Charcot, Carswell, Buss, Dawson before Schelling—all establish that vascular dysfunction was observed in the large majority of MS cases. Putnam’s and Adler’s drawings of a century ago clearly show the widenings along the points of the cranial veins in the manner of varicosity, but until recently recognition of this pathology had been lost to modern-day researchers mapping the brain. (Just imagine what these great physicians could have discovered with MRI, computed tomography, and angiographic imaging systems to enhance visualization in the cath lab!)

As it is, none of this strong evidence seems ever to have influenced the direction of any major MS drug studies. And it is easy to understand why. In establishing the basis for their hypothesis, drug company-sponsored medical investigators have repeated experiments in which they are able to reproduce a known order of phenomena. They can say with certainty that MS is a T cell mediated autoimmune disease. In isolation, that is a fact, and a cottage industry of research has sprung up around that truth in an attempt to develop immunomodulatory therapies that may have an ameliorating effect on the disease process.

Literally thousands of clinical study abstracts on the subject of MS etiology begin similarly. Multiple sclerosis is characterized as the body mistakenly attacking itself for an unknown reason. This attack results in demyelination and axonal damage, leading to progressive disability. Investigators conclude that MS is a disease that may be controlled by the enhancement of TGF-β signaling in certain T cell populations and therefore a candidate for a drug. (Lee et al, 2017)

But medicine is above all, the science of morphology and etiology. If we truly respect basic research principles, there still remains that awkward fact that there first exists a disruption of the homeostatic balance between the venous vasculature and central nervous system (CNS) prior to any other structural alterations (Davalos, 2012).

Investigators have clearly not gone back far enough to observe the primary antecedent, the vascular event that causes the autoimmune response. Why? Because it would mean that the current licensed medications would never have been developed. Billions of dollars in sales of disease modifying drugs (DMD) have been generated for the drug companies based on a hypothesis that researchers likely knew would lead down a blind alley with respect to a cure.

So it is that the anomalous autoimmune phenomenon continues to hang out there alone, blamed on defective regulatory T cells, without the connection ever being brought back a step further to hemorrhagic veins.

Where scientific objectivity and academic curiosity have loosed themselves of commercial forces, the investigations have different endpoints and clinical data is measured differently. Independent researchers are free to 'follow the evidence.' Research into the cause of MS is a perfect example. As an antecedent event in MS, blood-brain barrier (BBB) disruption results in activation of microglia, the resident immune cells in the CNS, as the earliest pathological signs in otherwise normal appearing white matter. The most characteristic feature of microglia cells is their rapid activation in response to even minor pathological changes in the CNS. Microglial activation is a key factor in the defense of the neural parenchyma against inflammation, trauma, ischemia and neurodegeneration. (Lassmann, 2007; Cottrell, 1999) It turns out that inflammatory activity and microglial activation corresponds precisely with increased fibrin deposition in active demyelinating MS lesions. And fibrin only comes from blood and should not be present on the central nervous system side of the BBB. (Wootla, 2012)

Fig 4

As Schelling so lucidly argues, the immune response in MS therefore, must be secondary to the BBB disruption. The T cell-mediated autoimmune response is just a phenomenon that occurs in the chain of events, it is not a starting point. This BBB disruption is a circumstance just now being recognized by new investigational theorems, but has never been part of a major drug study. Although vascular signs are well-known to be present as a hallmark of MS, for many decades it’s as if they didn’t exist or were unimportant. (Zlokovic, 2008)

Thirty-five years ago the “Poser criteria” was developed to classify MS. Diagnosis of MS relied mainly on eliminating other causes for symptoms and evidence of at least two relapses with signs and symptoms typical of MS as well as evidence of involvement of white matter in more than one site in the central nervous system. Building on this, with the development of the “McDonald Criteria,” new diagnostic criteria for multiple sclerosis that integrated magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The MacDonald criteria were updated in 2005 and again in 2010. (Polman, 2011) The MRI requirements were stringent and could not be used alone without other non-imaging criteria. But there is no recognition of lesions with veins in the McDonald criteria.

On this point, I can't help it if my thoughts go to the politics of MS and that the recognition of the vein-lesion relationship has been considered to be the 'thin edge of the wedge' that would allow academic researchers to start looking seriously at the diseased veins as a research imperative. It's a perspective that would be fought hammer and tong by the drug companies.

New recognition of vein-lesion relationship

In 2015, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative formed from a network of 27 academic centers, focusing their initiative on accelerating the pace of magnetic resonance imaging (MRI) research in multiple sclerosis (MS) through idea exchange and collaboration. They were guided by new evidence as a result of the advancing capabilities in MRI technology. The NAIMS group believes in the predictive value of the central vein sign (CVS) in MS. The evidence supports that the central vein inside white matter MS lesions is a definite biomarker of inflammatory demyelination. Where it exists, researchers are proposing that CVS will aid in the diagnosis of MS.

Recently, NAIMS completed its first project evaluating the feasibility of implementation and reproducibility of quantitative MRI measures. The group published its review findings in Nature Reviews Neurology. An article entitled: “The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis,” (Ontaneda et al, 2016)

A primary finding was as a result of an imaging study where Kilsdonk et al. examined 1,004 brain lesions in 33 patients with MS (19 with RRMS, nine with PPMS and five with SPMS). The study found that 78% of the lesions were located around a central vessel (Kilsdonk, 2014). The proportion of total lesions with a central vein was not related to the clinical phenotype—a finding that was also supported by Kuchling et al. (Kuchling, 2014) When lesions were further classified according to their location, the authors reported that central veins were most prevalent in periventricular lesions (94%). This finding was consistent across other studies.

The group made a 'consensus statement' intended to better define and evaluate the central vein sign (CVS) as detected by MRI for the diagnosis of MS. Among the significant statements and recommendations of the group were that: 1) the presence of central veins inside MS lesions is a well-established finding in both ex vivo pathological studies and in vivo imaging studies; 2) the proportion of MS lesions with a central vein in the cortical, infratentorial and spinal cord regions remains under-investigated, and additional imaging studies in these areas are recommended; 3) that the venocentric distribution of lesions exists in all MS clinical phenotypes (RRMS, SPMS and PPMS); 4) when imaging is used to examine the proportion of MS lesions with a central vein, the location of the lesion should be taken into account.

Above all, everything the NAIMS-associated academic researchers are recognizing about what is true of multiple sclerosis, starts with the vein-lesion association and that the great cerebral vein plays a major role in MS.

ND Sciences' hypothesis supported by NAIMS

Up until the NAIMS group articulated its findings and statements, there has been little consideration of the investigations of Schelling, Ge, Mistry or others with respect to a vein-lesion relationship in MS and its implications for new directions in MS research. Current conventional treatments start with attempting to mediate the immune response in the brain, not treat any particular underlying vascular cause. But although sometimes useful in reducing symptoms, expensive medications have not been effective in maintaining a response of decreased inflammation in the brain, indicating that drugs, if they are effective at all, only have a transitory effect.

Between 2008 and 2010, Italian radiologist Paolo Zamboni treated his MS-stricken wife, citing Schelling's hypothesis as his rationalization. His method of treatment consisted of expanding a balloon catheter in the internal jugular veins (IJV) and holding them open for a minute or two. He theorized that the veins may be kept open permanently as happens in occluded arteries where stents are often placed for that purpose. But veins and arteries are not the same. Arteries undergo forces that propel the blood whereas veins are required for drainage and aren’t meant to carry blood under pressure. There was some observed relief of symptoms post-therapy for some patients and Zamboni published a manuscript based on the research. He theorized that improved venous flow in the internal jugular veins reduced retrograde pressure on the great cerebral vein, thus relieving MS symptoms. He coined the term for collapsed jugular veins as "chronic cerebrospinal venal insufficiency" or "CCSVI."

Zamboni's published study started something of a popular movement. It caused an inundation of MS patients, seeking relief, taking matters in their own hands to cast about for clinics that would perform the venoplasty treatment. As might be expected with a new, unstudied and unfamiliar treatment, there were significant adverse events and even deaths. Anecdotally, some MS patients were observed to have improved symptoms for days, weeks or months after a minimally-invasive vein-widening treatment (venoplasty). But improvements, if they were experienced at all, weren’t sustained for very long. CCSVI was a misadventure that cost MS patients millions of dollars but “did not produce a single long-term response” (Schelling, 2014). Yet each new observation or failure of treatment reveals new questions and potential answers that point toward other scientific approaches to treatment. As with the central vein sign, each passing year sees the evidence change.

New Approaches

Current conventional disease modifying drugs (DMD) have not been successful in reducing the progression of disability in MS. Medications, especially suppressive immunomodulators, while commonly prescribed, do not account for the potential disease etiology and therefore targeted drug therapies are inadequate. (Goodin, 2012) Furthermore, whether or not clinical interventionists target the MS disease triggers, traditional, non-interventional surgical options are not possible deep within the brain. If Schelling's hypothesis is accurate, it is essential to develop a technique to halt the leakage of blood proteins across the BBB, and that is the theory on which the selective stem cell placement (SSCP) protocol was developed.

In consultation with researchers at the clinical study site locale, we proposed a method whereby a novel technique of percutaneous cannulation and radiological infusion of autologous marrow-derived mesenchymal stem cells (MSCs) directed towards the central vein is performed (Broeska, 2019). A multistage venous cannula is inserted through the femoral vein under radiological guidance. In this case, cannulation involves inserting a hollow balloon-tipped catheter into a patient’s internal jugular vein(s) (IJV) so that the stem cells can be infused directly into the patient’s blood flow, temporarily occluded and flow-reversed by the expansion of a balloon in order to selectively direct the stem cells towards areas of venous dysfunction in the central cerebral vein.

The treatment paradigm involving site-specific stem cell delivery is more precise than systemic treatments. (Fischer, 2009) It uses proprietary interventional radiological techniques in the manner described in the clinical development plan and the patent (Broeska, 2019). As a result of induced hemodynamic pressures, the method has the ability to suffuse parts of the brain with stem cells introduced through a catheter to the outflow side (now reversed) of the CNS. This has formed a rational basis for targeted intervention in the CNS to restore homeostatic balance. The usefulness of MSCs in brain repair is well-documented. Mezey, et al, have demonstrated that human adult cells sourced from the patient’s own bone marrow can enter the brain and develop into many tissue types including neurons.

Once directed to the cranial vein through the method described, stem cells are naturally stimulated through "chemotaxis." Chemotaxis is the natural ability of stem cells to adhere, conduct surveillance, attract and mobilize other stem cells to areas of disease identified by the signalling factors within the vasculature. Veins that demonstrate evidence of trauma may be thinner leading to varicosity causing the leakage of neurotoxic proteins across the Blood Brain Barrier (BBB). (Elsharawy, 2006) Once located at the site of this vascular pathology and if in present in therapeutic numbers, MSCs manifest the characteristic properties of stem cells; paracrine signalling in the recruitment of local cells, self-renewal and differentiation including non-thrombogenic properties that act to effectively regenerate normal vascular tissue and prevent or arrest leakage and the subsequent cascade of pathological events. (Bobis, 2006)

In the SSCP method, essentially the stem cells are being delivered into the central vein, thereby fulfilling one of the objectives articulated by the NAIMS group. As to other successful approaches using this methodology, Brazzini, et al, has been successfully treating Parkinson’s disease with marrow-derived autologous cells using the intra-arterial approach and selective placement of marrow-derived PRP with growth factors and other cytokines that can trigger and support healing of endothelial tissue.

Fig. 5 Stages in experimental autoimmune encephalomyelitis (EAE)

Selective Stem Cell Placement and future therapies

The selective stem cell placement (SSCP) technique is novel. By administering a therapeutic number of stem cells proximal to the site of injury in the central vein using a proprietary algorithm, we are potentially engaging the normal repair mechanism of stem cells and other cell types that conduct surveillance and effect tissue repair. We recognize that as people age, ‘healing cells’ or true stem cells diminish in number dramatically and are unable to either naturally reproduce enough cells or marshal themselves to provide therapeutic effect to traumatic injuries or pathology. (Sharpless, 2007) Neurological diseases such as MS and Parkinson’s are known as ‘age-related diseases’ for a reason. The novel SSCP protocol simply re-introduces the patient’s own repair cells in therapeutic numbers selectively to those targeted areas to effect repair to injury.

The healing effects of autologous stem cells in the treatment of MS is documented. The potential of autologous hematopoietic marrow-derived stem cells (MSCs) transferred to a chemically-eradicated immune system (HSCT) has been the subject of intensive study in the context of patients having a lymphoid or myeloid-derived malignant disease.

Some researchers have applied this same treatment to MS in that context. While in some clinical trials there was initial success with patients, review of the evidence demonstrates that relapse occurs in the majority of patients in the following two years. (Tyndall, 2011) Additionally, as a direct result of the treatment there are also many unavoidable deaths, acquired liver damage, and blood infections among other significant adverse events. As to long-term effect, whether the patients see improvements or not for their MS, their immune systems have been manipulated in ways that forever unbalance the vital mechanisms that regulate self-tolerance, antimicrobial resistance and positive autoantibody status. HSCT demonstrates advantages over conventional immunosuppression but with significant toxicity that disqualifies it from being considered as a candidate for becoming a 'first-line' treatment. In comparison to other treatment strategies using stem cells including HSCT, SSCP has significant advantages.

A recent clinical trial may be interpreted as having achieved proof of concept of SSCP. We undertook a Phase I clinical trial of a the SSCP protocol using autologous bone marrow mononuclear stem cells (BM-MNSCs) to treat patients with MS with post-operative functional changes measured by gait performance. Patients received a single round of therapies over 2 weeks using autologous bone marrow-derived cells, selectively infused to 2 points in the CNS on either side of the BBB.

Previous studies have demonstrated that clinically significant gait deviations occur at all stages of MS that involve walking. Consequently, to determine the functional benefit of SSCP, the timed 25-foot walk (T25FW) was administered to 31 MS patients before and after treatment. The time and number of steps taken to complete the test significantly decreased post-intervention in nearly 90% of the patient population regardless of the disease phase . This suggests that recovery of function in MS patients is possible. (Cohen et al, 2019)

Over half of the participants in this trial were in a progressive phase of their disease. This meant that there were no licensed drugs that were available for their treatment. Because of their stage or classification of their disease, many of these patients would not have qualified for other types of stem cell trials either. To date, no significant Adverse Events (SAEs) have been reported and no patient has died as a result of this therapy, or for any other reason related to MS.

The safety record of the Phase I data demonstrates at the very least, this protocol should be further studied. All current data suggests that a safe and effective ‘first-line’ therapy is potentially at hand for chronic neurological diseases that have been heretofore categorized as ‘incurable.’

"To learn how to treat a disease, one must learn how to recognize it. In the last analysis, we see only what we are ready to see, what we have been taught to see. We eliminate and ignore everything that is not a part of our prejudices.”

- Jean-Martin Charcot (1825-1893) considered to be the Father of Modern Neurology

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