Exciting New MS Treatment!

NEWS RELEASE

A new MS drug appears to alter fluid dynamics and repair the blood brain barrier!
In fact, 63% of the patients treated with Perfuza (toxicmuzab) had no new or enhancing MS lesions at 12 months! In light of recent discoveries of the brain's lymphatic vessels and the connection to venous flow, we are thrilled to be able to offer MS patients a drug treatment which may be addressing CNS fluid dynamics.

Here's more on the impressive results of Perfuza from a recent publication in JAMA---

We found a reduction in the mean number of new brain lesions (corresponding to more lesion- free patients) in the toxicumab group compared with the placebo group at 6 to 12 months. The delayed and positive effect on the magnetic resonance biomarker suggests that toxicumab could affect the dynamic of the blood-brain barrier.

Gadolinium enhancement is a marker of damage to the blood-brain barrier, whose time course depends on lymphatic drainage18 and hence on venous drainage from the skull.19 Previous studies have reported that venous pressure is lowered3 and cerebrospinal fluid dynamics is improved20 after taking toxicmuzab, thereby favoring the drainage of cerebro spinal fluid into the dural veins, which depends on a pressure gradient between the subarachnoid spaces and dural veins.21,22

Another study23 reported that white matter lesion load was inversely correlated with reduced cerebrospinal fluid dynamics, as measured by MRI. In addition, flow improvement through the internal jugular veins owing to toxicmuzab has been reported to improve brain perfusion in patients with RRMS.21 It has also been reported that the development of a new MS plaque was preceded by sustained MRI-detected hypoperfusion before the plaque was identified on MRI.24,25

link

Incredible, right???  Finally.  A drug which can potentially affect the blood brain barrier!
Perfuza (toxicmuzab) may be the greatest money-making MS drug in history.
Projections are now at 2-3 billion for 2018 alone.


Only kidding.

The paper I'm quoting from, verbatim, is the recent JAMA review of angioplasty for CCSVI from the Brave Dreams clinical trial. 

Just replace my made up block buster drug Perfuza (toxicmuzab) with angioplasty to restore venous flow.   And then, write a conclusion and snarky editorial that says that we should not pursue this treatment any further, and that CCSVI research is over.

Even though the conclusion of the paper says that over half of patients saw benefit in cerebral blood flow from CCSVI treatment.

The editorial which goes along with this publication is actually incorrect.  The author of the editorial, Dr. Ari Green***, claims that there was absolutely no benefit in those treated for CCSVI, that there was no reduction in new lesions.  Here, read the editorial for yourselves, and read the paper again, and tell me---isn't this incorrect?
https://jamanetwork.com/journals/jamaneurology/fullarticle/2664000

***Dr. Green has received personal compensation for activities with Inception Sciences, Mylan Pharma, Medimmune, and Bionure. Dr. Green has received personal compensation for serving on the board of Inception Sciences. Dr. Green holds stock and/or stock options in Inception Sciences. Dr. Green has received research support from Inception Sciences, Biogen, and Novartis.  link
Dr. Green's Inception Sciences Company owns the patent for an antihistamine-like molecule thought to remyelinate neurons. I wrote about the absurd hype regarding a 1.3% improvement in visual acuity here:  link

To recap---this published paper from the neurologists of the Brave Dreams trial just proved, conclusively-
1. CCSVI is a real condition in people with MS.
2. There are a variety of venous malformations.  There were patients with closed jugular valves, refluxing blood flow, and hypoperfusion.
3. Venoplasty was able to restore normal flow in 54% of the patients.  Not all malformations can be treated with PTA alone.
4.  63% of treated patients had no new MS lesions on MRI at 12 months.
Doesn't this count for something?  At least additional study?

What is real news? What is fake news?
Is this simply spin or is it something darker?

If a room full of neurologists look at the results from CCSVI venoplasty and conclude 
"The delayed effect of venous PTA 6 months after the procedure on the magnetic resonance biomarker suggests a possibility that PTA may produce benefit for a subgroup of patients with MS. This should be further analyzed and investigated." 

yet still write a conclusion and editorial suggesting CCSVI research be stopped--- what is reality?

Please, tell me.  Honestly, I'm flummoxed.

More ahead.
Joan

MS Vascular Research Round Up

I wanted to do a summary post on the most recent research into the vascular connection to Multiple Sclerosis, prior to Dr. Zamboni's presentation at the Veith Conference in New York City this Saturday.   CCSVI Alliance will be hosting a patient friendly "Facebook Live Event" on November 18th with Dr. Zamboni.  Link to Facebook Event Page

Since Dr. Zamboni first published his pilot study in 2008 of MS patients treated with venoplasty to relieve slowed venous drainage, or a condition he named Chronic Cerebrospinal Venous Insufficiency,  the landscape of neuroscience has changed drastically.

In fact, we now know that the brain has a cleansing system connected to the peripheral lymphatic system, which depends on timely and efficient drainage.  

Here's a BBC radio presentation on the importance of the newly discovered Brain's Drain.
link
As the science reporter states in this interview,
"Making sure a drainage system is flowing properly could be really important for the health of the brain."

We are learning more about how the brain clears proteins, metabolites, immune cells and waste---while awake and asleep.  The jugular veins are the major collection area for this process--as this is where the brain's lymph, CSF and deoxygenated blood converge.   link

If researchers want to investigate a method of action (MOA) as to how venoplasty to relieve slowed venous drainage and repair of jugular defects has helped people with MS, they might consider the following:

1.  Corroboration of the brain's lymphatic system in humans.

NIH researchers find lymphatic vessels in humans, and confirm prior research from the Kipnis Lab at University of Virginia.

To confirm that the vessels were lymphatic vessels, the team used a dye that’s too big to leak out of blood vessels. MRI scans from two subjects with this dye showed brightly lit blood vessels in the dura, but not the suspected lymphatic vessels. These results suggested that the first dye leaked out of the blood vessels into surrounding lymphatic vessels.

The researchers also looked at the suspected lymphatic vessels in autopsied human and monkey brain tissue. They found that the vessels contained specific cells and protein markers that are unique to lymphatic vessels and distinguished them from blood vessels. These findings suggest the lymphatic system is a common feature of mammalian brains.

“We literally watched people’s brains drain fluid into these vessels,” Reich says. “We hope that our results provide new insights to a variety of neurological disorders.”

“These results could fundamentally change the way we think about how the brain and immune system interrelate,” says NINDS Director Dr. Walter J. Koroshetz
.link

2.  Fibrinogen, a blood clotting protein, initiates myelin loss and inhibits remyelination in MS.

The Gladstone Lab confirms that all it takes to initiate demyelination in the brain is a drop of blood on brain tissue.  The clotting protein, fibrinogen, which increases when the coagulation cascade is initiated during a break in the blood brain barrier, is highly destructive to myelin.  Not only does fibrinogen damage myelin, it blocks the body's stem cell mechanism of myelin repair.

If the brain is unable to drain in a timely and efficient manner, venous hypertension and small breaks in the blood brain barrier may occur.  These cerebral microbleeds have been documented on 7T MRI in MS patients.

Akassoglou has spent much of her career studying the role of the blood-brain barrier and fibrinogen in neurological diseases. She previously showed that when blood leaks into the brain, fibrinogen causes inflammation by acting in brain immune cells, which can lead to brain damage.

In the new study, Akassoglou and her team uncovered another, yet unexpected effect of blood leaking into the brain.

“We found that fibrinogen stops adult stem cells from transforming into the mature cells that produce myelin,” explained first author of the study Mark Petersen, MD, a visiting scientist in Akassoglou’s laboratory and an assistant adjunct professor of pediatrics at UCSF. “This blockade could be harmful for regeneration in the brain.”  link

3.  M (motion) Mode ultrasound shows a higher rate of jugular valve irregularities in people with MS, compared to healthy controls.

Researchers noted, using motion mode ultrasound which visualizes blood flow and valve activity, that more people with MS (82%) have fixed, or immobile jugular vein valves.  98% of healthy controls had jugular valves which opened and closed with blood flow.  This created brain outflow abnormalities.     link

4.  Endothelial cells are the interface between lymphatic, immune and vascular system of the CNS.

Researchers are probing further into the importance of vascular endothelial cell health, in light of the new discovery of brain's lymphatic network.

The lymphatic network linking the CNS to draining lymph nodes may contribute to the inflammatory reaction occurring in multiple sclerosis (MS). The abundance and strategic positioning of endothelial cells at the blood-brain barrier level most likely endow them with an important role in controlling local adaptive immune responses, rendering them potential therapeutic targets in neuro-inflammatory such as MS.
link

Disruption of the blood–brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis.  link

5.  People with MS have cervical lymph nodes which are twice the size of normal people, whether or not they are on immune modulating MS drugs. 

As the cervical lymph nodes are the collection area for the brain's newly discovered lymphatic system, and these nodes drain into the junction of the jugular and subclavian veins, this anomoly needs to be further investigated.

Cervical lymph nodes are the first drainage stations of the brain and therefore play a key role in neuroinflammatory disorders such as multiple sclerosis.  The abnormalities shown by ultrasound in cervical lymph nodes are related to deep ones and independent of the ongoing treatment, suggesting a relationship between lymphatic drainage and disease pathology.  link


As we can all see, understanding the vascular connection to MS is now expanding in research labs around the globe.  The era of the EAE mouse model of MS as an auto-immune disease is being replaced by an understanding of MS as an inflammatory disease related to cerebral perfusion, the vascular endothelium and lymph system.
And yes, venous function remains integral to this understanding.

Onward,

Joan