Pharmaceuticals and devices: looking for answers.
[Since there have been a lot of questions: I am an MS specialist who sees a lot (~2000) of MS patients and what follows is an open-mided (hopefully) view of CCSVI.]
Well, with all this talk about pharmaceuticals, I thought (and with some prodding) that it was time for me to address CCSVI (Chronic cerebrospinal venous insufficiency). For those of you following the stock market, but ignoring the patient blogs, it is time for a serious discussion of this theory and how it may fit into MS diagnosis and treatment.
Analysts at Investor Village have even started discussing the role CCSVI will play in the MS "market." Before we go into the nitty gritty of CCSVI and unanswered questions, we need to take a step back and realize that this is not a case of "us vs. them." We (doctors,, patients and carepartners) are all in this together and we are working diligently to find out the cause and cure of MS.
An example of how heated these discussions are becoming is found in the following statement from another blog about an MS expert who raised doubts about the central role of CCSVI: "Doctors who downplay or dismiss this treatment should openly disclose their research grants from Big Pharma!" Don't forget that the device companies are going to profit from CCSVI procedures.
What is CCSVI?
Chronic Cerebrospinal Venous Insufficiency.
Let's go through some definitions to clear things up:
[As an aside (not to be confused with CCSVI), most MS patients are very (unfortunately) familiar with cerebrospinal fluid (CSF) from lumbar punctures (spinal taps). CSF is constantly overturned (this is why neurologists can safely remove some CSF -- ~500 mL of CSF is made everyday and we have ~150 mL of CSF in our CNS (central nervous system) at any one time.
CSF is (hopefully and normally) clear, colorless fluid that drains into our venous system.]
If the veins are constricted then there may be reduced drainage of the bloodstream in the veins; this may cause reduced outflow of the blood and a greater iron (a component of blood) deposition in the brain, optic nerves, cervical and thoracic spinal cord.
Iron may irritate the CNS and cause an inflammatory reaction that, in turn, causes the bright spots (T2 hyperintensities) we see on MRIs.
I thought MS was autoimmune ... is it?
Well, there have been many theories of MS over the years and actually Jean-Marie Charcot discussed the treatment of MS with other types of metals, such as gold and silver.
If iron is deposited in the CNS then inflammatory cells can attack this iron and this can cause damage; the iron may also have direct toxic effects on the CNS. So, is this a form of autoimmunity? Well, the iron is part of the a person's own blood and if the immune system attacks the iron, can't this be called autoimmune?
The question is not one of terminology, but of whether the observation that people with MS have narrowing of the veins draining the venous system leading to the CNS can actually undergo a balloon venoplasty to open up the venous constriction to allow a better venous outflow back to the heart (thus allowing the iron to be cleared out).
What came first: the chicken or the egg?
Even if venous constriction led to the development of MS early on, how do we know that opening up the veins will help resolve the MS? It may have no effect or it may only stop newer plaques (and damage) from forming, without actually clearing up old damage (this may also depend on whether the prior damage was permanent or not).
Before we even discuss the newer papers coming out, let's look at:
J Neurol Neurosurg Psychiatry. 2009 April; 80(4): 392–399.
The first concern I have is in the Background section of the abstract. Most people with MS know that CDMS is a category from the Schumacher and Poser criteria, and is Clinically Definite MS and not Clinically Defined MS. Although it may seem like I am focusing on minor terminology issues, it is important in that it reveals how much the Italian team needs even more support from more mainstream MS neurologists (this is a call to arms for my fellow neurologists to join the efforts of my friends in Buffalo and Detroit) [on page 313 of Walsh and Hoyt's clinical neuro-ophthalmology,
the phrase "clinically defined MS" does appear, but it is not used
synonymously with CDMS].
So, let's help:
1. It is possible that the previous findings will not pan out
in larger, well controlled studies (this is always true, as
with the disappointment surrounding Genentech and
Biogen Idec's Rituximab and BioMS and Eli Lilly's
Dirucotide or MBP8298). This is why we do big
(expensive) confirmatory studies.
2. These findings could be true in the Italian population
studied by Dr. Zamboni, but not generalizable to the
worldwide MS population.
3. Although healthy controls were looked at, it is possible
that there will be similar findings in other people with
non-MS autoimmune disorders.
4. If these findings are not associated with other
autoimmune disorders of the body, it may be associated
with other inflammatory diagnoses that affect the CNS,
such as: neuro-Behcet's, neuro-lupus, and neuromyelitis
optica (NMO or Devic's disease).
5. Even if the association with MS holds up, CCSVI and
MS may be caused by a third factor (MS may not be a
direct cause of CCSVI).
6. CCSVI may be caused by MS, instead of vice versa.
Chronic inflammation and neuro-degeneration may
cause the veins to constrict.
7. In the Canadian TV show on CCSVI, Dr. Zamboni's
patients seemed to describe progressive MS. It would
not be surprising, then, if they did not have relapses in
follow-up. What about people with relapsing-remitting
8. Even if venous constriction is responsible for MS, why
do some people have more brain vs. optic nerve vs.
brainstem vs. cervical spinal cord vs. thoracic spinal
cord? Are we going to see an association between the
type of venous constriction and the type of MS. The
4 patterns of CCSVI reminds us of the 4 pathological
types of MS.
9. Do people with CCSVI have more headaches than
people without? If the venous system is backed up,
we would expect the increased pressure to create
headaches (think about the Monro-Kellie hypothesis).
10. I am especially interested in the spinal cord lesions
At ECTRIMS 2008, I presented the following poster:
Perhaps CCSVI explains why we found a predilection for
MS at certain spinal levels.
11. CCSVI may explain MS in some patients, and not in
others -- so can we develop a predictor (like the
biomarkers we are looking for) of response.
This is important, as venoplasty is not without risk
(cerebral angioplasty carries a risk of stroke and
12. Even if you can treat MS by opening up the veins
draining from the CNS, is balloon venoplasty enough?
What are the rates of re-stenosis? Are we going to need
stents? What are the chances that these procedures will
need to be repeated? Will we have to wait for new
symptoms to repeat the venoplasty?
As you can see, there are a lot of unanswered questions.
This is why we need more research; the Canadians have
started us off by announcing that they will fund CCSVI
research, but this is only for Canadian institutions.
- What will we do here in the U.S.?
- Who is going to donate research funds?
If you are interested in us conducting trials regarding
CCSVI, let us know and help us make it happen.
- Dr. Daniel Kantor, MD BSE