Dr. Jackie Bakker Red Deer MS Clinic January, 2010 - Multiple ...

Dr. Jackie Bakker
Red Deer MS Clinic
January, 2010

OUTLINE
Welcome and Introductions
Review of known pathophysiology of MS
Review of CCSVI
What is it?
Anatomy
Review of recent literature
Research of new treatments
Where do we go from here?

Introduction
Thanks to MS Society and MS clinic staff
Strong MS patient network
Questions will be taken as written questions only at
the end of presentation
Various handouts available

Inflammation
Demyelination
Axonal Loss
Trapp et al. Curr Opin Neurol. 1999;12:295; Trapp et al. J
Neuroimmunol. 1999;98:49; Trapp et al. Neuroscientist. 1999;5:48.

Infectious agent
Genetic
predisposition
Abnormal immunologic response
Gilden et al. Lancet Neurol. 2005;4:195; Noseworthy et al. N Engl J Med. 2000;343:938.
Environmental
factors
MS

Female:Male = 2:1
Who gets MS?
70% present between ages 20 - 40 y.o.
Prevalence in Southern Alberta:
350 in 100,000 (0.35%)
Pediatric MS = 5% of MS population

CCVSI – what is it?
“Chronic cerebrospinal venous insufficiency (CCVSI)
– characterized by multiple stenoses of the principal
pathways of extracranial venous drainage, including
the internal jugular veins and azygos vein, with
opening of collaterals.
Substitute circles are activated that bypass the
blocked vessels to decrease resistance and avoid
intracranial hypertension. The time of venous
outflow is longer than normal, leading to insufficient
venous drainage.
J Vasc Surg 2009;50:1348 -58

Hypothetical Mechanism of Iron
Deposition in MS
Decreased venous outflow
Disturbs microcirculation (overloaded)
Erythrocyte extravasation in brain plaques
Iron deposition (iron laden macrophages)
Autoimmune attack to myelin
Zamboni et al, J of Cerebral Blood Flow and Metabolism: 2009

Review of Literature
Zamboni et al; Chronic cerebrospinal venous insufficiency in
patients with MS: J Neurol Neurosurg Psychiatry: 2009
Looked at 65 pts with MS
35 with RRMS
20 with SPMS
10 with PPMS
235 control subjects
60 healthy subjects (matched for age and gender)
82 healthy subjects (older than MS median age)
45 subjects with other neurologic conditions
48 subjects scheduled for venography for other reason

Review of literature
Noninvasive screening (Ultrasound) – looked at 5
different parameters
At least 2 of 5 parameters needed to be present for Dx
found the risk of MS was increased by 43x
None of the control subjects had 2 or more parameters
Invasive testing (venography)
Azygous vein – affected in 86%
Internal jugular veins – one or both were found to be
stenosed in 91%
Is this a cause or effect of MS?

Review of recent literature
A prospective open label study of endovascular
treatment of chronic cerebrospinal venous
insufficiency. Zamboni P et al; Journal of Vascular Surgery:Dec.2009
65 patients with MS
Followed for mean of 18 months
Tested with venous doppler and then
venography
Subsequent PTA (percutaneous transluminal
angioplasty) to open up veins

Outcomes
Patency rates – ie did they stay open?
Neurologic outcome
assessed by an unblinded neurologist
Disease severity (MSFC – looks at cognitive and
motor function)
Number who were relapse free at 1 year
Annual relapse rate
Quality of life (questionnaire)
MRI data

Patency –
Outcomes
azygous vein: 96% patency
IJV – 53% patency with restenosis rate = 47%
Disease severity
RR patients improved at 18 mos
No improvement with SPMS or PPMS
Patients who were relapse free at one year
27% pre PTA vs 50% after
Relapse rate in those that had relapses
No change in RR

Quality of Life
Outcomes
Improvement in RRMS (mental and physical)
No change with SPMS and PPMS
MRI
Gad lesions decreased from 50% 12%

Side Effects
No operative or postop complications were recorded
(ie vessel rupture, thrombosis, allergic reaction to
contrast media, infections)
Minor hemorrhages and hematomas at vascular
access sites
Post op headache

Not a blinded study
Study design
MRI was not done with same machine, same interval
or same protocol
Relapsing remitting patients were continued on their
disease modifying therapies
We know with the DMT there is a decrease in RR, Gad
and T2 lesions on MRI, increase in relapse free pts
? Efficacy in the 30 patients who had a second PTA

Some of the greatest ideas in medicine do not turn
out even when biologically plausible
For example:
Vit E is an antioxidant, antioxidants sweep up free
radicals, Coronary artery disease involves free
radicals therefore vit E will help CAD
Trials in Vit E with heart disease negative
Now it appears with population studies that those
taking vit E have earlier mortality
SO… if we said that this made sense so let’s just try it,
we could have harmed a lot of people

Association vs Cause
There are many associations in medicine that have
very good statistical evidence but have no meaning
For example, take the statement:
The # of stainless steel appliances you have predicts
your risk of having a child with birth defects
Very robust statistic but hard to see how this has any
relation with the health or your newborn…. There is a
missing link:
Stainless steel appliances correlates with your income,
your income correlates with accessibility to health
services, this correlates to better prenatal care, fetal
monitoring etc.

Steps to approving a new treatment
Look at example of approving a new medication:
1.Company develops new drug
2.Laboratory testing and animal testing
3.Application to gov’t regulating agency – Health
Canada (or FDA in USA)
4.Phase I clinical trial -
5.Phase II clinical trial
6.Phase III clinical trial
7.Submit application for approval again

Phase I clinical trial –
20 -80 patients to establish safety and profile over
one year
Phase II clinical trial
100 – 300 pt volunteers to assess effectiveness over
2 years
Phase III clinical trial
1000-3000 pts in clinics/hospitals to determine
effectiveness and identify S/E’s over 3 years
Submit application for approval again

What is the benefit of proper studies?
Patient safety
Ensure the treatment really works
Ensure the right patient receives the right treatment
Ensure that appropriate resources and funds are
used for appropriate patients
Government funding – requires evidence based
medicine

Validate findings
What’s next?
This will be done in various research centers
Diagnostic study – software and extra training
for technicians needs to occur
Standardized measurements and values are
required that can be used in various centers
and by various physicians

Once findings validated test the procedure in a
proper fashion to determine effectiveness and safety
Blinded study
Treatment vs placebo
Follow over time
What are the side effects
Do the benefits of the treatment outweigh the
risks?
Which patients benefit from this treatment?

A prospective open-label study of endovascular
treatment of chronic cerebrospinal venous
insufficiency
Paolo Zamboni, MD et al,Bologna, Italy; J Vasc Surg 2009.
“The major shortcoming of our study is that it is not a
blinded study. There is the great possibility that bias
could be playing an important role in trying to find
hope for the treatment of this chronic disease.”
“these data will be fundamental in planning a
multicenter randomized, controlled trial, with blinded
assessors of the neurologic outcome.”

Conclusions
This is exciting research and may help us
understand the cause and possible treatments in MS
BUT – we need to be cautious and ensure that it is
valid and safe
Stay tuned into the MS society website in regards to
research centers in Canada and updates
DO NOT stop your current treatment