DrSclafani answers some questions

[drsclafani]

During the procedure! Meaning it might contribute to the decision of whether or not to accept an endpoint.

But what is the Gold STandard by which it is going to be assessed. for specificity, sensitivey and positive and negative predictive value?

Now there's a vocab test....
I'd have to go back and reread to remember the difference between specificity and sensitivity (and I will be going back to reread that). But what is the difference between something that has positive predictive value and something that has negative predictive value? It predicts the positive or it predicts the negative.

In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed.

http://en.wikipedia.org/wiki/Positive_predictive_value

[Negative predictive power] is defined as the proportion of subjects with a negative test result who are correctly diagnosed.

http://en.wikipedia.org/wiki/Negative_predictive_value

I will just learn this chart. Statistics!


(Tiltawhirl has the right name for a discussion of plethysmography: it is essentially a blood pressure cuff for the neck, that measures change in neck volume as the patient is abruptly tilted from a flat position to an upright position. Dr. Zamboni started talking about it a year and a half ago and that is a long time to wait for more on the subject, considering its potential. http://www.thisisms.com/forum/chronic-c ... 14742.html )

cece

your turn, explain that in english for everyonoe

[David1949]

Dr. Sclafani
As an engineer I like to make decisions based on facts, figures and statistics. Unfortunately when it comes to CCSVI treatment there seems to be a relative lack of such information. For quantitative data the best I can find are the charts at http://www.ccsvi-tracking.com/ . The issue of most importance to me is my walking ability so for that I look to the EDSS chart. That chart shows that about 22% of patients got a significant improvement, 26% got some improvement, 40% saw no improvement and 12% got worse. Somewhere I read that patients who have had the disease longer than ten years are less likely to improve. It’s been 16 years for me so my chances of a good result would be somewhat less than the chart shows. Also based on anecdotal evidence and my own poll the odds of needing to be retreated are greater than 50%.

Would you agree with my assessment?

On the other hand if I do nothing the odds look like this:
Chance of improving Zero.
Chance of getting worse over time 100%

[Cece]

cece

your turn, explain that in english for everyonoe

If I knew it in english, I might not have had to go looking for a chart!
At the top it says, "Condition (as determined by the gold standard)," in the tan box. We are discussing the condition of CCSVI. We are in agreement that the gold standard is venogram plus ivus. Venogram plus ivus shows the truth, as best we can determine it. The left column, "Condition Positive," means that a patient truly has a blocked vein. The right column, "Condition negative," means the patient truly does not have a blocked vein.

In my own case, the gold standard of venogram plus ivus showed jugular stenoses in both jugulars but nothing in the azygous vein. I truly had bilateral jugular stenosis.

On the left, in a blue box, it says, "Test outcome." Some possible tests in CCSVI are doppler ultrasound, MRV, Haacke protocol MRV, plethysmography, and I recently read a post from someone who had their neck pinched in an attempt to feel the jugular and determine a stenosis.

Not all these tests are going to show the right answers.

The top row is for patients who had their test outcomes show positive. The doppler shows CCSVI, or the MRV showed CCSVI, or the pinch test showed CCSVI. This may or may not be the truth, but it is what the test shows. If it really is the truth, they land in the 'true positive' green square. But if it is not the truth, then they land in the 'false positive' pink square.

My doppler prior to my procedure showed that I had CCSVI (3 criteria met). Venogram plus ivus confirmed this. I truly had CCSVI and my test had showed this, so that was a true positive.

A patient posted recently, about his continuing search for answers. I hope it is ok to remember that his doppler had showed CCSVI, but when he went in for the venogram plus ivus, there was no CCSVI. His veins looked great. His test had been a false positive.

Take the total number of true positives and divide them by test outcome positives and you have the positive predictive value. It's interesting that in CCSVI, the number of true positives is very high if looking exclusively at patients with MS. Out of 100 patients with MS, the venogram plus ivus combination will show CCSVI in approximately 99 or 100 of them. Let's say 99 out of 100 are true positives. Let's say the doppler identified CCSVI in 90 of them. The positive predictive value would be 99 divided by 90, which comes to 1.1 or 110%. It looks as if the doppler is excellent at identifying patients who will have CCSVI. But then again, the simple question of asking, "Do you have MS?" is equally excellent at identifying who will have CCSVI.

All right, on to the next row. These are the patients who have had a test for CCSVI and, tears and distress, it came up negative. We have heard from patients who accept that and give up on pursuing CCSVI. And we have heard from patients who do not accept the negative test and go on to get a venogram done. If the doppler said there was no CCSVI but the truth as seen using venogram plus ivus is that the patient truly has CCSVI, then they land in the false negative square. If, sadly, the test showed no CCSVI and the venogram plus ivus showed no CCSVI, then they land in the true negative column. I would have to check back but I believe there have been some patients with Parkinsons or nonMS disorders that were true negatives. No CCSVI found, no CCSVI to treat, nothing gained except the knowledge that this is not the answer, for them.

Take the number of true negatives and divide by the total number of negatives and you get the negative predictive value. Let's say the doppler identified CCSVI in 90 out of 100 patients, so we'll take the 10 that were negative according to the test, and check them with venogram plus ivus, and 9 of them were false negatives (because they truly had CCSVI) but one was a true negative. 1 true negative divided by 10 test outcome negatives means the doppler has a negative predictive value of 10%. That's pretty bad.

(Explaining in plain english takes forever! But we are getting near the end now.)

The sensitivity square is at the bottom of the first column, which is the 'condition positive' column. Take the number of true positives divided by the number of condition positives? Ok... 99 out of 100 pwMS truly have CCSVI as shown by venogram plus ivus, going by the numbers I've used thus far. That's the bottom number, the number of condition positives. The doppler identified 90 out of 100 as having CCSVI, so it didn't get them all, but pretty good. 90 is the top number, the number of 'true positives' identifiable by the test. 90 divided by 99 comes out to 91%. Sensitivity is 91%. I don't know what to compare that to but it seems like a high sensitivity to me.

Next column, we've got the specificity square. The number of 'true negatives' as identified by the test needs to be divided by the number of 'condition negatives'? In my example, we had one true negative (because CCSVI is almost overwhelmingly found in pwMS both by doppler and by venogram plus ivus.) And in my example, the doppler correctly found that one true negative, even though it also identified nine others as negatives when they really weren't, but that part is addressed with the negative predictive power row, and this is the specificity column. So 1 true negative divided by 1 condition negative gives a specificity of 100%. Perfect specificity.

The big problem with the doppler was not the specificity or the sensitivity or the positive predictive power. The big problem was the negative predictive power, at 10%.

And when we hear references to venogram as the 'tarnished' gold standard, that is not good! If the gold standard does not represent the true truth, then the calculations will be off. There have not yet been any studies using venogram plus ivus as the gold standard.

Ok, that's my best attempt at plain english, if not concise english.

[HappyPoet]

DrS, is there a certain percentage of restenosis that is optimal for a second procedure? >50%, >75%, >90%, or some other percentage?

Well, i dont have any real knowledge about what constitutes a significant stenosis in a jugular vein. I think many of us, myself included, think that the arbitrary 50% stenosis is an artificial, and probably erroneous threshhold. I think venous pressure gradients as low as 3 mm may be significant and it could take less than 50% stenosis to cause this.

I think that the indication for a second procedure has nothing to do with %ages. it has to do with return of symptoms, new symptoms, and other signs and symptoms that we havent yet recognized. I have done second procedure after only two days based upon clinical symptom changes.

Thank you, DrS. I'm one year post-procedure and have whispers of tinnitus starting to return. Thanks to your new pricing policy, I'll be able to afford having a second procedure before I start wanting to bang my head against a wall trying to make the continuous, screaming, high-pitched noises stop.

Having quiet in my mind this past year has been like being on a wonderfully peaceful vacation every day of the year... except for the period when, due to medication side effects, the tinnitus started to return which I mistakenly thought was restenosis until a DUS showed fully patent jugulars with strong flow. My 'MS' is mostly psychological, cognitive, and emotional (with few sensory/motor issues), and I didn't handle my worries very well at the time for which I apologize to the entire forum.

Thank you again, DrS, for everything.

[Cece]

Somewhere I read that patients who have had the disease longer than ten years are less likely to improve.

http://www.jvir.org/article/S1051-0443(11%2901704-0/fulltext

PHS/MHS improvement was seen in 74%/71% with <5 yrs since dx, 78%/78% with 5-10 yrs since dx, and 66%/60% with >10 yrs since dx; these changes were significant in all groups (p<0.05).

66% of patients who had the disease longer than 10 years showed physical health improvement, and 60% showed mental health improvement. Not bad at all. This was without ivus and without checking the renal vein, so it is possible that outcomes could be better with venogram plus ivus and/or checking the renal.

[HappyPoet]

Somewhere I read that patients who have had the disease longer than ten years are less likely to improve.

www.jvir.org/article/S1051-0443(11%2901704-0/fulltext

PHS/MHS improvement was seen in 74%/71% with <5 yrs since dx, 78%/78% with 5-10 yrs since dx, and 66%/60% with >10 yrs since dx; these changes were significant in all groups (p<0.05).

66% of patients who had the disease longer than 10 years showed physical health improvement, and 60% showed mental health improvement. Not bad at all. This was without ivus and without checking the renal vein, so it is possible that outcomes could be better with venogram plus ivus and/or checking the renal.

DrS, mental health of 'MS' patients isn't often discussed, and I'm glad to see MHS measured in the study Cece posted which got me thinking... my mental health may not have improved post-procedure, but it didn't progress according to my family/friends and primary doctor (I ask all the time if those symptoms are worsening). Could not progressing be a good/useful/valid endpoint for future CCSVI studies/analysis? For the first time since my diagnosis in 2000, I have an upcoming new-patient appointment with a neuro-psychiatrist pharmacologist that I'm looking forward to very much--unfortunately, our community didn't have enough such doctors until now.

Cece, great job in explaining the chart and applying it to CCSVI. Thank you!

[David1949]

Somewhere I read that patients who have had the disease longer than ten years are less likely to improve.

www.jvir.org/article/S1051-0443(11%2901704-0/fulltext

PHS/MHS improvement was seen in 74%/71% with <5 yrs since dx, 78%/78% with 5-10 yrs since dx, and 66%/60% with >10 yrs since dx; these changes were significant in all groups (p<0.05).

66% of patients who had the disease longer than 10 years showed physical health improvement, and 60% showed mental health improvement. Not bad at all. This was without ivus and without checking the renal vein, so it is possible that outcomes could be better with venogram plus ivus and/or checking the renal.

Thanks for the info but I think PHS/MHS is not as direct a measure of my problem as the EDSS. BTW I think my MHS is fine ... except for being slightly crazy and having an affinity for participating in studies that involve beer.

I like the simplicity and directness of the EDSS. Basically it asks:
How far can you walk without a cane?
Do you need a cane?
Do you need a wheelchair?
Are you bedridden?
Are you dead?

From what I understand there aren't too many affirmative responses on the last question.

[the_r]

If your MHS is fine then maybe that explains why you like the simplicity and directness of the EDSS. If however you can still walk fine but feel like you're slowly losing your mind while being a spectator of your life rather than controlling it, then the EDSS doesn't even tell you that you're ill.

[David1949]

If your MHS is fine then maybe that explains why you like the simplicity and directness of the EDSS.

Bingo!

If however you can still walk fine but feel like you're slowly losing your mind while being a spectator of your life rather than controlling it, then the EDSS doesn't even tell you that you're ill.

Nope that's not my situation, but I can understand how horrible it would be. My problem is walking, but mental abilities are fine.

If you're contemplating CCSVI then I think cognitive issues are among those that respond well.

[drsclafani]

Dr. Sclafani
As an engineer I like to make decisions based on facts, figures and statistics. Unfortunately when it comes to CCSVI treatment there seems to be a relative lack of such information. For quantitative data the best I can find are the charts at http://www.ccsvi-tracking.com/ . The issue of most importance to me is my walking ability so for that I look to the EDSS chart. That chart shows that about 22% of patients got a significant improvement, 26% got some improvement, 40% saw no improvement and 12% got worse. Somewhere I read that patients who have had the disease longer than ten years are less likely to improve. It’s been 16 years for me so my chances of a good result would be somewhat less than the chart shows. Also based on anecdotal evidence and my own poll the odds of needing to be retreated are greater than 50%.

Would you agree with my assessment?

On the other hand if I do nothing the odds look like this:
Chance of improving Zero.
Chance of getting worse over time 100%

most of what you say is accurate. If you are 16 years into your disease, you are likely to be a patient with secondary progressive MS. It is n ot surprising that such patients would have less improvements in quality of life, especially with walking. Firstly, the degree of demyelinization and sclerosis is greater and with it one loses neurons and the pathology is more extensive. Walking is also complex. If your upper motor neuron disease has led to paralysis of muscles of the legs, one may end up with spasticity, a foot drop and sensory loss that makes integrated movement of the limbs more difficult. Similarly cerebellar damage may lead to gross incoordination. Finally loss of balance also is involved in walking. So there are so many problems with walking that even if improved, deficits are often present, rendering return to normal walking very much less likely. Without knowing and examining you David, it is very difficult to help you determine whether treatment is a worthy option for you.

Do you not have other symptoms that make your quality of life less than ideal? Cognition, balance, fatigue, heat intolerance, bladder troubles, pain, stiffness and tingling? You will have to decide whether improvement of your quality of life in some other form is also important.

We must always weigh the risks against the benefits against the cost. You will have to assess whether a 50:50 chance of some improvement is worth it.

Of course all of this must also be weighed against the possibility that treatment may impact on further progression. While we have some data that incidence of short term new inflammatory lesions is reduced after treatment, we do not know the impact of venoplasty on long term progression and disability, simply because the treatment has not been performed in the long term.

I don't envy any patient's challenges in deciding upon treatment.

[drsclafani]

cece,

your turn, explain that in english for everyonoe

If I knew it in english, I might not have had to go looking for a chart: blah blah blah

Ok, that's my best attempt at plain english, if not concise english.

Yikes!!

see how hard it is to teach this stuff.

I would have said it like this:

sensitivity of a test is the percentage of positive results that are accurately positive. in our case, the percentage of patients who get a diagnosis of ccsvi who actually have ccsvi
specificity is the percentage of negatives that are truly negative. in other words, the percentage of patients with a diagnosis of NO ccsvi who actually dont have the disease.

positive predictive value means the reliability of a positive result of the test. In other words what the odds that a positive result is accurate.
negative predictive value means the reliability of a negative result of a test. In other words the likelihood that a negative result can be relied upon as true.

[drsclafani]

Somewhere I read that patients who have had the disease longer than ten years are less likely to improve.

www.jvir.org/article/S1051-0443(11%2901704-0/fulltext

PHS/MHS improvement was seen in 74%/71% with <5 yrs since dx, 78%/78% with 5-10 yrs since dx, and 66%/60% with >10 yrs since dx; these changes were significant in all groups (p<0.05).

66% of patients who had the disease longer than 10 years showed physical health improvement, and 60% showed mental health improvement. Not bad at all. This was without ivus and without checking the renal vein, so it is possible that outcomes could be better with venogram plus ivus and/or checking the renal.

Thanks for the info but I think PHS/MHS is not as direct a measure of my problem as the EDSS. BTW I think my MHS is fine ... except for being slightly crazy and having an affinity for participating in studies that involve beer.

I like the simplicity and directness of the EDSS. Basically it asks:
How far can you walk without a cane?
Do you need a cane?
Do you need a wheelchair?
Are you bedridden?
Are you dead?

From what I understand there aren't too many affirmative responses on the last question.

While EDSS is good for lower extremity motor problems, it is less valuable to people with motor deficits in the upper extremities. I like 25 foot timed walk, 9hole peg test as the motor assessments.

[David1949]

Dr. Sclafani
As an engineer I like to make decisions based on facts, figures and statistics. Unfortunately when it comes to CCSVI treatment there seems to be a relative lack of such information. For quantitative data the best I can find are the charts at http://www.ccsvi-tracking.com/ . The issue of most importance to me is my walking ability so for that I look to the EDSS chart. That chart shows that about 22% of patients got a significant improvement, 26% got some improvement, 40% saw no improvement and 12% got worse. Somewhere I read that patients who have had the disease longer than ten years are less likely to improve. It’s been 16 years for me so my chances of a good result would be somewhat less than the chart shows. Also based on anecdotal evidence and my own poll the odds of needing to be retreated are greater than 50%.

Would you agree with my assessment?

On the other hand if I do nothing the odds look like this:
Chance of improving Zero.
Chance of getting worse over time 100%

most of what you say is accurate. If you are 16 years into your disease, you are likely to be a patient with secondary progressive MS. It is n ot surprising that such patients would have less improvements in quality of life, especially with walking. Firstly, the degree of demyelinization and sclerosis is greater and with it one loses neurons and the pathology is more extensive. Walking is also complex. If your upper motor neuron disease has led to paralysis of muscles of the legs, one may end up with spasticity, a foot drop and sensory loss that makes integrated movement of the limbs more difficult. Similarly cerebellar damage may lead to gross incoordination. Finally loss of balance also is involved in walking. So there are so many problems with walking that even if improved, deficits are often present, rendering return to normal walking very much less likely. Without knowing and examining you David, it is very difficult to help you determine whether treatment is a worthy option for you.

Do you not have other symptoms that make your quality of life less than ideal? Cognition, balance, fatigue, heat intolerance, bladder troubles, pain, stiffness and tingling? You will have to decide whether improvement of your quality of life in some other form is also important.

We must always weigh the risks against the benefits against the cost. You will have to assess whether a 50:50 chance of some improvement is worth it.

Of course all of this must also be weighed against the possibility that treatment may impact on further progression. While we have some data that incidence of short term new inflammatory lesions is reduced after treatment, we do not know the impact of venoplasty on long term progression and disability, simply because the treatment has not been performed in the long term.

I don't envy any patient's challenges in deciding upon treatment.

Dr. Sclafani
Thank you for your thoughtful reply. Well I've made the decision to go ahead with CCSVI treatment. When faced with a situation where the chances are slim and none, slim sounds good.

Neither of the neuros I've been to could tell me what type of MS I have. But since I don't have relapses and never did, I think PPMS is likely, albeit a slow case. If I could fix the walking problem I would feel normal. I don't have fatigue or cog fog or vision problems or pain. There is a little heat sensitivity and some bladder trouble but not too bad. And the bladder/prostate trouble could be due to age (63) as well as MS. Anyway if the treatment can stop the progression of the disease it would be well worth it. Thank you again for your answer.
Respectfully
Dave

[drsclafani]

Could not progressing be a good/useful/valid endpoint for future CCSVI studies/analysis?

Yes it is. currently we measure progression by worsening of EDSS, by quality of life scores, by lesion number, activity and volume on MRI, number of relapses.

so when the reports show that MSQOL scores improve, is this not an indication that they did not worsen.

[dlb]

Dr. Sclafani
As an engineer I like to make decisions based on facts, figures and statistics. Unfortunately when it comes to CCSVI treatment there seems to be a relative lack of such information. For quantitative data the best I can find are the charts at http://www.ccsvi-tracking.com/ . The issue of most importance to me is my walking ability so for that I look to the EDSS chart. That chart shows that about 22% of patients got a significant improvement, 26% got some improvement, 40% saw no improvement and 12% got worse. Somewhere I read that patients who have had the disease longer than ten years are less likely to improve. It’s been 16 years for me so my chances of a good result would be somewhat less than the chart shows. Also based on anecdotal evidence and my own poll the odds of needing to be retreated are greater than 50%.

Would you agree with my assessment?

On the other hand if I do nothing the odds look like this:
Chance of improving Zero.
Chance of getting worse over time 100%

most of what you say is accurate. If you are 16 years into your disease, you are likely to be a patient with secondary progressive MS. It is n ot surprising that such patients would have less improvements in quality of life, especially with walking. Firstly, the degree of demyelinization and sclerosis is greater and with it one loses neurons and the pathology is more extensive. Walking is also complex. If your upper motor neuron disease has led to paralysis of muscles of the legs, one may end up with spasticity, a foot drop and sensory loss that makes integrated movement of the limbs more difficult. Similarly cerebellar damage may lead to gross incoordination. Finally loss of balance also is involved in walking. So there are so many problems with walking that even if improved, deficits are often present, rendering return to normal walking very much less likely. Without knowing and examining you David, it is very difficult to help you determine whether treatment is a worthy option for you.

Do you not have other symptoms that make your quality of life less than ideal? Cognition, balance, fatigue, heat intolerance, bladder troubles, pain, stiffness and tingling? You will have to decide whether improvement of your quality of life in some other form is also important.

We must always weigh the risks against the benefits against the cost. You will have to assess whether a 50:50 chance of some improvement is worth it.

Of course all of this must also be weighed against the possibility that treatment may impact on further progression. While we have some data that incidence of short term new inflammatory lesions is reduced after treatment, we do not know the impact of venoplasty on long term progression and disability, simply because the treatment has not been performed in the long term.

I don't envy any patient's challenges in deciding upon treatment.

Dr. Sclafani
Thank you for your thoughtful reply. Well I've made the decision to go ahead with CCSVI treatment. When faced with a situation where the chances are slim and none, slim sounds good.

Neither of the neuros I've been to could tell me what type of MS I have. But since I don't have relapses and never did, I think PPMS is likely, albeit a slow case. If I could fix the walking problem I would feel normal. I don't have fatigue or cog fog or vision problems or pain. There is a little heat sensitivity and some bladder trouble but not too bad. And the bladder/prostate trouble could be due to age (63) as well as MS. Anyway if the treatment can stop the progression of the disease it would be well worth it. Thank you again for your answer.
Respectfully
Dave

David,

I would like to weigh in here if I could with a few comments. I was treated by Dr. Sclafani in July 2011. I had a terrible time wresting with the decision to have the treatment. I was diagnosed in 2005 after only 2 episodes, started Copaxone in 2006 & then have only had 1 exacerbation since. I had an EDSS of zero & I was (still am) a high functioning individual with MS. For me, the theory made so much sense because it explained all the things that I experienced for years before I started having symptoms of MS. So, the theory made sense to me, but on the other hand, I felt sooo well. It made my decision very difficult because felt like I was fixing something that wasn't broken. I am Canadian, so I went to Barrie, ON to have a doppler US to find out what that said & I met 3 of the criteria, so that helped me make the decision. The thing is, after I had a very successful treatment, I came to realize that I was having difficulties that I was not even aware of. The little things were creeping up on me slowly and over time I was just adjusting & coping. There are also things that were just a part of my life that I was experiencing long before I had MS (headaches, cold hand & feet, heat & cold intolerance). Those things I just lived with and did not know it was different for other people & could be different for me. I am so happy that I elected to seek treatment. It's early, but I really hope that improving that blood flow will help in delaying progression. That is ultimately why I made the choice. The bonus was in realizing such benefit. The shocker was that I had issues that I wasn't aware of until I had improved blood flow. Best wishes....
Deb