permissive lesions

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

permissive lesions

Postby Cece » Fri Mar 04, 2011 9:13 am

Is NIVL pathogenic?

Ever since its first description, controversy has surrounded NIVL with regard to its pathologic import, because the lesion appears to be largely silent in the overwhelming majority of the population in which it is found. In fact, some have argued that the lesion be considered a ‘normal’ anatomical variant because of its quiescence and high prevalence.7 On the other hand, NIVL is undeniably causative of pathology in several subsets of patients. Cockett and colleagues highlighted NIVL as a cause of clinical acute iliac vein thrombosis.10 Hundreds of welldocumented cases of this type have appeared in the literature since. In a large registry11 of patients with acute iliac vein thromboses, NIVL-like lesions are detected in about one-third or more of patients after catheter-directed thrombolysis. Stent placement to correct such lesions after successful clot lysis is now standard practice. Cockett and colleagues also described a chronic form of disease caused by NIVL presenting with leg pain and swelling.3 They popularized the notion that this form of the disease was prone to affect the left lower limb of young women, even though their clinical series included older patients, men, and involvement of the right leg as well. The notion that NIVL is pathogenic at least in some patients is now readily accepted,12,13 but the relationship between the symptomatic lesions in patients and the asymptomatic ones in the general population has remained obscure.

NIVL as a permissive lesion
One way to reconcile these apparent contradictions is to view NIVL as a permissive lesion.9 A permissive lesion is one that is generally silent until an additional pathology or sequela is superimposed and triggers symptoms. Numerous permissive lesions are known to play a role in human pathology. A well-known example is patent foramen ovale, which has a population incidence similar to that of NIVL (20% to 30%), but remains silent except occasionally when passage of a paradoxical embolus takes place. Some other examples include gastroesophageal reflux disease and asthma, ureteric reflux and pyelonephritis, cricopharyngeal spasm and Zenker’s diverticulum, Helicobacter and peptic ulceration, obesity and diabetes, diabetes and neuropathy, middle lobe syndrome and pneumonia, carotid stenosis, and transient ischemic attacks. A general principle in treating many of these complex pathologies is to address the permissive lesion first, which alone may remit symptoms. In nonresponders, the secondary pathology may need to be addressed in sequence.
NIVL displays many of these characteristics of a permissive lesion. Despite its high incidence in the general population, it remains largely silent. We hypothesize that additional pathologies or sequelae such as trauma, cellulitis, distal thrombosis, lymphatic exhaustion, or reflux may render the extremity symptomatic. In the elderly, atherosclerosis of the overlying artery, venosclerosis, decreasing mobility, and leg dependency or other comorbid conditions predisposing to pedal edema may be contributory factors in symptom expression. In some cases no such secondary aggravating factors are apparent and symptom expression may simply be related to further progression of the stenotic lesion or to another as yet obscure cause.

http://www.phlebolymphology.org/2009/07 ... s-disease/
(from a paper by Dr. Raju linked to by Nunzio over in my thread)

What I take from this is that even if the much-repeated concern about CCSVI being found in the healthy population is true, it doesn't mean much. Lesions can be "permissive lesions" as described here. (This article is specifically discussing iliac vein lesions, such as May Thurner.) A permissive lesion may be silent in some people but have an impact in others, often because of other secondary factors. The treatment is to treat the permissive lesion.
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Postby 1eye » Fri Mar 04, 2011 1:23 pm

I suspect, as CCSVI is congenital, the same genes may produce other CVIs, and that my own siblings, as well as both of my parents (now deceased) may have had asymptomatic CCSVI or CVIs. One has Lupus, one has type 2 diabetes, father had type 2, brother had leukemia (CLL), other brother had congenital hydrocephalus at birth, two other siblings have diseases thought to be autoimmune, mother had thyroid disease. Sounds like I shouldn't have been a bit surprised, but I was.

And I thought my worst problem was my neurologist... 8O
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Postby ozarkcanoer » Fri Mar 04, 2011 2:46 pm

It would be a logical fallacy to state that if A causes (or is associated with) B then A must cause B. CCSVI may indeed be discovered in people without MS. It must first be established that MS is associated with CCSVI and then (maybe) that MS is caused by (or partially by) CCSVI and then perhaps enough controls may also have been studied to determine the particular circumstances under which CCSVI does cause MS. That this will be difficult to untangle seems true to me : how fast will CCSVI/MS be proven beyond a reasonable doubt ? We live in interesting times.

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Postby DrCumming » Fri Mar 04, 2011 3:00 pm

Great article CeCe.

One analogy I like to use is varicose veins. We occasional will see patients with incredible leg varicosities that cause no symptoms while we see patients that have few varicosities but significant symptoms. No good explanation.

I have no doubt that the prevalance of CCSVI (or jugular vein stenosis) will be fairly common in asymptomatic patients. Maybe as high as 25%. That does not mean that CCSVI is not important in patients with MS.

And yes, we need to be careful about logic as OC points out.
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Postby Cece » Sun Jun 12, 2011 8:24 pm

The concept of 'permissive lesions' seems relevant again in the wake of Dr. Zivadinov's research on if CCSVI does or does not cause MS.
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Re: permissive lesions

Postby frodo » Mon Jun 13, 2011 1:13 am

What is NIVL? I had never heard about that.
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Postby Cece » Mon Jun 13, 2011 6:25 am

Iliac vein lesions. May Thurner....
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Postby 1eye » Mon Jun 13, 2011 8:26 am

I think it is time to ask if the question is even relevant, of whether CCSVI is the cause of something we used to call "MS" or not?

I remembered to add: my mother also had vasculitis, which would have killed her if she hadn't been nearly killed by lethal pain-killers which were supposed to be harmless. She decided that she didn't want another heart attack, so she went the DNR route and stopped dialysis, but it ended up being her heart anyway.
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Postby Cece » Mon Jun 13, 2011 10:12 am

exactly...because CCSVI is entangled with MS, it is going to take longer for research to be done and treatment of CCSVI to be common practice than it would if CCSVI were looked at on its own.

The relationship between MS and CCSVI is relevant but it is a complicating complexity and it will slow down getting this treatment out to the people that benefit from it. If slowing things down gives the IRs time to perfect their approach to this uniquely challenging disease so people do not end up with occluded veins and instead end up with the sorts of benefits I and others have had, then slowing down is not altogether terrible. But MS is awful and I don't want anyone suffering a minute longer than they have to if there is indeed some relief available through improving the cerebrospinal blood flow.

edited...1eye, I don't know if this was meant as a response to what you said, because it doesn't seem to be!! I am sorry to hear about your mother.
Last edited by Cece on Fri Mar 01, 2013 11:33 am, edited 1 time in total.
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Re: permissive lesions

Postby Cece » Thu Feb 28, 2013 11:23 am

I am on page three of the 2013 ISNVD abstracts (thank you Cheer for finding them) and it is already getting interesting. http://isnvd2013.euromedicpoland.com/us ... tracts.pdf
Dr. Raju is talking about permissive lesions. I recognized the term from this thread and previous thoughts on the matter!
DrRaju at ISNVD2013 wrote:2. Epidemiology: Venous stenoses are widely prevalent in the general population in silent form. A fraction become symptomatic when secondary insults are superimposed. The venous stenoses function in a “permissive” fashion. The incidence of the lesion in symptomatic patients therefore will be very high similar to the incidence of patent foramen ovale (a well-known permissive lesion) in patients with paradoxical embolus. Permissive lesions are ubiquitous in human pathology. Examples include obesity and diabetes, acid reflux and asthma, ureteral reflux and pyelonephritis to mention just a few examples. A general principle is to treat the permissive lesion first in symptomatic patients which is often curative; specific address of secondary trigger events will be required less frequently.

General principle: treat the permissive lesion first if patients are symptomatic
If CCSVI patients are symptomatic, then treat the permissive lesion, which in our case is the jugular or azygous stenoses.

If the permissive lesion is treated, then the secondary trigger may or may not need to be treated. If the secondary trigger is the misguided immune system, then maybe treating the permissive lesions will be enough and the immune system will not need to modified? Goodbye DMDs. To use the obesity and diabetes example listed above, if a diabetic obese person loses enough weight, then the diabetes may go away on its own. If the jugular and azygous lesions are treated, then the MS may go away on its own? This is the real best case scenario.
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Re: permissive lesions

Postby Cece » Fri Mar 01, 2013 11:11 am

No one else on the entire internet is excited about the concept of permissive lesions?

It helps resolve the dilemma over specificity and sensitivity and causation.

Sensitivity = how many people with MS also have CCSVI. If 100% of people with MS have CCSVI, then there is 100% sensitivity.
Specificity = how unique CCSVI is to people with MS. If no one has CCSVI except for people with MS, then there is 100% specificity.

Research seems to show that there are some people with MS who simply do not have CCSVI. Sensitivity is not 100%. Clinically it seems to be high but in the imaging studies it seems to be lower. In Fox's autopsy study it was five out of seven so if we go with that, that is 71% sensitivity. (71% of the time, the patient having MS correctly predicted that the patient would also have CCSVI.)

Research also shows that there are some people with CCSVI who do not have MS. Again with Fox's autopsy study there was 1 healthy control who had intraluminal abnormalities so that was 1/6 or 83% specificity. (83% of the time, knowing that the healthy control did not have MS meant that they would not have CCSVI.)

The higher the sensitivity and specificity, the more comfortable we can be saying that x causes y. The lower, the less likely.

But the concept of permissive lesions says that having x opens the door so that y is more likely to develop. X can exist without y. Y can exist without x. But if x is present, then y is more likely. If y has developed, then it is more likely that x was present.

This fits very well with what we're seeing with CCSVI in MS.

Plugging in obesity and diabetes for x & y: Obesity can exist without diabetes. Diabetes can exist without obesity. But if obesity is present, diabetes is more likely to develop. If diabetes develops, obesity is more likely to have been been present. And what do you do? Treat the obesity and the diabetes is likely to go away.

Plugging in CCSVI and MS: CCSVI can exist without MS. MS can exist without CCSVI. But if CCSVI is present, MS is more likely to develop. If MS develops, CCSVI is more likely to have been present. And what do you do? Treat the CCSVI and it might ameliorate the MS.
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