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When the Main Vein from the Brain Won’t Drain, Rooke thinks

it Might Cause Pain …

… Is he Insane?

Thom Rooke Krehbiel Professor of Vascular Medicine

Mayo Clinic

Sioux Falls 2016

30 min

Acute

Chronic

Renal vein (“nutcracker”) with gonadal

vein reflux

Venous obstruction / reflux has predictable effects …

http://radiologyinthai.blogspot.com/2011/06/cerebral-venous-sinus-thrombosis-cvst.html

Cerebral Venous Sinus Thrombosis (CVST) Posted by Rathachai Kaewlai, M.D

… including intracranial … Cerebral Sinus Thrombosis

The head and neck can be affected, too …

Volume 4, Issue 7, July 2005, Pages 437–444

Transient global amnesia (TGA) is one of the most striking syndromes in clinical neurology … Studies with … venous duplex … confirmed the importance of jugular-vein-valve insufficiency.

… headache probably results from stretching

of the … veins that drain into the sinuses, although elevated ICP may also play a role. In

addition to headache, clouding of consciousness and seizures are common …

https://www.dartmouth.edu/~dons/part_2/chapter_18.html

The head and neck can be affected, too …

Other effects

J Neurol Neurosurg Psychiatry 2009;80:392-399

Chronic cerebrospinal venous insufficiency in patients

with multiple sclerosis P Zamboni, et. al.

First in 2008

http://www.nature.com/nri/journal/v3/n6/fig_tab/nri1108_F1.html

Why not still more effects?

MS

http://missinglink.ucsf.edu/lm/ids_104_demyelination/didactic/msmicropath.htm

MS Plaques

Veins

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Alamelu V. Is chronic venous ulcer curable? A sample survey of a plastic surgeon. Indian J Plast Surg 2011;44:104-9

Venous Ulcer Multiple Sclerosis

Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1867–1878; 2 September 2009 Anomalous venous blood flow and iron deposition in multiple sclerosis Ajay Vikram Singh1 and Paolo Zamboni2

Venous Ultrasound … venous outflow anomalies were dramatically associated (with MS) (OR 43, p<0.0001).

“… MS is strongly associated with

CCSVI, a scenario that has not previously been described …”

J Neurol Neurosurg Psychiatry 2009;80:392-399

Chronic Cerebro-Spinal Venous Insufficiency (CCSVI)

The “Liberation Procedure”

“The results of this pilot study (65 pts) warrant a subsequent

randomized control study.”

Zamboni, J Vasc Surg. 2009 Dec;50(6):1348-58.

“… CCSVI endovascular treatment significantly improved MS clinical outcome measures … the rate of relapse-free patients changed from 27% to 50% postoperatively …

Focus on Obstruction Meta-Analysis of the Correlation Between Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis Vascular and Endovascular Surgery 47(8) 620-624

2013

Odds Ratio = 2.6

Looks very promising!

This triggered an effusive world-wide response. For example …

… it stirred rare hope among the … 75,000 Canadians suffering from the incurable, degenerative condition.”

“By June 2010, many were travelling out of country, paying upwards of $10,000 for CCSVI … The issue had become a flashpoint. … CCSVI was up for debate in the House of Commons.” “… the Ministry of Health … was under pressure to act.”

The silent treatment: How Canada has failed MS sufferers: Internal documents show why Canada has not kept its promise to accelerate

contentious clinical trials for MS Anne Kingston June 25, 2012

“Canada has one of the highest per capita MS populations: three people are diagnosed every day.

“… there is increasing worldwide acceptance of CCSVI … even though there is no supporting scientific evidence. … most of the information we have comes from one source only. The treatment is called “liberation treatment,” and the results of the treatment can be watched on YouTube. The current forum for the reporting of success … seems to be the Internet. There are … testimonies by MS patients who have gained improvement … (but not) …from patients who underwent unsuccessful treatments …”

Cardiovascular and Interventional Radiological Society of Europe Commentary on the Treatment of Chronic Cerebrospinal Venous Insufficiency Feb 2011, Volume

34, Issue 1, pp 1-2

CardioVascular and Interventional

Radiology

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PLoS One. 2013;8(2) Italy

Chronic cerebrospinal venous insufficiency is not associated with MS and its severity: a blind-verified study.

… CCSVI was not associated with MS … nor its severity.

Neurology. 2011 Aug 30;77(9):844-50. Italy

Progressive MS is not associated with chronic cerebrospinal venous insufficiency.

… CCSVI is not … associated with disability.

BMC Med. 2013 Jul 18;11:167 Buffalo, NY

Chronic cerebrospinal venous insufficiency is not associated with cognitive impairment in MS.

… We find no evidence of an association between the presence and severity of CCSVI … in patients with MS

Mult Scler October 2013 vol. 19 no. 11 1508-1517 multicenter Italy

Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple

sclerosis: results from the CoSMo study

1874 subjects aged 18–55.

Color … duplex sonography

The primary (goal) is to compare the prevalence of CCSVI in patients with MS versus patients affected by other neurodegenerative diseases (OND) and healthy volunteers.

Conclusions: CCSVI is not associated with MS.

Lancet. 2014 Jan 11;383(9912):138-45. Canada

Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis,

their siblings, and unrelated healthy controls: a blinded, case-control study.

Extracranial venous narrowing > 50% is a

frequent finding in patients with MS …

(and) controls.

The significance of venous

narrowing to MS symptomatology remains unknown …

Neurology Volume 83, Issue 5, 29 July 2014, Pages 441-449 USA

Prospective randomized trial of

venous angioplasty in MS (PREMiSe)

… sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). … endpoints included changes in disability, brain volume, cognitive tests, and quality of life.

Conclusion: Venous angioplasty is not an effective treatment for MS … and may exacerbate underlying

disease activity.

FDA NEWS RELEASE

For Immediate Release: May 10, 2012

FDA issues alert on potential dangers of unproven treatment for multiple sclerosis

The U.S. Food and Drug Administration is alerting

health care professionals and patients about injuries and death associated with the use of an

experimental procedure sometimes called “liberation therapy” or the “liberation procedure” to treat

chronic cerebrospinal venous insufficiency (CCSVI).

Mult Scler October 2013 vol. 19 no. 11 1508-1517

Observational case-control study of the prevalence of chronic cerebrospinal

venous insufficiency in multiple sclerosis: results from the CoSMo study

Conclusions: CCSVI is not

associated with MS.

Nobody wants to be associated with

CCSVI anymore – it’s embarrassing

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But … could venous insufficiency (obstruction) produce other (non-MS)

neurological/head symptoms?

What about?: • Headache • Visual changes • Speech difficulties • Imbalance • Cognitive issues • Elevated IC pressure

• Others

# of migraine sufferers … in the US = 12 million

Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657.

Prevalence of tension-type headache = 78%.

Rasmussen BK, et. al. Epidemiology of headache in a general population — a prevalence study. J Clin Epidemiol 1991;44:1147-1157.

These are Very Common Problems

How often does venous impairment play a role?

Non-Compliant

Mechanism of “Venous” HA ?

Intracranial blood flow increases

Vasodilators

If the venous blockage is not

“severe” …

More on this later …

#1 Problem -- How do we determine if a patient has CCSVI?

Very Complicated

Simpler?

Reflux

"Perhaps the most striking finding in our study was the range of venous outflow anomalies detected that did not reflect pathology, but

instead demonstrated the large natural variance in intracranial and extra-cranial venous anatomy …”

120 patients with multiple sclerosis and 60 healthy controls.

“… We detected no differences in the proportion of

venous outflow abnormalities between patients with multiple sclerosis and healthy controls.”

Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis

CMAJ June 2, 2014

Variants of “normal” causing venous compression (often asymptomatic) are common

Popliteal vein entrapment Thoracic outlet syndrome

Vasc Med. 2006 Nov;11(4):278-9.

Normal?

Normal?

Normal?

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Movement of the neck is much more complicated

Pinched

Open

Normal?

FINDINGS: “MR venography the cervical and intracranial vasculature is negative. The dural venous sinuses are widely patent. No evidence of obstruction of the internal jugular veins in the neck.”

Collateral vein? Or

congenital variant?

• Stenosis? • Compression? • Normal variant?

Is this congenitally “small” transverse sinus “too small?” Is flow obstructed?

“Pathology?” Or just a “Variant?”

Decisions based entirely on anatomical

appearance +/- catheter-assessed pressure gradient

Dilemma

Case #1 78 year-old woman with chronic, severe headache

Dilatation of jugular stenosis X 3 sessions. Each helped … for 3-6 weeks. Then symptoms – and stenosis – returned.

Finally treated with stent. Complete resolution of symptoms. No recurrence.

Gradient 2-3 mmHg

“No Dx” “Nothing to do”

Case #2

Stenosis

Collaterals

Nothing!

No stenosis

No gradient

38 year old male. Chronic visual “fatigue,” headache, “brain fog.”

He’s worried he may have MS MRV findings may have

been positional? Or “overcall?” Did we miss something?

Case #3 68 year-old man. DVT (Factor V positive). Subdural hematoma on Coumadin.

Hematoma evacuated X 2. Still unstable.

Bleeding Shift

Clot

Small transverse sinus. Possible obstruction?

Case #4

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Dominant jugular is occluded? Collateral

It gets worse … Do you attempt to open the jugular?

MRV X 2 – findings consistent

What we need is a “functional test …”

Ultrasound seems like a good place to start. It’s the basis for

many other hemodynamic / functional vascular tests …

… But can we see the area of interest with Duplex?

“Normal”

“Abormal?”

• Increase inflow (vasodilator)

• Outflow obstructed (Limits overall flow)

This produces:

• Symptoms?

• Increased venous velocity

• Increased ICP

• Brain “stiffness”?

• EEG / PET scan?

• Other changes?

How to Test?

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78 year old female Worsening “myoclonus” (Most often, myoclonus occurs as a result of a nervous system (neurological) disorder, such as epilepsy, or of a metabolic condition, or as a reaction to a medication. The cause of essential myoclonus is often unexplained (idiopathic) or, in some cases, hereditary.) http://www.mayoclinic.org/diseases-

conditions/myoclonus/basics/definition/con-20027364

Case Example? Work-up = negative

Attempted dobutamine echo (to assess possible CAD) – stopped because of severe exacerbation

of myoclonus.

MRV – Venous obstruction?

Does she have physiologically

significant venous obstruction?

Is it contributing to her myoclonus?

Chronic (Cervical) Venous Occlusive Disease:

• Probably exists and is under-recognized

• Does not appear to cause MS?

• May cause HA and other CNS symptoms

However …

• Diagnostic criteria are lacking (And thus all the controversy)

• There is a need for better anatomic / hemodynamic / functional testing