Chronic cerebrospinal venous insufficiency

Dejan Jakimovski MD (Dr. Jakimovski of the University of Buffalo at the State University of New York has no relevant financial relationships to disclose.)
Robert Zivadinov MD PhD FAAN (Dr. Zivadinov of the University of Buffalo at the State University of New York and Jacobs Neurological Institute received research grants from Novartis, Genzyme-Sanofi, and Biogen Idec and consulting fees from Teva, Biogen Idec, EMD Serono, Genzyme-Sanofi, Novartis, and Claret.)
Anthony T Reder MD, editor. (Dr. Reder of the University of Chicago served on advisory boards and as a consultant for Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Malinkrodt, Serono, and Teva-Marion.)
Originally released August 30, 2013; last updated February 20, 2017; expires February 20, 2020

Overview

Chronic cerebrospinal venous insufficiency, a newly proposed vascular condition, was initially described in patients with multiple sclerosis. Chronic cerebrospinal venous insufficiency is characterized by impaired brain venous drainage due to outflow obstruction in the extracranial venous system, mostly related to anomalies in the internal jugular and azygos veins. Chronic cerebrospinal venous insufficiency has triggered intense interest in better understanding the role of extracranial venous abnormalities and developmental variants. Although the diagnosis was originally based on Doppler sonography, there are no currently established diagnostic imaging modalities, noninvasive or invasive, that can serve as the “gold standard” for detection of venous abnormalities indicative of chronic cerebrospinal venous insufficiency. As a further step in standardizing use of diagnostic imaging, the International Society of Neurovascular Diseases (ISNVD) released an official recommendation for multimodal noninvasive and invasive approaches in determining venous anomalies indicative of chronic cerebrospinal venous insufficiency.

Key points

 

• Chronic cerebrospinal venous insufficiency is a vascular condition characterized by the obstruction of the extracranial venous system, which is associated with impaired brain venous drainage outflow.

 

• Chronic cerebrospinal venous insufficiency was initially described in multiple sclerosis patients.

 

• Although the diagnosis of chronic cerebrospinal venous insufficiency was originally based on the assessment of 5 criteria for Doppler sonography of extracranial and intracranial venous hemodynamics, there is no established diagnostic imaging modality, noninvasive or invasive, that can serve as the “gold standard” for detection of these extracranial venous anomalies.

 

• Multimodal imaging is the most comprehensive means to screen, diagnose, and monitor extracranial venous anomalies indicative of chronic cerebrospinal venous insufficiency.

 

• Further research has to establish whether the spectrum of extracranial venous anomalies indicative of chronic cerebrospinal venous insufficiency represents pathological findings in patients with multiple sclerosis, other neurologic diseases, and aging.

 

• The potential usefulness of endovascular treatment to correct venous anomalies indicative of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis, other neurologic diseases, and aging is unknown.

Historical note and terminology

The role of the extracranial venous system in the pathology of central nervous system disorders and aging is largely unknown (Zivadinov and Chung 2013). Compared to the peripheral venous and arterial systems, the complexity, asymmetry, and often inter-individual variability of the extracranial venous system makes exploration of the link between intracranial and extracranial pathology extremely difficult. Additional factors may influence correct assessments of the veins in regard to the presence of structural or hemodynamic extracranial venous abnormalities, including postural change, cardiac function, respiration, frequent change in lumen diameter, hydration status, hypovolemia, and the presence of nearby structures (Epstein et al 1970; Zamboni and Galeotti 2010; Dake et al 2011; Haacke 2011; Zivadinov et al 2011c; Dolic et al 2013; Valdueza et al 2013). Some studies have emphasized the variability of the venous system in healthy individuals and have associated it with cardiovascular risk factors that were previously not taken into account when interpreting extracranial venous anomalies indicative of chronic cerebrospinal venous insufficiency (Beggs et al 2016a; Beggs et al 2016b; Magnano et al 2016).

The embryogenesis of the extracranial venous system is subject to many variations, which do not necessarily represent pathological findings (Pascual-Castroviejo 1985; Lee et al 2010; Biceroglu et al 2012; Lee et al 2015). A range of congenital extracranial venous abnormalities or development variants have been described (Lee et al 2010; Lee et al 2015). Nevertheless, pathological investigations aimed to define the nature of these venous abnormalities or development variants are systematically lacking (Diaconu et al 2012; Coen et al 2013).

In 2009, Zamboni and colleagues described a vascular condition named chronic cerebrospinal venous insufficiency (Zamboni et al 2009a). Chronic cerebrospinal venous insufficiency is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that interfere with physiological venous outflow, mainly in the internal jugular veins and azygos vein (Zamboni et al 2009b; Zamboni et al 2009c). Although the condition was originally described in patients with multiple sclerosis, it became immediately clear from the first independent, controlled studies that patients with other CNS diseases and healthy individuals may also present with this condition (Doepp et al 2010; Baracchini et al 2011a; Zivadinov et al 2011b; Dolic et al 2013).

Diagnosis of chronic cerebrospinal venous insufficiency implies a condition for which diagnosis is based mainly on color Doppler sonography findings in the extracranial (neck) and intracranial veins (deep cerebral veins) by assessing 5 venous hemodynamic criteria (with a cutoff of 2 or more positive criteria used for the diagnosis of chronic cerebrospinal venous insufficiency) (Zamboni et al 2009b; Zamboni et al 2009c). The venous hemodynamic Doppler sonography criteria were revised by the ISNVD in 2011 and have been modified as follows (Nicolaides et al 2011; Zamboni et al 2011b; Zivadinov et al 2014):

 

(1) Reflux present in an outflow pathway (internal jugular veins and/or vertebral veins) with the head at 0° and 90°.

   

(a) Bidirectional flow in one or both internal jugular veins in both positions (supine and upright) or bidirectional flow in one position and absence of flow in the other.

   

(b) Bidirectional or reversal of flow in vertebral veins in both positions.

 

(2) Reflux in the intracranial veins or deep cerebral veins.

 

(3) High resolution B-mode evidence of proximal internal jugular vein stenosis or other B-mode anomalies.

   

(a) Reduction of proximal internal jugular vein cross-sectional area to no more than 0.3 cm2, which does not increase with Valsalva maneuver.

   

(b) Structural abnormalities and intraluminal defects like flaps, septa, or presence and/or immobility of malformed valve leaflets.

 

(4) Flow not detectable in the internal jugular veins or vertebral veins despite numerous deep inspirations.

 

(5) Abnormal posture control of internal jugular vein flow (cross-sectional area of the internal jugular vein is greater in the sitting position than in the supine, or essentially unchanged despite the change in position).

The reproducibility of using the Doppler sonography in the diagnosis of chronic cerebrospinal venous insufficiency is questionable without proper training (Menegatti et al 2010; Dolic et al 2011b; Dolic et al 2012a) and has been the focal point of recent statements from various scientific societies (Nicolaides et al 2011; Baracchini et al 2012). The largest multicentric, case-controlled chronic cerebrospinal venous insufficiency study, CoSMo, showed high negative and low positive agreement of chronic cerebrospinal venous insufficiency criteria between local and centralized readers (Comi et al 2013a; Comi et al 2013b).

A range of other noninvasive and invasive imaging modalities were proposed for the study or diagnosis of chronic cerebrospinal venous insufficiency. These include magnetic resonance venography (Sundstrom et al 2010; Doepp et al 2011; Wattjes et al 2011; Zaharchuk et al 2011; Zivadinov et al 2011a; Haacke et al 2012; McTaggart et al 2012; Utriainen et al 2012a; Utriainen et al 2012b), catheter venography (Ludyga et al 2010; Baracchini et al 2011a; Petrov et al 2011; Zaharchuk et al 2011; Zivadinov et al 2011a; Simka et al 2013a; Simka et al 2013b; Traboulsee et al 2014), intravascular ultrasound (Lugli et al 2012; Sclafani 2012; Karmon et al 2013; Scalise et al 2013; Zivadinov et al 2013a), and plethysmography (Zamboni et al 2012; Beggs et al 2014a). Prevalence of venous abnormalities and developmental variants, indicative of chronic cerebrospinal venous insufficiency, in multiple sclerosis patients is even higher when investigated with sophisticated invasive imaging techniques (Lugli et al 2012; Sclafani 2012; Karmon et al 2013; Scalise et al 2013; Zivadinov et al 2013a; Traboulsee et al 2014).

The concept of chronic cerebrospinal venous insufficiency existence, its diagnostic utility, and clinical impact was questioned by numerous studies that did not confirm a causal relationship between chronic cerebrospinal venous insufficiency and multiple sclerosis (Al-Omari and Rousan 2010; Doepp et al 2010; Doepp et al 2011; Krogias et al 2010; Yamout et al 2010; Baracchini et al 2011a; Baracchini et al 2011b; Bastianello et al 2011; Centonze et al 2011; Dolic et al 2011a; Dolic et al 2012a; Marder et al 2011; Mayer et al 2011; Monti et al 2011; Zaharchuk et al 2011; Zivadinov et al 2011b; Blinkenberg et al 2012; Garaci et al 2012; Mancini et al 2012; Patti et al 2012; Radak et al 2012; Chambers et al 2013; Simka et al 2013b; Zaniewski et al 2013). The chronic cerebrospinal venous insufficiency hypothesis has provoked great controversy and debate in the multiple sclerosis research community since it was first presented (Khan et al 2010; Baracchini et al 2013; Ghezzi 2013; Hutchinson 2013; Zivadinov and Weinstock-Guttman 2013). In addition, this controversy and debate around the concept of chronic cerebrospinal venous insufficiency was fueled by the postulated therapeutic effect of correcting venous insufficiency with endovascular procedures (Zamboni et al 2009a) before first determining a real need for the procedure itself and testing its safety and efficacy in properly designed randomized, controlled, and blinded trials (Khan et al 2010; Zivadinov and Weinstock-Guttman 2012; Baracchini et al 2013). Many multiple sclerosis patients have undergone endovascular treatment for chronic cerebrospinal venous insufficiency in either open-label or private care settings but largely in non-randomized, non-blinded, and poorly-controlled clinical trials (Zivadinov and Weinstock-Guttman 2012). The sole prospective, randomized, double-blind, sham-controlled trial of endovascular treatment failed to provide any sustained clinical, Doppler, or MRI improvements (Siddiqui et al 2014). To the contrary, there was more disease activity treatment–induced increase in venous outflow (Siddiqui et al 2014). A small sample of patients underwent bilateral surgical reconstruction on internal jugular veins with reported gradual symptom improvement (Spagnolo et al 2014). As with many yet unproven therapies, safety and efficacy concerns have been raised (Burton et al 2011; Dolezal et al 2012; Hubbard et al 2012; Mandato et al 2012; Zivadinov and Weinstock-Guttman 2012; Alroughani et al 2013; Denislic et al 2013; Ghezzi et al 2013a; Ghezzi et al 2013b).

It was at times underlined that chronic cerebrospinal venous insufficiency research is a waste of valuable time, money, and intellectual energy and its funding should be immediately abandoned (Ghezzi 2013; Hutchinson 2013). However, the concept of chronic cerebrospinal venous insufficiency triggered an intense accumulation of rapid knowledge of the extracranial venous system in the last 3 to 4 years. As a result, there is now better understanding of its function and role in relation to CNS disorders and aging (Zivadinov and Weinstock-Guttman 2013).

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