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Jun. 07, 2021
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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.
• 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.
The role of the extracranial venous system in the pathology of central nervous system disorders and aging is largely unknown (100). 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 (34; 91; 22; 43; 106; 31; 87). 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 (11; 12; 54).
The embryogenesis of the extracranial venous system is subject to many variations, which do not necessarily represent pathological findings (67; 50; 14; 51). A range of congenital extracranial venous abnormalities or development variants have been described (50; 51). Nevertheless, pathological investigations aimed to define the nature of these venous abnormalities or development variants are systematically lacking (25; 21).
In 2009, Zamboni and colleagues described a vascular condition named chronic cerebrospinal venous insufficiency (92). 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 (93; 95). 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 (26; 05; 105; 31).
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) (93; 95). The venous hemodynamic Doppler sonography criteria were revised by the ISNVD in 2011 and have been modified as follows (66; 97; 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 (61; 33; 29) and has been the focal point of recent statements from various scientific societies (66; 07). 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 (81; 27; 88; 90; 102; 42; 60; 85; 86), catheter venography (52; 05; 69; 90; 102; 78; 79; 84), intravascular ultrasound (53; 75; 47; 72; 103), and plethysmography (94; 09). 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 (53; 75; 47; 72; 103; 84).
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 (01; 26; 27; 49; 89; 05; 06; 08; 17; 30; 29; 58; 59; 62; 90; 105; 15; 37; 56; 68; 71; 18; 79; 98). The chronic cerebrospinal venous insufficiency hypothesis has provoked great controversy and debate in the multiple sclerosis research community since it was first presented (48; 04; 39; 46; 109). 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 (92) before first determining a real need for the procedure itself and testing its safety and efficacy in properly designed randomized, controlled, and blinded trials (48; 108; 04). 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 (108). The sole prospective, randomized, double-blind, sham-controlled trial of endovascular treatment failed to provide any sustained clinical, Doppler, or MRI improvements (77). To the contrary, there was more disease activity treatment–induced increase in venous outflow (77). A small sample of patients underwent bilateral surgical reconstruction on internal jugular veins with reported gradual symptom improvement (80). As with many yet unproven therapies, safety and efficacy concerns have been raised (16; 28; 44; 57; 108; 03; 23; 40; 41).
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 (39; 46). 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 (109).
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