Understanding jugular venous outflow disturbance

Summary

Extracranial venous abnormalities, especially jugular venous outflow disturbance, were originally viewed as nonpathological phenomena due to a lack of realization and exploration of their feature and clinical significance. The etiology and pathogenesis are still unclear, whereas a couple of causal factors have been conjectured. The clinical presentation of this condition is highly variable, ranging from insidious to symptomatic, such as headaches, dizziness, pulsatile tinnitus, visual impairment, sleep disturbance, and neck discomfort or pain. Standard diagnostic criteria are not available, and current diagnosis largely depends on a combinatory use of imaging modalities. Although few researches have been conducted to gain evidence‐based therapeutic approach, several recent advances indicate that intravenous angioplasty in combination with stenting implantation may be a safe and efficient way to restore normal blood circulation, alleviate the discomfort symptoms, and enhance patients’ quality of life. In addition, surgical removal of structures that constrain the internal jugular vein may serve as an alternative or adjunctive management when endovascular intervention is not feasible. Notably, discussion on every aspect of this newly recognized disease entity is in the infant stage and efforts with more rigorous designed, randomized controlled studies in attempt to identify the pathophysiology, diagnostic criteria, and effective approaches to its treatment will provide a profound insight into this issue.

1. INTRODUCTION

It is well acknowledged that cerebral arterial and venous diseases, such as acute and chronic ischemic or hemorrhagic brain lesions, cerebral venous thrombosis (CVT), and nonthrombotic cerebral venous sinus stenosis, have been commonly investigated.1, 2, 3, 4, 5, 6 However, the role of extracranial venous disorders in the central nervous system (CNS), particularly the jugular vein abnormality, is far from comprehensive. Recently, jugular venous outflow disturbance secondary to various factors that interfere with normal cerebral blood drainage has gained a particular interest. In our clinical practice, a cohort of nonthrombotic and nonosseous compressive internal jugular vein (IJV) stenosis patients with idiopathic intracranial hypertension‐mimic presentations have been noticed.7 Previous studies have also revealed that IJV anomalies are probably related to a wide range of neurological diseases and their corresponding clinical manifestations.8, 9, 10, 11, 12, 13, 14, 15, 16, 17 Herein, in this review, we highlight the need for a better understanding of IJV outflow disturbance‐related CNS disorders, and clinical aspects of IJV anomalies regarding the etiology, proposed pathogenesis, clinical manifestations, and diagnosis as well as therapeutic regimens are recapitulated.

2. ETIOLOGY

Based on the available evidence, a number of factors might be responsible for the abnormal IJV outflow and those can be briefly categorized as follows.

2.1. Intraluminal anomalies

Intraluminal anomalies of the IJV refer to the innate defective or acquired structures extending from the vessel wall, which may impair the normal blood flow draining from the brain. These anomalies generally include membrane, web, multisepta, flaps, and malformed venous valves such as long, ectopic, accessory or fused leaflet, inverted valves, and double valves (Figure 1).18, 19, 20, 21 Anatomical conditions such as arachnoid granulations may pose mass effect on venous vessels and simulate focal thrombosis as well. Doppler ultrasonography and intravascular ultrasound are two modalities that are able to clearly visualize intraluminal structures.21 Notably, the prevalence of intraluminal anomalies in the general population and their relevance to the extent of IJV narrowing are currently unknown.

Figure 1.

Proposed etiologies of internal jugular vein (IJV) outflow disturbance. IJV outflow disturbance may be secondary to either extraluminal compression or intraluminal anomalies. Extraluminal compression can result from enlarged thyroid gland (A), and adjacent artery (B) or bony structures (C). Intraluminal anomalies include thrombi (D), septum (E), and elongated valve (F)

2.2. Extraluminal anomalies

Anatomical variants and masses outside the IJV are vital factors that can compress the IJV and narrow the venous lumen. It has been proposed that mediastinal tumors or goiter, osseous impingement, particularly bony structures between the styloid process and lateral mass of cervical vertebra at C1 segment, and adjacent abnormally engorged arteries as well as aneurysms are correlated with IJV stenosis or occlusion (Figure 1).22, 23, 24, 25 Compelling studies have also unraveled a link between neurogenic thoracic outlet syndrome and IJV abnormalities.26

2.3. Systemic factor‐related IJV anomalies

The origin of either intraluminal or extraluminal structural anomalies may be a consequence of comorbidities including bacterial or viral infections, inflammatory processes, and chronic cardiovascular, renal osteodystrophy, or pulmonary diseases.27

Jugular venous reflux (JVR) occurs when there exists an abnormally elevated venous pressure gradient. Sustained JVR may render the IJV valves incompetent and pose a retrograde transmitted pressure into the CNS, whereby hampering the cerebral parenchyma and circulation.28, 29 It seems that the prevalence of JVR increases with age and the severity of JVR‐associated white matter lesions (WMLs) is aging‐dependent.29, 30 Moreover, a couple of vascular risk factors such as smoking, lack of exercise, and obesity have been reported in association with the presence of venous abnormalities in the IJV.31, 32

3. PROPOSED PATHOPHYSIOLOGY

So far, the understanding with regard to the underlying mechanisms of IJV outflow disturbance‐induced brain structural and functional disorders is limited. To the best of our knowledge, there are several hypotheses that might help answer these conundrums.

3.1. Anatomic characteristics of the IJV

The two IJVs are the largest cervical veins that play an indispensable role in draining cerebral venous blood flow. Physiologically, the paired IJVs can interconnect with each other via anastomosing venous plexi, which are considered as main collateral channels that maintain a fluent venous drainage when the IJVs are restricted.33, 34, 35 Communications are also present between the IJVs and the other extracranial cervical veins such as the anterior condylar confluent and its branches. In the condition of significant IJV narrowing, extrajugular venous collaterals will remarkably generate to compensate for the impeded primary venous outflow pathways. The IJV valve functions as a buffer that can prevent sustained retrograde transmitted venous blood and pressure into the cranium.

3.2. Decreased cerebral perfusion

Hemodynamic alterations such as a decline in the cerebral perfusion have been observed in patients with extracranial venous drainage abnormalities.36, 37 An association might be present between the extent of hypoperfusion in the brain parenchyma and the severity of IJV insufficiency.36 Additionally, there is evidence indicating that correction of the abnormal flow due to nonmobile jugular leaflets in the IJV is able to ameliorate cerebral hypoperfusion and decrease enlarged brain ventricles.38 Reduced cerebral blood flow (CBF) can result in the depletion of glucose and oxygen, followed by subsequent detrimental events such as neuronal mitochondrial dysfunction and neural cell death. Although it is still difficult to conclude how the IJV abnormalities impact the brain hemodynamics, altered vascular structure and compliance induced by elevated intracranial venous pressure are assumed to play requisite roles.20, 39 It is noteworthy that in the scenario of multiple sclerosis (MS) combined with impaired extracranial venous drainage, CBF reduction might result from vessel stenosis or occlusion secondary to iron overload, inflammatory cells, fibrin deposits, or others.40

3.3. Cerebral microvascular structures impairment

It has been speculated that impaired venous outflow may weaken the blood‐brain barrier (BBB), possibly via downregulating tight junction proteins and upregulating adhesion molecules in the vascular endothelium.41, 42 BBB damage enables the translocation of cells including monocytes, erythrocytes, and other inflammatory cells into the extracellular space, thus triggering cascades of responses such as immunological or inflammatory reactions, cell injury, and fibrin or iron deposition. Researchers also suggest that prolonged elevated intracranial venous pressure can lead to hyalinosis and thickening of venous vessel wall, endothelial dysfunction, and arteriolar regulation impairment.43, 44, 45, 46 Furthermore, in a previous study, it is interesting to notice that patients with extracranial venous drainage abnormalities displayed markedly decreased venous vasculature visibility on susceptibility‐weighted imaging (SWI) venography.47

3.4. Abnormal cerebrospinal fluid dynamics

Zamboni et al48 firstly reported a significantly lower net cerebrospinal fluid (CSF) flow in MS patients with venous outflow disturbances, the severity of which might be tightly correlated with the CSF flow. Following this, Zivadinov et al49 further discovered that relieving the impeded extracranial venous flow by percutaneous transluminal angioplasty could promote the CSF flow while lower the CSF velocity. Increased CSF pulsatility was also observed in IJV abnormalities patients without any history of MS, implying that altered intracranial CSF dynamics might primarily result from impaired cerebral venous drainage instead of MS itself.50 Even though the precise mechanisms involved are poorly understood, it is reasonable to postulate that IJV outflow disturbance‐related intracranial venous hypertension, particularly in the superior sagittal sinus, is capable of blunting the absorption of CSF through the arachnoid villi, leading to abnormal CSF dynamics.

3.5. Aging and IJV

Advancing age has been shown to be associated with a group of structural and functional changes of blood vessels, such as arteriolar stiffness and tortuosity, endothelial dysfunction, decreased microvascular density, and BBB impairment.51 Nevertheless, the extent to which the morphology and function of the IJV alters with senescence has not been fully explored. A high prevalence of JVR in the elderly as well as more prominent age‐related WMLs among those with severe JVR is suggestive of the role of aging in IJV disturbance‐associated CNS disorders.30 In addition, the cross‐sectional area (CAS) of the IJV in healthy volunteers seems to increase with aging even after adjusting for vascular risk factors, indicating a propensity to elevated venous pressure and vessel distension.52 Many questions remain unanswered at the moment, and it goes without saying that much more work is required to validate the association between aging and extracranial venous abnormalities.

4. CLINICAL MANIFESTATIONS

There is strong evidence showing that venous outflow abnormalities can contribute to the development of intracranial hypertension. The degree of clinical presentations of IJV outflow disturbance may vary from none to severe based on individual variation and compensatory capability. Broadly speaking, these characteristics such as headache, pulsatile tinnitus, visual impairment, sleep disturbance, and neck discomfort or pain may mimic, at least partially, those of idiopathic intracranial hypertension and chronic cerebral circulation insufficiency.2, 7, 53

Constant or intermittent head noises, known as intracerebral noise and unilateral or bilateral tinnitus, are specific features of the disease that are highly indicative of altered blood flow patterns in the IJV lumen. Some of other prevalent symptoms include headache, heavy‐headedness, dizziness, sleep disturbance, neck discomfort, and back pain. Ophthalmological discomforts such as eye soreness and eye dryness, dysmorphopsia, diplopia, blurred vision, and even visual loss are frequently complained in a certain amount of patients. Patients may also have decreased cognitive function and behavioral changes, which can be mistaken for psychiatric issues. Physical findings are of limited localizing value. Abducens nerve weakness and neck stiffness, although not usual, may sometimes be detected in this condition. Notably, abnormalities identified in the ophthalmic examination such as impaired visual acuity, visual field defects, and papilledema should raise urgent suspicion.

5. DIAGNOSIS

So far, there are no established standardized diagnostic criteria for extracranial venous abnormalities exist. Patients with unexplained aforementioned clinical features, particularly in the absence of obvious arterial vascular system‐related disorders, should be suspected as likely being at risk of venous issues. It should be noted that the IJV is easily influenced by a number of factors such as respiration, posture, cardiac function, hemodynamic status, and compression from surrounding structures.54, 55 More importantly, it is arduous to clearly differentiate clinically significant abnormalities form physiological variations considering the high anatomical variability of the IJV. Therefore, single diagnostic modality is definitely far from enough, and it is likely that a more comprehensive approach is warranted to screen, diagnose, and monitor these venous abnormalities.

5.1. Doppler ultrasonography

Doppler ultrasonography is a widely used imaging technique that has also been recently studied in the field of IJV abnormalities.56, 57, 58, 59, 60 Merits with respect to the noninvasiveness, free of ionizing radiation, easy portability, and low expenditure render it the first option for routine examination. Besides, it can provide dynamic hemodynamic information such as blood flow and blood velocity with high resolution and enable the assessment of intraluminal anomalies or developmental variants. Major drawbacks of ultrasonography include poor visualization of some parts of the IJV such as the cervical region and the jugular bulb, time‐consuming, and operator skill‐dependent.

5.2. Magnetic resonance venography

Compared with Doppler ultrasonography, magnetic resonance venography (MRV) is capable of depicting a more comprehensive view of the morphology of the head and neck veins, (Figure 2).61, 62, 63, 64, 65, 66, 67 Generally, it takes less time and is relatively operator‐independent, enabling the possibility of being utilized in the blinded and multicenter clinical study design. In addition to the identification of luminal stenosis, advanced MR sequences such as phase‐contrast MRV and 4D flow imaging hold the potential of evaluating intraluminal blood flow patterns and more notably, the condition of collateral circulation surrounding the IJV, which is viewed as a vital compensatory mechanism for impaired venous outflow.65, 66, 67 However, MRV cannot detect intraluminal anomalies such as malformed valves, membrane, and septa in more detail, and it may sometimes even underestimate the venous caliber.

Figure 2.

Neuroimaging examples of patients with bilateral internal jugular vein (IJV) stenosis. Magnetic resonance venography (MRV) images including (A,D) display the presence of bilateral IJV stenosis (short arrows) surrounded by abnormally engorged and tortuous collaterals (long arrows). Three‐dimensional reconstruction images of CT including (B,C,E,F) further reveal the IJV stenosis might due to the compression from nearby arteries

5.3. Computed tomography venography

Although the available evidence‐based literature regarding the effectiveness of computed tomography venography (CTV) techniques in the extracranial cervical veins is sparse, it may display similar advantages as MRV for assessing the global status of the IJV. Moreover, unlike MRV, CTV is able to visualize the conditions of the azygos vein, which is an important component for the diagnosis of chronic cerebrospinal venous insufficiency (CCSVI).7, 68 Contrast CT, usually performed along with CTV, is useful to help exclude the bony impingement‐associated IJV stenosis or occlusion (Figure 2). The main disadvantages concentrate on the use of contrast agents and exposure to low dose of radiation, both of which may limit the application of CTV in a certain group of patients, including those who have renal diseases or history of contrast allergy and get pregnant.

5.4. Cervical plethysmography

Strain‐gauge cervical plethysmography (SGCP) is considered to be an effective and noninvasive method that allows researchers to obtain an overall view of venous function on the basis of venous capacitance and resistance. Through a sensor encircling the cervical segment of the body, Zamboni et al69 discovered a profound difference in the extracranial venous return‐associated parameters between patients with CCSVI and healthy controls. In another study, Beggs demonstrated that the mean hydraulic resistance of the extracranial venous system measured by the means of SGCP in CCSVI patients was significantly higher than controls.70 Nonetheless, whether or not SGCP can be a complementary technique to other modalities for diagnosing venous drainage abnormalities requires further studies to validate.

5.5. Catheter venography and ultrasonography

Despite being viewed as a gold standard imaging technique for evaluating the degree of vascular stenosis and measuring the trans‐stenotic pressure gradient for planning endovascular procedures, catheter venography (CV) is unable to provide enough information regarding the intraluminal anomalies that affect the regular venous outflow (Figure 3).20, 71, 72, 73 Additionally, the features of invasiveness and being exposed to contrast agents or radiation render it a suboptimal choice in a clinical scenario where the IJV outflow disturbance is suspected.

Figure 3.

Cather venography of unilateral internal jugular vein (IJV) stenosis. A, shows severe stenosis of the IJV on the right side (blue arrow) and a significantly increased number of abnormal tortuous collateral veins (red arrows) before stenting. B, shows, after intervention with stenting, the former stenotic lumen is recanalized (blue arrow) and the abnormal collaterals were distinctly reduced (red arrows)

Similar to the conventional sonography, intravascular ultrasonography (IVUS) is significantly superior to CV in detecting intraluminal malformations such as IJV valves and thrombi among patients with abnormal extracranial venous abnormalities.19, 20, 21 Besides, IVUS is capable of measuring venous vascular cross‐sectional area and circumference more accurately, whereby providing a relatively reliable determination of the stenotic segments.20 It also allows a better visualization of the whole course of the IJVs, which may be neglected by the conventional sonography. These advantages might account for the higher rate of venous (IJVs and azygos veins) abnormalities measured by IVUS in comparison with CV.21 Currently, IVUS is not a routinely utilized modality for either the diagnosis of IJV outflow disturbance or the guidance of selecting the most appropriate stenting/angioplasty procedure, and there is no consensus available regarding the optimal procedural endpoint.

5.6. Other diagnostic techniques

MR black‐blood thrombus imaging technique (MRBTI), as a novel approach for the detection of CVT, has begun to garner an increasingly attention of researchers. This noncontrast method could suppress the blood signal and differentiate the thrombi from surrounding structures, enabling a direct visualization and quantitative measurement of intraluminal thrombi with high accuracy.74 To be noted, a set of patients with IJV outflow disturbance display thrombi inside the unilateral and/or contralateral IJV, and they sometimes concomitantly have CVT as well. In this regard, MRBTI may hold promise to serve as a valuable alternative to current techniques.

Severe papilledema, secondary to elevated intracranial hypertension, if not diagnosed and intervened promptly, may result in permanent visual damage or even blindness. Optical coherence tomography (OCT) has emerged as a noninvasive diagnostic tool for evaluating optic nerve status by measuring parameters such as retinal nerve fiber layer thickness and total retinal measurements.75 This kind of approach could be of interest in a wide cohort of patients who get admitted to medical facilities due to ophthalmological complaints.

6. TREATMENT

At present, there is no consensus among researchers with respect to the optimal strategy for IJV outflow disturbance due to an absence of robust evidence. The multidisciplinary team approach (a comprehensive strategy with two or more different techniques) has been gradually accepted as a novel notion aiming at preventing and controlling clinical manifestations as well as complications. The primary goal of treating IJV outflow disturbance focuses on the restoration of normal hemodynamics and relief of headaches, tinnitus, and other symptoms associated with elevated intracranial pressure.

After excluding the likelihood of hemorrhage, standard anticoagulant therapy, including subcutaneous low molecular weight or intravenous heparin for several days and subsequent bridging with oral anticoagulants, is recommended for patients with IJV outflow disturbance either secondary to or in combination with the following conditions: (i) thromboembolic events such as CVT and IJV thrombosis; (ii) planning for surgical revascularization; and (iii) the presence of venous valve malformation or other factor‐related IJV stenosis and coexisting hypercoagulability state.76, 77, 78, 79 Patients with IJV stenosis or thrombosis originated from suspected bacterial infection should be administered with antibiotics appropriately. Antiepileptic drugs are not indicated unless there is evidence of seizures with or without parenchymal lesions. Despite the lack of high‐quality randomized controlled trials on the effectiveness of carbonic anhydrase inhibitors or diuretics on the functional outcomes of patients with impeded extracranial venous outflow, acetazolamide is still a commonly utilized complementary therapy for lowering intracranial hypertension in clinical practice.7

For those with thrombosis‐related venous stenosis, endovascular intervention including intravenous thrombolysis and mechanical thrombectomy can be considered if aggravation of clinical symptoms occurs despite intensive medical treatment.79

Intraluminal defects are regarded as main etiologies, causing a significant delay of jugular flow. Percutaneous transluminal balloon angioplasty and stenting have been demonstrated to be feasible and safe with low procedure‐related morbidity and mortality among patients with CCSVI.80, 81 Moreover, fixing the flow in the IJV via endophlebectomy of the jugular valve or septum together with patch angioplasty using the autologous great saphenous vein seems to robustly ameliorate cerebral perfusion.38, 82 Nevertheless, it is noteworthy that not every venous valve malformations should be intervened surgically, especially if there is no indication such as uncontrolled symptoms and predicted severe complications of the lesions. These intraluminal anomalies with obstructive nature like membrane, web, flaps, and malformed venous valves may respond distinctly to different therapeutic strategies as well.

To evaluate the safety and efficacy of venous percutaneous transluminal angioplasty in patients with both relapsing‐remitting MS and CCSVI, a multicenter, randomized, and controlled clinical trial was conducted by Zamboni et al,83 who reported that this surgical intervention should not be recommended for treating patients with MS as there was no significant improvement on the functional outcome or reduction in new combined brain lesions over 1‐year follow‐up detected. A recent study concluded that nonthrombotic unilateral or bilateral IJV stenosis in the absence of any intracranial pathologies might account for a vital part of idiopathic intracranial hypertension.7 Considerable resolution of the trans‐stenotic mean pressure gradient and abnormal extracranial venous collaterals, reduction in intracranial pressure, and improvement of clinical manifestations including headache, tinnitus, and visual impairments were achieved following the correction of the IJV with intravenous balloon angioplasty combined with stenting (Figures 3 and 4). Of note, no stenting‐related adverse events occurred in this group of patients within 12 ± 5.6 months of follow‐up.

Figure 4.

Fundal photographs and corresponding optical coherence tomography in a patient with bilateral internal jugular vein (IJV) stenosis. Fundal photographs and corresponding optical coherence tomography (OCT) pictures of both eyes during hospital but before stenting: (A) Right and (B) left show severe papilledema with disk elevation, periphery halo, and congested/tortuous retinal vessels; hemorrhage is noticed in the right eye; the FPG scores are 5 and 4 for right and left eyes, respectively; OCT pictures show an significant increase in retinal nerve fiber layer thickness. Fundal photographs and corresponding OCT pictures of both eyes at approximately 15 mo of follow‐up after stenting: (C) Right and (D) left show remarkable improved papilledema with disappearance of tortuous vessels and optic disc edema; the FPG scores were 0 for both eyes; the retinal nerve fiber layer thickness of each eye recovers to normal range

Extrinsic compression of the IJV secondary to the osseous and muscular origins (such as the styloid process, the posterior belly of the digastric muscle, and the transverse process of an adjacent vertebra) has been found in a set of unselected patients who underwent computed tomography angiography (CTA).84 However, some of the IJV stenosis may not be taken as pathological considering no evidence of abnormal collateral formation. Patients may display central venous hypertension‐associated symptoms when this impingement either occurs bilaterally or affects the dominant IJV. Surgical resection of culprit structures is gradually emerging as the choice of treatment. Among patients with identified extrinsic impingement of the IJV between the styloid process and the lateral mass of cervical vertebra at C1 segment, venous stenting alone was deemed ineffective given the compressive nature and delayed stenting complications were also recorded.24, 25 In this setting, modified styloidectomy is regarded as a potential adjunctive therapeutic approach, which not only alleviates IJV stenosis‐associated intracranial hypertension but salvages the probable complications of stenting.

Fulminant ophthalmological issues, in which severe deterioration of the optic nerve function is rapid, occur in a few patients with IJV stenosis. Optic nerve sheath fenestration (ONSF) may serve as an intriguing surgical intervention to improve or stabilize visual functions when the origin of stenosis cannot be corrected as early as possible.85

7. CURRENT CHALLENGES

Unlike the arterial system, the role of extracranial venous drainage abnormalities is largely unknown and several conundrums lying ahead await to be tackled.

The IJV is complicated with variability between individuals, and it harbors the feature of asymmetry, where one IJV may be much larger than the other as a result of preferential intracranial venous drainage. IJV stenosis has also been reported in healthy subjects without any disease history. The characteristics of venous wall predispose the IJV to the impacts from a range of factors such as respiration, postural alteration, hydration condition, and nearby structures. Accordingly, differentiating what are physiological variants from what are truly anomalies is a huge challenge. Abnormal formed intracranial or extracranial collateral circulation is believed to be the most valuable evidence, which suggests the presence of impaired venous outflow and venous hypertension. To the best of our knowledge, it is necessary to take both the status of collaterals and clinical symptoms/signs into consideration when evaluating the IJV stenosis.

Current definition of venous stenosis is primarily based on the experience from the arterial criteria, which are obviously not appropriate. The exact degree of IJV stenosis that could result in hemodynamic alterations as well as increased cerebral venous pressure is not as well understood. More comprehensive diagnostic criteria derived from a combination of diverse imaging modalities and other novel techniques need to be established.

It remains unclear the real contribution of intra‐ or extraluminal anomalies to the severity of IJV outflow disturbance. Additionally, available data with respect to the association between the presence of abnormalities in the IJV and confounders, such as aging, gender, ethnicity, infection, immunological disorders, and other identified vascular risk factors are scarce. Figuring out these puzzles may promote a better understanding of the etiology of IJV outflow disturbance.

The proposed pathophysiology of impeded extracranial venous drainage can be briefly summarized as following three aspects: (i) reduced cerebral blood perfusion; (ii) altered CSF dynamics; and (iii) disrupted intracranial microvasculature. However, the detailed mechanism through which venous drainage abnormalities affect the cerebral circulation is basically unexplored that requires to be further addressed.

Given the complex and undetermined etiology and pathophysiology, treatment for IJV outflow disturbance remains a challenge. It also raises intriguing questions as to whether venous outflow obstruction is correlated with some CNS disorders including MS, migraine, Parkinson's disease, cough syncope, Alzheimer's disease, Meniere disease, transient global amnesia, transient monocular blindness, and leukoaraiosis, and if indeed a link exists, customized therapeutic regimens must be designed for different groups of patients.10, 12, 13, 16, 17, 29, 30, 86, 87, 88, 89, 90 Although preliminary findings regarding the efficacy of endovascular therapy in relieving symptoms from IJV stenosis are a step forward, further investigations are required to evaluate the short‐ and long‐term benefits of surgical interventions, as most of the pilot studies have been single‐center, retrospective, uncontrolled trials without quantifiable endpoint measures. Moreover, successful establishment of collaterals with nonsurgical maneuvers may be another novel direction for therapeutic intervention, particularly when there is no indication for surgery.

8. CONCLUSIONS

In summary, IJV outflow disturbance is an increasingly recognized disease entity among patients with or without other CNS disorders. The clinical manifestation of IJV outflow disturbance is heterogeneous and sometimes even insidious. So far, the understanding regarding its etiology, pathogenesis, diagnostic criteria, therapeutic strategies, and long‐term clinical outcomes is far from enough, which may have clinicians underestimate the scale of the problem, resulting in misdiagnosis and treatment delay. Future efforts with more rigorous designed clinical studies aiming at figuring out these unknown mysteries and exploring either surgical or nonsurgical interventions to optimize the treatment for IJV outflow disturbance will provide a profound insight into this issue.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Zhou D, Ding J‐Y, Ya J‐Y, et al. Understanding jugular venous outflow disturbance. CNS Neurosci Ther. 2018;24:473–482. 10.1111/cns.12859