Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. eISSN 2279-7483 https://www.pagepressjournals.org/index.php/vl/index Publisher's disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. The Early Access service lets users access peer-reviewed articles well before print / regular issue publication, significantly reducing the time it takes for critical findings to reach the research community. These articles are searchable and citable by their DOI (Digital Object Identifier). Veins and Lymphatics is, therefore, e-publishing PDF files of an early version of manuscripts that have undergone a regular peer review and have been accepted for publication, but have not been through the typesetting, pagination and proofreading processes, which may lead to differences between this version and the final one. The final version of the manuscript will then appear in a regular issue of the journal. E-publishing of this PDF file has been approved by the authors. All legal disclaimers applicable to the journal apply to this production process as well. Veins and Lymphatics 2023 [online ahead of print] To cite this article: Andrea Migliorelli, Andrea Ciorba. Cerebral venous outflow abnormalities and inner ear: an underestimated piece of the puzzle? Veins and Lymphatics. 2023;12:11585. doi:10.4081/vl.2023.11585 ©The Author(s), 2023 Licensee PAGEPress, Italy https://www.pagepressjournals.org/index.php/vl/index Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Cerebral venous outflow abnormalities and inner ear: an underestimated piece of the puzzle? Andrea Migliorelli, Andrea Ciorba ENT & Audiology Unit, Department of Neuroscience and Rehabilitation, University Hospital of Ferrara, Italy Corresponding author: Andrea Ciorba, Audiology Unit, Department of Neuroscience and Rehabilitation, University Hospital of Ferrara, 44124 Ferrara, Italy. E-mail: andrea.ciorba@unife.it mailto:andrea.ciorba@unife.it Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a medical disorder initially documented by Zamboni, which is distinguished by the impeded drainage of cerebrospinal fluid through the extracranial venous system. This obstruction mostly arises from the constriction or blockage of veins located in the cranial region and neck. This syndrome has the potential to result in the development of collateral circles, venous reflux, and iron accumulation within the central nervous system1,2. In the year 2011, a set of five ultrasonography parameters were identified and published, which precisely indicate anatomical and functional changes in the venous blood flow within the neck. These parameters were essential in establishing the distinct characteristics associated with CCSVI. The most suitable approach for investigating CCSVI involves the assessment of venous flow using echo- enhanced Doppler, in conjunction with transcranial Doppler. This combined method enables the evaluation of both deep cerebral veins and potential reflux. The role of CCSVI has been investigated as a potential etiological component in the development of many neurological and/or neurosensory conditions, including Multiple Sclerosis (MS)2-4. Nevertheless, in recent years, some investigations have also established a potential correlation between the existence of CCSVI and Inner Ear Disorders (IED). The venous drainage of the inner ear primarily consists of three veins: the cochlear aqueduct vein, also referred to as the cochlear canaliculus vein; the vestibular aqueduct vein; and the labyrinthine vein, alternatively known as the internal auditory vein. The venous drainage occurs via the inferior petrous sinus, which ultimately connects to the internal jugular vein (IJV)5-9. In a preliminary investigation conducted by Menegatti et al.4, it was shown that individuals diagnosed with both MS and IED had a greater prevalence of CCSVI as measured by abnormal Internal Jugular Vein (IJV) function, in comparison to a control group consisting of individuals without any known health conditions. The authors have provided evidence to support the notion that both groups had a notably larger occurrence of valvular system in the IJV compared to healthy participants. Furthermore, it was observed that these patients exhibited a malfunctioning valvular system, characterized by a higher prevalence of monocuspid valve. Undoubtedly, Meniere's Disease (MD) has garnered significant attention from the scientific community as one of the most prominent manifestations of CCSVI. MD is a clinical disorder distinguished by symptoms such as vertigo, sensorineural hearing loss, and tinnitus, as evidenced by several scholarly sources7-12. At present, the genesis of MD remains uncertain. Among the several explanations proposed, one of the most widely recognized in the academic literature is the hypothesis Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. suggesting that MD may be attributed to the inner ear's excess accumulation of endolymph, leading to the development of a condition known as Endolymphatic Hydrops (EH). According to some reports, the presence of an obstruction in the extracranial venous outflow may eventually lead to intracranial venous hypertension; this, in turn, can impede the reabsorption of Cerebrospinal Fluid (CSF), resulting in an elevation of CSF pressure. Consequently, these changes in pressure could give rise to variations in endolymphatic and perilymphatic pressures. Some authors have also attributed the hydropic ear to a dysregulation/impairment of the inner ear blood flow7,13, in particularly reporting that a venous obstruction may cause changes in the inner ear microcirculation, consequently hampering the function of the stria vascularis, and therefore of the outer and inner hair cells, as well as of the saccular, utricular and ampullary hair cells13. Interestingly, it has been suggested that the presence of distinct ultrasonography CCSVI vascular patterns may be associated to the manifestation of different clinical disorders, such as MS and MD. In the disease known as CCSVI the duration of blood flow via the neck is extended primarily as a result of functional stenosis caused by either the inadequate opening of faulty jugular valves or muscular entrapment. The MS pattern is distinguished by stenosis in the J1 segment (located at the confluence with the brachio-cephalic venous trunk), alterations of the trunk in the J2 segment (associated with the ipsilateral thyroid lobe), a higher occurrence of alterations in the medial-distal J1-J2 segments, and the presence of compensatory collaterals along with the vertebral venous system. The MD pattern is distinguished by the presence of modified trunks in the J3 region, specifically in the superior segment located at the carotid bifurcation and the mandibular angle. Additionally, there is a higher occurrence of medial-proximal modifications in the J3-J2 region, together with vertebral venous hyperplasia, without any other observable collateral vessels8. According to the available literature1,2, Percutaneous Angioplasty (PTA) has demonstrated excellent outcomes as the sole treatment for MD, making it the only IED to be effectively managed by this approach. Specifically, in 2014, Bruno et al. conducted a PTA procedure on the IJV and azygos vein in patients with both MD and CCSVI. Their study reported favorable outcomes in terms of the severity of symptoms and the rate of recurrence. The potential involvement of cerebral venous outflow abnormalities could be considered also in the pathogenic mechanism of further neurosensory diseases, including other IED disorders; in this way, some authors have also considered a possible link between CCSVI and Sudden Sensorineural Hearing Loss (SSNHL)5,14. The etiology of SSNHL remains unknown and continues to be a subject of ongoing Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. scholarly discourse. The vascular hypothesis (the impairment of the cochlear microcirculation) is widely supported as one of the potential etiological factors contributing to the development of this disease. Due to this rationale, certain researchers have also explored a potential correlation between severe SSNHL and CCSVI. The initial research findings indicate an elevated occurrence of CCSVI in individuals with severe SSNHL compared to those without the condition, as evidenced by some studies4,5,15. Despite the intriguing and encouraging first findings, the current body of literature lacks a substantial number of publications that assess the true impact of venous outflow blockage on the development of SSNHL. Furthermore, in recent studies, a possible correlation has been established between CCSVI and the occurrence of recurrent Benign Paroxysmal Positional Vertigo (BPPV)6. The etiology of recurrent BPPV as per other inner ear disorders, remains unknown at now. Nevertheless, some investigators have proposed the notion of inner ear microcirculation impairment as a potential mechanism. It is possible to hypothesize that a slowed venous drainage may damage the inner ear at different sites; if the damage is prevalent at the level of the stria vascularis, this could cause MD, while if the injury is prevalent at the level of the utricular macula, this could cause damage to the neuroepithelium and subsequent otolithic detachment generating recurrent BPPV1,4. In summary, our current understanding of the pathophysiology of IED remains limited15-19. Given the intricate nature of the inner ear circulation and the challenges associated with its in vivo assessment using current diagnostic methods, drawing definitive conclusions regarding the role of inner ear microcirculation in these disorders remains challenging. Enhancing our comprehension of the correlation between venous blood flow and IED could be very important for advancing our understanding of the pathophysiology of IED and subsequently assessing prospective targets for therapeutic intervention. Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. References 1) Zamboni P. The big idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J. R. Soc. Med. 2006;99:589–93. 2) Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392-9. 3) Zamboni P, Morovic S, Menegatti E, et al. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound--recommendations for a protocol. Int Angiol. 2011;30:571- 97. 4) Menegatti E, Tessari M, Vannini ME, et al. High resolution M-mode evaluation of jugular vein valves in patients with neurological and neurosensory disorders. Curr Neurovasc Res. 2017;14:316- 22. 5) Ciorba A, Tessari M, Mazzoli M, et al. Cerebral inflow and outflow discrepancies in severe sudden sensorineural hearing loss. Curr Neurovasc Res. 2018;15:220-5. 6) Ciorba A, Tessari M, Natale E, et al. Cerebral outflow discrepancies in recurrent benign paroxysmal positional vertigo: focus on ultrasonographic examination. Diagnostics (Basel) 2023;13:1902. 7) Alpini DC, Bavera PM, Di Berardino F, Barozzi, S., et al. Bridging the gap between chronic cerebrospinal venous insufficiency and Ménière disease. Veins and Lymphatics 2016;5:1-8. 8) Bavera PM, Di Berardino F, Cecconi P, et al. Chronic cerebro-spinal insufficiency in multiple sclerosis and meniere disease: same background, different patterns?. Veins and Lymphatics 2017;6:1- 4. 9) Toro EF, Borgioli F, Zhang Q, et al. Inner-ear circulation in humans is disrupted by extracranial venous outflow strictures: Implications for Ménière’s disease. Veins and Lymphatics 2018;7:1-12. Early Access Veins and Lymphatics Editorial The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries should be directed to the corresponding author for the article. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 10) Frau GN, Pagani R, Maronato F, et al. The role of omohyoid muscle entrapment of the internal jugular vein and is surgical transection in Ménière’s disease and other inner ear disorders. Veins and Lymphatics 2019;8:1. 11) Müller LO, Zhang Q, Contarino C, et al. Multi-compartment mathematical model for cerebrospinal fluid mechanics coupled to the systemic circulation: application to transverse sinus stenosis. Veins and Lymphatics 2019;8:1. 12) Bruno A, Califano L, Mastrangelo D, et al. Chronic cerebrospinal venous insufficiency in Ménière’s disease: diagnosis and treatment. Veins and Lymphatics 2014;3:1-4. 13) Foster CA, Breeze RE. The Meniere attack: an ischemia/reperfusion disorder of inner ear sensory tissues. Med Hypotheses. 2013;81(6):1108-15. 14) Alpini D, Bavera PM, Di Berardino F, Barozzi S, Cesarani A. Bilateral sudden sensorineural hearing loss and chronic venous cerebrospinal insufficiency: a case report. Phlebology. 2013;28:231- 3. 15) Tessari M, Ciorba A, Mueller LO, et al. Jugular valve function and petrosal sinuses pressure: a computational model applied to sudden sensorineural hearing loss. 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Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 19) Zamboni P, Galeotti R, Salvi F, et al. Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial. J Endovasc Ther. 2020;27:1526602819890110.