Chronic cerebro – Spinal insufficiency (CCSVI) in multiple sclerosis (MS) and manière disease (MD): same background, different pattern?
Submitted to Veins & Lymphatics
Research Gate DOI: 10.13140/RG.2.2.33687.57764
Bavera Pietro Maria1,3, Di Berardino Federica 2, Cecconi Piero 3, Mendozzi Laura3, Mattei Valentina 3, Alpini Dario Carlo3,4
Vascular Imaging Diagnostician for Medick-Up Vascular Lab, Milan, Italy
• Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, and Audiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore
• Policlinico, Milan, Italy
• IRCCS S. Maria Nascente “don Carlo Gnocchi Foundation”, via Capecelatro 66, 20148 Milan, Italy
• Vertigo School, via Lomellina 58, 20133, Milan Italy
Dario Carlo Alpini
Vertigo School, via Lomellina 58, 20133 Milan, Italy
Authors Contribution: Bavera PM designed the experiment and performed Duplex evaluations , Cecconi P designed the experiment and analyzed MRV data, Mattei V performed oto-neurological tests and selected audio-vestibular patients, Alpini DC designed the experiment and wrote the manuscript, Mendozzi L designed the experiment and selected multiple sclerosis patients, Di Berardino F analysed the data wrote the manuscript and critically revised the paper for important intellectual content. All the authors contributed to the preparation of the paper
Conflict of interest: the author declares no potential conflict of interest
Paper presentedat the Vth Meeting of International Society Neuro Vascular Disease (ISNVD), Naples, Italy, April 2015
Multiple Sclerosis (MS) is a chronic disease of the Central Nervous System characterized by demyelinating lesions with acute phases and progressive loss of sensori-motor functions. Mèniére Disease (MD) is a disorder of the inner ear characterized by acute spells of vertigo and hearing loss and progressive loss of cochleo-vestibular function. Both the diseases have a multifactorial pathogenesis and quite the same chronic cerebro-spinal insufficiency (CCSVI) frequence. However, as far as Author’s knowledge concern, no patients affected with both the diseases are described. The aim of this paper is investigate if MS and MD present different CCSVI patterns. Three groups of patients were enrolled: 70 definite MS – 27 definite unilateral MD (MEN) – 51 with Other, no-Mèniére, audio-Vestibular disorders (OVD). All subjects underwent magnetic resonance venography (MRV) and venous eco-Duplex (ECD) and only patients that satisfied both MRV and ECD CCSVI diagnostic criteria were considered. J1 was normal in 57% of MS, 88% of MEN and 95% of OVD. Stenosis (ST) were detected, respectively, in 30% in MS and 2% in MEN and OVD. J2 was normal in 78% of MS, 64% of MEN and 95% of OVD. At this level alterations of the trunk (AT) were detected in 17% in MS and 26% in MEN J3 was normal in 74% of MS, 64% of MEN and 86% of OVD. AT were found in 15% of MS, 26% of MEN and 8% of OVD. Hyperplasia of the Vertebral Venous system was observed in 35% of MS, 40% of MEN and in 15% of OVD. Other compensatory collaterals were detected in 25% in MS and only in 5% in MEN and OVD. Our results indicates that the MS pattern is characterized by J1 stenosis, J2 alterations trunk, a prevalence of J1-2 medio-distal alterations, compensatory collaterals besides vertebral venous system. MEN pattern is characterized by alteration trunks in J3, a prevalence of J3-2 medio-proximal alterations and vertebral veins hypertrophy without other detectable collaterals. although the group of patients with venous alterations is very small, OVD patients show a CCSVI pattern more similar to MD than MS pattern. The difference between MS and MD patterns indicates that that CCSVI is not an unique entity and it is an explanation of the fact that subjects affected with both the diseases are reported.
Multiple Sclerosis [Multiple Sclerosis (MS)] is a chronic disease of the Central Nervous System characterized by demyelinating lesions. Typical course is alternating of acute phases followed by unpredictable periods of remission but, usually, with a progressive loss of sensori-motor functions. A multifactorial pathogenesis is nowadays accepted  even if a unique final autoimmune mechanism is usually considered. Mèniére Disease [Mèniére Disease (MD)] is a disorder of the inner ear characterized by acute spells of vertigo, tinnitus and hearing loss followed by unpredictable period of remission but, usually, with a progressive loss of vestibular and cochlear function. A multifactorial pathogenesis is accepted  even if an unique final hydraulic mechanism, the so called Endolymphatic Hydrops [Endolymphatic Hydrops (EH)], is usually considered . Both MS [4,5,6] and MD [7,8,9] presents quite the same frequence of cerebro-cervical venous abnormalities as evaluated by means of Magnetic Resonance Venography [Magnetic Resonance Venography (MRV)] or ecoDuplex exam [eco-Duplex (ECD)] adopting the criteria for the diagnosis of chronic cerebro-spinal insufficiency [chronic cerebro-spinal insufficiency (CCSVI)]. Despite this, as far as Author’s knowledge concern, no patients affected with MS and MD are reported in Literature.
The aim of this paper is to investigate if MS and MD present CCSVI different patterns.
Material and Methods
Three groups of patients were enrolled:
70 definite Multiple Sclerosis (MS, 43 females and 17 males, mean age 43,7 yy) –
27 definite unilateral Ménière Disease  (MEN, 17 females and 10 males, mean age 41,5 yy) 
51 Other Vestibular Disorders (OVD, 28 females and 13 males, mean age 43, 3 yy) .
Multiple Sclerosis diagnosis was performed by a trained neurologist (ML). Diagnosis of MEN or OVD was based on clinical and audio-vestibular investigation by the same audiologist (MV) that was unaware of the MRV and ECD results. The exclusion criteria comprised, for all three groups of patients: retro cochlear lesion or other known anatomic/structural lesions of the ear, temporal bone or head trauma, syndromic features or congenital otological abnormalities. Furthermore in MEN and OVD groups any known central nervous system disease.
The work was carried out in accordance with the Declaration of Helsinki, including, but not limited to there being no potential harm to participants, guaranteed anonymity of participants, and informed consent.
All subjects underwent magnetic resonance imaging (MRI) of the brain during which contrast enhanced imaging of the venous cerebro cervical system was also performed in order to assess the condition of the IJVs and vertebral veins (VVs) and evaluated by the same neuroradiologist (CP) who had no knowledge of the clinical diagnosis. MRI was performed using a 1.5 T scanner with a standardized imaging protocol consisting of axial and coronal fast spin-echo T2-weighted imaging and axial and sagittal spin-echo T1-weighted imaging. The intracranial and cervical venous systems were investigated using computer-based magnetic resonance venography (MRV) performed in three standard orientations (transverse, coronal, and sagittal). A maximum-intensity projection (MIP) algorithm was used to display three-dimensional MRV reconstruction angiograms. The subjects underwent contrast-enhanced MRV in the supine position and the right and left cross-sectional areas (CSAs) of the IJVs and VVs were compared. Asymmetrical venous flow in the IJVs and VVs was functionally investigated using venous Duplex (ECD) (randomly carried out by Esaote or General Electric with the similar probes and settings), by a well-trained specialists (BPM), that was unaware of the clinical diagnosis but not of the MRV findings. Duplex was performed at 0° and 90° according to the CCSVI protocol and was considered confirmation of MRV findings when at least two of the five CCSVI criteria were satisfied. 
For the purposes of the paper only patients that satisfied CCSVI diagnostic criteria both by MRV and ECD were considered. Between-group comparisons were made using analysis of variance (ANOVA). Frequencies were compared using the Chi-squared and p value of < 0.05 was considered to be statistically significant. The statistical analysis was carried out with Statistics 6.1 software (Stat. Soft Inc., Tulsa, OK, USA) by an independent well-trained audiologist.(DF)
At the three Jugular levels stenosis (ST) and alterations of the trunk (AT) were taken in account. ST are detected both by MRV and ECD while AT is based on ECD findings. MRV-ECD showed IJVs alterations, any level, in 53% in MS, 46% in MEN and 16% in OVD with significant difference between MS-MD and OVD but not between MS and MD.
J1 was normal in 57% of MS, 88% of MEN and 95% of OVD. While comparison between MS and MEN was significant (p<0.001), difference between MEN and OVD were not. ST were detected, respectively, in 30% in MS and 2% in MEN and OVD; AT in 13% of MS, 10% of MEN and 3% of OVD. Thus J1 stenosis specifically regards MS rather than MEN and OVD (p<0,001)
J2 was normal in 78% of MS, 64% of MEN and 95% of OVD. While comparison between MS and MEN versus OVD was significant (p<0.001) difference between MS and MEN were not, but AT were detected in 17% in MS and 26% in MEN. Thus, even if the p-level is low ( p<0.05) J2 AT is more represented in MS than in MEN.
J3 was normal in 74% of MS, 64% of MEN and 86% of OVD. At this level difference between MEN and OVD is low (p=0.04). Even difference between MS and MEN is less strong than in J1 and J2 (p=0.005).
ST were detected, respectively, in 11% in MS and 10% in MEN and 6% in OVD; AT were found in 15% of MS, 26% of MEN and 8% of OVD. Even differences are not statistically significant, J3 AT seems more represented in MEN than in the other two groups.
Fig. 1 clearly shows the different pattern of topographic segments alterations distribution into the three groups with prevalence of the anatomic alterations (ST+AT) in J1 in MS and in J3 in MEN.
Fig 2 Distribution of IJVs anatomic alterations (ST+ AT) in relationship with topographic segments. It is clear how IJVs alterations are substantially rare in OVD and, especially, how in MS J1 alterations are more represented while J3 is the “specific” MEN abnormal segment
Adopting a “regional” criterion. J1-2 may be considered as medio-distal IJVs alterations while J2-3 medio-proximal alterations. “Regional” IJVs abnormalities difference through between MS and MD (Fig. 1) with a higher prevalence of J2-J3 alterations in MEN (37%) than in MS (23%) and a higher prevalence of J1-2 in MS (32%) than in MEN (22%). Differences are significant at p<0,05 level at Student t-test J1-2 is considered a medio-distal district while J2-3 medio-proximal. Regional distribution is significantly different between MS and MEN with medio-distal prevalence in MS and medio-proximal prevalence in MEN
Hyperplasia of the Vertebral Venous system was observed in 35% of MS, 40% of MEN and in 15% of OVD. While difference between MS and MEN versus OVD was significant, difference between MS and MEN was not. Other compensatory collaterals were detected in 25% in MS and only in 5% in MEN and OVD.
Our results clearly show that CCSVI may be considered as a typical condition both in MS and MD but is substantially rare in no-Méniere audio-vestibular disorders.
If CCSVI may be considered a cause per se or the anatomical condition for triggering the effect of other factors may be debated. Anyway, our experience point out that CCSVI is not a unique disorder and that the venous abnormalities pattern might be disease specific. MS is a typical demyelinating disease but demyelination of the vestibular nerve has been described in patients affected with MD, too . Although the hydraulic mechanism of EH is substantially worldwide accepted, there are evidence of MD patients without EH  and EH without MD symptoms  and Gacek  proposed a neuropathic viral mechanism in MD pathogenesis.
May CCSVI, that is considered to be correlated to MS Central Nervous System demyelination, to be connectable to vestibular nerve demyelination in MD, too? It is difficult to answer but our experience highlights the fact that in MD patients IJVs alterations regard the proximal segment.
Anyway, CCSVI pattern seems to be substantially different in MS and in MD.
Our results indicates that the MS pattern is characterized by J1 stenosis, J2 alterations trunk, a prevalence of J1-2 medio-distal alterations, compensatory collaterals besides vertebral venous system. On the other hand, MEN pattern is characterized by alteration trunks in J3, a prevalence of J3-2 medio-proximal alterations and vertebral venous hypertrophy without other detectable collaterals.
On the other hand the role of the origin of the IJVs, that to say the jugular bulb [jugular bulb (JB)] in Ménière Disease is known. 
Several studies analyzing the temporal bone imaging  or anatomy in MD patients have found consistent alterations in the arrangement of the sigmoid sinus, anteriorly or medially displaced, and JB abnormalities. According to Redfern et al.  and Park et al.  there is a higher frequency of JB abnormalities in patients with MD than in patients without inner ear symptoms, particularly, the mediolateral and anteroposterior position of the jugular bulb determines encroachment of the surrounding structures. Authors postulated that abnormal position contributes to MD development and that temporal bones of MD patients might be constituted anatomically different, carrying predisposing factors for the development of clinically apparent MD. These findings resemble to our findings: IJVs in general and J3 alterations are significantly highest in MD than in OVD.
The disease-specificity of venous abnormalities has been recently reported also by Vannini et al. [ 22 ] that described different morphology of IJVs’ valves in MD patients with respect to Normals and Sudden Neurosensorial Hearing Loss (SNHL) patients.
It is interesting to note that Burcon  observed in MD patients frequent involvement of the upper cervical spine dysfunction, particularly C1 and C2, that the author correlated to vertigo, C1, and hearing loss, C2. It is interesting to underline that in OVD VVs hypertrophy is highly represented than J1-J2 alterations (5%) but similarly to J3 abnormalities: VVs 15% -J3 14%. Both Vertebral Veins and proximal Jugular segment are anatomically placed in C1-C2 region and this fact support the role of upper cervical venous drainage to explain Burcon’s paper. Furthermore, Franz et al  postulated a cervicogenic disorder, mainly trigeminal based mechanism, as forerunner of MD. Also in this case a venous explantion might be coupled to Franz’s trigeminal mechanism as happens in migraine patients. 
The key point of the paper of Merchant et al  conducted on temporal bone cases with a clinical diagnosis of MD or a histopathologic EH diagnosis, is that hydrops per se is not the cause of MD while there are evidences of cellular and molecular bases of the various MD symptoms .
Thus, a specific anatomical abnormality of the temporal bone, regarding the jugular bulb, and/or the highest portion of the cerebro-cervical venous drainage system, CCSVI as shown in this paper through MRV and ECD, may lead to abnormal clearance of audio-vestibular structures inducing citochemical changement similar to those observed in MS CCSVI positive patients.
It is interesting to reveal that, although the group of patients with venous alterations is very small, OVD patients show a CCSVI pattern more similar to MD than MS pattern, thus it is reasonable to conclude that CCSVI is not an unique entity and that neurological (MS) pattern is distinguishable from the audiologic (MD and OVD) pattern. In Author’s opinion this explains the fact that no patients affected with MS and MD are reported. in Literature.
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