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1.  Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors 
Annals of neurology  2013;73(5):637-645.
Background
Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in greater than 40% of individuals with (MS). How demyelination alters neuronal gene expression is unknown.
Methods
To explore if loss of hippocampal myelin alters expression of neuronal microRNAs (miRNA), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.
Findings
A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124, was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors, AMPA 2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes.
Conclusion
We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.
doi:10.1002/ana.23860
PMCID: PMC3679350  PMID: 23595422
Multiple sclerosis; myelin; microRNA
2.  MS disease activity in RESTORE 
Neurology  2014;82(17):1491-1498.
Objective:
RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.
Methods:
Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.
Results:
Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%–29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4–8 weeks (n = 2 in weeks 4–8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.
Conclusions:
MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.
Classification of evidence:
This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.
doi:10.1212/WNL.0000000000000355
PMCID: PMC4011468  PMID: 24682966
3.  Health Literacy Association With Health Behaviors and Health Care Utilization in Multiple Sclerosis: A Cross-Sectional Study 
Background
Low health literacy is generally associated with poor health outcomes; however, health literacy has received little attention in multiple sclerosis (MS).
Objective
The aim of this study was to investigate the health literacy of persons with MS using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry.
Methods
In 2012, we conducted a cross-sectional study of health literacy among NARCOMS participants. Respondents completed the Medical Term Recognition Test (METER) which assesses the ability to distinguish medical and nonmedical words, and the Newest Vital Sign (NVS) instrument which evaluates reading, interpretation, and numeracy skills. Respondents reported their sociodemographic characteristics, health behaviors, comorbidities, visits to the emergency room (ER), and hospitalizations in the last 6 months. We used logistic regression to evaluate the characteristics associated with functional literacy, and the association between functional literacy and health care utilization.
Results
Of 13,020 eligible participants, 8934 (68.6%) completed the questionnaire and were US residents. Most of them performed well on the instruments with 81.04% (7066/8719) having functional literacy on the METER and 74.62% (6666/8933) having adequate literacy on the NVS. Low literacy on the METER or the NVS was associated with smoking, being overweight or obese (all P<.001). After adjustment, low literacy on the METER was associated with ER visits (OR 1.28, 95% CI 1.10-1.48) and hospitalizations (OR 1.19, 95% CI 0.98-1.44). Findings were similar for the NVS.
Conclusions
In the NARCOMS cohort, functional health literacy is high. However, lower levels of health literacy are associated with adverse health behaviors and greater health care utilization.
doi:10.2196/ijmr.2993
PMCID: PMC3936300  PMID: 24513479
multiple sclerosis; health literacy; health care utilization; comorbidity; health behaviors
4.  Treatment Discontinuation and Disease Progression with Injectable Disease-Modifying Therapies 
International Journal of MS Care  2013;15(4):194-201.
Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.
doi:10.7224/1537-2073.2012-034
PMCID: PMC3883017  PMID: 24453783
5.  CORTICAL REMYELINATION: A NEW TARGET FOR REPAIR THERAPIES IN MULTIPLE SCLEROSIS 
Annals of neurology  2012;72(6):918-926.
Objective
Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis. (MS). Since demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.
Methods
Postmortem brain tissue from 22 patients with MS (age 27 to 77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.
Results
“New” oligodendrocytes that were actively forming myelin sheaths were identified in 30/42 remyelinated subpial cortical lesions, including lesions from three patients in their 70's. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes and fewer reactive astrocytes. Astrocytes in the white-matter, but not in cortical portions of these lesions, significantly up-regulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.
Interpretation
Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
doi:10.1002/ana.23693
PMCID: PMC3535551  PMID: 23076662
multiple sclerosis; remyelination
6.  Preferred Sources of Health Information in Persons With Multiple Sclerosis: Degree of Trust and Information Sought 
Background
Effective health communication is important for informed decision-making, yet little is known about the range of information sources used by persons with multiple sclerosis (MS), the perceived trust in those information sources, or how this might vary according to patient characteristics.
Objective
We aimed to investigate the sources of health information used by persons with MS, their preferences for the source of health information, and levels of trust in those information sources. We also aimed to evaluate how these findings varied according to participant characteristics.
Methods
In 2011, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry were asked about their sources of health information using selected questions adapted from the 2007 Health Information National Trends (HINTS) survey.
Results
Of 12,974 eligible participants, 66.18% (8586/12,974) completed the questionnaire. Mass media sources, rather than interpersonal information sources, were the first sources used by 83.22% (5953/7153) of participants for general health topics and by 68.31% (5026/7357) of participants for MS concerns. Specifically, the Internet was the first source of health information for general health issues (5332/7267, 73.40%) and MS (4369/7376, 59.23%). In a logistic regression model, younger age, less disability, and higher annual income were independently associated with increased odds of use of mass media rather than interpersonal sources of information first. The most trusted information source was a physician, with 97.94% (8318/8493) reporting that they trusted a physician some or a lot. Information sought included treatment for MS (4470/5663, 78.93%), general information about MS (3378/5405, 62.50%), paying for medical care (1096/4282, 25.59%), where to get medical care (787/4282, 18.38%), and supports for coping with MS (2775/5031, 55.16%). Nearly 40% (2998/7521) of participants had concerns about the quality of the information they gathered.
Conclusions
Although physicians remain the most trusted source of health information for people with MS, the Internet is the first source of health information for most of them. This has important implications for the dissemination of health information.
doi:10.2196/jmir.2466
PMCID: PMC3650929  PMID: 23635393
multiple sclerosis; Internet; social media; trust; health information
7.  Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments 
Neurology: Clinical Practice  2013;3(5):386-391.
Summary
We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30–45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.
doi:10.1212/CPJ.0b013e3182a78f15
PMCID: PMC3806929  PMID: 24175155
8.  Clinically feasible MTR is sensitive to cortical demyelination in MS 
Neurology  2013;80(3):246-252.
Objective:
Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.
Methods:
MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density–weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MMctx), mostly demyelinated (MDctx), or intermediately demyelinated (IDctx). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex.
Results:
We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (IDctx or MDctx) compared to MMctx (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MMctx: LSM = 0.837, SE = 0.006; p = 0.01, n = 89).
Conclusions:
This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.
doi:10.1212/WNL.0b013e31827deb99
PMCID: PMC3589181  PMID: 23269598
10.  Advanced MRI in Multiple Sclerosis: Current Status and Future Challenges 
Neurologic clinics  2011;29(2):357-380.
Synopsis
Magnetic resonance imaging (MRI) has rapidly become a leading research tool in the study of multiple sclerosis (MS). Conventional imaging is useful in diagnosis and management of the inflammatory stages of MS, but has limitations in describing the degree of tissue injury as well as the cause of progressive disability seen in the later stages of disease. Advanced MRI techniques hold promise to fill this void. Magnetization transfer imaging is a widely available technique that can characterize demyelination and may be useful in measuring putative remyelinating therapies. Diffusion tensor imaging describes the three-dimensional diffusion of water and holds promise in characterizing neurodegeneration and putative neuroprotective therapies. Spectroscopy measures the imbalance of cellular metabolites and could help unravel the pathogenesis of neurodegeneration in MS. Functional (f) MRI can be used to understand the functional consequences of MS injury, including the impact on cortical function and compensatory mechanisms. These imaging tools hold great promise to increase our understanding of MS pathogenesis and provide greater insight into the efficacy of new MS therapies.
doi:10.1016/j.ncl.2010.12.011
PMCID: PMC3073625  PMID: 21439446
MRI; imaging; magnetization transfer imaging; spectroscopy; functional MRI; diffusion tensor imaging
11.  Demyelination Causes Synaptic Alterations in Hippocampi from Multiple Sclerosis Patients 
Annals of neurology  2011;69(3):445-454.
Background
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. While the clinical impact of gray matter pathology in MS brains is unknown, 30–40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients.
Method
To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains.
Findings
Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains.
Interpretation
Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.
doi:10.1002/ana.22337
PMCID: PMC3073544  PMID: 21446020
Multiple Sclerosis; hippocampus; demyelination; memory
12.  Web-Based Self-Management for Patients with Multiple Sclerosis: A Practical, Randomized Trial 
Abstract
Objective
No studies have addressed the use of electronic personal health records (e-PHRs) for self-management in complex neurological disorders. We assessed and tested an Internet-based self-management system that utilized the e-PHR and determined its impact on self-assessed well-being, clinician-assessed well-being, and healthcare utilization in patients with multiple sclerosis (MS).
Materials and Methods
Subjects were randomized to usual care (a secure Web-based messaging system) or active intervention, which included secure messaging, self-monitoring, self-management of MS symptoms, and communication about upcoming clinic visits. Computers and Internet access were provided. Subjects were included if they had MS, lived within the county or region surrounding our MS center, had at least two appointments at our center in the previous 12 months, and demonstrated basic typing and computer skills. Study duration was 12 months.
Results
Of 220 subjects completing informed consent, 206 met the inclusion criteria. At the study's end, 83 subjects remained in the usual care group and 84 in the enhanced care group. Both groups used the available system components. The groups did not significantly differ on the primary endpoints or healthcare utilization.
Conclusions
Self-management support is an emerging aspect of chronic care management. We established the feasibility of conducting a randomized, controlled trial using e-PHRs for patient self-management. We did not find that e-PHR–enabled self-management augmented multidisciplinary MS center-based care, possibly because the differences between interventions were not great enough.
doi:10.1089/tmj.2010.0133
PMCID: PMC3064874  PMID: 21214498
clinical trials randomized controlled (CONSORT agreement); multiple sclerosis; outcome research
13.  Imaging correlates of leukocyte accumulation and CXCR4/CXCR12 in multiple sclerosis 
Archives of neurology  2009;66(1):44-53.
OBJECTIVE
To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair, CXCR4/CXCL12, in MRI-defined regions of interest (ROIs) from chronic multiple sclerosis (MS) brains. We studied the following ROIs: NAWM (normal appearing white matter); T2-only (regions abnormal only on T2-WI); T2/T1/MTR (regions abnormal on T2-weighted, T1-weighted images (-WI) and magnetization transfer ratio (MTR).
DESIGN
MRI-pathology correlations were performed on five secondary progressive MS (SPMS) cases. Based on imaging characteristics, thirty ROIs were excised. Using immunohistochemistry, we evaluated myelin status, leukocyte accumulation and CXCR4/CXCL12 expression in the MS ROIs and white matter regions from five non-neurological control cases.
RESULTS
Eight of ten T2/T1/MTR regions were chronic-active or chronic-inactive demyelinated lesions, whereas only two of ten T2-only regions were demyelinated and characterized as active or chronic active lesions. Equivalent numbers of CD68+ leukocytes (the predominant cell type) were present in myelinated T2-only regions as compared to NAWM. Parenchymal T-cells were significantly increased in T2/T1/MTR ROIs as compared to T2-only regions and NAWM. Expression of CXCR4 and phospho-CXCR4 was found on reactive microglia and macrophages in T2-only and T2/T1/MTR lesions. CXCL12 immunoreactivity was detected in astrocytes, astrocytic processes and vascular elements in inflamed MS lesions.
CONCLUSIONS
Inflammatory leukocyte accumulation was not increased in myelinated MS ROIs with abnormal T2 signal as compared with NAWM. Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in CNS inflammation.
doi:10.1001/archneurol.2008.512
PMCID: PMC2792736  PMID: 19139298
multiple sclerosis; MRI; inflammation; CXCR4; CXCL12; microglia
14.  Neurogenesis in the chronic lesions of multiple sclerosis 
Brain  2008;131(9):2366-2375.
Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.
doi:10.1093/brain/awn157
PMCID: PMC2525445  PMID: 18669500
multiple sclerosis; white matter neurons; neurogenesis
15.  Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS 
Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
doi:10.1177/1352458512458169
PMCID: PMC3573679  PMID: 22917690
multiple sclerosis; progressive multiple sclerosis; neuroprotection; rehabilitation; research agenda
16.  Chemokine Receptors as Biomarkers in Multiple Sclerosis 
Disease Markers  2006;22(4):227-233.
Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.
doi:10.1155/2006/694283
PMCID: PMC3850832  PMID: 17124344
17.  A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis 
Neurological Research  2012;34(8):810-818.
Objective: To establish a detailed technical procedure for studying the anatomical correlates of chronic cerebrospinal venous insufficiency in cadavers of multiple sclerosis and control subjects, and to present our findings of the normal anatomic venous structures, with reference to previous descriptions from the literature.
Methods: This study examined the internal jugular veins (IJVs), the brachiocephalic veins, and the azygos vein from 20 cadavers (10 control and 10 multiple sclerosis). These veins were exposed, isolated by clamps from the rest of the venous system, flushed with water, and then injected with fluid silicone from the superior ends of both IJVs. After the silicone cured to its solid state, the venous tree was removed en bloc and dissected longitudinally to expose the luminal surface. All vein segments were analyzed for anatomic variation. Anatomical analysis for this manuscript focused on normal vein architecture and its variants.
Results: Thirty-seven of 40 IJVs contained valves: 29 bicuspid, 6 tricuspid, and 2 unicuspid. The average circumferences of the right and left IJVs were 2·2 and 1·8 cm, respectively. Thirteen of 20 azygos veins contained a valve, located on average 3·6 cm away from the superior vena cava junction. Nine of the 13 azygos valves were bicuspid; four were tricuspid. Only one of the 40 brachiocephalic veins contained a valve.
Discussion: We detailed a technical approach for harvesting cadaveric neck and thoracic veins with relevance to chronic cerebrospinal venous insufficiency. The anatomy of the venous system has significant variability, including differing number of valves in different regions and variable characteristics of the valves. Average vein circumference was less than that typically reported in imaging studies of live patients.
doi:10.1179/1743132812Y.0000000071
PMCID: PMC3678575  PMID: 22971470
CCSVI; Chronic cerebrospinal venous insufficiency; Multiple sclerosis; Extracranial veins; Internal jugular vein; Vein valves; Valves; Azygos

Results 1-17 (17)