Delayed Decline of Cognitive Function by Antihypertensive Agents: A Cohort Study Linked with Genotype Data.

BACKGROUND: Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results. METHODS: We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI). RESULTS: The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus ß-blockers (ßBs), and α1-AB plus ßBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug. CONCLUSION: Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.

Disability Improvement Is Associated with Less Brain Atrophy Development in Multiple Sclerosis.

BACKGROUND AND PURPOSE: It is unknown whether deceleration of brain atrophy is associated with disability improvement in patients with MS. Our aim was to investigate whether patients with MS with disability improvement develop less brain atrophy compared with those who progress in disability or remain stable. MATERIALS AND METHODS: We followed 980 patients with MS for a mean of 4.8 ± 2.4 years. Subjects were divided into 3 groups: progress in disability (n = 241, 24.6%), disability improvement (n = 101, 10.3%), and stable (n = 638, 65.1%) at follow-up. Disability improvement and progress in disability were defined on the basis of the Expanded Disability Status Scale score change using standardized guidelines. Stable was defined as nonoccurrence of progress in disability or disability improvement. Normalized whole-brain volume was calculated using SIENAX on 3D T1WI, whereas the lateral ventricle was measured using NeuroSTREAM on 2D-T2-FLAIR images. The percentage brain volume change and percentage lateral ventricle volume change were calculated using SIENA and NeuroSTREAM, respectively. Differences among groups were investigated using ANCOVA, adjusted for age at first MR imaging, race, T2 lesion volume, and corresponding baseline structural volume and the Expanded Disability Status Scale. RESULTS: At first MR imaging, there were no differences among progress in disability, disability improvement, and the stable groups in whole-brain volume (P = .71) or lateral ventricle volume (P = .74). During follow-up, patients with disability improvement had the lowest annualized percentage lateral ventricle volume change (1.6% ± 2.7%) followed by patients who were stable (2.1% ± 3.7%) and had progress in disability (4.1% ± 5.5%), respectively (P < .001). The annualized percentage brain volume change values were -0.7% ± 0.7% for disability improvement, -0.8% ± 0.7% for stable, and -1.1% ± 1.1% for progress in disability (P = .001). CONCLUSIONS: Patients with MS who improve in their clinical disability develop less brain atrophy across time compared with those who progress.

Leptomeningeal Contrast Enhancement Is Related to Focal Cortical Thinning in Relapsing-Remitting Multiple Sclerosis: A Cross-Sectional MRI Study.

BACKGROUND AND PURPOSE: Leptomeningeal inflammation is associated with the development of global cortical gray matter atrophy in multiple sclerosis. However, its association with localized loss of tissue remains unclear. The purpose of this study was to evaluate the relationship between leptomeningeal contrast enhancement, a putative marker of leptomeningeal inflammation, and focal cortical thinning in MS. MATERIALS AND METHODS: Forty-three patients with relapsing-remitting MS and 15 with secondary-progressive MS were imaged on a 3T scanner. Cortical reconstruction was performed with FreeSurfer. Leptomeningeal contrast-enhancement foci were visually identified on 3D-FLAIR postcontrast images and confirmed using subtraction imaging. Leptomeningeal contrast-enhancement foci were mapped onto the cortex, and ROIs were obtained by dilating along the surface multiple times (n = 5, 10, 15, 20, 25, 30, 35, 40). Resulting ROIs were then mapped onto the homologous region of the contralateral hemisphere. Paired t tests compared the thickness of the cortex surrounding individual leptomeningeal contrast-enhancement foci and the corresponding contralateral region. Results were corrected for the false discovery rate. RESULTS: Differences between ipsilateral and contralateral ROIs progressively decreased with larger ROIs, but no significant effects were detected when considering the entire MS sample. In patients with relapsing-remitting MS only, significantly reduced cortical thickness was found for 5 dilations (-8.53%, corrected P = .04) and 10 dilations (-5.20%, corrected P = .044). CONCLUSIONS: Focal leptomeningeal contrast enhancement is associated with reduced thickness of the surrounding cortex in patients with relapsing-remitting MS, but not in those with secondary-progressive MS. Our results suggest that pathology associated with the presence of leptomeningeal contrast-enhancement foci has a stronger, localized effect on cortical tissue loss earlier in the disease.

Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal study.

BACKGROUND: Cardiovascular diseases (CVDs) are more frequent in multiple sclerosis (MS) patients when compared to controls. In particular, CVDs are linked with higher accumulation of lesions and advanced brain atrophy. OBJECTIVE: To investigate whether CVDs contribute to accelerated lesion accumulation and brain atrophy over 5 years in patients with MS. METHODS: 194 MS patients and 43 controls without neurologic disease were followed for 5 years. Full physical, neurological evaluation, and structured questionnaire investigating CVD and risk factors (hypertension, hyperlipidemia, heart disease, smoking, diabetes, obesity/overweight) were collected using interview-based questionnaire and further cross-reference with electronic medical records. Lesion and brain atrophy outcomes were assessed with 3T MRI. ANCOVA adjusted for age, gender, and disease duration were used accordingly. False discovery rate correction was performed using Benjamini-Hochberg correction. RESULTS: Patients with diagnosis of heart disease showed higher white matter and whole brain volume loss compared to those without (-4.2% vs. -0.7%, P = 0.01 and -3.4% vs. -1.6%, P = 0.01, respectively). The percentage lateral ventricle volume change in MS patients with hypertension was higher compared to non-hypertensive patients (24.5% vs. 14.1%, P = 0.05). Hyperlipidemia, smoking, and obesity/overweight were not associated with progression of MRI-derived outcomes. CVDs did not contribute to larger lesion volume accrual over the 5-year period. The presence of CVDs was not associated with MRI-derived changes in the controls. CONCLUSIONS: Hypertension and heart disease contribute to advanced brain atrophy in MS patients. CVDs did not contribute to additional lesion accrual. CVD comorbidities in MS patients may contribute to neurodegenerative tissue injury that can be detected with brain MRI.

Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine.

BACKGROUND AND PURPOSE: The assessment of brain atrophy in a clinical routine is not performed routinely in multiple sclerosis. Our aim was to determine the feasibility of brain atrophy measurement and its association with disability progression in patients with MS followed in a clinical routine for 5 years. MATERIALS AND METHODS: A total of 1815 subjects, 1514 with MS and 137 with clinically isolated syndrome and 164 healthy individuals, were collected retrospectively. Of 11,794 MR imaging brain scans included in the analysis, 8423 MRIs were performed on a 3T, and 3371 MRIs, on a 1.5T scanner. All patients underwent 3D T1WI and T2-FLAIR examinations at all time points of the study. Whole-brain volume changes were measured by percentage brain volume change/normalized brain volume change using SIENA/SIENAX on 3D T1WI and percentage lateral ventricle volume change using NeuroSTREAM on T2-FLAIR. RESULTS: Percentage brain volume change failed in 36.7% of the subjects; percentage normalized brain volume change, in 19.2%; and percentage lateral ventricle volume change, in 3.3% because of protocol changes, poor scan quality, artifacts, and anatomic variations. Annualized brain volume changes were significantly different between those with MS and healthy individuals for percentage brain volume change (P < .001), percentage normalized brain volume change (P = .002), and percentage lateral ventricle volume change (P = .01). In patients with MS, mixed-effects model analysis showed that disability progression was associated with a 21.9% annualized decrease in percentage brain volume change (P < .001) and normalized brain volume (P = .002) and a 33% increase in lateral ventricle volume (P = .004). CONCLUSIONS: All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible.

Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid-attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement. MATERIALS AND METHODS: We enrolled 258 consecutive patients with MS (212 with relapsing-remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D-FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard). RESULTS: In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C (κ agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001). CONCLUSIONS: 3D-FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine.

Effect of natalizumab on brain atrophy and disability progression in multiple sclerosis patients over 5 years.

BACKGROUND AND PURPOSE: The long-term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years. METHODS: This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006-2007. RESULTS: At the 5-year follow-up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted P = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. At the follow-up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow-up. There was another case of non-fatal PML over the follow-up. CONCLUSIONS: In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk-benefit therapeutic assessment is mandatory.

Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The effect of comorbidities on disease severity in MS has not been extensively characterized. We determined the association of comorbidities with MR imaging disease severity outcomes in MS. MATERIALS AND METHODS: Demographic and clinical history of 9 autoimmune comorbidities confirmed by retrospective chart review and quantitative MR imaging data were obtained in 815 patients with MS. The patients were categorized on the basis of the presence/absence of total and specific comorbidities. We analyzed the MR imaging findings, adjusting for key covariates and correcting for multiple comparisons. RESULTS: Two hundred forty-one (29.6%) study subjects presented with comorbidities. Thyroid disease had the highest frequency (n = 97, 11.9%), followed by asthma (n = 41, 5%), type 2 diabetes mellitus (n = 40, 4.9%), psoriasis (n = 33, 4%), and rheumatoid arthritis (n = 22, 2.7%). Patients with MS with comorbidities showed decreased whole-brain and cortical volumes (P < .001), gray matter volume and magnetization transfer ratio of normal-appearing brain tissue (P < .01), and magnetization transfer ratio of gray matter (P < .05). Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with decreased whole-brain, cortical, and gray matter volumes (P < .05). Psoriasis was associated with a decreased magnetization transfer ratio of normal-appearing brain tissue (P < .05), while type 2 diabetes mellitus was associated with increased mean diffusivity (P < .01). CONCLUSIONS: The presence of comorbidities in patients with MS is associated with brain injury on MR imaging. Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with more severe nonconventional MR imaging outcomes.

Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The exact prevalence of WM signal abnormalities in healthy relatives of MS patients and their impact on disease development has not been fully elucidated. The purpose of this study was to compare WM signal abnormality characteristics and the prevalence of radiologically isolated syndrome in healthy control subjects selected randomly from the population with the healthy relatives of patients with MS. MATERIALS AND METHODS: Healthy control subjects (n = 150) underwent physical and 3T MR imaging examinations. Healthy control subjects were classified as non-familial healthy control subjects (n = 82) if they had no family history of MS or as healthy relatives of patients with MS (n = 68) if they had ≥1 relative affected with MS. The presence of radiologically isolated syndrome was evaluated according to the Okuda criteria; dissemination in space on MR imaging and fulfillment of radiologically isolated syndrome criteria were also evaluated according to Swanton criteria. RESULTS: There was a significantly higher total volume of WM signal abnormality in the healthy relatives of patients with MS compared with the non-familial healthy control subjects (P = .024 for signal abnormality ≥3 mm in size and P = .025 for all sizes). Periventricular localization and the number of lesions in all groups (P = .034 and P = .043) were significantly higher in the healthy relatives of patients with MS; 8.8% of the healthy relatives of patients with MS and 4.9% of non-familial healthy control subjects showed ≥9 WM signal abnormalities; 2.9% of subjects in the healthy relatives of patients with MS group and 2.4% of non-familial healthy control subjects fulfilled radiologically isolated syndrome according to the Okuda criteria, whereas 10.3% and 3.7% of subjects fulfilled radiologically isolated syndrome according to the Swanton criteria. In the healthy relatives of patients with MS, smoking was associated with the presence of WM signal abnormalities, whereas obesity was related to the presence of ≥9 WM signal abnormalities and to fulfillment of radiologically isolated syndrome according to the Swanton criteria. CONCLUSIONS: The frequency of WM signal abnormalities and radiologically isolated syndrome is higher in the healthy relatives of patients with multiple sclerosis patients compared with non-familial healthy control subjects.

No association between conventional brain MR imaging and chronic cerebrospinal venous insufficiency in multiple sclerosis.

BACKGROUND AND PURPOSE: CCSVI has been reported to occur at high frequency in MS. Its significance in relation to MR imaging parameters also needs to be determined, both in patients with MS and HCs. Therefore, this study determined the associations of CCSVI and conventional MR imaging outcomes in patients with MS and in HCs. MATERIALS AND METHODS: T2, T1, and gadolinium lesion number, LV, and brain atrophy were assessed on 3T MR imaging in 301 subjects, of whom 162 had RRMS, 66 had secondary-progressive MS subtype, and 73 were HCs. CCSVI was assessed using extracranial and transcranial Doppler evaluation. The MR imaging measure differences were explored with 27 borderline cases for CCSVI, added to both the negative and positive CCSVI groups to assess sensitivity of the results of these cases. RESULTS: No significant differences between subjects with and without CCSVI were found in any of the individual diagnostic subgroups or MS disease subtypes for lesion burden and atrophy measures, independently of the CCSVI classification criteria used, except for a trend for higher T2 lesion number (irrespective of how borderline cases were classified) and lower brain volume (when borderline cases were included in the positive group) in patients with RRMS with CCSVI. No CCSVI or MR imaging differences were found between 26 HCs with, or 47 without, a familial relationship. CONCLUSIONS: CCSVI is not associated with more severe lesion burden or brain atrophy in patients with MS or in HCs.

Comparison of a 1.5T standard vs. 3T optimized protocols in multiple sclerosis patients.

AIM: Use of postcontrast T1-weighted imaging (WI) is an important tool in diagnosing and predicting the course of multiple sclerosis (MS). Application of optimized imaging strategies has the potential to increase detection of magnetic resonance imaging (MRI) disease activity. This study investigated the superiority of the 3T optimized vs. the 1.5T standardized protocols in detecting gadolinium enhancing (GD-E) lesions in patients with MS. METHODS: A standard protocol was defined as a 1.5T scan with a single-dose of Gd and a 5-minute scanning delay after injection. An optimized protocol was defined as a 3T MRI scan, using a triple dose of Gd, 20 min scan delay, and using an off-resonance saturated magnetization transfer pulse to reduce the background signal. Fourteen relapsing-remitting MS patients and 3 healthy controls (HC) were scanned with 1.5T standardized and a 3T optimized protocols in random order over 72 hours. RESULTS: There were 47 Gd-E lesions in the MS patients on 3T optimized and 34 on 1.5T standard protocols, a 38.2% increase. There was a significant increase in Gd-enhanced lesion volume (LV) detected with the optimized protocol (179.6%, P<0.05), with 94.6% of the mean Gd-enhanced LV detected only on the 3T optimized protocol. No Gd-E lesions were detected in HC on either protocol. CONCLUSION: The 3T optimized protocol is a useful technique for increasing sensitivity of MRI to detect Gd-E lesions.

Iron deposition on SWI-filtered phase in the subcortical deep gray matter of patients with clinically isolated syndrome may precede structure-specific atrophy.

BACKGROUND AND PURPOSE: Increasing evidence suggests that iron deposition is present in the later stages of MS. In this study we examined abnormal phase values, indicative of increased iron content on SWI-filtered phase images of the SDGM in CIS patients and HC. We also examined the association of abnormal phase with conventional MR imaging outcomes at first clinical onset. MATERIALS AND METHODS: Forty-two patients with CIS (31 female, 11 male) and 65 age and sex-matched HC (41 female, 24 male) were scanned on a 3T scanner. Mean age was 40.1 (SD = 10.4) years in patients with CIS, and 42.8 (SD = 14) years in HC, while mean disease duration was 1.2 years (SD = 1.3) in patients with CIS. MP-APT, NPTV, and normalized volume measurements were derived for all SDGM structures. Parametric and nonparametric group-wise comparisons were performed, and associations were determined with other MR imaging metrics. RESULTS: Patients with CIS had significantly increased MP-APT (P = .029) and MP-APT volume (P = .045) in the pulvinar nucleus of the thalamus compared with HC. Furthermore, the putamen (P = .004), caudate (P = .035), and total SDGM (P = .048) displayed significant increases in MP-APT volume, while MP-APT was also significantly increased in the putamen (P = .029). No global or regional volumetric MR imaging differences were found between the study groups. Significant correlations were observed between increased MP-APT volumes of total SDGM, caudate, thalamus, hippocampus, and substantia nigra with white matter atrophy and increased T2 lesion volume (P < .05). CONCLUSION: Patients with CIS showed significantly increased content and volume of iron, as determined by abnormal SWI-phase measurement, in the various SDGM structures, suggesting that iron deposition may precede structure-specific atrophy.

Voxel-wise magnetization transfer imaging study of effects of natalizumab and IFNß-1a in multiple sclerosis.

OBJECTIVE: To determine the effects of intravenous natalizumab and intramuscular interferon beta-1a (IFNß-1a) on the volume of white-matter (WM) lesions and normal appearing brain tissue (NABT) undergoing voxel-wise (VW) increases in magnetization transfer ratio (MTR) suggestive of remyelination in patients with relapsing multiple sclerosis. METHODS: This prospective, open-label, single-blinded study enrolled patients with relapsing-remitting multiple sclerosis (RRMS) and relapsing secondary progressive multiple sclerosis (RSPMS) as well as a group of age/sex-matched healthy controls (n=22). Patients with multiple sclerosis were assigned to receive natalizumab monotherapy (n=77; RRMS/RSPMS) or intramuscular IFNß-1a (n=26) as either monotherapy (RRMS) or combined with pulsed i.v. methylprednisolone, as needed (RSPMS). The primary endpoint was the two-year change in volume of NABT VWMTR, by quantifying the number of voxels that increased (suggesting remyelination) or decreased (suggesting demyelination) in their MTR value. RESULTS: The volume of tissue undergoing increases in VWMTR was significantly larger in natalizumab compared with IFNß-1a-treated patients (year 1: p=0.001 in NABT and p<0.006 in WM lesions; year 2: p=0.008 in NABT) and compared with healthy control subjects (year 1: p=0.05 and year 2: p=0.007 in NABT). The larger volume within NABT undergoing decreases in VWMTR was detected in multiple sclerosis patients compared with healthy controls (p<0.001), and in the IFNß-1a group compared with the natalizumab group (year 1: p=0.05; year 2: p=0.002). One patient on natalizumab died from progressive multifocal leukoencephalopathy eight months after completing the study. CONCLUSION: Natalizumab may promote remyelination and stabilize demyelination in lesions and NABT in relapsing multiple sclerosis, compared with intramuscular IFNß-1a.

Intra- and extraluminal structural and functional venous anomalies in multiple sclerosis, as evidenced by 2 noninvasive imaging techniques.

BACKGROUND AND PURPOSE: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the main extracranial cerebrospinal venous routes that interfere with normal venous outflow. Research into CCSVI will determine its sensitivity and specificity for a diagnosis of MS, its prevalence in MS patients, and its clinical, MRI, and genetic correlates. Our aim was to investigate the prevalence and number of intra- and extraluminal structural and functional extracranial venous abnormalities by using DS and MRV, in patients with MS and HCs. MATERIALS AND METHODS: One hundred fifty patients with MS, 104 (69.3%) with RR and 46 (30.7%) with a progressive MS course, and 63 age- and sex-matched HCs were scanned with 3T MR imaging by using TOF and TRICKS sequences (only patients with MS). All subjects underwent DS examination for intra- and extraluminal structural and functional abnormalities of the IJVs. Absent/pinpoint IJV flow morphology on MRV was considered an abnormal finding. Prominence of collateral extracranial veins was assessed with MRV. RESULTS: Patients with MS had a significantly higher number of functional (P < .0001), total (P = .001), and intraluminal (P = .005) structural IJV DS abnormalities than HCs. There was a trend for more patients with MS with extraluminal IJV DS abnormalities (P = .023). No significant differences were found on the MRV IJV flow morphology scale between patients with MS and HCs. Patients with progressive MS showed more extraluminal IJV DS abnormalities (P = .01) and more MRV flow abnormalities on TOF (P = .006) and TRICKS (P = .01) than patients with nonprogressive MS. There was a trend for a higher number of collateral veins in patients with MS than in HCs (P = .016). CONCLUSIONS: DS is more sensitive than MRV in detecting intraluminal structural and functional venous abnormalities in patients with MS compared with HCs, whereas MRV is more sensitive in showing collaterals.

Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). A subject is considered CCSVI positive if ≥ 2 venous hemodynamic (VH) criteria are fulfilled. OBJECTIVE: To determine prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases (OND), and healthy controls (HC), using specific proposed echo-color Doppler (ECD) criteria. METHODS: Transcranial and extracranial ECD were carried out in 499 enrolled subjects (289 MS, 163 HC, 26 OND, 21 CIS). Prevalence rates for CCSVI were calculated in 3 ways: first, using only the subjects for whom diagnosis was certain (i.e., borderline subjects were excluded); secondly, including the borderline subjects in the "no CCSVI" group; and finally, taking into account subjects who presented any of the VH criteria. RESULTS: CCSVI prevalence with borderline cases included in the "no CCSVI" group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC (p < 0.001). The CCSVI prevalence figures were 62.5% for MS, 45.8% for OND, 42.1% for CIS, and 25.5% for HC when borderline cases were excluded (p < 0.001). The prevalence of one or more positive VH criteria was the highest in MS (81.3%), followed by CIS (76.2%), OND (65.4%), and HC (55.2%) (p < 0.001). CCSVI prevalence was higher in patients with progressive than in nonprogressive MS (p = 0.004). CONCLUSIONS: Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.

Value of MR venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study.

BACKGROUND AND PURPOSE: CCSVI was recently described in patients with MS. CCSVI is diagnosed noninvasively by Doppler sonography and invasively by catheter venography. We assessed the role of conventional MRV for the detection of IJV anomalies in patients with MS diagnosed with CCSVI and in healthy controls who underwent MRV and Doppler sonography examinations during 6 months. MATERIALS AND METHODS: Ten patients with MS underwent TOF, TRICKS, Doppler sonography, and catheter venography at baseline. They were treated at baseline with percutaneous angioplasty and re-evaluated 6 months' posttreatment with MRV and Doppler sonography. In addition, 6 healthy controls underwent a baseline and a 6-month follow-up evaluation by Doppler sonography and MRV. RESULTS: At baseline, the sensitivity, specificity, PPV, and NPV of Doppler sonography for detecting IJV abnormalities relative to catheter venography in patients with MS were calculated, respectively, at 82%, 100%, 99%, and 95%. The figures were 99%, 33%, 33%, 99% for TOF and 99%, 39%, 35%, and 99% for TRICKS. Venous anomalies included the annulus, septum, membrane, and malformed valve. No agreement was found between TOF and catheter venography in 70% of patients with MS and between TRICKS and catheter venography in 60% of patients with MS. At follow-up, 50% of the patients with MS presented with abnormalities on Doppler sonography but only 30% were diagnosed with restenosis. CONCLUSIONS: Conventional MRV has limited value for assessing IJV anomalies for both diagnostic and posttreatment purposes.

Sensitivity and specificity for screening of chronic cerebrospinal venous insufficiency using a multimodal non-invasive imaging approach in patients with multiple sclerosis.

The aim of this study was to investigate whether a combination of Doppler sonography (DS) and magnetic resonance venography (MRV) on 3T MRI increases specificity for detection of chronic cerebrospinal venous insufficiency (CCSVI) in 171 (113 relapsing-remitting, 47 secondary-progressive, 11 primary progressive) patients with multiple sclerosis (MS) and 79 age- and sex matched healthy controls (HCs). One hundred ten (64.3%) MS patients and 30 (38%) HCs presented ≥2 venous hemodynamic CCSVI criteria (p<.0001). Both DS and MRV showed relatively high specificity but lower sensitivity for determining a CCSVI diagnosis in patients with MS vs HCs and between MS subgroups. In MS patients this diagnostic specificity increased to over 90% by combining internal jugular vein and vertebral vein abnormal DS and MRV findings, reflux in deep cerebral veins and MRV findings of >1 collateral veins. This study suggests that a multimodal non-invasive approach (DS and MRV) increases the specificity for a diagnosis of CCSVI in patients with MS.

Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls.

AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of primary veins outside the skull that restrict normal outflow of blood from the brain. CCSVI was recently described as highly prevalent in patients with multiple sclerosis (MS), and can be non-invasively diagnosed by Doppler sonography (DS) and invasively by selective venography (SV). The aim of this paper was to investigate the value of neck magnetic resonance venography (MRV) for the diagnosis of CCSVI compared to DS and SV in patients with MS and in healthy controls (HC). METHODS: Ten MS patients and 7 HC underwent DS, 2D-Time-Of-Flight venography (TOF) and 3D-Time Resolved Imaging of Contrast Kinetics angiography (TRICKS). MS patients also underwent SV. The internal jugular veins (IJVs) and the vertebral veins (VVs) were assessed by both MRV sequences, and the findings were validated against SV and DS. SV has been considered the diagnostic gold standard for MS patients. RESULTS: All MS patients and none of the HC presented CCSVI, according to the DS criteria. This was confirmed by SV. For CCSVI diagnosis, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, whereas the figures were 40%, 85%, 58%, 80% and 50% for 3D-TRICKS, and 30%, 85%, 52%, 75% and 46% for 2D-TOF in the IJVs. In MS patients, compared to SV, DS showed sensitivity, specificity, accuracy, PPV and NPV of 100%, 75%, 95%, 94% and 100%, whereas the figures were 31%, 100%, 45%, 100% and 26% for 3D-TRICKS and 25%, 100%, 40%, 100% and 25% for 2D-TOF in the IJVs. CONCLUSION: The use of MRV for diagnosis of CCSVI in MS patients has limited value, and the findings should be interpreted with caution and confirmed by other imaging techniques such as DS and SV.

CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study.

AIM: We previously reported unexpectedly robust associations between vascular haemodynamic (VH) anomalies in the principal extracranial cerebral veins, causing chronic cerebrospinal venous insufficiency (CCSVI), and multiple sclerosis (MS). Aim of this study was to investigate the relationship between the VH changes and MRI measures of MS disease severity in a cross sectional survey. METHODS: The number of anomalous VH criteria were measured using an echo-color Doppler, whereas CSF flow, atrophy and lesion measures were obtained from quantitative magnetic resonance imaging (MRI) analysis in sixteen consecutive relapsing-remitting MS patients, (mean age: 36.1+/-SD 7.3 years, disease duration: 7.5+/-1.9 years and median EDSS: 2.5) and in 8 healthy controls (HC) with similar age and sex distributions. RESULTS: All 16 MS patients investigated and none of the HCs met the VH criteria for CCSVI (P<0.0001). MS patients showed significantly lower net CSF flow compared to the HC (P=0.038) that was associated with number of anomalous VH criteria present (r=0.79, P<0.001). Moreover, increases in the number of anomalous VH criteria present were negatively associated with lower whole brain volume (Spearman R=-0.5, P=0.05). CONCLUSION: VH changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.

Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study.

AIM: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular phenomenon recently described in multiple sclerosis (MS) that is characterized by stenoses affecting the main extracranial venous outflow pathways and by a high rate of cerebral venous reflux that may lead to increased iron deposition in the brain. Aim of this study was to investigate the relationship between CCSVI and iron deposition in the brain of MS patients by correlating venous hemodynamic (VH) parameters and iron concentration in deep-gray matter structures and lesions, as measured by susceptibility-weighted imaging (SWI), and to preliminarily define the relationship between iron measures and clinical and other magnetic resonance imaging (MRI) outcomes. METHODS: Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched healthy controls (HC) were scanned on a GE 3T scanner, using SWI. RESULTS: All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC. In MS patients, the higher iron concentration in the pulvinar nucleus of the thalamus, thalamus, globus pallidus, and hippocampus was related to a higher number of VH criteria (P<0.05). There was also a significant association between a higher number of VH criteria and higher iron concentration of overlapping T2 (r=-0.64, P=0.007) and T1 (r=-0.56, P=0.023) phase lesions. Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume. CONCLUSION: The findings from this pilot study suggest that CCSVI may be an important mechanism related to iron deposition in the brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a modest-to-strong predictor of disability progression, lesion volume accumulation and atrophy development in patients with MS.