Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis.

BACKGROUND AND PURPOSE: The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. METHODS: In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. RESULTS: There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. CONCLUSIONS: Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.

Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow-up.

BACKGROUND AND PURPOSE: Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS). METHODS: This prospective, longitudinal study (n = 154) included 41 healthy controls, 76 relapsing-remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol and the apolipoproteins ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped. RESULTS: Greater percentage increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low-density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL-C (P = 0.032) and ApoA-I (P = 0.007) were smaller in patients with relapsing-remitting MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status. CONCLUSIONS: Increases in HDL-C and ApoA-I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

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.

Effect of dimethyl fumarate on gray and white matter pathology in subjects with relapsing multiple sclerosis: a longitudinal study.

BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) is an oral treatment for relapsing-remitting multiple sclerosis (MS) with anti-inflammatory and possible neuroprotective properties. Its effect on white matter and gray matter pathology is still not fully understood. The aim of the study was to characterize the effect of DMF on normal-appearing white matter (NAWM) and thalamic pathology longitudinally. METHODS: In this observational, longitudinal, 24-month magnetic resonance imaging study, 75 patients with relapsing-remitting MS treated with DMF and 40 age- and sex-matched healthy individuals were enrolled. Regional diffusion tensor imaging metrics and tract-based spatial statistics analyses were used to assess differences between groups. Mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy were measured in the thalamus and NAWM. Baseline differences and changes over time were evaluated within and between study groups. RESULTS: At baseline, patients with MS showed significantly increased diffusivity and decreased fractional anisotropy in the thalamus (P < 0.001 for mean diffusivity, axial diffusivity and radial diffusivity) and NAWM (all P < 0.016) compared with healthy individuals. No significant within-group difference was found in diffusion tensor imaging measures over 24 months in either group. Healthy individuals showed a significantly greater rate of increased diffusivity parameters in the thalamus and NAWM compared with patients with MS, over 24 months (P < 0.05). CONCLUSIONS: The lack of changes in diffusion tensor imaging metrics in patients with MS over 24 months possibly indicates a neuroprotective role of DMF. These findings provide additional evidence of the beneficial effect of DMF on MS-related pathology.

Hemostasis biomarkers in multiple sclerosis.

BACKGROUND AND PURPOSE: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. METHODS: In all, 138 MS patients [85 with relapsing-remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. RESULTS: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. CONCLUSIONS: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.

Infectious exposure, antibiotic use, and multiple sclerosis: A population-based incident case-control study.

BACKGROUND: The existing reports regarding the potential role of infections as well as antibiotic use in multiple sclerosis (MS) etiology are inconclusive. OBJECTIVES: We aimed to investigate the association of viral infections as well as antibiotic use and the risk of developing MS. MATERIALS & METHODS: This was a population-based incident case-control study of 547 incident cases and 1057 general population controls obtained from 22 municipality areas of Tehran (7/8/2013-17/2/2015). Multiple logistic regression models were used to determine the adjusted associations. RESULTS: Overall antibiotic use for ≥14 days during 3 years before the index date, significantly decreased the odds of MS OR 0.69 (95%CI: 0.53-0.91, P = .008). The results were consistent for different types of antibiotics, including penicillin OR 0.50 (95%CI: 0.34-0.75, P = .001) and cephalosporins OR 0.25 (95%CI: 0.12-0.50, P < .001). History of IM was associated with a more than 5fold increased risk of MS OR = 5.7 (95%CI, 1.28-25.37). There was no statistically significant association between any other single or cumulative number of viral infections with subsequent risk of MS (P > .05). CONCLUSIONS: Considering the possibility of reverse causation, the results of this large case-control study suggest that use of antibiotics may be associated with a decreased risk of MS. However, viral disease other than infectious mononucleosis was not associated with MS risk.

Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

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.

Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network.

BACKGROUND: Approximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time. OBJECTIVE: Changes in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers. METHODS: A total of 67 individuals with pediatric MS (n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8-17 years of age (mean age ± standard deviation (SD)=14.37 ± 2.02) completed initial and follow-up neuropsychological testing after an average of 1.64 ± 0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning. RESULTS: Rate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure. CONCLUSION: Findings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.

Cholesterol affects retinal nerve fiber layer thickness in patients with multiple sclerosis with optic neuritis.

BACKGROUND AND PURPOSE: To evaluate the associations between retinal nerve fiber layer (RNFL) thickness and lipid profiles in multiple sclerosis (MS). METHODS: This study enrolled 136 patients with MS (n = 272 eyes; 108 females, 28 males, mean age: 46.7 ± 8.9 years); 45% had a history of optic neuritis (ON). Subjects received optical coherence tomography (OCT) testing to assess RNFL thickness and visual acuity testing with Snellen charts. A subset of 88 patients received pattern reversal visual-evoked potential (PRVEP) testing. Lipid profiles consisting of serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and total cholesterol (TC) levels were obtained within ± 6 months of OCT. Regression analyses were used to assess the associations between RNFL thickness and lipid profile variables. RESULTS: Low RNFL thickness (P = 0.008) and higher PRVEP latency (P = 0.017) were associated with high LDL cholesterol > 100 mg/dl status. Low RNFL thickness (P = 0.008) and higher PRVEP latency (P = 0.043) were associated with high HDL cholesterol levels. Low RNFL thickness was also associated with HDL cholesterol > 60 mg/dl status (P = 0.001) and with TC > 200 mg/dl status (P = 0.015). The probability of average RNFL thickness in the lowest tertile (≤ 33rd percentile) was associated with interactions between TC > 200 mg/dl status (P = 0.001, odds ratio = 7.5, 95% confidence interval = 2.7-21) with affected/unaffected by ON status. CONCLUSIONS: High cholesterol adversely affects RNFL thickness in patients with MS with ON.

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.

Venous angioplasty in patients with multiple sclerosis: results of a pilot study.

OBJECTIVES: Chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS). The objective of the study was to see if percutaneous transluminal angioplasty (PTA) of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe, burdened by a significant restenosis rate, and whether there was any evidence that treatment reduced MS disease activity. DESIGN: This was a case-control study. MATERIALS: We studied 15 patients with relapsing-remitting MS and duplex-detected CCSVI. METHODS: Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas seven had treatment with PTA after 6 months of medical therapy alone (delayed treatment group (DTG)). RESULTS: No adverse events occurred. At 1 year, there was a restenosis rate of 27%. Overall, PTA was followed by a significant improvement in functional score compared with baseline (p < 0.02). The annualised relapse rate was 0.12% in the ITG compared with 0.66% in the DTG (p = NS). Magnetic resonance imaging (MRI) blindly demonstrates a trend for fewer T2 lesions in the ITG (p = 0.081), corresponding to a 10% decrease in the ITG compared with a 23% increase in the DTG over the first 6 months of the study. CONCLUSIONS: This study further confirms the safety of PTA treatment in patients with CCSVI associated with MS. The results, despite the significant rate of restenosis, are encouraging and warrant a larger multicentre double-blinded, randomised study.

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.

Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon {beta}-1a.

BACKGROUND: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNß-1a) in relapsing-remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). OBJECTIVE: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. METHODS: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. RESULTS: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (p=0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNß-1a significantly improved Physical SIP subscores. CONCLUSIONS: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNß-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

Visual-cognitive processing deficits in pediatric multiple sclerosis.

BACKGROUND: Children with multiple sclerosis (MS) can suffer significant cognitive deficits. This study investigates the sensitivity and validity in pediatric MS of two visual processing tests borrowed from the adult literature, the Brief Visuospatial Memory Test-Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT). OBJECTIVE: To test the hypothesis that visual processing is disproportionately impacted in pediatric MS by comparing performance with that of healthy controls on the BVMTR and SDMT. METHODS: We studied 88 participants (43 MS, 45 controls) using a neuropsychological assessment battery including measures of intelligence, language, visual memory, and processing speed. Patients and demographically matched controls were compared to determine which tests are most sensitive in pediatric MS. RESULTS: Statistically significant differences were found between the MS and control groups on BVMTR Total Learning (t (84) = 4.04, p < 0.001, d = 0.87), BVMTR Delayed Recall (t (84) = 4.45, p < 0.001, d = 0.96), and SDMT (t (38) = 2.19, p = 0.035, d = 0.69). No significant differences were found between groups on confrontation naming or general intellectual ability. Validity coefficients exploring correlation between BVMTR, SDMT, and disease characteristics were consistent with the adult literature. CONCLUSIONS: This study found that BVMTR and SDMT may be useful in assessing children and adolescents with MS.

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.

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test.

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative. MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test-retest interval of 2.3 +/- 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability. All MSFCs had similar test-retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC. Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis.

The purpose of this study was to compare the clinical and quantitative magnetic resonance imaging metrics of paediatric-onset multiple sclerosis to adult-onset multiple sclerosis. It was a prospective comparison of clinical and magnetic resonance imaging characteristics of two paediatric onset multiple sclerosis and two adult onset multiple sclerosis groups that were matched for disease duration. The paediatric-onset-C group consisted of children with paediatric-onset multiple sclerosis with mean disease duration of 2.7 years, whereas the paediatric onset-A group consisted of adults with mean disease duration of 20 years. The adult onset multiple sclerosis-1 and adult onset multiple sclerosis-2 groups were matched to the paediatric onset-C and paediatric onset-A groups. The brain magnetic resonance imaging measures included: T(1)-, T(2)- and gadolinium contrast-enhancing volumes and the T(2)-lesion volume relative magnetization transfer ratio, global and tissue specific white and grey matter brain atrophy and normal appearing grey and white matter magnetization transfer ratio. Regression analyses were employed for magnetic resonance imaging measures. The paediatric onset multiple sclerosis-C (n = 17) and adult onset multiple sclerosis-1 (n = 81) groups had mean disease duration values of 2.7 +/- standard deviation 2.0 and 2.6 +/- 1.1 years, respectively. The paediatric onset multiple sclerosis-A group (n = 33) and adult onset multiple sclerosis-2 group (n = 300) had mean disease durations of 20 +/- standard deviation 10.9 and 20 +/- 9.3 years, respectively. In regression analysis, the T(2)- lesion volume of the paediatric onset multiple sclerosis-C and adult onset multiple sclerosis-1 groups were similar but there was a trend toward higher T(1)- lesion volume (P = 0.028) in the paediatric onset group. The brain parenchymal fraction and grey matter fraction in the paediatric-onset multiple sclerosis-C group were higher than those for the adult onset multiple sclerosis-1 group (both P < 0.001). The frequency of progressive multiple sclerosis in the paediatric onset multiple sclerosis-A group (27.3%) trended lower (odds ratio = 0.43, P = 0.042) than that in the adult onset multiple sclerosis-2 group (46.3%). The Expanded Disability Status Scale (median; inter-quartile range) in the paediatric onset multiple sclerosis-A group (2.25; 2.5) trended lower (P = 0.058) compared with the adult onset multiple sclerosis-2 group (3.5; 4.0). There was a trend toward lower magnetization transfer ratio values in T(2)-lesions, normal appearing grey matter and normal appearing white matter and higher grey matter fraction in the paediatric onset multiple sclerosis-A group compared with the adult onset multiple sclerosis-2 group. There was no evidence for differences on T(2)-lesion volume, T(1)-lesion volume, brain parenchymal fraction or white matter fraction. Paediatric-onset multiple sclerosis is characterized by a significant disease burden both early and later in the disease course. Despite this, disability is slower to accrue in paediatric onset multiple sclerosis than adult onset multiple sclerosis.