Detecting isolated cognitive relapses in persons with MS.

BACKGROUND: The existence of isolated cognitive relapses (ICRs) in persons with MS (PwMS) has been debated. OBJECTIVE: To examine relapses with decline on Symbol Digit Modalities Test (SDMT) but no change on Expanded Disability Status Scale (EDSS). METHODS: This 3-year prospective cohort study identified PwMS experiencing a relapse with decrease on SDMT. Participants with SDMT decline/stable EDSS were labeled "ICR," while those with a corresponding decrease on EDSS were classified "Relapse with Cognitive Decline (RCD)." Two definitions of SDMT decline were explored: (1) ⩾ 8 points, and (2) ⩾ 4 points. Logistic regression was used to analyze the relationship between ICR and RCD. RESULTS: The full cohort had 592 participants: 83 experienced relapses; 22 (26.5%) had an SDMT decrease of ⩾ 8 points; 14 (63.6%) met ICR criteria. Logistic regression (X2(1) = 5.112, p = 0.024) using demographics and disease characteristics explained 28.4% of the variance in ICR versus RCD. Only the MS Neuropsychological Questionnaire was associated with ICR (odds ratio (OR): 8.6; 95% confidence interval (CI): 1.1-16.4) 40 relapsing participants with SDMT decrease of ⩾ 4 points were identified: 26 (65%) had a stable EDSS (ICR). Logistic regression did not find any variable predictive of ICR. CONCLUSION: This prospective study demonstrates evidence of ICR in PwMS.

Quantifying cognition and fatigue to enhance the sensitivity of the EDSS during relapses.

BACKGROUND: Cognition is affected by relapses in persons with multiple sclerosis (PwMS), yet the Expanded Disability Status Scale (EDSS) does not readily detect cognitive changes. OBJECTIVE: The objective of this study is to improve the detection of cognitive decline during relapses, by incorporating the Symbol Digit Modalities Test (SDMT) into the cerebral Functional System Score (CFSS) of the EDSS. METHODS: This prospective study recruited PwMS from three dedicated MS centers. All subjects had EDSS, SDMT, and Fatigue Severity Scale (FSS) administered. Subjects experiencing a relapse were assigned to the relapse group (RG). Matched controls from the larger cohort were assigned to the stable group (SG). RG and SG subjects underwent the same evaluation at relapse and 3 months later. Our main outcomes were a modified CFSS (m-CFSS) and modified EDSS (m-EDSS), incorporating SDMT and FSS, accounting for cognitive performance and fatigue rating, during relapse. RESULTS: The full cohort included 592 subjects; 80 qualified for RG and 72 were matched to the SG. The m-CFSS was significantly higher than CFSS at baseline (median = 2 vs. median = 0, p < 0.001) and relapse (median = 2 vs. median = 1, p < 0.001). The m-EDSS was higher than EDSS (median 3.0 vs. 2.5, p = 0.02) at relapse, where 35 RG subjects (43.8%) had higher m-EDSS than EDSS at relapse. CONCLUSION: This study demonstrates that incorporating the SDMT and FSS improves the accuracy of the EDSS, by accounting for cognitive changes, during relapse activity.

Recovery of cognitive function after relapse in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) but its manifestation as acute disease activity is underappreciated. OBJECTIVE: The aim of this study is to examine recovery after MS relapse on multiple tests of cognitive and motor function and explore correlates of change with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI), and cognitive reserve. METHODS: Fifty relapsing group (RG) and matched stable participants were examined at baseline, during relapse, and at 3-month follow-up. Tests of cognitive processing speed (Symbol Digit Modalities Test (SDMT)) and consensus opinion measures of memory, ambulation, and manual dexterity were administered. All RG patients were treated with a 5-day course of Acthar Gel (5 mL/80 IU). RESULTS: In RG patients, SDMT declined from 55.2 to 44.6 at relapse and recovered to 51.7, a slope differing from stable controls (p = 0.001). A statistical trend (p = 0.07) for the same effect was observed for verbal memory and was significant for ambulation (p = 0.03). The Cerebral Function Score from the EDSS also changed in the RG and recovered incompletely relative to controls (p = 0.006). CONCLUSION: These results replicate earlier reports of cognitive worsening during relapse in MS. Clinically meaningful improvements followed relapse on SDMT and ambulation. Cognitive decline during relapse can be appreciated on neurological exam but not patient-reported outcomes.

Dalfampridine benefits ambulation but not cognition in multiple sclerosis.

BACKGROUND: Impaired cognition and ambulation are common in multiple sclerosis (MS). Dalfampridine is the first Food and Drug Administration (FDA)-approved medication to treat impaired ambulation in MS. Dalfampridine may benefit patients with cognitive impairment, given its effects on saltatory conduction and the association between cognitive and motor function. OBJECTIVE: To examine the effects of dalfampridine on cognition in MS. To determine if the anticipated improved cognition is grounded in dalfampridine's effects on ambulation. METHODS: Adults with MS were randomized to dalfampridine (n = 45) or placebo (n = 16) for 12 weeks. Cognition and motor function were assessed at baseline and end-point. RESULTS: T25FW and 6-minute walk (6MW) performance improved at end-point in the treatment group but not in the placebo group (p < 0.05). Our primary outcome, performance on the Symbol Digit Modalities Test, did not improve. About 30% (n = 12) of the dalfampridine group demonstrated ⩾20% improved ambulation and were categorized "responders." Among "responders", Symbol Digit Modalities test performance did not improve. However, performance on the Paced Auditory Serial Addition Test improved among "responders" (p < 0.05). CONCLUSION: Dalfampridine benefits timed ambulation but not cognition. Some improvement among ambulation "responders" is consistent with prior reports of cognition-motor coupling in MS ( ClinicalTrials.gov #: NCT02006160).

Atrophied Brain T2 Lesion Volume at MRI Is Associated with Disability Progression and Conversion to Secondary Progressive Multiple Sclerosis.

Background Atrophied T2 lesion volume at MRI is an imaging measure that reflects the replacement of T2 lesions by cerebrospinal fluid spaces in patients with multiple sclerosis (MS). Purpose To investigate the association of atrophied T2 lesion volume and development of disability progression (DP) and conversion to secondary progressive MS (SPMS). Materials and Methods This retrospective study included 1612 participants recruited from 2006 to 2016 and followed up for 5 years with clinical and MRI examinations. Accumulation of T2 lesion volume, atrophied T2 lesion volume, percentage brain volume change (PBVC), and percentage ventricular volume change (PVVC) were measured. Disability progression and secondary progressive conversion were defined by using standardized guidelines. Analysis of covariance (ANCOVA) adjusted for age and Cox regression adjusted for age and sex were used to compare study groups and explore associations between MRI and clinical outcomes. Results A total of 1314 patients with MS (1006 women; mean age, 46 years ± 11 [standard deviation]) and 124 patients with clinically isolated syndrome (100 women; mean age, 39 years ± 11) along with 147 healthy control subjects (97 women; mean age, 42 years ± 13) were evaluated. A total of 336 of 1314 (23%) patients developed DP, and in 67 of 1213 (5.5%) the disease converted from clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) to SPMS. Patients with conversion to DP had higher atrophied T2 lesion volume (+34.4 mm3; 95% confidence interval [CI]: 17.2 mm3, 51.5 mm3; d = 0.27; P < .001) and PBVC (-0.21%; 95% CI: -0.36%, -0.05%; d = 0.19; P = .042) but not PVVC (0.36%; 95% CI: -0.93%, 1.65%; d = 0.04; P = .89) or T2 lesion volume change (-64.5 mm3; 95% CI: -315.2 mm3, 186.3 mm3; d = 0.03; P = .67) when compared with DP nonconverters. ANCOVA showed that atrophied T2 lesion volume was associated with conversion from CIS or RRMS to SPMS (+26.4 mm3; 95% CI: 4.2 mm3, 56.9 mm3; d = 0.23; P = .002) but not PBVC (-0.14%; 95% CI: -0.46%, 0.18%; d = 0.11; P = .66), PVVC (+0.18%; 95% CI: -2.49%, 2.72%; d = 0.01; P = .75), or T2 lesion volume change (-46.4 mm3; 95% CI: -460.8 mm3, 367.9 mm3; d = 0.03; P = .93). At Cox regression analysis, only atrophied T2 lesion volume was associated with the DP (hazard ratio, 1.23; P < .001) and conversion to SPMS (hazard ratio, 1.16; P = .008). Conclusion Atrophied brain T2 lesion volume is a robust MRI marker of MS disability progression and conversion into a secondary progressive disease course. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chiang in this issue.

No association between variations in extracranial venous anatomy and clinical outcomes in multiple sclerosis patients over 5 years.

BACKGROUND: No longitudinal, long-term, follow-up studies have explored the association between presence and severity of variations in extracranial venous anatomy, and clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVE: This prospective 5-year follow-up study assessed the relationship of variations in extracranial venous anatomy, indicative of chronic cerebrospinal venous insufficiency (CCSVI) on Doppler sonography, according to the International Society for Neurovascular Disease (ISNVD) proposed consensus criteria, with clinical outcomes and disease progression in MS patients. METHODS: 90 MS patients (52 relapsing-remitting, RRMS and 38 secondary-progressive, SPMS) and 38 age- and sex-matched HIs were prospectively followed for 5.5 years. Extracranial and transcranial Doppler-based venous hemodynamic assessment was conducted at baseline and follow-up to determine the extent of variations in extracranial venous anatomy. Change in Expanded Disability Status Scale (∆EDSS), development of disability progression (DP) and annualized relapse rate (ARR) were assessed. RESULTS: No significant differences were observed in MS patients, based on their presence of variations in extracranial venous anatomy at baseline or at the follow-up, in ∆EDSS, development of DP or ARR. While more MS patients had ISNVD CCSVI criteria fulfilled at baseline compared to HIs (58% vs. 37%, p = 0.03), no differences were found at the 5-year follow-up (61% vs. 56%, p = 0.486). DISCUSSION: This is the longest follow-up study assessing the longitudinal relationship between the presence of variations in extracranial venous anatomy and clinical outcomes in MS patients. CONCLUSION: The presence of variations in extracranial venous anatomy does not influence clinical outcomes over the 5-year follow-up in MS patients.

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis.

Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (ß = -0.42; P = .002), higher degree of disability (ß = -0.64; P = .03), and secondary-progressive course (ß = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (ß = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

BACKGROUND: Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. OBJECTIVES: To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. METHODS: The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. RESULTS: In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. CONCLUSION: In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.

Cerebral Microbleeds in Multiple Sclerosis Evaluated on Susceptibility-weighted Images and Quantitative Susceptibility Maps: A Case-Control Study.

Purpose To assess cerebral microbleed (CMB) prevalence in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and associations with clinical outcomes. Materials and Methods CMBs are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established. In this study, 445 patients with MS (266 with relapsing-remitting MS, 138 with secondary progressive MS, and 41 with primary progressive MS), 45 patients with CIS, 51 patients with other neurological diseases, and 177 healthy control subjects (HCs) underwent 3-T magnetic resonance (MR) imaging and clinical examinations. A subset of 168 patients with MS and 50 HCs underwent neuropsychological testing. Number of CMBs was assessed on susceptibility-weighted minimum intensity projections by using the Microbleed Anatomic Rating Scale; volume was calculated by using quantitative susceptibility maps. Differences between groups were analyzed with the χ2 test, Fisher exact test, Student t test, and analysis of variance; associations of CMBs with clinical and other MR imaging outcomes were explored with correlation and regression analyses. Because CMB frequency increases with age, prevalence was investigated in participants at least 50 years of age and younger than 50 years. Results Significantly more patients with MS than HCs had CMBs (19.8% vs 7.4%, respectively; P = .01) in the group at least 50 years old. A trend toward greater presence of CMBs was found in patients with MS (P = .016) and patients with CIS who were younger than 50 years (P = .039) compared with HCs. In regression analysis adjusted for age, hypertension, and normalized brain volume, increased number of CMBs was significantly associated with increased physical disability in the MS population (R2 = 0.23, P < .0001). In correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory and verbal learning and memory (P = .006) and visual information processing speed trends (P = .049) in patients with MS. Conclusion Monitoring CMBs may be relevant in patients with MS and CIS at higher risk for developing cognitive and physical disability. © RSNA, 2016 Online supplemental material is available for this article.

Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation.

OBJECTIVES: To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period. BACKGROUND: Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study. METHODS: A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion. RESULTS: A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6-12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0-12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG. CONCLUSIONS: Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.

Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.

BACKGROUND: Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVES: To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. METHODS: In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. RESULTS: Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. CONCLUSIONS: Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy.

Prior Asymptomatic Parenchymal Hemorrhage Does Not Increase the Risk for Intracranial Hemorrhage after Intravenous Thrombolysis.

BACKGROUND: The NINDS trial demonstrated the efficacy of intravenous (IV) recombinant tissue plasminogen activator (rtPA) in improving the neurologic outcome in patients presenting with acute ischemic strokes. Patients who had a prior history of intracranial hemorrhage (ICH) were excluded from this trial, possibly due to a hypothetical increase in the subsequent bleeding risk. Thus, there is little data available, whether against or in favor of, the use of IV rtPA in patients with prior ICH. We aim to aid in determining the safety of IV rtPA in such patients through a retrospective hospital-based single center study. METHODS: We reviewed the brain imaging of all patients who received IV rtPA at our comprehensive stroke center from January 2006 to April 2014 for evidence of prior ICH at the time of IV rtPA administration. Their outcomes were determined in terms of subsequent development of symptomatic ICH as defined by the NINDS trial. RESULTS: Brain imaging for 640 patients was reviewed. A total of 27 patients showed evidence of prior ICH at the time of IV thrombolysis, all intra-parenchymal. Only 1 patient (3.7%) developed subsequent symptomatic ICH after the administration of IV rtPA. Of the remaining 613 patients who received IV rtPA, 25 patients (4.1%) developed symptomatic ICH. CONCLUSION: This retrospective study provides Level C evidence that patients with imaging evidence of prior asymptomatic intra-parenchymal hemorrhage presenting with an acute ischemic stroke do not show an increased risk of developing symptomatic ICH after IV thrombolysis.

Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial.

BACKGROUND: Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS). METHODS: Brain volume changes were evaluated in 23 patients with RRMS treated with interferon ß-1a 44 µg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. RESULTS: Interferon ß-1a 44 µg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. CONCLUSIONS: These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon ß-1a 44 µg SC tiw, rather than disease-related tissue loss. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01085318.

Aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow.

PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled ≥2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.

Characterizing cognitive function during relapse in multiple sclerosis.

OBJECTIVE: To characterize neuropsychological (NP) test performance during multiple sclerosis (MS) relapse and recovery. METHODS: Clinical status was assessed with NP testing and Expanded Disability Status Scale (EDSS) in 24 relapsing patients, and 24 individually-matched, stable controls. All presented with cognitive symptoms as indicated by patient, clinician or caregiver perceived decline, but were free of optic neuritis, ataxia and upper extremity weakness that could compromise NP testing. The presence of enhancing magnetic resonance imaging (MRI) lesions was considered confirmatory of relapse. Relapsing patients were treated with corticosteroids. NP testing and EDSS were compared to pre-relapse baseline levels, and three-month, post-relapse, follow-up. RESULTS: Analyses revealed significant decline on the Symbol Digit Modalities Test (SDMT) (p=0.005) and worsening on EDSS (p=0.019). Impairment was observed at the point of relapse in cases but not controls. The groups were no longer different at three-month follow-up. The increment of decline on SDMT was 3.5 raw score points, or roughly 6%. CONCLUSIONS: This is the first study to assess NP status changes during MS relapse using well established, reliable metrics. The presence of a clinically meaningful event is substantiated by decline in NP testing, observed or reported cognitive change, and in a subset of patients, gadolinium-enhancing MRI lesions.

Dynamic disability measures decrease the clinico-radiological gap in people with severely affected multiple sclerosis.

BACKGROUND: Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). OBJETIVE: To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. METHODS: PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. RESULTS: Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. CONCLUSION: Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS.

Neuroimaging assessment of facility-bound severely-affected MS reveals the critical role of cortical gray matter pathology: results from the CASA-MS case-controlled study.

BACKGROUND: A subgroup of people with multiple sclerosis (pwMS) will develop severe disability. The pathophysiology underlying severe MS is unknown. The comprehensive assessment of severely affected MS (CASA-MS) was a case-controlled study that compared severely disabled in skilled nursing (SD/SN) (EDSS ≥ 7.0) to less-disabled (EDSS 3.0-6.5) community dwelling (CD) progressive pwMS, matched on age-, sex- and disease-duration (DDM). OBJECTIVES: To identify neuroimaging and molecular biomarker characteristics that distinguish SD/SN from DDM-CD progressive pwMS. METHODS: This study was carried at SN facility and at a tertiary MS center. The study collected clinical, molecular (serum neurofilament light chain, sNfL and glial acidic fibrillary protein, sGFAP) and MRI quantitative lesion-, brain volume-, and tissue integrity-derived measures. Statistical analyses were controlled for multiple comparisons. RESULTS: 42 SD/SN and 42 DDM-CD were enrolled. SD/SN pwMS showed significantly lower cortical volume (CV) (p < 0.001, d = 1.375) and thalamic volume (p < 0.001, d = 0.972) compared to DDM-CD pwMS. In a logistic stepwise regression model, the SD/SN pwMS were best differentiated from the DDM-CD pwMS by lower CV (p < 0.001) as the only significant predictor, with the accuracy of 82.3%. No significant differences between the two groups were observed for medulla oblongata volume, a proxy for spinal cord atrophy and white matter lesion burden, while there was a statistical trend for numerically higher sGFAP in SD/SN pwMS. CONCLUSIONS: The CASA-MS study showed significantly more gray matter atrophy in severe compared to less-severe progressive MS.

Chronic cerebrospinal venous insufficiency is not associated with cognitive impairment in multiple sclerosis.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has been reported in multiple sclerosis (MS) yet its significance in relation to cognitive function is undetermined.This study measured the association between the presence and severity of CCSVI and cognitive impairment in patients with MS. METHODS: CCSVI was assessed using extra-cranial and trans-cranial Doppler sonography in 109 MS patients (79 with relapsing-remitting, 23 with secondary-progressive and 7 with primary-progressive disease subtype). A subject was considered CCSVI-positive if ≥2 venous hemodynamic criteria were fulfilled. The Minimal Assessment of Cognitive Function in MS (MACFIMS) battery was administered assessing the full spectrum of cognitive domains known to be affected by MS. Depression was quantified using the Beck Depression Inventory Fast Screen (BDIFS). Partial correlations, analysis of variance (or covariance) and linear regression were used to examine the hypothesis that CCSVI status is related to cognition or depression after controlling for education and gender. RESULTS: There were 64 (58.7%) patients who were considered CCSVI-positive. The regression models predicting venous hemodynamic insufficiency severity score were not statistically significant for any of the MACFIMS predictor variables. The analysis of variance tests showed a significant effect of CCSVI-positive diagnosis on cognitive ability in only one of the 10 MACFIMS outcomes, and that one was in the opposite direction of the tested hypothesis. There was no correspondence between CCSVI diagnosis and depression, as measured by the BDIFS. CONCLUSIONS: We find no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS.

MRI characteristics of familial and sporadic multiple sclerosis patients.

PURPOSE: To investigate the MRI characteristics in a large cohort of multiple sclerosis (MS) patients with and without a family history of MS. METHODS: Enrolled in this prospective study were 758 consecutive MS patients (mean age 46.2 ± 10.1 years, disease duration 13.6 ± 9.2 years and EDSS 3.4 ± 2.1), of whom 477 had relapsing-remitting, 222 secondary-progressive, and 30 primary-progressive disease courses and 29 had clinically isolated syndrome. One hundred and ninety-six patients (25.9%) had a positive family history of MS. Patients were assessed using measurements of lesions, brain atrophy, magnetization transfer ratio (MTR) and diffusion-weighted imaging. RESULTS: The familial MS group had greater T1-lesion volume (p=0.009) and a trend for lower MTR of T1-lesion volume (p=0.047) than the sporadic MS group. No clinical differences were found between familial versus sporadic group, or by a degree of affected relative subgroups. CONCLUSIONS: While familial MS was associated with more severe T1-lesion volume and its MTR characteristics, there were no clinical status differences between familial and sporadic MS patients. Therefore, a better understanding of the genetic and/or epigenetic influences causing these differences can advance the understanding and management of MS.