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.

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.

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.

Tixagevimab and Cilgavimab (Evusheld™) Prophylaxis Prevents Breakthrough COVID-19 Infections in Immunosuppressed Population: 6-Month Prospective Study.

BACKGROUND: Persons with neuroinflammatory diseases (pwNID) treated with potent immunosuppressives are at risk of severe COVID-19 outcomes and reduced vaccine seroconversion. We aimed at determining the real-world efficacy of tixagevimab and cilgavimab (Evusheld™) in immunosuppressed pwNID in preventing breakthrough COVID-19 infections. METHODS: 31 immunosuppressed pwNID were followed for 6 months after administration of tixagevimab and cilgavimab as a prophylactic COVID-19 medication (January 2022-July 2022). Only pwNID treated with anti-CD20 monoclonal antibodies and sphingosine-1-phosphate modulators were considered eligible for the study. A control group of 126 immunosuppressed pwNID (38 seropositive and 88 seronegative after SARS-CoV-2 vaccination) were included. Breakthrough COVID-19 infections rate and their severity was determined over the follow-up. RESULTS: The pwNID treated with tixagevimab and cilgavimab had more comorbidities when compared with the total and seronegative pwNID control group (54.8% vs. 30.2% vs. 27.3%, p = 0.02 and p = 0.005, respectively). After a 6-month follow-up, significantly lower numbers of pwNID treated with tixagevimab and cilgavimab had breakthrough COVID-19 when compared with the control pwNID group (6.5% vs. 34.1%, p = 0.002) and seronegative control pwNID group (6.5% vs. 38.6%, p < 0.001). All COVID-19 infections in Evusheld-treated pwNID were mild, whereas 9/43 COVID-19 infections in the control group were moderate/severe. No side effects to tixagevimab and cilgavimab were recorded. CONCLUSION: In pwNID treated with immunosuppressive therapies, tixagevimab and cilgavimab (Evusheld™) significantly reduced the numbers and severity of breakthrough COVID-19 infections during the Omicron (BA.2-BA.5 variants) wave.

Communicating the relevance of neurodegeneration and brain atrophy to multiple sclerosis patients: patient, provider and researcher perspectives.

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial. This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring. The following recommendations were created based on application of patient's and provider's surveys, and various workshops held over a period of 2 years: (1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration; (2) the expertise for atrophy measurements should be characterized as evolving; (3) quality patient education materials on these topics should be provided; (4) the need for standardization of MRI exams has to be explained and communicated; (5) providers should discuss background on volumetric changes, including references to normal aging; (6) the limitations of brain volume assessments at an individual-level should be explained; (7) the timing and language used to convey this information should be individualized based on the patient's background and disease status; (8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions; (9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes; (10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and (11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs.

COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections.

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4−12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

Clinical feasibility of longitudinal lateral ventricular volume measurements on T2-FLAIR across MRI scanner changes.

BACKGROUND: Greater brain atrophy is associated with disability progression (DP) in patients with multiple sclerosis (PwMS). However, methodological challenges limit its routine clinical use. OBJECTIVE: To determine the feasibility of atrophy measures as markers of DP in PwMS scanned across different MRI field strengths. METHODS: A total of 980 PwMS were scanned on either 1.5 T or 3.0 T MRI scanners. Demographic and clinical data were retrospectively collected, and the presence of DP was determined according to standard clinical trial criteria. Lateral ventricular volume (LVV) change was measured with the NeuroSTREAM technique on clinical routine T2-FLAIR images. Percent brain volume change (PBVC) was measured using SIENA and ventricular cerebrospinal fluid (vCSF) % change was measured using VIENA and SIENAX algorithms on 3D T1-weighted images (WI). Stable vs. DP PwMS were compared using analysis of covariance (ANCOVA). Mixed modeling determined the effect of MRI scanner change on MRI-derived atrophy measures. RESULTS: Longitudinal LVV analysis was successful in all PwMS. SIENA-based PBVC and VIENA-based changes failed in 37.6% of cases, while SIENAX-based vCSF failed in 12.9% of cases. PwMS with DP (n = 241) had significantly greater absolute (20.9% vs. 8.7%, d = 0.66, p < 0.001) and annualized LVV % change (4.1% vs. 2.3%, d = 0.27, p < 0.001) when compared to stable PwMS (n = 739). In subjects with both analyses available, both 3D-T1 and T2-FLAIR-based analyses differentiated PwMS with DP (n = 149). However, only NeuroSTREAM and VIENA-based LVV/vCSF were able to show greater atrophy in PwMS that were scanned on different scanners. PBVC and SIENAX-based vCSF % changes were significantly affected by scanner change (Beta = -0.16, t-statistics = -2.133, p = 0.033 and Beta = -2.08, t-statistics = -4.084, p < 0.001), whereas no MRI scanner change effects on NeuroSTREAM-based PLVVC and VIENA-based vCSF % change were noted. CONCLUSIONS: LVV-based atrophy on T2-FLAIR is a clinically relevant measure in spite of MRI scanner changes and mild disability levels.

Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis.

BACKGROUND: Leptomeningeal contrast enhancement (LMCE) has previously shown potential to be an indirect marker for leptomeningeal inflammation in multiple sclerosis (MS). Dura mater (DME), inclusive falx cerebri (FCE) enhancement and meningeal vessel wall enhancement (VWE) represent two other meningeal enhancement patterns in MS that have not been extensively studied. OBJECTIVES: To investigate the frequency of LMCE, DME/FCE and VWE in patients with MS and their associations with demographic, clinical and MRI characteristics in a longitudinal retrospective study. METHODS: 217 MS patients (193 relapsing-remitting MS, 24 progressive MS) were assessed at baseline and over 18 months follow-up using 3T 3D FLAIR pre- and post-contrast and subtraction images. Lesion and brain volume outcomes were additionally calculated. Analyses were adjusted for age, and corrected for multiple comparisons. RESULTS: LMCE and VWE frequency was associated with higher age (p<0.02), but the presence of DME/FCE was not (p=0.402). 24% of MS patients revealed LMCE and VWE, respectively, and 47% showed DME/FCE. Presence of LMCE, VWE and DME/FCE was not significantly associated with clinical or imaging markers of disease severity. All three patterns of meningeal enhancement showed a high persistence in shape and size at follow-up. CONCLUSIONS: LMCE, DME/FCE and VWE can be identified by gadolinium-enhanced 3D FLAIR MR imaging. Meningeal enhancement is associated with higher age. DME/FCE is the most frequent meningeal enhancement pattern in MS, however further case-control studies should determine whether this represents abnormal lymphatic drainage in these patients or is an age-dependent physiologic phenomenon.

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.

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.

Late onset multiple sclerosis is associated with more severe ventricle expansion.

BACKGROUND: Late-onset multiple sclerosis (LOMS) is associated with faster disability progression than persons with adult-onset MS (PwAOMS). The differences in brain atrophy are currently unknown. OBJECTIVES: To determine MRI-derived atrophy rates in persons with late-onset MS (PwLOMS) and compare them to an age-matched and disease duration-matched sample of PwAOMS. METHODS: 870 persons with MS (290 PwLOMS, 290 age-matched PwAOMS, and 290 disease duration-matched PwAOMS), and 150 healthy controls (HCs), were followed for 5 years and 3 years, respectively. Cross-sectional and longitudinal measures of T2-lesion volume (LV), lateral ventricular volume (LVV) and whole brain volume (WBV) were derived. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) were calculated. Both analyses were corrected for false discovery rate. RESULTS: Persons with MS exhibited significantly greater annualized WBV loss (-0.88% vs. -0.38%, p<0.001) and annualized LVV expansion (3.1% vs. 1.7%, p=0.002) when compared to HCs. PwLOMS had significantly higher baseline and follow-up median MSSS when compared to both age-matched and disease duration-matched PwAOMS (p<0.026). PwLOMS showed significantly greater percent LVV change (14.3% vs. 9.3% p=0.001) and greater annualized percent LVV change (4.1% vs. 1.6%, p<0.001) compared to age-matched PwAOMS. CONCLUSION: PwLOMS had higher MSSS and greater ventricle expansion when compared to PwAOMS.

Functional Connectivity and Structural Disruption in the Default-Mode Network Predicts Cognitive Rehabilitation Outcomes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity. METHODS: For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls. RESULTS: Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R2 = .385, P = .017, Interaction ß = -.415). CONCLUSION: Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.

Sex-Specific Differences in Life Span Brain Volumes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Numerous sex-specific differences in multiple sclerosis (MS) susceptibility, disease manifestation, disability progression, inflammation, and neurodegeneration have been previously reported. Previous magnetic resonance imaging (MRI) studies have shown structural differences between female and male MS brain volumes. To determine sex-specific global and tissue-specific brain volume throughout the MS life span in a real-world large MRI database. METHODS: A total of 2,199 MS patients (female/male ratio of 1,651/548) underwent structural MRI imaging on either a 1.5-T or 3-T scanner. Global and tissue-specific volumes of whole brain (WBV), white matter, and gray matter (GMV) were determined by utilizing Structural Image Evaluation using Normalisation of Atrophy Cross-sectional (SIENAX). Lateral ventricular volume (LVV) was determined with the Neurological Software Tool for REliable Atrophy Measurement (NeuroSTREAM). General linear models investigated sex and age interactions, and post hoc comparative sex analyses were performed. RESULTS: Despite being age-matched with female MS patents, a greater proportion of male MS patients were diagnosed with progressive MS and had lower normalized WBV (P < .001), GMV (P < .001), and greater LVV (P < .001). In addition to significant stand-alone main effects, an interaction between sex and age had an additional effect on the LVV (F-statistics = 4.53, P = .033) and GMV (F-statistics = 4.59, P = .032). The sex and age interaction was retained in both models of LVV (F-statistics = 3.31, P = .069) and GMV (F-statistics = 6.1, P = .003) when disease subtype and disease-modifying treatment (DMT) were also included. Although male MS patients presented with significantly greater LVV and lower GMV during the early and midlife period when compared to their female counterparts (P < .001 for LVV and P < .019 for GMV), these differences were nullified in 60+ years old patients. Similar findings were seen within a subanalysis of MS patients that were not on any DMT at the time of enrollment. CONCLUSION: There are sex-specific differences in the LVV and GMV over the MS life span.

Long-standing multiple sclerosis neurodegeneration: volumetric magnetic resonance imaging comparison to Parkinson's disease, mild cognitive impairment, Alzheimer's disease, and elderly healthy controls.

Multiple sclerosis (MS) exhibits neurodegeneration driven disability progression. We compared the extent of neurodegeneration among 112 long-standing MS patients, 37 Parkinson's disease (PD) patients, 34 amnestic mild cognitive impairment (aMCI) patients, 37 Alzheimer's disease (AD) patients, and 184 healthy controls. 3T MRI volumes of whole brain (WBV), white matter (WMV), gray matter (GMV), cortical (CV), deep gray matter (DGM), and nuclei-specific volumes of thalamus, caudate, putamen, globus pallidus, and hippocampus were derived with SIENAX and FIRST software. Аge and sex-adjusted analysis of covariance was used. WBV was not significantly different between diseases. MS had significantly lower WMV compared to other disease groups (p < 0.021). Only AD had smaller GMV and CV when compared to MS (both p < 0.001). MS had smaller DGM volume than PD and aMCI (p < 0.001 and p = 0.026, respectively) and lower thalamic volume when compared to all other neurodegenerative diseases (p < 0.008). Long-standing MS exhibits comparable global atrophy with lower WMV and thalamic volume when compared to other classical neurodegenerative diseases.

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.

Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS.

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used. RESULTS: The mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up. CONCLUSIONS: DN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.

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.