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.

Peripheral nervous system electrodiagnostic abnormalities in predominantly Hispanic Multiple Sclerosis patients.

BACKGROUND: Peripheral nervous system (PNS) abnormalities in Multiple Sclerosis (MS) have been reported in case reports and small case series over the past several decades. Little is known, however, about the prevalence of electrodiagnostic abnormalities in patients with MS, including not only demyelinating neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but also axonal peripheral neuropathy and sympathetic dysfunction. METHODS: This is an observational, cross-sectional study with the objective of identifying the prevalence of the electrodiagnostic abnormalities in predominantly Hispanic MS patients in Miami, Florida. Electrodiagnostic data including nerve conduction study (NCS), electromyography (EMG) and sympathetic skin response (SSR) information was prospectively collected in 18 patients (16 females; 43.7±15.2 years) with a diagnosis of MS compared to 18 healthy (16 females; 39.9±11 years), age- and height-matched controls. The study was offered to all-comers in the MS Clinic over a period of 3 months, regardless of clinical suspicion for an underlying neuropathic process, in an effort to estimate the prevalence of abnormalities. Demographic data including age, sex, race/ethnicity was evaluated in addition to MS-specific characteristics including MS subtype, duration of disease, duration of therapy, clinical symptoms and laboratory data. RESULTS: There were no significant differences in baseline characteristics of patients and controls for age (p=0.4) and height (164.0±6.4 vs 162.3±4.6 centimeters; p=0.3). The mean disease duration was 106±27 months (median 107 months; range 5-336 months). The mean Expanded Disability Status Scale (EDSS) was 2.4±1.87 (median: 2.5; range 1.0-6.5). The ethnicity of patients (15 Hispanic, 3 non-Hispanic) and controls (13 Hispanic, 5 non-Hispanic; p=0.56) was similar. The frequency of electrophysiological axonal polyneuropathy (PN) was 77.8% (14/18 patients), and 85.6% of these patients had clinical sensory symptoms. Interestingly, 1 patient had previously unrecognized CIDP. All 18 patients displayed prolonged SSR latencies consistent with autonomic dysfunction. Thirteen patients (72.2%) reported autonomic symptoms such as bladder abnormalities and blood pressure fluctuations. CONCLUSION: The prevalence of electrodiagnostic abnormalities, especially axonal polyneuropathy, in the MS population may be higher than traditionally considered. The relationship between axonal polyneuropathy and central axonopathy in the context of neurodegeneration in MS should be further explored. Analytic studies may identify common symptomatic and pathophysiologic etiologies to further understanding and potentially guide treatment of MS subtypes with PNS involvement.

Voluntary Cooling during Exercise Is Augmented in People with Multiple Sclerosis Who Experience Heat Sensitivity.

INTRODUCTION: We tested the hypothesis that people with multiple sclerosis (MS) who experience heat sensitivity voluntarily engage in cool-seeking behavior during exercise to a greater extent than healthy controls. METHODS: In a 27.0°C ± 0.2°C, 41% ± 2% RH environment, seven participants with relapsing-remitting MS who exhibited heat sensitivity and seven healthy controls completed two randomized trials cycling for 40 min (EX) at 3.5 W·kg-1 metabolic heat production, followed by 30 min recovery (REC). In one trial, participants were restricted from engaging in cooling (CON). In the other trial, participants voluntarily pressed a button to receive 2 min of ~2°C water perfusing a top (COOL). Mean skin and core temperatures and mean skin wettedness were recorded continuously. Total time in cooling provided an index of cool-seeking behavior. RPE, total symptom scores (MS only), and subjective fatigue (MS only) were recorded every 10 min. RESULTS: Core temperature (+0.5°C ± 0.1°C) and skin wettedness (+0.53 ± 0.02 a.u.) increased but were not different between groups or trials at end exercise (P = 0.196) or end recovery (P = 0.342). Mean skin temperature was reduced in COOL compared with CON at end exercise (P ≤ 0.002), with no differences between groups (P ≥ 0.532). MS spent more total time in cooling during EX (MS, 13 ± 3 min; healthy, 7 ± 4 min; P < 0.001) but not REC (MS, 2 ± 1 min; healthy, 0 ± 1 min; P = 0.496). RPE was greater at end exercise in MS (P = 0.001). Total symptom scores increased during exercise (P = 0.005) but was not different between trials (P = 0.321), whereas subjective fatigue was not attenuated in the cooling trial (P = 0.065). CONCLUSION: Voluntary cooling is augmented in MS but does not consistently mitigate perceptions of heat-related symptoms or subjective fatigue.

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.

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.

Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives.

Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual's mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.

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.

Effect of Teriflunomide and Dimethyl Fumarate on Cortical Atrophy and Leptomeningeal Inflammation in Multiple Sclerosis: A Retrospective, Observational, Case-Control Pilot Study.

Background: Pathologic changes in cortical gray matter (GM) and leptomeninges contribute to disability worsening in patients with multiple sclerosis (MS), but there is little evidence whether disease-modifying treatments can slow down cortical pathology in MS. Objectives: To investigate the effect of teriflunomide (TFM) and dimethyl fumarate (DMF) in reducing cortical pathology, as determined by percentage cortical volume change (PCVC) and leptomeningeal contrast enhancement (LMCE) on MRI. Methods: This was a retrospective, single-center, observational study that selected 60 TFM- and 60 DMF-treated MS patients over 24 months. Results: TFM had a lower rate of PCVC compared to DMF over 24 months (-0.2% vs. -2.94%, p = 0.004). Similar results were observed for percentage GM volume change over 0⁻12 (p = 0.044) and 0⁻24 (-0.44% vs. -3.12%, p = 0.015) months. No significant differences were found between the TFM and DMF groups in the frequency and number of LMCE foci over the follow-up. TFM showed a numerically lower rate of whole brain atrophy over 24 months (p = 0.077), compared to DMF. No significant clinical or MRI lesion differences between TFM and DMF were detected over follow-up. Conclusions: These findings suggest that TFM has a superior effect on the preservation of cortical GM volume, compared to DMF.

Medical History and Multiple Sclerosis: A Population-Based Incident Case-Control Study.

BACKGROUND: Consistent evidence regarding the potential role of medical history in multiple sclerosis (MS) etiology is lacking. OBJECTIVE: The association of medical history variables, that is, head injury and 9 autoimmune diseases with MS onset was investigated. METHODS: This was a population-based incident case-control study in Iran with 547 incident cases and 1,057 general population controls (August 7, 2013 - February 17, 2015). Multiple logistic regression models were used for estimating the adjusted ORs. RESULTS: Lifetime history of head trauma was not significantly associated with risk of MS after adjustment for well-known confounders (OR 1.24 [0.93-1.66, p = 0.14]). Similarly, there was no statistically significant association between cumulative numbers of head injury and MS (OR 1.02 [0.90-1.15, p = 0.79]). A history of autoimmune disease did not increase the risk of MS (p > 0.1). Similarly, the cumulative number of autoimmune diseases is not significantly associated with the risk of MS (p > 0.70). CONCLUSION: Lifetime histories of head trauma as well as 9 investigated autoimmune diseases are not associated with increased risk of MS.

Getting Rid of Weakness in the ICU: An Updated Approach to the Acute Management of Myasthenia Gravis and Guillain-Barré Syndrome.

After prompt diagnosis, severe myasthenia gravis and Guillain-Barré syndrome (GBS) usually require management in the intensive care unit. In the myasthenic patient, recognition of precipitating factors is paramount, and frequent monitoring of bulbar, upper airway, and/or respiratory muscle strength is needed to identify impending myasthenic crisis. Noninvasive ventilation can be attempted prior to intubation and mechanical ventilation in the setting of respiratory failure. Cholinesterase inhibitors should be discontinued, but resumed prior to extubation, and steroid dosage could be increased once the airway is secured. In GBS, hemodynamic and respiratory monitoring are essential; however, respiratory failure can develop rapidly and intubation with mechanical ventilation is often required and can be prolonged. Guillain-Barré syndrome can also be complicated by dysautonomia necessitating specific therapies. Prompt recognition and initiation of immunotherapy including intravenous immunoglobulin or plasmapheresis, together with supportive care including treatment of underlying infections and physical therapy, can improve outcomes in both myasthenic crisis and GBS.