Fall Prediction Based on Instrumented Measures of Gait and Turning in Daily Life in People with Multiple Sclerosis.

This study investigates the potential of passive monitoring of gait and turning in daily life in people with multiple sclerosis (PwMS) to identify those at future risk of falls. Seven days of passive monitoring of gait and turning were carried out in a pilot study of 26 PwMS in home settings using wearable inertial sensors. The retrospective fall history was collected at the baseline. After gait and turning data collection in daily life, PwMS were followed biweekly for a year and were classified as fallers if they experienced >1 fall. The ability of short-term passive monitoring of gait and turning, as well as retrospective fall history to predict future falls were compared using receiver operator curves and regression analysis. The history of retrospective falls was not identified as a significant predictor of future falls in this cohort (AUC = 0.62, p = 0.32). Among quantitative monitoring measures of gait and turning, the pitch at toe-off was the best predictor of falls (AUC = 0.86, p < 0.01). Fallers had a smaller pitch of their feet at toe-off, reflecting less plantarflexion during the push-off phase of walking, which can impact forward propulsion and swing initiation and can result in poor foot clearance and an increased metabolic cost of walking. In conclusion, our cohort of PwMS showed that objective monitoring of gait and turning in daily life can identify those at future risk of falls, and the pitch at toe-off was the single most influential predictor of future falls. Therefore, interventions aimed at improving the strength of plantarflexion muscles, range of motion, and increased proprioceptive input may benefit PwMS at future fall risk.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Lipoic acid modulates inflammatory responses of monocytes and monocyte-derived macrophages from healthy and relapsing-remitting multiple sclerosis patients.

Multiple sclerosis (MS) is a disabling neuroinflammatory disease. Its etiology is unknown, but both oxidative stress and inflammation appear to be involved in disease pathology. Macrophages are the predominant cell type in acute inflammatory brain lesions in MS. Macrophages produce proinflammatory and toxic molecules that promote demyelination and are key players in phagocytosis/degradation of myelin sheathes. Lipoic acid (LA) is an inexpensive, endogenously produced small molecule that exhibits antioxidant and anti-inflammatory effects. Treatment with LA is protective in MS and other inflammatory diseases. To examine the mechanism(s) by which LA may attenuate inflammatory lesion activity in MS, we used healthy control and MS cells to evaluate the effects of LA on levels of inflammatory cytokines, phagocytosis and the immunomodulator cyclic adenosine monophosphate (cAMP) in monocytes and monocyte-derived macrophages (MDMs). LA treatment resulted in a generally less inflammatory phenotype of monocytes and MDMs from healthy controls, and (to a lesser degree) MS donors. LA inhibited monocyte secretion of cytokines relevant to MS in monocytes, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß; LA effects on secretion of these cytokines in MDMs were mixed with inhibition of TNF-α and IL-6, but stimulation of IL-1ß, the latter perhaps as a result of altered macrophage polarization. LA inhibited phagocytosis in both monocytes and MDMs, and increased cAMP levels in monocytes. LA may modulate inflammatory cytokine secretion and phagocytosis via a cAMP-mediated mechanism.

Laboratory versus daily life gait characteristics in patients with multiple sclerosis, Parkinson's disease, and matched controls.

BACKGROUND AND PURPOSE: Recent findings suggest that a gait assessment at a discrete moment in a clinic or laboratory setting may not reflect functional, everyday mobility. As a step towards better understanding gait during daily life in neurological populations, we compared gait measures that best discriminated people with multiple sclerosis (MS) and people with Parkinson's Disease (PD) from their respective, age-matched, healthy control subjects (MS-Ctl, PD-Ctl) in laboratory tests versus a week of daily life monitoring. METHODS: We recruited 15 people with MS (age mean ± SD: 49 ± 10 years), 16 MS-Ctl (45 ± 11 years), 16 people with idiopathic PD (71 ± 5 years), and 15 PD-Ctl (69 ± 7 years). Subjects wore 3 inertial sensors (one each foot and lower back) in the laboratory followed by 7 days during daily life. Mann-Whitney U test and area under the curve (AUC) compared differences between PD and PD-Ctl, and between MS and MS-Ctl in the laboratory and in daily life. RESULTS: Participants wore sensors for 60-68 h in daily life. Measures that best discriminated gait characteristics in people with MS and PD from their respective control groups were different between the laboratory gait test and a week of daily life. Specifically, the toe-off angle best discriminated MS versus MS-Ctl in the laboratory (AUC [95% CI] = 0.80 [0.63-0.96]) whereas gait speed in daily life (AUC = 0.84 [0.69-1.00]). In contrast, the lumbar coronal range of motion best discriminated PD versus PD-Ctl in the laboratory (AUC = 0.78 [0.59-0.96]) whereas foot-strike angle in daily life (AUC = 0.84 [0.70-0.98]). AUCs were larger in daily life compared to the laboratory. CONCLUSIONS: Larger AUC for daily life gait measures compared to the laboratory gait measures suggest that daily life monitoring may be more sensitive to impairments from neurological disease, but each neurological disease may require different gait outcome measures.

Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort.

BACKGROUND: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Nicolau syndrome and localized panniculitis: a report of dual diagnoses with an emphasis on morphea profunda-like changes following injection with glatiramer acetate.

Glatiramer acetate, given as a 40 mg subcutaneous injection thrice weekly, was recently approved by the FDA based on data suggesting better compliance and a more favorable side effect profile compared to lower dose, daily dosing. The most commonly reported adverse events are transient injection site reactions involving redness and pain at the site; however, more pronounced panniculitis and lipoatrophy have also been reported. Here, we present the case of a 51-year-old female treated with higher dose glatiramer acetate who presented with a cutaneous injection site reaction consistent with Nicolau syndrome. The excised specimen revealed typical glatiramer acetate-associated panniculitis, alongside subcutaneous sclerosis. This case shows the spectrum of cutaneous complications possible with glatiramer acetate injections, the finding of sclerosis being relatively infrequently reported. Given the relatively short duration of trials leading to FDA approval of thrice weekly dosing of glatiramer acetate, clinicians should perform careful clinical and histopathological evaluation and reporting of patients who experience injection site reactions.

Characterization of Compensatory Stepping in People With Multiple Sclerosis.

OBJECTIVE: To characterize postural responses to forward and backward external perturbations in people with multiple sclerosis (PwMS), and to relate performance to commonly used clinical outcomes. DESIGN: Cross-sectional study. Postural responses were tested during large stepping and smaller feet-in-place perturbations in forward and backward directions. SETTING: University research laboratory. PARTICIPANTS: PwMS (n=54) and age-matched controls (n=21) (N=75). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Center of mass displacement and step latency after external perturbations. RESULTS: PwMS exhibited larger center of mass displacements and step latencies than control participants in response to stepping perturbations (P=.003 and P=.028, respectively). Stepping deficits were more pronounced during backward stepping and were significantly correlated to increased severity on clinical measures (European Database for Multiple Sclerosis disability score and Timed 25-Foot Walk). CONCLUSIONS: Compensatory stepping is impaired in PwMS and correlates with clinical disability. Measurement of backward compensatory stepping may be more effective at identifying postural dysfunction in PwMS than forward compensatory steps. Prolonged step latencies, large anticipatory postural adjustments, and multiple compensatory steps are especially altered in PwMS, suggesting possible targets for neurorehabilitation.

Postural response latencies are related to balance control during standing and walking in patients with multiple sclerosis.

OBJECTIVE: To understand and examine the relation between postural response latencies obtained during postural perturbations and representative measures of balance during standing (sway variables) and walking (trunk motion). DESIGN: Cross-sectional. SETTING: University medical center. PARTICIPANTS: Persons with multiple sclerosis (MS) (n=40) were compared with similar aged control subjects (n=20). There were 20 subjects with MS in the normal walking velocity group and 20 subjects with MS who had slow walking velocity based on a timed 25-foot walk (T25FW) of <5 seconds. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Postural response latency, sway variables, trunk motion variables. RESULTS: We found that subjects with MS with both slow or normal walking velocities had significantly longer postural response latencies than the healthy control group. Postural response latency was not correlated with the T25FW. Postural response latency was significantly correlated with center of pressure sway variables during quiet standing (root mean square: ρ=.334, P=.04; range: ρ=.385, P=.017; mean velocity: ρ=.337, P=.038; total sway area: ρ=.393, P=.015). Postural response latency was also significantly correlated with motion of the trunk during walking (sagittal plane range of motion: ρ=.316, P=.05; SD of transverse plane range of motion: ρ=-.43, P=.006). CONCLUSIONS: These findings clearly indicate that slow postural responses to external perturbations in patients with MS contribute to disturbances in balance control during both standing and walking.

Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers.

Introduction: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. Methods: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Results: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96). Conclusion: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

Protocol for an exploratory, randomised, single-blind clinical trial of aerobic exercise to promote remyelination in multiple sclerosis.

INTRODUCTION: There is an urgent need for remyelinating therapies that restore function in people with multiple sclerosis (pwMS). Aerobic exercise is a promising remyelinating strategy because it promotes remyelination in animal models both independently and synergistically with medications. Here, in this study, we present an innovative, randomised, single-blind, clinical trial designed to explore: the relationship between demyelination and mobility (part 1), and if 24 weeks of aerobic exercise promotes remyelination in pwMS (part 2). METHODS AND ANALYSIS: Sedentary participants (n=60; aged 18-64 years) with stable MS will undergo a baseline visit with the following outcomes to assess associations between demyelination and mobility (part 1): spinal cord demyelination (somatosensory-evoked potentials, SSEPs), mobility (6-Minute Timed Walk, Timed 25-Foot Walk, Timed Up and Go, 9-Hole Peg Test) and patient-reported outcomes (PROs). After baseline testing, participants with significantly prolonged SSEP latency will advance to the clinical exercise trial (part 2) and will be randomised 1:1 to active or control conditions for 24 weeks. The active condition will be aerobic stationary cycling three times per week with graded virtual supervision. The control condition will be monthly virtual MS symptom education groups (six sessions). SSEP latency (remyelination endpoint), mobility outcomes and PROs will be measured at 12 and 24 weeks in all clinical trial participants. A subset of 11 active and 11 control participants will undergo a brain MRI with quantitative T1 myelin water fraction at baseline and 24 weeks (exploratory remyelination endpoint). ETHICS AND DISSEMINATION: Ethical approval was obtained from the Oregon Health & Science University Institutional Review Board (#21045). Dissemination of findings will include peer-reviewed publications, conference presentations and media releases. The proposed study will inform the feasibility, study design and sample size for a fully powered clinical trial of aerobic exercise to promote remyelination in pwMS. TRIAL REGISTRATION NUMBER: NCT04539002.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Approach to Symptom Management in Multiple Sclerosis With a Focus on Wellness.

PURPOSE OF REVIEW: This article describes an approach to symptom management in people with multiple sclerosis (MS), emphasizing healthy lifestyles and evidence-based treatments. RECENT FINDINGS: Growing evidence supports healthy nutrition, exercise, and emotional well-being (wellness) as foundational for MS symptom management. A stepped approach starts with healthy lifestyle practices and adds nonpharmacologic, pharmacologic, and procedural-based therapies balancing levels of evidence, risks, and potential benefits. The growing availability of cannabis and widespread use of dietary supplements in self-management of MS symptoms raise both therapeutic promises and challenges. SUMMARY: Wellness approaches for MS symptom management foster self-reliance and should be reinforced early and often. Recognition of symptom clusters and medical comorbidities helps limit polypharmacy.

Effect of Vascular Comorbidity on Visual and Disability Outcomes in a Secondary Progressive Multiple Sclerosis Clinical Trial Cohort.

BACKGROUND: Vascular comorbidity (VC) is associated with multiple sclerosis (MS) disease progression and visual dysfunction. The longitudinal effect of VC in people with secondary progressive MS (SPMS) is unclear. This study explored the impact of VC on standard clinical, MRI, and visual outcomes in people with SPMS enrolled in a clinical trial. METHODS: Data were extracted from a 2-year randomized controlled trial (N = 51) testing the supplement lipoic acid in people with SPMS who underwent annual Expanded Disability Status Scales, Timed 25-Foot Walk tests, MRIs, visual acuity testing, and retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) thicknesses per optical coherence tomography (OCT). Post hoc linear mixed-effects regression analysis compared baseline and annualized outcomes between participants without VC (VC-) and with 1 or more VCs (VC+) (hypertension, dyslipidemia, obesity, diabetes, peripheral or cardiovascular disease, tobacco use). RESULTS: The VC- (n = 19) and VC+ (n = 28) participants were similar in age, sex, and MS disease duration and had comparable MS disability, mobility, and brain atrophy at baseline and throughout the 2-year parent study. The VC+ participants had worse baseline visual acuity than those in the VC- group by 0.13 logMAR (P = .041). No significant differences were detected in RNFL or GCIPL baseline thickness or atrophy between groups. CONCLUSIONS: In an SPMS cohort, VC had an inconsistent effect on standard clinical, MRI, and exploratory OCT outcomes, suggesting that the effect of VC may not be evident in smaller cohort studies. Using a more refined definition of VC in future, adequately powered investigations may help effectively elucidate and account for the interaction between vascular risk burden and MS disability.

Oxidative stress in multiple sclerosis-Emerging imaging techniques.

While conventional magnetic resonance imaging (MRI) is central to the evaluation of patients with multiple sclerosis, its role in detecting the pathophysiology underlying neurodegeneration is more limited. One of the common outcome measures for progressive multiple sclerosis trials, atrophy on brain MRI, is non-specific and reflects end-stage changes after considerable neurodegeneration has occurred. Identifying biomarkers that identify processes underlying neurodegeneration before it is irreversible and that reflect relevant neurodegenerative pathophysiology is an area of significant need. Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple neurodegenerative diseases, including multiple sclerosis. Imaging markers related to inflammation, myelination, and neuronal integrity have been areas of advancement in recent years but oxidative stress has remained an area of unrealized potential. In this article we will begin by reviewing the role of oxidative stress in the pathogenesis of multiple sclerosis. Chronic inflammation appears to be directly related to the increased production of reactive oxygen species and the effects of subsequent oxidative stress appear to be amplified by aging and accumulating disease. We will then discuss techniques in development used in the assessment of MS as well as other models of neurodegenerative disease in which oxidative stress is implicated. Multiple blood and CSF markers of oxidative stress have been evaluated in subjects with MS, but non-invasive imaging offers major upside in that it provides real-time assessment within the brain.

Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors.

BACKGROUND: TNF alpha inhibitor (TNFAI) therapy has been associated with inflammatory neurological syndromes. OBJECTIVES: To present 10 new cases of TNFAI associated neurological disease and a review of the literature. METHODS: The design and methods were based on case series collected from Oregon Health & Sciences University and the Department of Veterans Affairs Hospital in Portland, Oregon and PubMed review. RESULTS: We describe eight demyelinating central nervous system syndromes and two peripheral nervous system syndromes associated with TNFAI therapy. Characteristics from these cases are analyzed with data from 141 additional cases from the literature. Onset was between the ages of 36 and 65 years in 84% of CNS cases, distinguishing TNFAI-associated disease from sporadic multiple sclerosis. Symptoms occurred within one year of TNFAI therapy in 71%. Etanercept therapy was reported in the majority of cases of CNS syndromes and infliximab therapy in the majority of neuromuscular syndromes. Significant disability remained in 67% of cases although 82% had been followed for less than one year. CONCLUSIONS: Our case series and literature review demonstrates an association between TNFAI therapy and inflammatory neurological disease. While a causal relationship is suggested, this remains uncertain. TNFAI-associated neurological syndromes are associated with significant disability and longer follow-up is needed to better determine natural history and evaluate appropriate treatment interventions.

The radiologically isolated syndrome: look (again) before you treat.

The advent and wide use of magnetic resonance brain imaging has led to in the unexpected detection of lesions that appear typical of multiple sclerosis (MS) in otherwise asymptomatic patients. Several cohorts of patients with the "radiologically isolated syndrome (RIS)" have been studied mainly retrospectively, and a proportion of them do go on to have clinical symptoms of MS. This has led to the not infrequent clinical conundrum of whether or not to treat patients with MRI lesions suggestive of MS, given the knowledge that MS disease-modifying therapies work best when given early in the disease course. However, the decision to proactively treat patients with RIS is countered by the increasing risks associated with MS disease-modifying therapies as well as the uncertain prognostic outcome of RIS. This review will highlight what is and is not known about the long-term outcomes of RIS and present recommendations for clinicians when faced with this challenging situation.

COVID-19 vaccination willingness among people with multiple sclerosis.

BACKGROUND: Hesitancy to receive COVID-19 vaccination is a major public health concern. COVID-19 vaccine willingness and the factors contributing to willingness in adults with multiple sclerosis (MS) is unknown. We administered an online survey from 1 December 2020 to 7 January 2021 to adults with MS to estimate COVID-19 vaccine willingness among adults with MS. Bivariate analysis with chi-square testing compared categorical variables associated with vaccine willingness. RESULTS: Of 401 respondents, 70.1% were willing to receive an authorized COVID-19 vaccination if it was available to them, 22.7% were unsure, and 7.2% were unwilling. The most frequent concern for those unsure was vaccine safety. Vaccine willingness was associated with increased perceived personal risk of COVID-19 (χ2 = 45.4; p < 0.0001), prior influenza vaccine acceptance (χ2 = 97.6; p < 0.0001), higher educational level (χ2 = 50.2; p < 0.0001), and if respondents discussed or planned to discuss the COVID-19 vaccine with their neurologists (χ2 = 64.3; p < 0.0001). CONCLUSION: While COVID-19 vaccination willingness is high among people with MS, nearly 30% were either unwilling or unsure about being vaccinated. Neurologists should be aware of patient-centered factors associated with COVID-19 vaccine willingness and address COVID-19 vaccine safety concerns in discussions with their vaccine-unsure MS patients.

Gray matter blood-brain barrier water exchange dynamics are reduced in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: To compare transcapillary wall water exchange, a putative marker of cerebral metabolic health, in brain T2 white matter (WM) lesions and normal appearing white and gray matter (NAWM and NAGM, respectively) in individuals with progressive multiple sclerosis (PMS) and healthy controls (HC). METHODS: Dynamic-contrast-enhanced 7T MRI data were obtained from 19 HC and 23 PMS participants. High-resolution pharmacokinetic parametric maps representing tissue microvascular and microstructural properties were created by shutter-speed (SS) paradigm modeling to obtain estimates of blood volume fraction (vb ), water molecule capillary efflux rate constant (kpo ), and the water capillary wall permeability surface area product (Pw S ≡ vb *kpo ). Linear regression models were used to investigate differences in (i) kpo and Pw S between groups in NAWM and NAGM, and (ii) between WM lesions and NAWM in PMS. RESULTS: High-resolution parametric maps were produced to visualize tissue classes and resolve individual WM lesions. Normal-appearing gray matter kpo and Pw S were significantly decreased in PMS compared to HC (p ≤ .01). Twenty-one T2 WM lesions were analyzed in 10 participants with PMS. kpo was significantly decreased in WM lesions compared to PMS NAWM (p < .0001). CONCLUSIONS: Transcapillary water exchange is reduced in PMS NAGM compared to HC and is further reduced in PMS WM lesions, suggesting pathologically impaired brain metabolism. kpo provides a sensitive measure of cerebral metabolic activity and/or coupling, and can be mapped at higher spatial resolution than conventional imaging techniques assessing metabolic activity.

A cross-sectional survey of cannabis use by people with MS in Oregon and Southwest Washington.

BACKGROUND: Evidence supports that cannabinoids reduce self-reported spasticity and neuropathic pain in people with MS (PwMS), and legal access to cannabis for medical and recreational use continues to rise. However, there are limited data regarding patterns of cannabis use and perceived benefits of cannabis among PwMS in the US. This study describes the prevalence of cannabis use, routes of administration, perceived benefit of cannabis for MS, and characteristics associated with cannabis use and perception of benefit among a population of PwMS living in two states where cannabis is legal for both medical and recreational use. METHODS: A survey about treatments used by PwMS, focusing on complementary and alternative medicine (CAM), was sent to PwMS living in Oregon and Southwest Washington. This survey included questions about current and past cannabis use, route of cannabis administration, and perceived benefits, as well as personal demographics. RESULTS: Of the 1188 returned surveys, 1000 had at least 75% complete survey responses and also completed the questions about current and past cannabis use. Thirty percent (n=303) of respondents reported currently using cannabis, 21% (n=210) used in the past but not currently, and 49% (n=487) had never used cannabis. Among current users, rates of use by smoking, vaping, topicals, tinctures and oils, or edibles were similar (35-46%), and most (59%) reported using multiple routes of administration. Most (64-78%, varying by route) current and past users reported cannabis being very or somewhat beneficial for their MS. The odds of current cannabis use were higher in PwMS who: 1) were younger (OR 2.24 [95% CI 1.39-3.61] for those age 18-40 compared with age >60]; 2) had lower household income (OR 3.94 [95% CI 2.55-6.09] with annual income <$25k compared with those with >$100k); 3) had secondary progressive MS (OR 1.77 [95% CI 1.07-2.92]); and 4) had more than minimal MS disability (OR 2.05 [95% CI 1.03-4.10] for those using a walker compared to those with none/minimal disability). The odds of perceiving cannabis as beneficial for MS were higher in: 1) younger individuals (OR 5.61 [95% CI 2.62-11.98] for those age 18-40 compared with age >60); 2) those with lower household income (OR 3.35 [95% CI 1.65-6.80] with annual income <$25k compared with those with >$100k), 3) those not currently using disease modifying therapies (OR 2.32 [95% CI 1.30-4.13]), and 4) those with the greatest disability (OR 17.96; [95% CI 2.00-161.22]). CONCLUSION: In this survey, 30% of PwMS reported currently using cannabis for their MS, mostly by multiple routes of administration, and most of these people report this being helpful for their MS. People who were younger, had lower household income, had progressive disease, and had more than minimal disability were more likely to use cannabis and report it was beneficial for their MS. People who were not using disease modifying therapies were also more likely to report benefit from cannabis use.

Effects of Fragmentation and the Case for Greater Cohesion in Neurologic Care Delivery.

GOALS: To define fragmentation in neurological care delivery; explain the positive and negative drivers in neurologic practice that contribute to fragmentation; illustrate situations that increase fragmentation risk; emphasize the costs and impact on both patients and providers; propose solutions that allow for more cohesive care. WORK GROUP: The Transforming Leaders Program (TLP) class of 2020 was tasked by American Academy of Neurology (AAN) leadership to identify the leading trends in inpatient and outpatient neurology and to predict their effects on future neurologic practice. METHODS: Research material included AAN data bases, PubMed searches, discussion with topic experts and AAN leadership. RESULTS: Trends in care delivery are driven by changes in the work force, shifts in health care delivery, care costs, changes in evidence-based care and patient factors. These trends can contribute to care fragmentation. Potential solutions to these problems are proposed based on care models developed in oncology and medicine. LIMITATIONS: This paper shares our opinions as there is a lack of evidence-based guidelines as to optimal neurological care delivery.