Polypharmacy in Multiple Sclerosis: Prevalence, Risks, and Mitigation Strategies.

PURPOSE OF REVIEW: Polypharmacy, the use of ≥ 5 medications, is common in people with multiple sclerosis and is associated with negative outcomes. The use of multiple medications is common for symptom management in people with multiple sclerosis, but risks drug-drug interactions and additive side effects. Multiple sclerosis providers should therefore focus on the appropriateness and risks versus benefits of pharmacotherapy in each patient. This review describes the prevalence and risks associated with polypharmacy in people with multiple sclerosis and offers strategies to identify and mitigate inappropriate polypharmacy. RECENT FINDINGS: Research in people with multiple sclerosis has identified risk factors and negative outcomes associated with polypharmacy. Medication class-specific investigations highlight their contribution to potentially inappropriate polypharmacy in people with multiple sclerosis. People with multiple sclerosis are at risk for inappropriate polypharmacy. Multiple sclerosis providers should review medications and consider their appropriateness and potential for deprescribing within the context of each patient.

Chronic Demyelination and Axonal Degeneration in Multiple Sclerosis: Pathogenesis and Therapeutic Implications.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). Inflammatory attacks in MS lead to both demyelination and axonal damage. However, due to incomplete remyelination most MS lesions remain chronically demyelinated. In parallel, there is axonal degeneration in the CNS of MS patients, contributing to progressive disability. There are currently no approved therapies that adequately restore myelin or protect axons from degeneration. In this review, we will discuss the pathophysiology of axonal loss and chronic demyelination in MS and how understanding this pathophysiology is leading to the development of new MS therapeutics. RECENT FINDINGS: Ongoing research into the function of oligodendrocytes and myelin has revealed the importance of their relationship with neuronal health. Demyelination in MS leads to a number of pathophysiologic changes contributing to axonal generation. Among these are mitochondrial dysfunction, persistent neuroinflammation, and the effects of reactive oxygen and nitrogen species. With this information, we review currently approved and investigational therapies designed to restore lost or damaged myelin and protect against neuronal degeneration. The development of therapies to restore lost myelin and protect neurons is a promising avenue of investigation for the benefit of patients with MS.

MIF and D-DT are potential disease severity modifiers in male MS subjects.

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a -794CATT5-8 microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

Repository Corticotropin Versus Glucocorticoid for Nephrotic Syndrome: When Will We See the Evidence?

Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for repository corticotropin (rACTH) injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications.

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.

A multicenter randomized controlled trial of two group education programs for fatigue in multiple sclerosis: Long-term (12-month) follow-up at one site.

BACKGROUND: A four-site RCT of Fatigue: Take Control (FTC), a multicomponent group program, found no significant differences from a control program, MS: Take Control (MSTC), in fatigue on the Modified Fatigue Impact Scale (MFIS) through 6 months. OBJECTIVE: Assess FTC for a delayed effect on fatigue. METHODS: Of 78 subjects at one site, 74 randomized to FTC or MSTC completed the MFIS at 12 months. RESULTS: Compared to baseline, FTC produced greater improvements in MFIS scores than MSTC (FTC -8.9 (confidence interval (CI): 32.2, 45), MSTC -2.5 (CI 39.6, 47.7), p = 0.03) at 12 months. CONCLUSION: The delayed effect of FTC on fatigue suggests the need for longer follow-up when assessing interventions for fatigue.

Impact of mindfulness-based stress reduction for people with multiple sclerosis at 8 weeks and 12 months: A randomized clinical trial.

BACKGROUND: Mindfulness training is often used as a therapeutic intervention to manage stress and enhance emotional well-being, yet trials for multiple sclerosis (MS) are limited and few have used an active control. OBJECTIVE: Assess the feasibility of mindfulness-based stress reduction (MBSR) for people with MS and evaluate the efficacy of MBSR compared to an education control. METHODS: We conducted a single-blind, randomized trial of MBSR versus education control among 62 adults with MS. Primary outcomes were measures of feasibility. Secondary outcomes included perceived stress, anxiety, depression, fatigue, pain, resilience, and the Paced Auditory Serial Addition Test, assessed at baseline, 8 weeks, and 12 months. Mean scores for secondary outcome measures were compared between groups at each time point and within groups across time by analyses of covariance or paired t-tests, respectively. RESULTS: Successful recruitment and retention demonstrated feasibility. Improvements in several secondary outcomes were observed among both MBSR and control groups. However, differences between the groups were not statistically significant at either 8 weeks or 12 months. CONCLUSION: Emotional well-being improved with both MBSR and education. Spontaneous improvement cannot be ruled out as an explanation for findings and additional studies that evaluate the impact of mindfulness training to improve emotional health are warranted.

A multicenter randomized controlled trial of two group education programs for fatigue in multiple sclerosis: Short- and medium-term benefits.

BACKGROUND: Fatigue occurs in 75%-95% of people with multiple sclerosis (MS) and is frequently reported as the most disabling symptom. A multicomponent group program of six weekly 2-hour sessions, Fatigue: Take Control (FTC), was developed from an international MS fatigue management guideline. OBJECTIVE: To determine whether FTC is associated with greater improvements in fatigue than MS: Take Control (MSTC), a similarly structured general MS education program. METHODS: This four-site, parallel, single-blind, randomized controlled trial compared FTC and MSTC in 204 ambulatory participants with MS. The primary outcome, the Modified Fatigue Impact Scale (MFIS), and secondary outcomes of self-efficacy, physical activity, sleep, and medications were assessed at baseline, program completion, and 3 and 6 months later. RESULTS: Mean MFIS scores improved in both groups between baseline and program completion (FTC -4.4, p < 0.001; MSTC -3.8, p < 0.001), between baseline and 3 months after program completion (FTC -3.2, p = 0.01; MSTC -3.3, p = 0.01), and between baseline and 6 months after program completion (FTC -5.2, p < 0.001; MSTC -4.8, p < 0.001). These improvements were not statistically different between groups ( p = 0.64, 0.92, and 0.82, respectively). CONCLUSION: Participation in FTC modestly improved self-reported fatigue for up to 6 months. This improvement did not differ significantly from that occurring with the control program.

Using the Anterior Visual System to Assess Neuroprotection and Remyelination in Multiple Sclerosis Trials.

PURPOSE OF REVIEW: Clinical trials using agents directed at neuroprotection and remyelination in multiple sclerosis (MS) are needed. As optic neuritis (ON) is common in people with MS and the pathology of ON is similar to other MS lesions in the brain, measurements of the anterior visual system are frequently utilized in neuroprotection and remyelination trials. Understanding the strengths and weaknesses of the measurements is vital when interpreting the results of this research. RECENT FINDINGS: Techniques such as visual evoked potentials (VEP) and optical coherence tomography (OCT) are well established in MS and are thought to measure axonal integrity and myelination. Novel imaging techniques can also be used in conjunction with these measurements to provide better insight into optic nerve structure and function. Magnetization transfer imaging (MTR) together with optic nerve area and volume measures neurodegeneration; diffusion tensor imaging (DTI) measures myelination status and neurodegeneration. However, these techniques require various levels of experience to interpret, and all can be confounded by ocular motion and surrounding fat and bone. This article provides a review of established and novel techniques to measure the anterior visual system in multiple sclerosis with a focus on the evidence to support their use as outcome measures in clinical trials focused on neuroprotection and remyelination therapies.

Sex-dependent treatment of chronic EAE with partial MHC class II constructs.

BACKGROUND: One of the main challenges in treating multiple sclerosis (MS) is reversing the effects of accumulated damage in the central nervous system (CNS) of progressive MS subjects. While most of the available drugs for MS subjects are anti-inflammatory and thus are limited to relapsing-remitting MS subjects, it is not clear to what extent their effects are capable of inducing axonal repair and remyelination in subjects with chronic MS. METHODS: A chronic model of experimental autoimmune encephalomyelitis (EAE) was used to evaluate the potency of partial MHC (pMHC) class II constructs in treating progressive EAE. RESULTS: We demonstrated an estrogen receptor alpha (ERα)-dependent increased dose requirement for effective treatment of female vs. male mice using pMHC. Such treatment using 100-µg doses of RTL342M or DRα1-mMOG-35-55 constructs significantly reversed clinical severity and showed a clear trend for inhibiting ongoing CNS damage, demyelination, and infiltration of inflammatory cells into the CNS in male mice. In contrast, WT female mice required larger 1-mg doses for effective treatment, although lower 100-µg doses were effective in ovariectomized or ERα-deficient mice with EAE. CONCLUSIONS: These findings will assist in the design of future clinical trials using pMHC for treatment of progressive MS.

Sleep and its associations with perceived and objective cognitive impairment in individuals with multiple sclerosis.

Problems with sleep and cognitive impairment are common among people with multiple sclerosis (MS). The present study examined the relationship between self-reported sleep and both objective and perceived cognitive impairment in MS. Data were obtained from the baseline assessment of a multi-centre intervention trial (NCT00841321). Participants were 121 individuals with MS. Nearly half (49%) of participants met the criteria for objective cognitive impairment; however, cognitively impaired and unimpaired participants did not differ on any self-reported sleep measures. Nearly two-thirds (65%) of participants met the criteria for 'poor' sleep, and poorer sleep was significantly associated with greater levels of perceived cognitive impairment. Moreover, the relationships between self-reported sleep and perceived cognitive impairment were significant beyond the influence of clinical and demographic factors known to influence sleep and cognitive functioning (e.g. age, sex, education level, disability severity, type of MS, disease duration, depression and fatigue). However, self-reported sleep was not associated with any measures of objective cognitive impairment. Among different types of perceived cognitive impairment, poor self-reported sleep was most commonly related to worse perceived executive function (e.g. planning/organization) and prospective memory. Results from the present study emphasize that self-reported sleep is significantly and independently related to perceived cognitive impairment in MS. In terms of clinical implications, interventions focused on improving sleep may help improve perceived cognitive function and quality of life in this population; however, the impact of improved sleep on objective cognitive function requires further investigation.

Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration.

Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.

Early Fever As a Predictor of Paroxysmal Sympathetic Hyperactivity in Traumatic Brain Injury.

OBJECTIVE: Paroxysmal sympathetic hyperactivity (PSH) is characterized by episodic, hyperadrenergic alterations in vital signs after traumatic brain injury (TBI). We sought to apply an objective scale to the vital sign alterations of PSH in order to determine whether 1 element might be predictive of developing PSH. SETTING/PARTICIPANTS/DESIGN: We conducted an observational study of consecutive TBI patients (Glasgow Coma Scale score ≤12) and monitored the cohort for clinical evidence of PSH. PSH was defined as a paroxysm of 3 or more of the following characteristics: (1) tachycardia, (2) tachypnea, (3) hypertension, (4) fever, (5) dystonia (rigidity or decerebrate posturing), and (6) diaphoresis, with no other obvious causation (ie, alcohol withdrawal, sepsis). MAIN MEASURES: The Modified Clinical Feature Severity Scale (mCFSS) was applied to each participant once daily for the first 5 days of hospitalization. RESULTS: Nineteen (11%) of the 167 patients met criteria for PSH. Patients with PSH had a higher 5-day cumulative mCFSS score than those without PSH (median [interquartile range] = 36 [29-42] vs 29 [22-35], P = .01). Of the 4 components of the mCFSS, elevated temperature appeared to be most predictive of the development of PSH, especially during the first 24 hours (odds ratio = 1.95; 95% confidence interval, 1.12-3.40). CONCLUSION: Early fever after TBI may signal impending autonomic dysfunction.

Dimethyl fumarate activates the prostaglandin EP2 receptor and stimulates cAMP signaling in human peripheral blood mononuclear cells.

Dimethyl fumarate (DMF) was recently approved by the FDA for the treatment of relapsing remitting MS. The pathology of MS is a result of both immune dysregulation and oxidative stress induced damage, and DMF is believed to have therapeutic effects on both of these processes. However, the mechanisms of action of DMF are not fully understood. To determine if DMF is able to activate signaling cascades that affect immune dysregulation, we treated human peripheral blood mononuclear cells with DMF. We discovered that DMF stimulates cyclic adenosine monophosphate (cAMP) production after 1 min treatment in vitro. cAMP is a small molecule second messenger that has been shown to modulate immune response. Using pharmacological inhibitors, we determined that adenylyl cyclase mediates DMF induced cAMP production; DMF activated the prostaglandin EP2 receptor to produce cAMP. This response was not due to increased endogenous production of prostaglandin E2 (PGE2), but was enhanced by addition of exogenous PGE2. Furthermore, we determined that the bioactive metabolite of DMF, monomethyl fumarate (MMF), also stimulates cAMP production. These novel findings suggest that DMF may provide protection against MS by inhibiting immune cell function via the cAMP signaling pathway.

Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging.

Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ(b)) and blood volume fraction (v(b); capillary density-volume product (ρ(†)V)) in a high-resolution (1)H2O MRI voxel (40 µL) or ROI. The equilibrium water extravasation rate constant, k(po) (τ(b)(-1)), averages 3.2 and 2.9 s(-1) in resting-state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k(po) differences are dominated by capillary water permeability (P(W)(†)), not size, differences. NWM and NGM voxel k(po) and v(b) values are independent. Quantitative analyses of concomitant population-averaged k(po), v(b) variations in normal and normal-appearing MS brain ROIs confirm P(W)(†) dominance. (B) P(W)(†) is dominated (>95%) by a trans(endothelial)cellular pathway, not the P(CA)(†) paracellular route. In MS lesions and GBM tumors, P(CA)(†) increases but P(W)(†) decreases. (C) k(po) tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k(po) correlates with literature MRSI ATP (positively) and Na(+) (negatively) tissue concentrations. This suggests that the P(W)(†) pathway is metabolically active. Excellent agreement of the relative NGM/NWM k(po)v(b) product ratio with the literature (31)PMRSI-MT CMR(oxphos) ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k(io)) is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form "gliovascular units." We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k(po), letting it report neurogliovascular unit Na(+),K(+)-ATPase activity. Cerebral k(po) maps represent metabolic (functional) neuroimages. The NGM 2.9 s(-1) k(po) means an equilibrium unidirectional water efflux of ~10(15) H2O molecules s(-1) per capillary (in 1 µL tissue): consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.

Cognitive Impairment and Community Integration Outcomes in Individuals Living With Multiple Sclerosis.

OBJECTIVES: To determine the association between unique domains of cognitive impairment and community integration in individuals with multiple sclerosis (MS), and to determine the contributions of cognitive impairment to community integration beyond the influence of demographic and clinical variables. DESIGN: Cross-sectional analysis of objective neuropsychological assessment and self-report data. Data were collected during baseline assessment of a randomized, multisite controlled trial of ginkgo biloba for cognitive impairment in MS. Hierarchical regression analyses examined the association between subjective and objective measures of cognitive impairment and 3 domains of community integration, adjusting for relevant covariates. SETTING: Two Veterans Affairs medical center MS clinics. PARTICIPANTS: Adults (N=121; ages 24-65y) with a confirmed MS diagnosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Primary outcomes were scores on the Home Integration (CIQ-H), Social Integration (CIQ-S), and Productivity (CIQ-P) domains of the Community Integration Questionnaire (CIQ). RESULTS: Cognitive impairment was associated with lower scores on the CIQ-H and CIQ-S, but not the CIQ-P. Greater levels of subjective cognitive impairment were associated with lower scores on the CIQ-H and CIQ-S. Greater levels of objective cognitive impairment, specifically slower processing speed and poorer inhibitory control, were related to lower CIQ-S scores. Subjective and objective measures of cognitive impairment were significantly and independently associated with CIQ-S. CONCLUSIONS: Objective cognitive impairment may interfere with participation in social activities. Subjective cognitive impairment is also important to assess, because individuals who perceive themselves to be cognitively impaired may be less likely to participate in both home and social activities. Clinical interventions to enhance community integration in individuals with MS may benefit from addressing objective and subjective cognitive impairment by integrating cognitive rehabilitation approaches with self-efficacy-enhancing strategies.

The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis.

Applying different technologies to monitor disease activity and treatment efficacy are essential in a complex disease such as multiple sclerosis. Combining current assays with flow cytometry could create a powerful tool for such analyses. The cell surface expression level of CD74, the MHC class II invariant chain, is a potential disease biomarker that could be monitored by FACS analysis in order to assess disease progression and the clinical efficacy of partial MHC class II constructs in treating MS. These constructs, which can bind to and down-regulate CD74 cell-surface expression on monocytes and inhibit macrophage migration inhibitory factor (MIF) effects, can reverse clinical and histological signs of EAE. These properties of partial class II constructs are highly compatible with a flow cytometry approach for monitoring CD74 expression as a possible biomarker for disease activity/progression and as a treatment response marker.