Abstract

With the availability of nearly 20 medications approved for relapsing forms of multiple sclerosis (MS), there is growing pressure to better define how to select the most appropriate treatment for a given individual, particularly at the time of diagnosis. MS disease-modifying therapies differ in efficacy in reducing risks of relapse and lesions on brain magnetic resonance imaging (MRI) at the group level. However, these data can be hard to apply to an individual person with MS, who may have no further discernable MS activity after starting a specific therapy or may have dramatic breakthrough disease. Further, it is not entirely clear how different treatment approaches relate to longer-term disability risk. Randomized clinical trials have demonstrated short-term benefits of some specific higher-efficacy therapies with respect to disability outcomes compared to another, specific moderate-efficacy therapy, but these trials have not tested treatment strategies; in particular, escalation after ongoing MS activity is not typically allowed in such protocols. In the real world, people with MS who have breakthrough disease on a moderate-efficacy therapy often change medication, switching to a different moderate-efficacy medication or escalating to a higher-efficacy therapy. Some observational data suggest early use of higher-efficacy therapies may reduce longer-term risk of disability, but these studies were not able to account for confounding by indication or other biases.

To provide an overview of the state of knowledge surrounding the effects of various treatment strategies on longer-term MS outcomes.

In this session, we will review the literature that addresses treatment strategies in early MS, particularly assessing the impacts of using a more aggressive therapy as the first treatment versus adopting an escalation approach. We will also discuss two ongoing randomized trials, TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) and Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS), which seek to systematically determine if a given treatment strategy best prevents longer-term disability and brain atrophy.

There remains a large gap in knowledge regarding how specific treatment strategies during early MS in the real world optimally prevent, delay, or reduce intermediate- to longer-term disability accrual. The infectious risks and other complications associated particularly with higher-efficacy treatments are a major concern for people with MS and their clinicians, perhaps made even more clear during the COVID-19 pandemic.

It is critical to define if applying a specific treatment strategy across the board confers long-term benefits for functioning. Ongoing pragmatic randomized clinical trials will provide key information about the relative benefits and risks of various treatment strategies.

Background

Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis (MS); however, the evidence supporting their efficacy is sparse and conflicting.

Objectives

Our goal was to compare the efficacy of these three medications against each other and placebo in patients with MS-related fatigue.

Methods

In this randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, patients with MS fatigue received twice-daily oral amantadine, modafinil, methylphenidate, or placebo, each given for up to six weeks. The primary outcome measure was the Modified Fatigue Impact Scale (MFIS) measured while taking the highest tolerated dose. Secondary outcomes included measures of sleepiness, adverse events, and the maximal tolerated dose of each medication.

Results

A total of 141 patients were enrolled and randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the intent-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51.3 at baseline, 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P=0.20 for the overall medication effect). As compared to placebo (30.6%), higher proportions of participants reported adverse events while taking amantadine (38.6%), modafinil (40.0%), and methylphenidate (39.5%).

Conclusions

Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, and methylphenidate for the treatment of fatigue in MS. (ClinicalTrials.gov number, NCT03185065.)

Background

Prior studies have suggested that retinal neuro-axonal loss may occur in aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) in the absence of optic neuritis (ON), but data are conflicting.

Objectives

To examine whether patients with AQP4-IgG seropositive NMOSD exhibit progressive retinal neuro-axonal loss, independently of optic neuritis (ON) attacks.

Methods

In this single-center, longitudinal study, 32 AQP4-IgG+ NMOSD patients and 48 healthy controls (HC) were followed with serial spectral-domain optical coherence tomography (OCT). NMOSD patients with ON less than 6 months prior to baseline were excluded, while data from patients with ON during follow-up were censored at the last visit prior to ON. Rates of peri-papillary retinal nerve fiber layer (pRNFL) and macular ganglion cell+inner plexiform layer (GCIPL) thinning were compared between groups utilizing mixed-effects linear regression models adjusted for age, race and sex.

Results

Median follow-up duration was 4.3 years (IQR: 2.6 -7.5) for the NMOSD cohort and 4.0 years (IQR: 1.8 – 7.5) for the HC. We observed faster pRNFL (β=-0.25µm/year, 95%CI: -0.45 to -0.05, p=0.014) and GCIPL thinning (β=-0.09µm/year, 95%CI: -0.17 to 0, p=0.05) in NMOSD compared to HC eyes. This difference appeared to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared to HC (GCIPL: β=-0.15µm/year, 95%CI: -0.25 to -0.05, p=0.005; pRNFL: β=-0.43µm/year, 95%CI: -0.67 to -0.19, p<0.001), while rates of pRNFL (β=-0.07µm/year , 95%CI: -0.31 to 0.16, p=0.53) and GCIPL (β=-0.01µm/year, 95%CI: -0.11 to 0.10, p=0.90) thinning did not differ between NMOSD-ON and HC eyes .

Furthermore, we explored the effects of non-ON relapses during follow-up on rates of pRNFL and GCIPL thinning. Ten patients had relapses during follow-up (9 transverse myelitis, 1 area postrema syndrome). Patients with relapses did not exhibit differences in rates of GCIPL (β=0.05µm/year, 95%CI:-0.10 to 0.20, p=0.51) or pRNFL thinning (pRNFL: β=0.08µm/year, 95%CI: -0.28 to 0.43, p=0.67), compared to those who were clinically stable.

Conclusions

In this longitudinal study, we observed progressive pRNFL and GCIPL atrophy in AQP4-IgG+ NMOSD eyes unaffected by ON. These results support that subclinical involvement of the anterior visual pathway may occur in AQP4-IgG+ NMOSD.

Abstract

With the availability of nearly 20 medications approved for relapsing forms of multiple sclerosis (MS), there is growing pressure to better define how to select the most appropriate treatment for a given individual, particularly at the time of diagnosis. MS disease-modifying therapies differ in efficacy in reducing risks of relapse and lesions on brain magnetic resonance imaging (MRI) at the group level. However, these data can be hard to apply to an individual person with MS, who may have no further discernable MS activity after starting a specific therapy or may have dramatic breakthrough disease. Further, it is not entirely clear how different treatment approaches relate to longer-term disability risk. Randomized clinical trials have demonstrated short-term benefits of some specific higher-efficacy therapies with respect to disability outcomes compared to another, specific moderate-efficacy therapy, but these trials have not tested treatment strategies; in particular, escalation after ongoing MS activity is not typically allowed in such protocols. In the real world, people with MS who have breakthrough disease on a moderate-efficacy therapy often change medication, switching to a different moderate-efficacy medication or escalating to a higher-efficacy therapy. Some observational data suggest early use of higher-efficacy therapies may reduce longer-term risk of disability, but these studies were not able to account for confounding by indication or other biases.

To provide an overview of the state of knowledge surrounding the effects of various treatment strategies on longer-term MS outcomes.

In this session, we will review the literature that addresses treatment strategies in early MS, particularly assessing the impacts of using a more aggressive therapy as the first treatment versus adopting an escalation approach. We will also discuss two ongoing randomized trials, TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) and Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS), which seek to systematically determine if a given treatment strategy best prevents longer-term disability and brain atrophy.

There remains a large gap in knowledge regarding how specific treatment strategies during early MS in the real world optimally prevent, delay, or reduce intermediate- to longer-term disability accrual. The infectious risks and other complications associated particularly with higher-efficacy treatments are a major concern for people with MS and their clinicians, perhaps made even more clear during the COVID-19 pandemic.

It is critical to define if applying a specific treatment strategy across the board confers long-term benefits for functioning. Ongoing pragmatic randomized clinical trials will provide key information about the relative benefits and risks of various treatment strategies.

Abstract

With the availability of nearly 20 medications approved for relapsing forms of multiple sclerosis (MS), there is growing pressure to better define how to select the most appropriate treatment for a given individual, particularly at the time of diagnosis. MS disease-modifying therapies differ in efficacy in reducing risks of relapse and lesions on brain magnetic resonance imaging (MRI) at the group level. However, these data can be hard to apply to an individual person with MS, who may have no further discernable MS activity after starting a specific therapy or may have dramatic breakthrough disease. Further, it is not entirely clear how different treatment approaches relate to longer-term disability risk. Randomized clinical trials have demonstrated short-term benefits of some specific higher-efficacy therapies with respect to disability outcomes compared to another, specific moderate-efficacy therapy, but these trials have not tested treatment strategies; in particular, escalation after ongoing MS activity is not typically allowed in such protocols. In the real world, people with MS who have breakthrough disease on a moderate-efficacy therapy often change medication, switching to a different moderate-efficacy medication or escalating to a higher-efficacy therapy. Some observational data suggest early use of higher-efficacy therapies may reduce longer-term risk of disability, but these studies were not able to account for confounding by indication or other biases.

To provide an overview of the state of knowledge surrounding the effects of various treatment strategies on longer-term MS outcomes.

In this session, we will review the literature that addresses treatment strategies in early MS, particularly assessing the impacts of using a more aggressive therapy as the first treatment versus adopting an escalation approach. We will also discuss two ongoing randomized trials, TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) and Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS), which seek to systematically determine if a given treatment strategy best prevents longer-term disability and brain atrophy.

There remains a large gap in knowledge regarding how specific treatment strategies during early MS in the real world optimally prevent, delay, or reduce intermediate- to longer-term disability accrual. The infectious risks and other complications associated particularly with higher-efficacy treatments are a major concern for people with MS and their clinicians, perhaps made even more clear during the COVID-19 pandemic.

It is critical to define if applying a specific treatment strategy across the board confers long-term benefits for functioning. Ongoing pragmatic randomized clinical trials will provide key information about the relative benefits and risks of various treatment strategies.

Background

Dimethyl fumarate (DMF) treatment is associated with a decrease in serum neurofilament light chain (sNfL) in patients with relapsing-remitting multiple sclerosis (RRMS). sNfL is an exploratory biomarker of MS disease activity. Additional data describing the association between sNfL and disease activity are needed to further investigate this biomarker as a potential predictor of treatment response, which could enable a more holistic disease monitoring approach to treatment.

Objectives

To describe variation in sNfL levels with respect to clinical and radiological disease activity in DMF-treated patients.

Methods

DMF-treated patients with RRMS and complete 2Y follow-up data were analyzed. Serum samples were collected, and routine clinical and radiological assessments were conducted at baseline (BL) and at regular intervals. sNfL concentrations were measured by Single Molecule Array (SiMoA). Normative sNfL data from a cohort of 135 healthy adult controls (age range 21-82 years) were used as a comparator. Age-normative sNfL cutoffs were defined based on the 95^th percentile of sNfL levels.

Results

Forty-one patients with 2Y follow-up data were included. Mean (SD) age and disease duration were 37.5 (10.1) and 6.0 (6.5) years, respectively, with mean (SD) time on DMF treatment 43.8 (9.15) months. Twenty-nine (70.7%) patients were treated with a previous MS therapy. Nineteen (46.3%) and 22 (53.7%) patients were below and above age-normative sNfL level at BL, respectively. Over 2Y, mean (95% CI) sNfL level decreased from 8.5 (7.1, 10.2) to 3.4 (2.0, 4.0) pg/ml, representing a 36.6% annual decrease, and 60% decrease over 2Y. Patients experienced a 71.1% (95% CI: 38.8%, 86.3%) reduction in ARR from 1Y prior to BL (0.463, 95% CI [0.279, 0.724]) to 2Y (0.134 [0.067, 0.24]), and 75.6% (59.4%, 87.1%) patients were free of new T2 lesions at 2Y. sNfL was below age-normative level in 53.7% (37.6%, 69%) of patients at BL vs 97.6% (85.6%, 99.9%) at 2Y. Patients with sNfL below age-normative level at BL generally remained below this threshold. At 2Y, patients both above and below age-normative sNfL level at BL experienced low cumulative ARR (95% CI) of 0.132 (0.043, 0.307) and 0.136 (0.05, 0.297), respectively, representing reductions of 75% and 66.7%.

Conclusions

DMF-treated patients reached NfL levels approaching that of healthy controls over 2Y with a reduction in disease activity, regardless of sNfL level at BL in this real-world setting. These data support a correlation between reductions in sNfL levels and decreased disease activity over 2Y of treatment, and potential of sNfL as a biomarker of treatment response that could be assessed during treatment in addition to standard of care monitoring.

Supported by: Biogen.

Background

Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.

Objectives

To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.

Methods

We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.

Results

Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.

Conclusions

Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.

Background

Migraine headaches are common in people with multiple sclerosis (MS). Whether migraine has a role in MS course or symptom severity is poorly understood.

Objectives

To assess the association between a history of migraine, disability and neurological function in MS patients. Secondly, to evaluate the association between migraine and frequency of MS relapses, and to determine whether migraine co-occurs with other comorbid conditions in MS patients.

Methods

We conducted an observational study of MS patients who completed the MS Performance Test-based (MSPT) (iPad version of the MS Functional Composite) assessment of neurologic function and had a documented diagnosis of migraine in their electronic medical record. Other queried comorbidities included: diabetes, hypertension, dyslipidemia, history of myocardial infarction, sleep apnea, depression and anxiety. We evaluated the association between a positive history of migraines and MS outcomes, including disability (Patient Determined Disease Steps [PDDS]), annualized relapse rate, rate of brain lesion development on MRI, and objective neurological outcomes (walking speed, manual dexterity and processing speed) using generalized linear models adjusting for age, sex, race, employment status, insurance status, BMI and MS subtype/duration. We also tested whether the pre-specified comorbidities were overrepresented in MS-migraineurs vs. MS-non-migraineurs.

Results

We analyzed cross-sectional data from 2017 participants with MS, 336 of whom had one mention of migraine diagnosis in their chart in either the problem list or past medical history, who completed the MSPT. Relative to MS-non-migraineurs, MS-migraineurs tended to be younger (mean age 42.6y[11.7y] vs. 46.6y[12.6y]; p<0.001), and have a history of depression (46.52[7.64] vs 48.16[7.72]; p<0.001), anxiety (50.29[9.08] vs 52.81[8.76]; p<0.01) as measured by NeuroQoL scores, and obstructive sleep apnea (109 [6.5] vs 53[15.8]); p<0.001). MS-migraineurs were less likely to have severe disability (5.4% vs 12%, p<0.003), and did not show differences in objective neurological outcomes such as walking speed, manual dexterity or processing speed. There was similarly no significant difference in annualized relapse rate or rate of new brain lesion development in MS-migraineurs vs non-migraineurs.

Conclusions

Traditional migraine risk factors such as depression, anxiety as well as obstructive sleep apnea were overrepresented in our cohort of MS-migraineurs. A history of migraine was not associated with greater disability. Migraine may not be adequately captured in the electronic medical record when patients are presenting for MS related care. Evidence to date on this topic is conflicting and warrants future longitudinal studies.

Background

Background: Multiple sclerosis (MS) incidence in Hispanic Americans (HA) is increasing, highlighting the need to understand disease features and clinical course trends among this subpopulation.

Objectives

Objective: To compare demographic features and clinical characteristics of a large population of HA and non-Hispanic Caucasian Americans (NHCA) with MS.

Methods

Methods: MS PATHS is a network of MS Centers in the United States (n=7) and Europe (n=3) contributing standardized data acquired during routine care. US-based MS PATHS participants who self-reported as HA (irrespective of race) or as NHCA, and compared the groups according to demographic (sex, years of education, smoking status, BMI, employment, and insurance status), MS clinical (self-reported disability via Patient Determined Disease Steps [PDDS]), and neuro-performance (via the MS Performance Test (MSPT): walking, manual dexterity, and processing speed) features. Odds ratios and mean differences for PDDS and neuro-performance outcomes were adjusted for age, sex, disease duration and subtype, smoking status, BMI, insurance status, employment status, and years of education. Z-score is compared to a representative healthy population.

Results

Results: Compared to NHCA (n=9003), HA (n=609) had earlier MS symptom onset (mean 28.6y [SD:10.7y] vs 33.6y [11.3y]; p<0.001) and younger age at diagnosis (31.6y [10.9y] vs 36.6y [10.9y]; p<0.001). HA were more likely to have mild disability by the PDDS, compared to NHCA (OR 0.62, 95% CI [-0.89, -0.06], p=0.02). However, HA had worse performance on both manual dexterity times (z score: 0.31 [0.14, 0.47], p<0.001), and cognitive processing speed score (# correct: 0.37 [0.27-0.47], p<0.0001). 25-foot walking speed was not different between the groups (z score:0.09 [-0.23,0.41], p=0.56).

Conclusions

Conclusion: Using standardized data collection in this large MS sample, HA compared to NHCA patients were found to have younger age of onset and diagnosis and higher levels of cognitive and manual dexterity slowing. However, HA were less likely to rate themselves with severe disability on the PDDS. As the groups did not differ in walking speed, this may reflect the scale relatively weighting ambulation over other functions or other language/cultural differences.

Background

Psychiatric comorbidities are common in multiple sclerosis (MS) and are associated with diminished quality of life and non-adherence to disease-modifying therapy (DMT). Depression is linked to immune activation in inflammatory disorders. We hypothesized that persons with self-reported MS not receiving DMT and those on lower efficacy DMT (low [LED] and moderate [MED]) had more symptoms of anxiety, depression, and fatigue, as compared to those on DMT and on high efficacy DMT (HED).

Objectives

Our team sought to determine if symptoms of depression, anxiety, and fatigue in MS correlate with the use and efficacy of DMT.

Methods

We developed a web-based survey including the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7) scale, and the Modified Fatigue Impact Scale 5-item version (MFIS-5). Invitations to complete the survey were distributed electronically by MS organizations. DMTs were classified in LED (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, glatiramer acetate), MED (teriflunomide, fingolimod, siponimod, dimethyl fumarate), and HED (alemtuzumab, ocrelizumab, rituximab, natalizumab, cladribine). Analyses were conducted using linear models adjusted for age, sex, ethnicity, disease duration, employment status, and whether the individual has an MS provider.

Results

2121 persons completed the survey (age 51.1±12.4 years, 18% male, and 52% have had MS for >10 years). 1650 were on DMT (465 LED, 546 MED, 624 HED, 15 other). MFIS-5 and GAD-7 scores were lower for those on DMT as compared to those not on DMT (for MFIS-5: 0.79 points lower, 95% CI -1.37, -0.21; p=0.007; for GAD-7: 0.68 points lower; 95% CI -1.29, -0.07, p=0.03). Those on LED had -1.18 (95% CI -1.97, -0.38; p=0.004) lower PHQ-9 scores compared to those on no DMT. Among individuals on a DMT, those on HED had higher MFIS-5 and PHQ-9 scores relative to those on LED (for MFIS-5: 1.78 points higher, 95% CI 1.13, 2.24, p<0.001; for PHQ-9: 1.00 points higher; 95% CI 0.25, 1.74, p=0.009).

Conclusions

In this cross-sectional study, untreated patients had more fatigue and anxiety than those on DMT and greater depression than those on LED. LED-treated patients had lower fatigue and depression scores compared to those on HED. Indication biases may have influenced our results; longitudinal studies taking into account prior DMT history and indicators for specific DMTs should evaluate whether certain DMT classes affect future depression, anxiety, or fatigue levels.

Background

Vascular comorbidities like diabetes, hypertension and dyslipidemia are overrepresented in people with multiple sclerosis (MS) and may contribute to adverse MS outcomes. Existing studies evaluating vascular comorbidity and MS course were often limited by relatively small sample sizes or lack large-scale corresponding quantitative neuroimaging studies.

Objectives

To assess the association between vascular comorbidity burden with clinical and imaging features of disease severity in a large population of people with MS.

Methods

We included participants from the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if metabolic and vascular comorbidities (diabetes, hypertension and dyslipidemia) or a composite sum of vascular comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain MRI measurements, after adjusting for covariates using propensity score weighted models.

Results

11,506 participants (6409 [55%] with brain MRI) were included in the analysis. Participants were on average aged 48.9 years (standard deviation [SD]: 12.4 years), were 74% female, and were 24% non-white; 1881 (16.3%) individuals had 2+ comorbidities. Individuals with 2+ vascular comorbidities had slower walking speed (-0.49 SD times slower; 95% CI: -0.78 to -0.19; p=0.001), slower manual dexterity (-0.41 SD times slower; 95% CI: -0.57 to -0.26; p<0.0001), and fewer correct scores on cognitive processing speed (-0.11 SD lower scores; -0.20 to -0.02; p=0.03) relative to those with none of these comorbidities. Those with 2+ had lower brain parenchymal (-0.41%, 95% CI -0.64%, -0.17%; p=-0.0001) and gray matter fractions (-0.30%, 95% CI -0.49, -0.10; p=0.002), including reduced cortical (-10.10 mL, 95% CI -15.42, -4.78; p=0.0002) and deep (-0.44 mL, 95% CI -0.84, -0.04; p=0.03) gray matter volumes, when compared to those with no comorbidity. Comorbidity burden was not associated with T2 lesion volume. Individually, diabetes and dyslipidemia were generally associated with poorer neuroperformance and brain imaging outcomes.

Conclusions

Increased vascular comorbidity burden was associated with clinical and imaging markers of MS severity in this large study. Strategies to optimize comorbidity management in people with MS are warranted.

Background

Aquaporin-4-IgG (AQP4-IgG) seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD) typically presents with discrete attacks of optic neuritis (ON) and transverse myelitis, and insidious subclinical disease activity is considered a rare occurrence. Prior optical coherence tomography (OCT) studies have suggested that subclinical retinal abnormalities, including lower foveal thickness and altered foveal morphology, may be present in AQP4-IgG+ NMOSD in the absence of a clinical history of ON; however, existing studies were relatively small.

Objectives

To compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC).

Methods

In this single-center cross-sectional study, 83 AQP4-nonON and 153 HC eyes were studied with spectral-domain OCT. Statistical analyses were performed with generalized estimating equations (GEE) and were adjusted for age, sex and race.

Results

Total foveal thickness did not differ between AQP4-nonON and HC eyes (-3.55±3.79μm, p=0.35). AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01±2.03μm, p=0.049; IS: -0.32±0.14μm, p=0.029) and surrounding macula (ONL: -1.98±0.95μm, p=0.037; IS: -0.16±0.07μm, p=0.023), compared to HC. Macular retinal nerve fiber layer (mRNFL: -1.34±0.51μm, p=0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44±0.93μm, p=0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. The magnitude of the estimated differences was similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye (n=33 patients; mRNFL: -1.33±0.60μm, p=0.026; GCIPL: -2.59±1.12μm, p=0.021; macular ONL: -2.01±1.04μm, p=0.052; macular IS: -0.16±0.08μm, p=0.031; foveal ONL: -3.78±2.28μm, p=0.10; foveal IS: -0.28±0.19μm, p=0.14).

Conclusions

AQP4-nonON eyes exhibited evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These results remained largely unaltered in analyses limited to patients who had never experienced ON, suggesting that they are likely related to processes that are independent of clinically overt ON attacks. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD, and may relate to a primary retinal process or subclinical optic neuropathy.

Background

Designing data collection methods is a vital, yet challenging part of conducting multiple sclerosis (MS) clinical studies. Emerging technologies, such as wearable activity monitors (i.e. Accelerometers) and mobile applications (apps), provide innovative methods of objectively measuring MS patient outcomes. However, there is a gap in scientific knowledge about MS patients’ experiences with using these technologies in clinical research. This knowledge is imperative because patients’ perceptions of these technologies can affect adherence to study protocols. Research is needed to understand the feasibility of using these technologies for continuous long-term monitoring and data collection.

Objectives

To describe how persons living with MS perceived an accelerometer and diet-tracking app in a longitudinal clinical study and to apply this knowledge to the design and conduct of future clinical research.

Methods

This was a qualitative study nested in a larger observational study, which collected data using the Actigraph accelerometer and Calorie-Mama AI mobile app. Semi-structured qualitative interviews were conducted during final study visits (September 2018- March 2019), audio recorded, and transcribed verbatim. We continued interviewing participants until data saturation occurred. Qualitative data were analyzed using the constant comparative method. To further explore qualitative results, we did chi-squared tests to examine relationships between 1. age and successful diet tracking and 2. disability and interest in an MS self-management app.

Results

We interviewed 28 persons living with MS: 68% were female, mean age was 45.5 years, and median Expanded Disability Status Score (EDSS) was 2 (indicating low disability). Participants’ perceptions of the accelerometer were that it was “bulky” (n=21) and attracted unwanted attention (n=9), and that the band was uncomfortable (n=20). Participants (n=12) also mentioned they would have liked feedback from the device during or after the study. Despite stated issues, 93% of participants indicated they would use the device again in future studies. The mobile app was perceived as difficult to use to accurately track food (n=21) and time-consuming (n=10). As a result, half of participants did not correctly record their diet for the study. Younger age was associated with successful app use [X² (1, N=27)= 4.46, p=0.035]. Also, many persons living with MS were interested in an MS self-management app, and interest was associated with higher EDSS [X² (1, N=27)= 6.01, p=0.022].

Conclusions

Although participants had negative perceptions of the accelerometer, they were willing to use it for future studies, suggesting only minor design modifications may be needed. Mobile apps also should be easy to navigate and use, especially among older persons living with MS. A surprising finding was that MS mobile apps may be more appealing to younger persons living with MS who have greater disability.

Abstract

There are many considerations as to whether or not to focus one’s neurology career on conducting primary clinical research and clinical trials in multiple sclerosis (MS). While the milestones for earlier stages of training are relatively straightforward, identifying and prioritizing goals and steps towards them as an early faculty member is often more difficult.

To evaluate the pros and cons of a career in MS clinical research, to evaluate the typical elements of the career path, and to describe strategies to succeed.

This presentation will describe key elements of success in the early and middle stages of a career in MS clinical research.

There are several strategies one can employ to meet career milestones and overcome barriers, which will be discussed in detail during the presentation.

Developing a comprehensive understanding of the elements that require attention and development during a clinical research career provides for a successful and rewarding experience.

Abstract

There are many considerations as to whether or not to focus one’s neurology career on conducting primary clinical research and clinical trials in multiple sclerosis (MS). While the milestones for earlier stages of training are relatively straightforward, identifying and prioritizing goals and steps towards them as an early faculty member is often more difficult.

To evaluate the pros and cons of a career in MS clinical research, to evaluate the typical elements of the career path, and to describe strategies to succeed.

This presentation will describe key elements of success in the early and middle stages of a career in MS clinical research.

There are several strategies one can employ to meet career milestones and overcome barriers, which will be discussed in detail during the presentation.

Developing a comprehensive understanding of the elements that require attention and development during a clinical research career provides for a successful and rewarding experience.

Abstract

There are many considerations as to whether or not to focus one’s neurology career on conducting primary clinical research and clinical trials in multiple sclerosis (MS). While the milestones for earlier stages of training are relatively straightforward, identifying and prioritizing goals and steps towards them as an early faculty member is often more difficult.

To evaluate the pros and cons of a career in MS clinical research, to evaluate the typical elements of the career path, and to describe strategies to succeed.

This presentation will describe key elements of success in the early and middle stages of a career in MS clinical research.

There are several strategies one can employ to meet career milestones and overcome barriers, which will be discussed in detail during the presentation.

Developing a comprehensive understanding of the elements that require attention and development during a clinical research career provides for a successful and rewarding experience.