Background

Neuroglial cells are implicated in the pathobiology of Multiple sclerosis (MS). Müller glia, specialized radial glial cells of the retina responsible for helping maintain retinal neuronal integrity, are postulated to be activated in MS. Müller glia activation is also implicated in epiretinal membrane (ERM) formation, an aberrant healing response to retinal damage.

Objectives

To examine ERM prevalence in MS, and differences in expanded disability status scale (EDSS) and optical coherence tomography (OCT) measured retinal layer thicknesses, between MS patients with (ERM-MS) and without ERMs (non-ERM-MS).

Methods

In this cross-sectional study, 1463 MS patients (2926 eyes) underwent Cirrus spectral-domain OCT (with automated macular layer segmentation). All scans underwent qualitative and quantitative quality control (QC), and ERM presence was recorded. Excluding patients with optic neuritis history, ERM-MS (n=48) were matched 1:1 to non-ERM-MS based on age, body mass index (BMI) and sex. Fellow eye layer thicknesses of ERM-MS were compared to the average binocular layer thicknesses of non-ERM-MS patients, to investigate the possibility of a phenotype effect. Mixed effects linear regression models were used in analyses.

Results

ERM prevalence in this MS cohort was 4.9%. Post-matching mean age and BMI were respectively 60.7 years (SD 6.3) and 28.2 kg/m² (SD 9.6) in ERM-MS, and 60.4 years (SD 5.7) and 27.5 kg/m² (SD 8.9) in non-ERM-MS (p=0.7 for both). Both groups had 77.1% females. Median EDSS was 4 (IQR 2.5-6.5) in ERM-MS and 3 (IQR 1.5-6) in non-ERM-MS (difference: 1.1, CI: 0.2 – 1.9, p=0.021). Mean ganglion cell-inner plexiform layer (GCIPL) thickness was 67.1 um (SD 6.5) in ERM-MS and 70.2 um (SD 6.2) in non-ERM-MS (difference: -3.1, CI: -6.3 – -0.1, p=0.049). Moreover, mean retinal pigment epithelium (RPE) thickness was 31.6 um (SD 1.3) in ERM-MS and 32.4 um (SD 0.9) in non-ERM-MS (difference: -0.7 um, CI: -1.3 - -0.1, p=0.017).

Conclusions

Our findings suggest ERM-MS patients phenotypically have higher EDSS scores, and lower GCIPL and RPE thicknesses, as compared to non-ERM-MS patients. Blood-retinal barrier disruption due to retinal inflammation, among other reasons, may activate Müller glia in MS. This may help explain our finding that ERM presence in MS may be associated with disability. Moreover, RPE cells may be recruited in the ERM formation process, similarly explaining our finding of reduced RPE thickness among ERM-MS patients.

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.

Background

Oxidative stress is implicated in inflammation and neurodegeneration in multiple sclerosis (MS). Similar to the brain, the retina is susceptible to reactive oxygen species (ROS). Macular pigment (MP), consisting primarily of the carotenoids lutein (L) and zeaxanthin (Z) blocks deleterious blue light, and provides anti-oxidant protection. To date, there has been a paucity of study of MP in MS.

Objectives

To examine MP concentration and distribution in MS eyes relative to healthy control (HC) eyes using macular pigment optical density (MPOD) imaging.

Methods

In this cross-sectional study, 27 MS patients (47 eyes) and 19 HCs (37 eyes) underwent MPOD imaging on a Spectralis (Heidelberg) device. MP absorbs blue light, but allows the free passage of green light. MPOD imaging involves the subtraction of blue from green wavelength auto-fluorescence macular scans, providing the optical density (OD) of MP. Radii of interest for MPOD were 0°, 0.23°, 0.51°, 0.98° and 1.99° degrees of eccentricity from the fovea, as well as peak, and half-peak MPOD locations. Study participants completed dietary L & Z screening questionnaires. Mixed effects linear regression models were used in analyses.

Results

Mean MPOD at 0° was 0.52 density units (d.u.) (SD 0.14) in MS and 0.63 d.u. (SD 0.18) in HC eyes (difference: -0.10 d.u., CI: -0.18 - -0.01, p=0.027). The median MPOD peak location eccentricity was 0.08° (IQR: 0 - 0.12) in MS and 0.04° (IQR: 0 - 0.08) in HC eyes (difference: 0.10°, CI: 0.01 - 0.20, p=0.031). Mean MPOD at the peak location was -0.09 d.u. lower in MS eyes relative to HC eyes (CI: -0.18 - -0.01, p=0.04). In addition, the half-peak MPOD location, similar to the MPOD peak location, was situated further from the fovea in MS eyes relative to HC eyes (difference: 0.28°, CI: 0.10 - 0.47, p=0.002). Analyses adjusted for age, body mass index, sex, and L & Z dietary scores, showed similar differences for MPOD at 0° eccentricity, and at the peak MPOD location, between MS and HC eyes.

Conclusions

Our findings suggest MP concentrations are reduced in MS eyes, with peak and half-peak MPOD locations shifted further from the fovea than in HC eyes. Increases in ROS consuming antioxidant MPs, and/or dysfunction in proteins transferring carotenoids to the fovea, among other reasons, may help explain reductions in MPOD in MS eyes. Our preliminary finding warrant further study, in larger, prospective MS cohorts, including determination of their clinical relevance.

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO₂; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO₂ trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO₂: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO₂ was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO₂ was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

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

Neuro-performance testing has been used extensively in MS clinical trials, resulting in a large literature on processing speed (Symbol Digit Modalities Test [SDMT]), manual dexterity (9-Hole Peg Test [9HPT]), and walking speed (25-foot walk [25FW]). Computer adapted versions were developed and validated, to support widespread use in clinical practice. The Multiple Sclerosis Performance Test (MSPT) includes a self-administered Processing Speed Test (PST), simulating SDMT; Manual Dexterity Test (MDT), simulating 9HPT; and Walking Speed Test (WST), simulating 25FW. MSPT is deployed within the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network. Optimal test thresholds associated with employment status in a real-world population have not been reported.

Objectives

To determine thresholds for standardized test scores of processing speed, manual dexterity, and walking speed as predictors of employment status in a real world MS population.

Methods

Neuroperformance testing was done as part of clinical visits in MS PATHS. Employment status was collected via standardized questionnaire. Patients aged 18 to 60 in the US were divided into a training set (n=3210) and a test set (n=1605). PST, MDT and WST benchmarks predicting unemployment at baseline and employment worsening at 2 years were identified as the test scores with the minimum p-value in logistic regression models adjusting for age, sex and education. Odds ratios representing the risk of unemployment or employment worsening were calculated based on the identified benchmarks.

Results

4815 of 9585 participants (50%) were employed full-time at baseline. In the training set benchmarks for unemployment were: PST ≤44 correct, OR (95% CI) 5.3 (4.7, 6.0); MDT >28.7 seconds, OR 7.2 (6.3, 8.1); and WST >8 seconds, OR 6.7 (5.8, 7.7). For patients employed at baseline, benchmarks for worsening employment status were: PST ≤44 correct, OR 4.3 (3.1, 6.0); MDT >24 seconds, OR 3.3 (2.3, 4.6); and WST >7.6 seconds, OR 6.4 (4.7, 8.8). Benchmarks were confirmed in the validation set.

Conclusions

Clinically relevant neuroperformance test benchmarks for predicting unemployment and employment worsening were identified in a training set and confirmed in a validation set using a large real world MS population. Future research will determine early risk factors for these benchmarks in order to identify potential employment preservation strategies.

Disclosures: MS PATHS is sponsored by Biogen

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

Safety and effectiveness information for peginterferon beta-1a or intramuscular interferon (IM IFN) beta-1a in older patients (≥60 years [y]) with multiple sclerosis (MS) are limited. MS PATHS, an international network of MS centers, provides access to real-world (RW) data generated from a broad MS patient population.

Objectives

Evaluate the clinical outcomes of patients ≥60 y of age in MS PATHS treated with peginterferon beta-1a or IM IFN beta-1a.

Methods

Included patients were currently taking peginterferon beta-1a or IM IFN beta-1a or began taking either therapy at a follow-up visit, and had ≥1 follow-up clinical assessment as of November 2019. Assessments included Patient-Determined Disease Steps (PDDS), and Multiple Sclerosis Performance Test (MSPT) assessments, including Processing Speed Test (PST), Manual Dexterity Test (MDT), and Walking Speed Test (WST). Z-scores were based on normative data from 500 healthy volunteers.

Results

Analysis included 817 patients, of whom 218 (27%) were aged ≥60 y at baseline (BL). Follow-up times were similar for ≥60 y and <60 y patients (mean [SD] 1.35 [0.97] y and 1.27 [0.94] y, respectively). Older patients had higher BL PDDS score (mean [SD] 1.82 [2.14] vs 0.91 [1.48]) and higher rates of comorbidities including pain, cardiovascular, and dyslipidemia than younger patients. At BL, patients ≥60 y had significantly greater functional impairment than patients <60 y on MDT (Z-score mean [SD] -0.85 [1.79] vs -0.23 [1.56]) and WST (-1.66 [3.35] vs -0.52 [2.30]; both P<0.001), but not PST (-0.48 [1.00] vs. -0.37 [1.11]; P=0.197). Change from BL in PST, MDT or WST Z-scores at 6 months (mo), 1 y or 2 y was not significant for patients ≥60 y, whereas those <60 y showed significant improvement in PST at all 3 time points (mean change in Z-score 0.11–0.26; all P≤0.006) and in MDT at 1 and 2 y (mean change in Z-score 0.24 and 0.36; both P≤0.003). Approximately half of the ≥60-y and <60-y subgroups were relapse free at 6 mo (57% and 58%), 1 y (48% and 61%) and 2 y (49% and 60%).

Conclusions

In this RW study of patients with MS aged ≥60 or <60 y treated with peginterferon beta-1a or IM IFN beta-1a, younger patients had significantly improved PST and MDT ≥6 mo post-BL, and approximately equal proportions of patients in both age groups were relapse-free over 2 y. These results indicate that peginterferon beta-1a and IM IFN beta-1a may provide RW treatment benefits to patients with MS, including those aged 60 and above.

This study was supported by Biogen.

Background

Understanding patient-reported changes in physical, mental, and social health after starting MS therapy is important in optimizing treatment.

Objectives

Assess changes in the Quality of Life in Neurological Disorders (Neuro-QoL; NQ) questionnaire after starting natalizumab (NAT) and compare to another high efficacy therapy - ocrelizumab (OCR).

Methods

T-scores of 12 NQ domains were obtained at routine visits in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network. NQ scores from visits post NAT initiation were compared to last previous NQ (baseline, BL) to calculate the annualized rate of change and the likelihood of clinically meaningful change (≥5-point) in the overall cohort and in patients with abnormal BL NQ (T-score worse than 50; 36%-76% of the population). Subgroup analyses in NAT- and OCR-treated patients were conducted with multivariate mixed-effects regression models after propensity score weighting and adjustment for antidepressants, year and drug*year interaction.

Results

164 NAT patients were analyzed; mean (SD) follow-up was 6 (6) months and number of assessments was 2.3 (1.6). Significant improvements from pre-NAT BL were seen in 8 of 12 NQ domains. Patients with BL impairment had significant improvements in 10 NQ domains and higher rates of improvement compared to the overall cohort (p<0.05). In this subgroup, the largest number of patients with ≥5-point improvement was seen for positive affect and well-being (PAF) (43%), emotional and behavioral dyscontrol (EBD) (38%) and sleep disturbances (35%). In the subgroup of NAT (n=145)- and OCR (n=520)-treated patients, the annualized improvement rates were higher with NAT than with OCR, reaching statistical significance for PAF (p=0.02), sleep disturbances (p=0.003), and satisfaction with social roles and activities (SRA) (p=0.03). In patients with impaired BL NQ, significantly higher rates of improvement were seen with NAT than with OCR for EBD (p=0.01), participation in SRA (p=0.0001) and satisfaction with SRA (p=0.02). The percentage of patients with ≥5-point improvement was numerically higher with NAT than OCR for 9 of 12 NQ domains; differences in the likelihood of ≥5-point improvement were not significant.

Conclusions

NAT can lead to clinically meaningful improvements in mental and social health. Such improvements are unlikely to be primarily driven by expectation bias as their magnitude exceeded improvements with another high-efficacy therapy (OCR).

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.