Publications by authors named "Elias S Sotirchos"

47 Publications

Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis.

Neurotherapeutics 2021 Jul 14. Epub 2021 Jul 14.

Department of Neurology, Johns Hopkins, Baltimore, MD, USA.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, gliosis, and neurodegeneration. While the currently available disease-modifying therapies effectively suppress the immune attack on the CNS, there are no therapies to date that directly mitigate neurodegeneration. Glucagon-like peptide-1 (GLP-1) is a small peptide hormone that maintains glucose homeostasis. A novel GLP-1 receptor (GLP-1R) agonist, NLY01, was recently shown to have neuroprotective effects in the animal models of Parkinson's disease and is now in a phase 2 clinical trial. In this study, we investigated the therapeutic potential of NLY01 in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our data show that NLY01 delays the onset and attenuates the severity of EAE in a prevention paradigm, when given before disease onset. NLY01 inhibits the activation of immune cells in the spleen and reduces their trafficking into the CNS. In addition, we show that NLY01 suppresses the production of chemokines that are involved in leukocyte recruitment to the site of inflammation. The anti-inflammatory effect of NLY01 at the early stage of EAE may block the expression of the genes associated with neurotoxic astrocytes in the optic nerves, thereby preventing retinal ganglion cell (RGC) loss in the progressive stage of EAE. In the therapeutic paradigm, NLY01 significantly decreases the clinical score and second attack in a model of relapsing-remitting EAE. GLP-1R agonists may have dual efficacy in MS by suppressing peripheral and CNS inflammation, thereby limiting neuronal loss.
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http://dx.doi.org/10.1007/s13311-021-01088-5DOI Listing
July 2021

Optic Neuritis-Independent Retinal Atrophy in Neuromyelitis Optica Spectrum Disorder.

J Neuroophthalmol 2021 May 17. Epub 2021 May 17.

Department of Neurology (AGF, ESV, KCF, GK, JL, MAM, EMM, SS, PAC, ESS), Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Electrical and Computer Engineering (YH, YL, JLP), Johns Hopkins University, Baltimore, Maryland; Viela Bio (MAM), Gaithersburg, Maryland; and Department of Neurology (ML), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: A limited number of studies have investigated the presence of ongoing disease activity independent of clinical relapses in neuromyelitis optica spectrum disorder (NMOSD), and data are conflicting. The objective of our study was to examine whether patients with aquaporin-4 (AQP4)-IgG seropositive NMOSD exhibit progressive retinal neuroaxonal 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 and visual acuity (VA) assessments. NMOSD patients with ON less than 6 months before baseline were excluded, whereas data from patients with ON during follow-up were censored at the last visit before ON. VA worsening was defined as a decrease in monocular letter acuity ≥5 letters for high-contrast VA and ≥7 letters for low-contrast VA. Analyses were performed with mixed-effects linear regression models adjusted for age, sex, and race.

Results: The median follow-up duration was 4.2 years (interquartile range: 1.8-7.5). Relative to HC, NMOSD eyes had faster peripapillary retinal nerve fiber layer (pRNFL) (β = -0.25 µm/year faster, 95% confidence interval [CI]: -0.45 to -0.05, P = 0.014) and GCIPL thinning (β = -0.09 µm/year faster, 95% CI: -0.17 to 0, P = 0.05). This difference seemed to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared with HC (GCIPL: β = -0.15 µm/year faster; P = 0.005; pRNFL: β = -0.43 µm/year faster, P < 0.001), whereas rates of pRNFL (β: -0.07 µm/year, P = 0.53) and GCIPL (β = -0.01 µm/year, P = 0.90) thinning did not differ between NMOSD-ON and HC eyes. Nine NMOSD eyes had VA worsening during follow-up.

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.
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http://dx.doi.org/10.1097/WNO.0000000000001282DOI Listing
May 2021

Risk Factors For Infection And Health Impacts Of The Covid-19 Pandemic In People With Autoimmune Diseases.

Clin Infect Dis 2021 May 6. Epub 2021 May 6.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health.

Results: 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income.

Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1093/cid/ciab407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135997PMC
May 2021

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis.

Neurology 2021 05 7;96(20):e2525-e2533. Epub 2021 Apr 7.

From the Department of Neurology (J.L., H.R., A.G.F., O.C.M., E.S.S., H.E., E.O., N.P., B.T., N.J.L., S.D., N.F., O.K., P.A.C., K.C.F., S.S.), Johns Hopkins University School of Medicine; and Department of Electrical and Computer Engineering (J.L.P.), Johns Hopkins University, Baltimore, MD.

Objective: To investigate the effects of rituximab on retinal atrophy in patients with relapsing-remitting multiple sclerosis (RRMS), we performed serial optical coherence tomography (OCT) scans among a cohort of patients with RRMS on rituximab and compared rates of ganglion cell + inner plexiform layer (GCIPL) atrophy to those observed among age- and sex-matched glatiramer acetate (GA)-and natalizumab-treated patients with RRMS and healthy controls (HCs).

Methods: In this observational study, patients with RRMS treated with a single disease-modifying therapy and HCs were followed with serial OCT for a median duration of 2.8 years. Participants with uncontrolled hypertension, diabetes mellitus, or glaucoma, and eyes with optic neuritis ≤6 months prior to baseline OCT, or during follow-up, were excluded. Statistical analyses were performed using linear mixed-effects regression.

Results: During the overall follow-up period, rates of GCIPL atrophy were -0.28 ± 0.11 µm/y among rituximab-treated patients with RRMS (n = 35). This was similar to GA-treated (n = 49; -0.33 ± 0.05 µm/y; = 0.69) and natalizumab-treated patients (n = 88; -0.17 ± 0.10 µm/y; = 0.13) and faster than HCs (n = 78; -0.15 ± 0.03 µm/y; = 0.006). Rituximab-treated patients exhibited 0.55 ± 0.23 µm/y faster rates of GCIPL atrophy during the first 12 months of treatment, relative to afterwards (n = 25; = 0.02), during which period GCIPL atrophy rates were -0.14 ± 0.13 µm/y.

Conclusions: Retinal atrophy in RRMS is modulated by rituximab. Greater attenuation of retinal atrophy may occur after 12 months of rituximab treatment, following which time GCIPL atrophy rates are similar to those observed among natalizumab-treated patients with RRMS and HCs. Our findings raise the possibility that the neuroprotective therapeutic response with rituximab in RRMS may take up to 12 months, which should be confirmed by larger studies.

Classification Of Evidence: This study provides Class IV evidence on the difference in rate of change of the GCIPL thickness in patients with RRMS comparing rituximab to other disease-modifying therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205480PMC
May 2021

Association of Spectral-Domain OCT With Long-term Disability Worsening in Multiple Sclerosis.

Neurology 2021 04 2;96(16):e2058-e2069. Epub 2021 Mar 2.

From the Department of Neurology (J.L., K.C.F., O.C.M., A.G.F., E.S.S., G.K., E.V., N.P., E.O., B.T., N.J.L., S.D., N.F., O.K., H.R., S.D.N., E.M.M., S.S., P.A.C.), Johns Hopkins University School of Medicine; and Departments of Biostatistics (C.M.C.) and Electrical and Computer Engineering (J.L.P.), Johns Hopkins University, Baltimore, MD.

Objective: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.

Methods: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0.

Results: A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio [OR] 3.97, 95% confidence interval [CI] 1.24-12.70; = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13; = 0.04).

Conclusions: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS.

Classification Of Evidence: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.
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http://dx.doi.org/10.1212/WNL.0000000000011788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166450PMC
April 2021

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care.

Design: Longitudinal registry study.

Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins.

Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare.

Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption.

Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported.

Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1101/2021.02.03.21251069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872366PMC
February 2021

Optical Coherence Tomography and Optical Coherence Tomography Angiography Findings After Optic Neuritis in Multiple Sclerosis.

Front Neurol 2020 15;11:618879. Epub 2020 Dec 15.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, United States.

In people with multiple sclerosis (MS), optic neuritis (ON) results in inner retinal layer thinning, and reduced density of the retinal microvasculature. To compare inter-eye differences (IEDs) in macular optical coherence tomography (OCT) and OCT angiography (OCTA) measures in MS patients with a history of unilateral ON (MS ON) vs. MS patients with no history of ON (MS non-ON), and to assess how these measures correlate with visual function outcomes after ON. In this cross-sectional study, people with MS underwent OCT and OCTA. Superficial vascular plexus (SVP) density of each eye was quantified using a deep neural network. IEDs were calculated with respect to the ON eye in MS ON patients, and with respect to the right eye in MS non-ON patients. Statistical analyses used mixed-effect regression models accounting for intra-subject correlations. We included 43 MS ON patients (with 92 discrete OCT/OCTA visits) and 14 MS non-ON patients (with 24 OCT/OCTA visits). Across the cohorts, mean IED in SVP density was -2.69% (SD 3.23) in MS ON patients, as compared to 0.17% (SD 2.39) in MS non-ON patients ( = 0.002). When the MS ON patients were further stratified according to time from ON and compared to MS non-ON patients with multiple cross-sectional analyses, we identified that IED in SVP density was significantly increased in MS ON patients at 1-3 years ( = < 0.001) and >3 years post-ON ( < 0.001), but not at <3 months ( = 0.21) or 3-12 months post-ON ( = 0.07), while IED in ganglion cell + inner plexiform layer (GCIPL) thickness was significantly increased in MS ON patients at all time points post-ON ( ≦ 0.01 for all). IED in SVP density and IED in GCIPL thickness demonstrated significant relationships with IEDs in 100% contrast, 2.5% contrast, and 1.25% contrast letter acuity in MS ON patients ( < 0.001 for all). Our findings suggest that increased IED in SVP density can be detected after ON in MS using OCTA, and detectable changes in SVP density after ON may occur after changes in GCIPL thickness. IED in SVP density and IED in GCIPL thickness correlate well with visual function outcomes in MS ON patients.
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http://dx.doi.org/10.3389/fneur.2020.618879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769949PMC
December 2020

Serum ceramide levels are altered in multiple sclerosis.

Mult Scler 2020 Dec 14:1352458520971816. Epub 2020 Dec 14.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Sphingolipids are myelin components and inflammatory signaling intermediates. Sphingolipid metabolism may be altered in people with multiple sclerosis (PwMS), but existing studies are limited by small sample sizes.

Objectives: To compare the levels of serum ceramides between PwMS and healthy controls (HCs) and to determine whether ceramide levels correlate with disability status, as well as optical coherence tomography (OCT)-derived rates of retinal layer atrophy.

Methods: We performed targeted lipidomics analyses for 45 ceramides in PwMS ( = 251) and HCs ( = 68). For a subset of PwMS, baseline and 5-year Expanded Disability Status Scale (EDSS) assessments ( = 185), or baseline and serial spectral-domain OCT ( = 180) were assessed.

Results: Several ceramides, including hexosylceramides, lactosylceramides, and dihydroceramides, were altered in PwMS compared with HCs. Higher levels of Cer16:0 were associated with higher odds of EDSS worsening at 5 years in univariable (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 1.41-10.43) and multivariable analyses accounting for age, sex, and race (OR = 2.97, 95% CI = 1.03-8.59). Each 1 ng/mL higher concentration of Hex-Cer22:0 and DH-HexCer22:0 was associated with accelerated rates (μm/year) of ganglion cell + inner plexiform layer (-0.138 ± 0.053,  = 0.01; -0.158 ± 0.053,  = 0.003, respectively) and peripapillary retinal nerve fiber layer thinning (-0.305 ± 0.107,  = 0.004; -0.358 ± 0.106,  = 0.001, respectively).

Conclusion: Ceramide levels are altered in PwMS and may be associated with retinal neurodegeneration and physical disability.
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http://dx.doi.org/10.1177/1352458520971816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200368PMC
December 2020

Evidence of subclinical quantitative retinal layer abnormalities in AQP4-IgG seropositive NMOSD.

Mult Scler 2020 Dec 14:1352458520977771. Epub 2020 Dec 14.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Prior studies have suggested that subclinical retinal abnormalities may be present in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD), in the absence of a clinical history of optic neuritis (ON).

Objective: Our aim was 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 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT).

Results: Total foveal thickness did not differ between AQP4-nonON and HC eyes. AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01 ± 2.03 μm,  = 0.049; IS: -0.32 ± 0.14 μm,  = 0.029) and surrounding macula (ONL: -1.98 ± 0.95 μm,  = 0.037; IS: -0.16 ± 0.07 μm,  = 0.023), compared to HC. Macular retinal nerve fiber layer (RNFL: -1.34 ± 0.51 μm,  = 0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44 ± 0.93 μm,  = 0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. Results were similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye.

Conclusions: AQP4-nonON eyes exhibit evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD.
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http://dx.doi.org/10.1177/1352458520977771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200372PMC
December 2020

AQP4-IgG and MOG-IgG Related Optic Neuritis-Prevalence, Optical Coherence Tomography Findings, and Visual Outcomes: A Systematic Review and Meta-Analysis.

Front Neurol 2020 8;11:540156. Epub 2020 Oct 8.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Optic neuritis (ON) is a cardinal manifestation of multiple sclerosis (MS), aquaporin-4 (AQP4)-IgG-, and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. However, the prevalence of AQP4-IgG seropositivity and MOG-IgG seropositivity in isolated ON is unclear, and studies comparing visual outcomes and optical coherence tomography (OCT)-derived structural retinal measures between MS-ON, AQP4-ON, and MOG-ON eyes are limited by small sample sizes. (1) To assess the prevalence of AQP4-IgG and MOG-IgG seropositivity among patients presenting with isolated ON; (2) to compare visual outcomes and OCT measures between AQP4-ON, MOG-ON, and MS-ON eyes. In this systematic review and meta-analysis, a total of 65 eligible studies were identified by PubMed search. Statistical analyses were performed with random effects models. In adults with isolated ON, AQP4-IgG seroprevalence was 4% in non-Asian and 27% in Asian populations, whereas MOG-IgG seroprevalence was 8 and 20%, respectively. In children, AQP4-IgG seroprevalence was 0.4% in non-Asian and 15% in Asian populations, whereas MOG-IgG seroprevalence was 47 and 31%, respectively. AQP4-ON eyes had lower peri-papillary retinal nerve fiber layer (pRNFL; -11.7 μm, 95% CI: -15.2 to -8.3 μm) and macular ganglion cell + inner plexiform layer (GCIPL; -9.0 μm, 95% CI: -12.5 to -5.4 μm) thicknesses compared with MS-ON eyes. Similarly, pRNFL (-11.2 μm, 95% CI: -21.5 to -0.9 μm) and GCIPL (-6.1 μm, 95% CI: -10.8 to -1.3 μm) thicknesses were lower in MOG-ON compared to MS-ON eyes, but did not differ between AQP4-ON and MOG-ON eyes (pRNFL: -1.9 μm, 95% CI: -9.1 to 5.4 μm; GCIPL: -2.6 μm, 95% CI: -8.9 to 3.8 μm). Visual outcomes were worse in AQP4-ON compared to both MOG-ON (mean logMAR difference: 0.60, 95% CI: 0.39 to 0.81) and MS-ON eyes (mean logMAR difference: 0.68, 95% CI: 0.40 to 0.96) but were similar in MOG-ON and MS-ON eyes (mean logMAR difference: 0.04, 95% CI: -0.05 to 0.14). AQP4-IgG- and MOG-IgG-associated disease are important diagnostic considerations in adults presenting with isolated ON, especially in Asian populations. Furthermore, MOG-IgG seroprevalence is especially high in pediatric isolated ON, in both non-Asian and Asian populations. Despite a similar severity of GCIPL and pRNFL thinning in AQP4-ON and MOG-ON, AQP4-ON is associated with markedly worse visual outcomes.
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http://dx.doi.org/10.3389/fneur.2020.540156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578376PMC
October 2020

Reply to "Retinal INL Thickness in Multiple Sclerosis: A Mere Marker of Neurodegeneration?"

Ann Neurol 2021 01 29;89(1):193-194. Epub 2020 Oct 29.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1002/ana.25936DOI Listing
January 2021

MOGAD: How It Differs From and Resembles Other Neuroinflammatory Disorders.

AJR Am J Roentgenol 2021 04 17;216(4):1031-1039. Epub 2021 Feb 17.

Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University Medical Institution, 600 N Wolfe St, Phipps B112D, Baltimore, MD 21287.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct CNS inflammatory disease with symptoms and imaging findings that overlap other neuroinflammatory disorders. We highlight the imaging characteristics of MOGAD and contrast them with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Intracranial features that suggest MOGAD include childhood acute disseminated encephalomyelitis pattern with diffuse signal abnormality in the cortical gray matter, subcortical white matter, deep white matter, and deep gray matter on T2-weighted and FLAIR images; few bilateral T2-hyperintense fluffy and poorly demarcated lesions; pontine or thalamic involvement (or both); and cerebellar peduncle lesions in children. Intraorbitally, one sees edematous, enlarged, tortuous optic nerve or nerves; bilateral long-segment T2 hyperintensity of anterior segments of the optic nerve; sparing of the optic chiasm and retrochiasmatic pathways; and perioptic nerve sheath and surrounding orbital fat enhancement. Spinal involvement is seen as longitudinally extensive transverse myelitis with a sagittal T2-hyperintense intramedullary spinal line, the axial "H" spinal cord sign (central cord gray matter T2 hyperintensity), and conus medullaris involvement. Early accurate diagnosis of MOGAD is important because prognosis and treatment differ from those for NMOSD and MS.
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http://dx.doi.org/10.2214/AJR.20.24061DOI Listing
April 2021

Association of body mass index with longitudinal rates of retinal atrophy in multiple sclerosis.

Mult Scler 2020 06 16;26(7):843-854. Epub 2020 Apr 16.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Studies evaluating associations between body mass index (BMI) and optical coherence tomography (OCT) measures in multiple sclerosis (MS) are lacking.

Objective: To assess whether elevated BMI is associated with accelerated retinal atrophy.

Methods: In this observational study, 513 MS patients were followed with serial spectral-domain OCT for a median of 4.4 years. Participants were categorized as normal weight (BMI: 18.5-24.9 kg/m), overweight (BMI: 25-29.9 kg/m), and obese (BMI: ⩾30 kg/m). Participants with diabetes mellitus or uncontrolled hypertension and eyes with optic neuritis (ON) ⩽6 months prior to baseline OCT or during follow-up were excluded. Statistical analyses were performed with mixed-effects linear regression.

Results: Obese patients ( = 146) exhibited accelerated rates of ganglion cell + inner plexiform layer (GCIPL) atrophy relative to normal weight patients ( = 214; -0.57%/year (95% confidence interval (CI): -0.65% to -0.48%) versus -0.42%/year (95% CI: -0.49% to -0.35%);  = 0.012). GCIPL atrophy rate did not differ between overweight ( = 153) and normal weight patients (-0.47%/year vs -0.42%/year;  = 0.41). Each 1 kg/m higher BMI was associated with accelerated GCIPL (-0.011%/year; 95% CI: -0.019% to -0.004%;  = 0.003) atrophy. Multivariable analyses accounting for age, sex, race, MS subtype, and ON history did not alter the above findings.

Conclusions: Elevated BMI, in the absence of overt metabolic comorbidities, may be associated with accelerated GCIPL atrophy. Obesity, a modifiable risk factor, may be associated with accelerated neurodegeneration in MS.
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http://dx.doi.org/10.1177/1352458519900942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293552PMC
June 2020

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy.

Ann Neurol 2020 06 28;87(6):885-896. Epub 2020 Apr 28.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS).

Methods: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years.

Results: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (-0.34 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:-0.09 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS.

Interpretation: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes. ANN NEUROL 2020;87:885-896.
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http://dx.doi.org/10.1002/ana.25738DOI Listing
June 2020

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation.

J Clin Invest 2020 07;130(7):3467-3482

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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http://dx.doi.org/10.1172/JCI129401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324171PMC
July 2020

Aquaporin-4 IgG seropositivity is associated with worse visual outcomes after optic neuritis than MOG-IgG seropositivity and multiple sclerosis, independent of macular ganglion cell layer thinning.

Mult Scler 2020 10 31;26(11):1360-1371. Epub 2019 Jul 31.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Comparative studies of characteristics of optic neuritis (ON) associated with myelin oligodendrocyte glycoprotein-IgG (MOG-ON) and aquaporin-4-IgG (AQP4-ON) seropositivity are limited.

Objective: To compare visual and optical coherence tomography (OCT) measures following AQP4-ON, MOG-ON, and multiple sclerosis associated ON (MS-ON).

Methods: In this cross-sectional study, 48 AQP4-ON, 16 MOG-ON, 40 MS-ON, and 31 healthy control participants underwent monocular letter-acuity assessment and spectral-domain OCT. Eyes with a history of ON >3 months prior to evaluation were analyzed.

Results: AQP4-ON eyes exhibited worse high-contrast letter acuity (HCLA) compared to MOG-ON (-22.3 ± 3.9 letters;  < 0.001) and MS-ON eyes (-21.7 ± 4.0 letters;  < 0.001). Macular ganglion cell + inner plexiform layer (GCIPL) thickness was lower, as compared to MS-ON, in AQP4-ON (-9.1 ± 2.0 µm;  < 0.001) and MOG-ON (-7.6 ± 2.2 µm;  = 0.001) eyes. Lower GCIPL thickness was associated with worse HCLA in AQP4-ON (-16.5 ± 1.5 letters per 10 µm decrease;  < 0.001) and MS-ON eyes (-8.5 ± 2.3 letters per 10 µm decrease;  < 0.001), but not in MOG-ON eyes (-5.2 ± 3.8 letters per 10 µm decrease;  = 0.17), and these relationships differed between the AQP4-ON and other ON groups ( < 0.01 for interaction).

Conclusion: AQP4-IgG seropositivity is associated with worse visual outcomes after ON compared with MOG-ON and MS-ON, even with similar severity of macular GCIPL thinning.
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http://dx.doi.org/10.1177/1352458519864928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992495PMC
October 2020

DeepHarmony: A deep learning approach to contrast harmonization across scanner changes.

Magn Reson Imaging 2019 12 10;64:160-170. Epub 2019 Jul 10.

Department of Electrical and Computer Engineering, The Johns Hopkins University, 105 Barton Hall, 3400 N. Charles St., Baltimore, MD 21218, USA; Department of Computer Science, The Johns Hopkins University, Baltimore, MD, USA; Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Magnetic resonance imaging (MRI) is a flexible medical imaging modality that often lacks reproducibility between protocols and scanners. It has been shown that even when care is taken to standardize acquisitions, any changes in hardware, software, or protocol design can lead to differences in quantitative results. This greatly impacts the quantitative utility of MRI in multi-site or long-term studies, where consistency is often valued over image quality. We propose a method of contrast harmonization, called DeepHarmony, which uses a U-Net-based deep learning architecture to produce images with consistent contrast. To provide training data, a small overlap cohort (n = 8) was scanned using two different protocols. Images harmonized with DeepHarmony showed significant improvement in consistency of volume quantification between scanning protocols. A longitudinal MRI dataset of patients with multiple sclerosis was also used to evaluate the effect of a protocol change on atrophy calculations in a clinical research setting. The results show that atrophy calculations were substantially and significantly affected by protocol change, whereas such changes have a less significant effect and substantially reduced overall difference when using DeepHarmony. This establishes that DeepHarmony can be used with an overlap cohort to reduce inconsistencies in segmentation caused by changes in scanner protocol, allowing for modernization of hardware and protocol design in long-term studies without invalidating previously acquired data.
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http://dx.doi.org/10.1016/j.mri.2019.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874910PMC
December 2019

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures.

Mult Scler 2020 06 16;26(7):815-828. Epub 2019 May 16.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.

Background: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes.

Objective: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability.

Methods: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol.

Results: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes,  < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes ( < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes,  = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS):  = 0.26,  = 0.004; multiple sclerosis functional composite (MSFC):  = 0.27,  = 0.03) and lower letter acuity scores (100% contrast:  = 0.29; 2.5% contrast:  = 0.40; 1.25% contrast:  = 0.31;  < 0.001 for all).

Conclusions: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.
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http://dx.doi.org/10.1177/1352458519845116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858526PMC
June 2020

Retinal measurements predict 10-year disability in multiple sclerosis.

Ann Clin Transl Neurol 2019 02 19;6(2):222-232. Epub 2019 Jan 19.

Department of Neurology Johns Hopkins University Baltimore Maryland.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later.

Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing ( = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status.

Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39;  = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models.

Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.
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http://dx.doi.org/10.1002/acn3.674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389740PMC
February 2019

Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis.

Mult Scler 2020 03 11;26(3):312-321. Epub 2019 Feb 11.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The effects of disease-modifying therapies (DMTs) on region-specific brain atrophy in multiple sclerosis (MS) are unclear.

Objective: To determine the effects of higher versus lower efficacy DMTs on rates of brain substructure atrophy in MS.

Methods: A non-randomized, observational cohort of people with MS followed with annual brain magnetic resonance imaging (MRI) was evaluated retrospectively. Whole brain, subcortical gray matter (GM), cortical GM, and cerebral white matter (WM) volume fractions were obtained. DMTs were categorized as higher (DMT-H: natalizumab and rituximab) or lower (DMT-L: interferon-beta and glatiramer acetate) efficacy. Follow-up epochs were analyzed if participants had been on a DMT for ⩾6 months prior to baseline and had at least one follow-up MRI while on DMTs in the same category.

Results: A total of 86 DMT epochs (DMT-H:  = 32; DMT-L:  = 54) from 78 participants fulfilled the study inclusion criteria. Mean follow-up was 2.4 years. Annualized rates of thalamic (-0.15% vs -0.81%;  = 0.001) and putaminal (-0.27% vs -0.73%;  = 0.001) atrophy were slower during DMT-H compared to DMT-L epochs. These results remained significant in multivariate analyses including demographics, clinical characteristics, and T2 lesion volume.

Conclusion: DMT-H treatment may be associated with slower rates of subcortical GM atrophy, especially of the thalamus and putamen. Thalamic and putaminal volumes are promising imaging biomarkers in MS.
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http://dx.doi.org/10.1177/1352458519826364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689465PMC
March 2020

Reporting of R2 Statistics for Mixed-Effects Regression Models.

JAMA Neurol 2019 04;76(4):507

Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jamaneurol.2018.4720DOI Listing
April 2019

Spinal cord and infratentorial lesions in radiologically isolated syndrome are associated with decreased retinal ganglion cell/inner plexiform layer thickness.

Mult Scler 2019 12 3;25(14):1878-1887. Epub 2018 Dec 3.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The role of retinal imaging with optical coherence tomography (OCT) in assessing individuals with radiologically isolated syndrome (RIS) remains largely unexplored.

Objective: To assess retinal layer thicknesses in RIS and examine their associations with clinical features suggestive of increased risk for conversion to multiple sclerosis (MS).

Methods: A total of 30 RIS subjects and 60 age- and sex-matched healthy controls (HC) underwent retinal imaging with spectral-domain OCT, followed by automated segmentation of retinal layers.

Results: Overall, retinal layer thicknesses did not differ between RIS and HC. However, RIS subjects with spinal cord (SC) lesions had lower ganglion cell + inner plexiform layer (GCIP) thickness compared to HC (-4.41 μm;  = 0.007) and RIS without SC lesions (-3.53 μm;  = 0.041). Similarly, RIS subjects with infratentorial (IT) brain lesions had lower GCIP thickness compared to HC (-4.07 μm;  < 0.001) and RIS without IT lesions (-3.49 μm;  = 0.029). Multivariate analyses revealed that the presence of SC or IT lesions were independently associated with lower GCIP thickness in RIS ( = 0.04 and  = 0.03, respectively). Other patient characteristics, including sex, abnormal cerebrospinal fluid, and presence of gadolinium-enhancing or juxtacortical lesions, were not associated with retinal layer thicknesses.

Conclusion: The presence of SC or IT lesions in RIS may be associated with retinal neuro-axonal loss, supporting the presence of more disseminated disease.
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http://dx.doi.org/10.1177/1352458518815597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546560PMC
December 2019

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.

Brain 2018 11;141(11):3115-3129

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awy245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202573PMC
November 2018

OCT is an alternative to MRI for monitoring MS - YES.

Mult Scler 2018 05 19;24(6):701-703. Epub 2018 Mar 19.

Johns Hopkins Hospital and Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1177/1352458517753722DOI Listing
May 2018

Characteristics of morphologic macular abnormalities in neuroimmunology practice.

Mult Scler 2019 03 10;25(3):361-371. Epub 2017 Nov 10.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Morphologic macular abnormalities (MMAs) are frequently seen on macular optical coherence tomography (OCT) imaging in neuroimmunology practice, yet studies pragmatically assessing prevalence and risk factors of MMAs to date are limited.

Objective: To describe the characteristics of MMAs in a neuroimmunology-based academic practice.

Methods: Cross-sectional study of 1450 patients (2900 eyes) who underwent spectral-domain macular OCT between June 2010 and June 2012. The association between MMAs and demographic variables was analyzed using mixed-effects logistic regression. Odds ratios (ORs) were calculated per 5-year age increments.

Results: MMAs were observed in 338/2872 eyes (11.7%) of 232/1445 participants (16.1%). The most common abnormalities identified, included drusen (6.0%), epiretinal membrane (ERM; 5.5%), and microcystoid macular pathology (MMP; 1.9%). Overall, patients with MMAs were older (OR: 1.79, p = 5 × 10) and more likely to be males (OR: 2.45, p = 0.014). In particular, advancing age was associated with higher risk of drusen and ERM (OR: 1.80 and 4.26, p = 2 × 10 and 7 × 10, respectively). MMP prevalence declined with age (OR: 0.73, p = 0.015) and was associated with African-American ethnicity (OR: 15.0, p = 5 × 10).

Conclusion: Unexpected or incidental MMAs are common in patients assessed with OCT in neuroimmunology practice, emphasizing the importance of comprehensive OCT image review for risk stratification and appropriate ophthalmology referral.
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http://dx.doi.org/10.1177/1352458517741206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929206PMC
March 2019

JC virus granule cell neuronopathy onset two months after chemotherapy for low-grade lymphoma.

Cerebellum Ataxias 2017 23;4. Epub 2017 Jun 23.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA.

Background: Granule cell neuronopathy (GCN) is a rare disease caused by the JC virus, leading to degeneration of cerebellar granule cell neurons. Primarily described in patients with AIDS, it has also been diagnosed in patients with lymphoproliferative diseases and after long-term treatment with immune-suppressing medications such as natalizumab.

Case Presentation: A 69 year old woman presented with progressive ataxia which began 2 months after initiation of treatment for follicular low-grade B cell lymphoma with rituximab/bendamustine, and progressed for 2 years prior to admission. Extensive prior evaluation included MRI that showed atrophy of the cerebellum but normal CSF analysis and serum studies. Neurologic exam on admission was notable for severe appendicular ataxia and fatigable end-gaze direction-changing horizontal nystagmus. FDG-PET/CT scan was unremarkable and repeat lumbar puncture revealed 2 WBCs/mm, 148 RBCs/mm, glucose 70 mg/dL, protein 37.7 mg/dL and negative flow cytometry/cytopathology. Standard CSF JC virus PCR testing was negative, but ultrasensitive TaqMan real-time JC virus PCR testing was positive, consistent with JC virus-related GCN.

Conclusions: Because of the diagnostic challenges in identifying GCN, a high threshold of suspicion should be maintained in patients with an immune-suppressing condition such as lymphoma or on immune-suppressing agents such as rituximab, even shortly after initiation of therapy.
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http://dx.doi.org/10.1186/s40673-017-0066-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481904PMC
June 2017

Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis.

Neurology 2016 Jan 30;86(4):382-90. Epub 2015 Dec 30.

From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.

Objective: To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS).

Methods: In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months.

Results: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17(+)CD4(+) T cells (p = 0.016), CD161(+)CD4(+) T cells (p = 0.03), and effector memory CD4(+) T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4(+) T cells (p = 0.018) and naive CD4(+) T cells (p = 0.04). These effects were not observed in the low-dose group.

Conclusions: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4(+) T cells and decreased proportion of effector memory CD4(+) T cells with concomitant increase in central memory CD4(+) T cells and naive CD4(+) T cells.

Classification Of Evidence: This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.
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http://dx.doi.org/10.1212/WNL.0000000000002316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776090PMC
January 2016
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