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BACKGROUND: Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored. METHODS: Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period. RESULTS: NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power. CONCLUSIONS: In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination. TRIAL REGISTRATION NUMBER: NCT02040298.
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BACKGROUND: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS). OBJECTIVES: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD). METHODS: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS (n = 38, confirmatory cohort n = 43), NMOSD (n = 13) and healthy controls (n = 33). RESULTS: NFM was lower compared with controls in MS (B = -12.37, p < 0.001) and NMOSD (B = -34.5, p < 0.001). NFM was lower in ON than in non-ON eyes (B = -30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity (B = -139.4, p < 0.001/B = -77.2, p < 0.001) and low contrast letter acuity (B = 0.99, p = 0.002/B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer (B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer (B = 64.8, p < 0.001/B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer (B = 1.351, p < 0.001) and increased mfVEP P100 latencies (B = -1.159, p < 0.001). CONCLUSIONS: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.
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Percepção de Movimento , Esclerose Múltipla , Neuromielite Óptica , Neurite Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Vias Visuais/diagnóstico por imagemRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD. METHODS: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years. RESULTS: In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD. CONCLUSION: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.
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Biomarcadores/sangue , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Neuromielite Óptica/sangue , Adulto , Idoso , Autoanticorpos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de DoençaRESUMO
Myelitis is an acute or subacute inflammatory syndrome of the spinal cord. Myelopathy, often used as a synonym and presenting with similar symptoms in clinical practice, can be caused by numerous, not primarily inflammatory etiologies and might also show a progressive disease course. Within the last decade the spectrum of autoimmune myelitis was significantly broadened as was the spectrum of diagnostic methods. Apart from the characteristic example of multiple sclerosis with short-length myelitis and neuromyelitis optica spectrum disorders with longitudinally extensive transverse myelitis, multiple rare but important differential diagnoses should also be considered. Magnetic resonance imaging and laboratory analyses of serum antibodies and cerebrospinal fluid are the most important diagnostic methods and are fundamental for rapid treatment decisions, subsequently with better prognosis. This article reviews representative diseases within the spectrum of autoimmune spinal cord diseases and their differential diagnoses.
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Esclerose Múltipla , Mielite Transversa , Neuromielite Óptica , Doenças da Medula Espinal , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Mielite Transversa/diagnóstico , Neuromielite Óptica/diagnóstico , Medula Espinal , Doenças da Medula Espinal/diagnósticoRESUMO
BACKGROUND: Serum antibodies against myelin-oligodendrocyte-glycoprotein (MOG-IgG) are detectable in a proportion of patients with acute or relapsing neuroinflammation. It is unclear, if neuro-axonal damage occurs only in an attack-dependent manner or also progressively. Therefore, this study aimed to investigate longitudinally intra-retinal layer changes in eyes without new optic neuritis (ON) in MOG-IgG-seropositive patients. METHODS: We included 38 eyes of 24 patients without ON during follow-up (F/U) [median years (IQR)] 1.9 (1.0-2.2) and 56 eyes of 28 age- and sex-matched healthy controls (HC). The patient group's eyes included 18 eyes without (EyeON-) and 20 eyes with history of ON (EyeON+). Using spectral domain optical coherence tomography (OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIP), inner nuclear layer (INL), and macular volume (MV). High-contrast visual acuity (VA) was assessed at baseline. RESULTS: At baseline in EyeON-, pRNFL (94.3 ± 15.9 µm, p = 0.36), INL (0.26 ± 0.03 mm3, p = 0.11), and MV (2.34 ± 0.11 mm3, p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm3; p = 0.008), and VA was reduced (logMAR 0.05 ± 0.15 vs. - 0.09 ± 0.14, p = 0.008) in comparison to HC. Longitudinally, we observed pRNFL thinning in models including all patient eyes (annual reduction - 2.20 ± 4.29 µm vs. - 0.35 ± 1.17 µm, p = 0.009) in comparison to HC. Twelve EyeON- with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 EyeON- without other clinical relapses. CONCLUSIONS: We observed pRNFL thinning in patients with MOG-IgG during F/U, which was not accompanied by progressive GCIP reduction. This effect could be caused by a small number of EyeON- with other than ipsilateral ON attacks within 6 months before baseline. One possible interpretation could be a reduction of the swelling, which could mean that MOG-IgG patients show immune-related swelling in the CNS also outside of an attack's target area.
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Autoanticorpos/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/diagnóstico por imagem , Retina/diagnóstico por imagem , Adolescente , Adulto , Idoso , Criança , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neurite Óptica/sangue , Neurite Óptica/imunologia , Tomografia de Coerência Óptica , Adulto JovemRESUMO
OBJECTIVES: Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD. METHODS: Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (EyeON -) and 34 eyes with a history of ON prior to enrolment (EyeON+). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT). RESULTS: At baseline, GCIP, FT and TMV were reduced in EyeON+ (GCIP p<2e-16; FT p=3.7e-4; TMV p=3.7e-12) and in EyeON - (GCIP p=0.002; FT p=0.040; TMV p=6.1e-6) compared with HC. Longitudinally, we observed GCIP thinning in EyeON- (p=0.044) but not in EyeON+. Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003). CONCLUSION: This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation.
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Neuromielite Óptica/patologia , Células Ganglionares da Retina/patologia , Adolescente , Adulto , Idoso , Aquaporina 4/imunologia , Estudos de Casos e Controles , Contagem de Células/estatística & dados numéricos , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Neurite Óptica/patologia , Tomografia de Coerência Óptica , Adulto JovemAssuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Degeneração Retiniana , Atrofia/patologia , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Retina/diagnóstico por imagem , Retina/patologia , Degeneração Retiniana/diagnóstico por imagem , Degeneração Retiniana/patologiaRESUMO
BACKGROUND: Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. METHODS: Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. RESULTS: Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 µm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 µm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 µm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. CONCLUSIONS: Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.
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Aquaporina 4/imunologia , Imunoglobulina G/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica , Doenças Retinianas/etiologia , Adulto , Potenciais Evocados Visuais/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurite Óptica/sangue , Neurite Óptica/complicações , Neurite Óptica/imunologia , Estimulação Luminosa , Tempo de Reação/fisiologia , Retina/patologia , Estatísticas não Paramétricas , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Vias Visuais/patologia , Vias Visuais/fisiopatologiaRESUMO
Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.
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Progressão da Doença , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Retina , Degeneração Retiniana , Tomografia de Coerência Óptica , Humanos , Degeneração Retiniana/diagnóstico por imagem , Degeneração Retiniana/patologia , Masculino , Feminino , Tomografia de Coerência Óptica/métodos , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Retina/diagnóstico por imagem , Retina/patologia , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Prognóstico , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologiaRESUMO
While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.
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Esclerose Múltipla , Animais , Humanos , Esclerose Múltipla/patologia , Retina/patologia , Neurônios/patologia , Modelos Animais , Atrofia/patologiaRESUMO
BACKGROUND AND OBJECTIVES: To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement. METHODS: Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL). RESULTS: This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL (p < 0.001) and GCIPL (p = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL (p = 0.027) and GCIPL (p = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses. DISCUSSION: DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.
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Aquaporina 4 , Neuromielite Óptica , Tomografia de Coerência Óptica , Humanos , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/imunologia , Neuromielite Óptica/sangue , Feminino , Masculino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Aquaporina 4/imunologia , Estudos Retrospectivos , Autoanticorpos/sangue , Retina/diagnóstico por imagem , Retina/patologia , Retina/imunologiaRESUMO
OBJECTIVE: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). METHODS: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. RESULTS: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). INTERPRETATION: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.
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Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Exposure: Association between NfL z scores and CDW. Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.
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Avaliação da Deficiência , Esclerose Múltipla , Proteínas de Neurofilamentos , Adulto , Feminino , Humanos , Biomarcadores/sangue , Estudos de Coortes , Progressão da Doença , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla Recidivante-Remitente , Proteínas de Neurofilamentos/sangue , RecidivaRESUMO
BACKGROUND AND OBJECTIVES: Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. METHODS: To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. RESULTS: We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. DISCUSSION: We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies.
Assuntos
Vasos Retinianos , Tomografia de Coerência Óptica , Humanos , Consenso , Angiofluoresceinografia/métodos , Retina/diagnóstico por imagemRESUMO
Optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) regularly leads to more profound vision loss compared to multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody associated disease (MOGAD). Here we investigate ON-related vision loss in NMOSD compared to MS and MOGAD in order to identify neuroaxonal and retinal contributors to visual dysfunction. In this retrospective study we included patients with aquaporin-4-antibody seropositive NMOSD (n = 28), MOGAD (n = 14), MS (n = 29) and controls (n = 14). We assessed optic nerve damage and fovea morphometry by optical coherence tomography. Visual function was assessed as high (HCVA) and low contrast visual acuity (LCVA), and visual fields' mean deviation (MD). In all diseases, lower visual function was associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer (GCIP) thinning following a broken stick model, with pRNFL and GCIP cutoff point at ca. 60 µm. HCVA loss per µm pRNFL and GCIP thinning was stronger in NMOSD compared with MOGAD. Foveal inner rim volume contributed to MD and LCVA in NMOSD eyes, only. Together these data supports that visual dysfunction in NMOSD is associated with neuroaxonal damage beyond the effect seen in MS and MOGAD. A primary retinopathy, respectively Müller cell pathology, may contribute to this effect.
Assuntos
Aquaporinas , Esclerose Múltipla , Neuromielite Óptica , Neurite Óptica , Humanos , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Transtornos da Visão/complicações , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Glicoproteínas , Aquaporina 4RESUMO
BACKGROUND AND OBJECTIVES: The timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course. METHODS: We analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models. RESULTS: The rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years). DISCUSSION: An age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Doenças Neurodegenerativas , Adulto , Atrofia/patologia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Doenças Neurodegenerativas/patologia , Retina/diagnóstico por imagem , Retina/patologia , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: Aquaporin-4 immunoglobulin-G positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy associated with optic neuritis (ON). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an oligodendrocytopathy with a similar phenotype. Serum glial fibrillary acidic protein (sGFAP), an astrocyte-derived protein, is associated with disease severity in AQP4-IgG+ NMOSD. Serum neurofilament light (sNfL) indicates neuroaxonal damage. The objective was to investigate the association of sGFAP and sNfL with subclinical afferent visual system damage in clinically stable AQP4-IgG+ NMOSD and MOGAD patients. METHODS: In this cross-sectional study, clinically stable patients with AQP4-IgG+ NMOSD (N = 33) and MOGAD (N = 16), as diseased controls, underwent sGFAP and sNfL measurements by single molecule array, retinal optical coherence tomography and visually evoked potentials. RESULTS: Higher sGFAP concentrations were associated with thinner ganglion cell-inner plexiform layer (ß (95% confidence interval (CI)) = -0.75 (-1.23 to -0.27), p = 0.007) and shallower fovea (average pit depth: ß (95%CI) = -0.59 (-0.63 to -0.55), p = 0.020) in NMOSD non-ON eyes. Participants with pathological P100 latency had higher sGFAP (median [interquartile range]: 131.32 [81.10-179.34] vs. 89.50 [53.46-121.91] pg/ml, p = 0.024). In MOGAD, sGFAP was not associated with retinal structural or visual functional measures. CONCLUSIONS: The association of sGFAP with structural and functional markers of afferent visual system damage in absence of ON suggests that sGFAP may be a sensitive biomarker for chronic disease severity in clinically stable AQP4-IgG+ NMOSD.