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.
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.
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 mm
) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm
, 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 mm
; 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.
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.
Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing inflammatory disorders of the central nervous system (CNS). Optic neuritis (ON) is the first NMOSD-related clinical event in 55% ...of the patients, which causes damage to the optic nerve and leads to visual impairment. Retinal optical coherence tomography (OCT) has emerged as a promising method for diagnosis of NMOSD and potential individual monitoring of disease course and severity. OCT not only detects damage to the afferent visual system caused by ON but potentially also NMOSD-specific intraretinal pathology, i.e. astrocytopathy. This article summarizes retinal involvement in NMOSD and reviews OCT methods that could be used now and in the future, for differential diagnosis, for monitoring of disease course, and in clinical trials.
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.
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.
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 75
age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG
NMOSD.
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.
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.
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 (Eye
) and 20 eyes with history of ON (Eye
). 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.
At baseline in Eye
, pRNFL (94.3 ± 15.9 μm, p = 0.36), INL (0.26 ± 0.03 mm
, p = 0.11), and MV (2.34 ± 0.11 mm
, p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm
; 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 Eye
with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 Eye
without other clinical relapses.
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 Eye
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.
Abstract 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.
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.
To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients ...without clinically overt visual symptoms or visual pathway lesions.
Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab-seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab-seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.
FT was reduced in both patients with NMOSD-LETM (
= 3.52e
) and NMOSD-ON (
= 1.24e
) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM (
= 0.046) and NMOSD-ON (
= 1.50e
) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.
Patients with AQP4-ab-seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.
Neuromyelitis optica spectrum disorders are rare relapsing inflammatory central nervous system diseases with a heterogenous immunological and clinical spectrum. International collaborations are ...required to: (i) reach a better understanding of the disease and its subtypes; (ii) develop laboratory and imaging biomarkers; and (iii) ultimately improve treatments.
Severe visual impairment is one of the major symptoms in neuromyelitis optica spectrum disorder (NMOSD), but functional network reorganization induced by the diminished sensory input has not been ...investigated thus far.
To examine adaptive visual network connectivity changes in NMOSD.
In this cross-sectional study, data were collected from May 1, 2013, through February 31, 2016, from 31 patients with aquaporin-4 antibody-positive NMOSD and 31 age- and sex-matched healthy control individuals at the Department of Neurology and NeuroCure Clinical Research Center at Charité-Universitätsmedizin Berlin, Berlin, Germany.
Visual function (high-contrast visual acuity and contrast sensitivity), optical coherence tomography (peripapillary retinal nerve fiber layer and ganglion cell layer thickness), and resting-state functional magnetic resonance imaging (functional connectivity of large-scale brain networks).
Thirty-one patients with NMOSD (mean SD age, 48.2 13.9 years; 28 women and 3 men) and 31 healthy controls (mean SD age, 47.2 15.3 years; 28 women and 3 men) participated in the study. Patients had a selective and pronounced increase of functional connectivity in the primary and secondary visual networks. Increased primary visual network connectivity correlated with reduced high-contrast visual acuity (r = -0.39, P = .006), reduced low-contrast sensitivity (r = -0.33, P = .03), and more severe retinal damage measured by optical coherence tomography (r = -0.4, P = .01). Furthermore, visual functional connectivity was significantly higher in patients with a history of optic neuritis compared with patients without optic neuritis (mean SD regression coefficients, 50.0 4.3 vs 34.6 5.6; P = .04).
Impaired visual function and retinal damage are associated with selective reorganization of the visual network in NMOSD. These findings advance the understanding of visual system dysfunction in NMOSD and, more generally, provide insight into pathophysiologic responses of the visual system to impaired visual input.
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