Retinal small vessel pathology is associated with disease burden in multiple sclerosis.

BACKGROUND: Alterations of the superficial retinal vasculature are commonly observed in multiple sclerosis (MS) and can be visualized through optical coherence tomography angiography (OCTA). OBJECTIVES: This study aimed to examine changes in the retinal vasculature during MS and to integrate findings into current concepts of the underlying pathology. METHODS: In this cross-sectional study, including 259 relapsing-remitting MS patients and 78 healthy controls, we analyzed OCTAs using deep-learning-based segmentation algorithm tools. RESULTS: We identified a loss of small-sized vessels (diameter < 10 µm) in the superficial vascular complex in all MS eyes, irrespective of their optic neuritis (ON) history. This alteration was associated with MS disease burden and appears independent of retinal ganglion cell loss. In contrast, an observed reduction of medium-sized vessels (diameter 10-20 µm) was specific to eyes with a history of ON and was closely linked to ganglion cell atrophy. CONCLUSION: These findings suggest distinct atrophy patterns in retinal vessels in patients with MS. Further studies are necessary to investigate retinal vessel alterations and their underlying pathology in MS.

Optical coherence tomography angiography suggests different retinal pathologies in multiple sclerosis and Sjögren's syndrome.

BACKGROUND: While retinal vessel changes are evident in the eyes of patients with relapsing-remitting multiple sclerosis (RRMS), changes in the vasculature of possible MS mimics such as primary Sjögren's syndrome (pSS) remain to be determined. We investigated the potential of retinal optical coherence tomography (OCT) angiography (OCTA) as diagnostic tool to differentiate between patients with RRMS and pSS. METHODS: This cross-sectional study included patients with RRMS (n = 36), pSS (n = 36) and healthy controls (n = 30). Participants underwent clinical examination, assessment of visual acuity, retinal OCT, OCTA, and serum markers of glial and neuronal damage. We investigated the associations between OCTA parameters, visual functions, and serum markers. Eyes with a history of optic neuritis (ON) were excluded from analysis. RESULTS: We observed a significant thinning of the combined ganglion cell and inner plexiform layer in the eyes of patients with RRMS but not with pSS, when compared to healthy controls. Retinal vessel densities of the superficial vascular complex (SVC) were reduced in both patients with RRMS and pSS. However, retinal vessel rarefication of the deep vascular complex (DVC) was only evident in patients with pSS but not RRMS. Using multivariate regression analysis, we found that DVC vessel loss in pSS patients was associated with worse visual acuity. CONCLUSIONS: Compared to patients with RRMS, rarefication of deep retinal vessels is a unique characteristic of pSS and associated with worse visual function. Assuming a disease-specific retinal vessel pathology, these data are indicative of a differential affliction of the gliovascular complex in the retina of RRMS and pSS patients.

Association of retinal vessel pathology and brain atrophy in relapsing-remitting multiple sclerosis.

Background: Optical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS. Material and methods: This study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded. Results: We included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex. Discussion: ON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS.

All eyes on PCS: analysis of the retinal microvasculature in patients with post-COVID syndrome-study protocol of a 1 year prospective case-control study.

Since widespread vaccination against COVID-19, the development of effective antiviral drugs, and the decreasing number of patients with COVID-19 in intensive care, the risk from SARS-CoV-2 infection appears less threatening. However, studies show that a significant number of patients suffer from long-term sequelae, even months after SARS-CoV-2 infection. The so-called post-COVID syndrome (PCS) often presents a diagnostic and treatment challenge for physicians. This study protocol describes the "All Eyes on PCS" study, which aims to investigate the retinal microvasculature in PCS patients and COVID-19-recovered patients to provide new insights into the pathophysiology of PCS. "All Eyes on PCS" is a prospective, case-control study with the primary objective of detecting endothelial dysfunction (ED) in patients with PCS. Therefore, we intend to recruit patients with PCS, fully SARS-CoV-2-infection-recovered (CR) participants, and SARS-CoV-2-infection-naïve (CN) participants. Baseline measurements will include: (1) patient-specific characteristics, (2) biochemistry, (3) retinal vessel analysis (RVA), (4) survey questionnaires as patient-reported outcomes measurements (PROMs), (5) optical coherence tomography (OCT), OCT angiography (OCTA), and adaptive optics (AO), (6) blood pressure recordings, (7) handgrip strength test. After 6 months, baseline measurements will be repeated in the PCS cohort, and after 1 year, a telephone query will be conducted to assess residual symptoms and treatment needs. The aim of this study is to gain insight into the pathophysiology of PCS and to provide an objective biomarker for diagnosis and treatment, while also creating a comprehensive clinical database of PCS patients.ClinicalTrials.gov Identifier: NCT05635552; Date: 2.12.2022.

The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography.

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.

Retinal ganglion cell loss is associated with future disability worsening in early relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Thinning of the retinal combined ganglion cell and inner plexiform layer (GCIP) as measured by optical coherence tomography (OCT) is a common finding in patients with multiple sclerosis. This study aimed to investigate whether a single retinal OCT analysis allows prediction of future disease activity after a first demyelinating event. METHODS: This observational cohort study included 201 patients with recently diagnosed clinically isolated syndrome or relapsing-remitting multiple sclerosis from two German tertiary referral centers. Individuals underwent neurological examination, magnetic resonance imaging, and OCT at baseline and at yearly follow-up visits. RESULTS: Patients were included at a median disease duration of 2.0 months. During a median follow-up of 59 (interquartile range = 43-71) months, 82% of patients had ongoing disease activity as demonstrated by failing the no evidence of disease activity 3 (NEDA-3) criteria, and 19% presented with confirmed disability worsening. A GCIP threshold of ≤77 µm at baseline identified patients with a high risk for NEDA-3 failure (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1-2.8, p = 0.04), and GCIP measures of ≤69 µm predicted disability worsening (HR = 2.2, 95% CI = 1.2-4.3, p = 0.01). Higher rates of annualized GCIP loss increased the risk for disability worsening (HR = 2.5 per 1 µm/year increase of GCIP loss, p = 0.03). CONCLUSIONS: Ganglion cell thickness as measured by OCT after the initial manifestation of multiple sclerosis may allow early risk stratification as to future disease activity and progression.

Progressive Multifocal Leukoencephalopathy Treated by Immune Checkpoint Inhibitors.

OBJECTIVE: Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML). METHODS: We conducted a multicenter survey compiling retrospective data from 79 PML patients, including 38 published cases and 41 unpublished cases, who received immune checkpoint inhibitors as add-on to standard of care. One-year follow-up data were analyzed to determine clinical outcomes and safety profile. Logistic regression was used to identify variables associated with 1-year survival. RESULTS: Predisposing conditions included hematological malignancy (n = 38, 48.1%), primary immunodeficiency (n = 14, 17.7%), human immunodeficiency virus/acquired immunodeficiency syndrome (n = 12, 15.2%), inflammatory disease (n = 8, 10.1%), neoplasm (n = 5, 6.3%), and transplantation (n = 2, 2.5%). Pembrolizumab was most commonly used (n = 53, 67.1%). One-year survival was 51.9% (41/79). PML-immune reconstitution inflammatory syndrome (IRIS) was reported in 15 of 79 patients (19%). Pretreatment expression of programmed cell death-1 on circulating T cells did not differ between survivors and nonsurvivors. Development of contrast enhancement on follow-up magnetic resonance imaging at least once during follow-up (OR = 3.16, 95% confidence interval = 1.20-8.72, p = 0.02) was associated with 1-year survival. Cerebrospinal fluid JC polyomavirus DNA load decreased significantly by 1-month follow-up in survivors compared to nonsurvivors (p < 0.0001). Thirty-two adverse events occurred among 24 of 79 patients (30.4%), and led to treatment discontinuation in 7 of 24 patients (29.1%). INTERPRETATION: In this noncontrolled retrospective study of patients with PML who were treated with immune checkpoint inhibitors, mortality remains high. Development of inflammatory features or overt PML-IRIS was commonly observed. This study highlights that use of immune checkpoint inhibitors should be strictly personalized toward characteristics of the individual PML patient. ANN NEUROL 2023;93:257-270.

Peripapillary hyper-reflective ovoid mass-like structures (PHOMS) in AQP4-IgG-positive neuromyelitis optica spectrum disease (NMOSD) and MOG-IgG-associated disease (MOGAD).

BACKGROUND: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) have recently been described as new optical coherence tomography (OCT) marker. It is not yet clear whether the occurrence of PHOMS is disease-specific or disease-spanning. PHOMS have been described in 16-18% of patients with multiple sclerosis (MS). Currently, no data on the prevalence of PHOMS in other demyelinating diseases including aquaporine-4-IgG-positive neuromyelitis optica spectrum disease (AQP4 + NMOSD) or myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) are reported. METHODS: We performed a cross-sectional, retrospective spectral domain OCT study evaluating the frequency of PHOMS in AQP4 + NMOSD (n = 47) and MOGAD (n = 44) patients. To test the association with retinal neuroaxonal damage, we compared demographic and clinical data as well as retinal layer thicknesses between eyes with vs. eyes without PHOMS. RESULTS: PHOMS were detected in 17% of AQP4 + NMOSD and 14% of MOGAD patients. Intra-cohort analysis revealed that AQP4 + NMOSD patients with PHOMS were significantly older [mean (years): 57.5 vs. 50.0; p value = 0.04]. We found no association of PHOMS with retinal neuroaxonal degeneration. In addition, in subjects with only one eye affected by PHOMS compared with the unaffected fellow eye, no differences in retinal parameters were observed (n = 4). CONCLUSIONS: In summary, we found PHOMS in 17% of AQP4 + NMOSD and 14% of MOGAD patients. This is comparable to the prevalence of published MS PHOMS data. Therefore, a disease-specific occurrence of PHOMS is unlikely. Interestingly, PHOMS do not seem to depend on retinal neuroaxonal degeneration.

Association of the retinal vasculature, intrathecal immunity, and disability in multiple sclerosis.

Background: Optical coherence tomography angiography (OCT-A) is a novel technique allowing non-invasive assessment of the retinal vasculature. During relapsing remitting multiple sclerosis (RRMS), retinal vessel loss occurs in eyes suffering from acute optic neuritis and recent data suggest that retinal vessel loss might also be evident in non-affected eyes. We investigated whether alterations of the retinal vasculature are linked to the intrathecal immunity and whether they allow prognostication of the future disease course. Material and methods: This study includes two different patient cohorts recruited at a tertiary German academic multiple sclerosis center between 2018 and 2020 and a cohort of 40 healthy controls. A total of 90 patients with RRMS undergoing lumbar puncture and OCT-A analysis were enrolled into a cross-sectional cohort study to search for associations between the retinal vasculature and the intrathecal immune compartment. We recruited another 86 RRMS patients into a prospective observational cohort study who underwent clinical examination, OCT-A and cerebral magnetic resonance imaging at baseline and during annual follow-up visits to clarify whether alterations of the retinal vessels are linked to RRMS disease activity. Eyes with a history of optic neuritis were excluded from the analysis. Results: Rarefication of the superficial vascular complex occured during RRMS and was linked to higher frequencies of activated B cells and higher levels of the pro-inflammatory cytokines interferon-γ, tumor necrosis factor α and interleukin-17 in the cerebrospinal fluid. During a median follow-up of 23 (interquartile range 14 - 25) months, vessel loss within the superficial (hazard ratio [HR] 1.6 for a 1%-point decrease in vessel density, p=0.01) and deep vascular complex (HR 1.6 for a 1%-point decrease, p=0.05) was associated with future disability worsening. Discussion: Optic neuritis independent rarefication of the retinal vasculature might be linked to neuroinflammatory processes during RRMS and might predict a worse disease course. Thus, OCT-A might be a novel biomarker to monitor disease activity and predict future disability.

Dynamics of Retinal Vessel Loss After Acute Optic Neuritis in Patients With Relapsing Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Rarefication of the retinal vasculature as measured by optical coherence tomography angiography (OCT-A) is a novel finding in patients with multiple sclerosis (MS). This study aimed to analyze longitudinal dynamics of the retinal vasculature following an acute inflammatory relapse including acute optic neuritis (ON) and to search for associations with alterations of the retinal architecture and visual function. METHODS: This prospective longitudinal cohort study included patients with relapsing-remitting MS or clinically isolated syndrome having an acute ON (n = 20) or a non-ON relapse (n = 33). Patients underwent examinations at baseline and after 7, 14, 28, 90, and 180 days with OCT, OCT-A, and assessment of the high- (HCVA) and low-contrast visual acuity (LCVA). RESULTS: Retinal vessel loss of the superficial vascular complex (SVC) evolves early after ON and reaches a plateau between 90 and 180 days (relative vessel loss 15% ± 8% [mean ± SD]). In addition, an 18% ± 18% intraindividual increase of the foveal avascular zone (FAZ) is evident within 180 days after acute ON. Both SVC thinning and FAZ enlargement were associated with worse HCVA and LCVA. Rarefication of the SVC evolved simultaneously to thinning of the common ganglion cell and inner plexiform layer (GCIP) after ON. No alterations of the deep vascular complex were seen in eyes with ON, and no alterations of the retinal vasculature were recognized in patients having acute non-ON relapses. DISCUSSION: Rarefication of the SVC and growing of the FAZ evolve rapidly after ON and are linked to persistent visual disability. ON-related SVC thinning might be closely linked to GCIP atrophy and might occur due to an altered local metabolic activity within inner retinal layers.

RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development.

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Association of peripapillary hyper-reflective ovoid masslike structures and disease duration in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Peripapillary hyper-reflective ovoid masslike structures (PHOMS) are a novel finding during retinal optical coherence tomography in patients with multiple sclerosis (MS). To date, there are no data on the occurrence of PHOMS in early MS. The aim of this study was to investigate the frequency of PHOMS in patients with first diagnosed early relapsing-remitting MS (RRMS) and to search for associations of PHOMS with disease patterns in different MS subtypes. METHODS: This was a cross-sectional analysis in two different cohorts: cohort 1, consisting of early RRMS patients (n = 349); cohort 2, consisting of patients with primary progressive MS (PPMS) (n = 66) and RRMS (n = 65). RESULTS: Peripapillary hyper-reflective ovoid masslike structures were detected in 18.3% of patients with early RRMS. The occurrence of PHOMS was not associated with age, disease duration and disability. Investigating clinical patterns and the occurrence of PHOMS (cohort 2), an association of PHOMS with higher Expanded Disability Status Scale measures (PHOMS 4.9, 3.7-6.1; no PHOMS 3.5, 3.0-5.3; p = 0.03) and longer disease durations (PHOMS 6.5 years, 1.9-11.0; no PHOMS 1.0 years, 0.0-4.0, p = 0.0007) was found in patients with PPMS but not RRMS. After p value adjustment, the disease duration appeared to be more relevant (ß = 0.16, p = 0.06). CONCLUSION: Peripapillary hyper-reflective ovoid masslike structures were found in 18% of patients with early MS. The presence of PHOMS might be associated with disease progression only in PPMS but not RRMS, suggesting that PHOMS might be embedded in neurodegenerative processes.

Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy: A Case Report.

OBJECTIVE: We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML). RESULTS: A 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits. DISCUSSION: This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.