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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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Traumatic brain injury (TBI) is estimated to rank as the third most important disease burden worldwide. About 60% of the survivors develop chronic headaches and visual symptoms, and the long-term management of headaches in these patients is controversial. Importantly, the care pathway of most patients is fragmented, complicating conclusive headache management. Here we review the epidemiology and aetiology of post traumatic headaches (PTH), discuss the diagnostic work up and summarise the acute and long-term management.
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INTRODUCTION/AIMS: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). METHODS: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. RESULTS: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. DISCUSSION: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.
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Comorbidities in patients with multiple sclerosis (MS) and antibody-mediated diseases of the central nervous system (CNS) including neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease (MOGAD) are common and may influence the course of their neurological disease. Comorbidity may contribute to neuronal injury and therefore limit recovery from attacks, accelerate disease progression, and increase disability. This study aims to explore the impact of comorbidity, particularly vascular comorbidity, and related risk factors on clinical and paraclinical parameters of MS, NMOSD and MOGAD. We propose COMMIT, a prospective multicenter study with longitudinal follow-up of patients with MS, NMOSD, and MOGAD, with or without comorbidities, as well as healthy subjects as controls. Subjects will be stratified by age, sex and ethnicity. In consecutive samples we will analyze levels of inflammation and neurodegeneration markers in both fluid and cellular compartments of the peripheral blood and cerebrospinal fluid (CSF) using multiple state-of-the-art technologies, including untargeted proteomics and targeted ultrasensitive ELISA assays and quantitative reverse transcription polymerase chain reaction (RT-qPCR) as well as high-dimensional single-cell technologies i.e., mass cytometry and single-cell RNA sequencing. Algorithm-based data analyses will be used to unravel the relationship between these markers, optical coherence tomography (OCT) and magnetic resonance imaging (MRI), and clinical outcomes including frequency and severity of relapses, long-term disability, and quality of life. The goal is to evaluate the impact of comorbidities on MS, NMOSD, and MOGAD which may lead to development of treatment approaches to improve outcomes of inflammatory demyelinating diseases of the CNS.
Subject(s)
Comorbidity , Multiple Sclerosis , Neuromyelitis Optica , Humans , Multiple Sclerosis/epidemiology , Multiple Sclerosis/immunology , Prospective Studies , Neuromyelitis Optica/epidemiology , Neuromyelitis Optica/immunology , Neuromyelitis Optica/diagnosis , Male , Female , Myelin-Oligodendrocyte Glycoprotein/immunology , Adult , Biomarkers/blood , Autoantibodies/blood , Autoantibodies/immunology , Middle AgedABSTRACT
BACKGROUND AND OBJECTIVES: To test the performance of the 2023 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) criteria in adults and children with inflammatory demyelinating conditions who were tested for MOG antibodies (Abs). METHODS: This was a retrospective study of patients tested for MOG-Abs from 2018 to 2022 in 2 specialist hospitals. The inclusion criteria comprised ≥1 attendance in an adult or pediatric demyelinating disease clinic and complete clinical and MRI records. The final clinical diagnosis of MOGAD, made by the treating neurologist, was taken as the benchmark against which the new criteria were tested. The international MOGAD diagnostic criteria were applied retrospectively; they stipulate at least 1 clinical or MRI supporting feature for MOGAD diagnosis in positive fixed MOG cell-based assay without a titer. The performance MOG-Ab testing alone for MOGAD diagnosis was also assessed and compared with that of MOGAD criteria using the McNemar test. RESULTS: Of the 1,879 patients tested for MOG-Abs, 539 (135 pediatric and 404 adults) met the inclusion criteria. A clinical diagnosis of MOGAD was made in 86/539 (16%) patients (37 adults, 49 children), with a median follow-up of 3.6 years. The MOGAD diagnostic criteria had sensitivity of 96.5% (adults 91.9%, children 100%), specificity of 98.9% (adults 98.8%, children 98.9%), positive predictive value of 94.3% (adults 89.4%, children 98%), negative predictive value of 99.3% (adults 99.2%, children 100%), and accuracy of 98.5% (adults 98.3%, children 99.2%). When compared with MOG-Ab testing alone, a difference was seen only in adults: a significantly higher specificity (98.9% vs 95.6%, p = 0.0005) and nonstatistically significant lower sensitivity (91.9% vs 100%, p = 0.08). DISCUSSION: The international MOGAD diagnostic criteria exhibit high performance in selected patients with inflammatory demyelinating diseases (who had a high pretest probability of having MOGAD) compared with best clinical judgment; their performance was better in children than in adults. In adults, the MOGAD criteria led to an improvement in specificity and positive predictive value when compared with MOG-Ab testing alone, suggesting that the requirement of at least 1 clinical or MRI supporting feature is important. Future work should address the generalizability of the diagnostic criteria to cohorts of greater clinical diversity seen within neurologic settings.
Subject(s)
Autoantibodies , Myelin-Oligodendrocyte Glycoprotein , Humans , Myelin-Oligodendrocyte Glycoprotein/immunology , Child , Adult , Male , Female , Retrospective Studies , Adolescent , Autoantibodies/blood , Child, Preschool , Young Adult , Middle Aged , Magnetic Resonance Imaging , Infant , Aged , Cohort Studies , Sensitivity and SpecificityABSTRACT
Optic neuritis (ON) is an inflammation of or around the optic nerve, frequently caused by infectious or immune-mediated inflammatory disorders. In the UK, its strongest association is with Multiple Sclerosis (MS), though the combined prevalence of other associated infectious and immune-mediated inflammatory diseases (I-IMID) is similar to that of MS-ON. Prompt identification and understanding of ON's underlying cause informs tailored management and prognosis. Several IMIDs linked to ON, such as aquaporin-4 antibody-associated optic neuritis (AQP4-ON), myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON), and neuro-sarcoidosis, show remarkable response to corticosteroid treatment. Therefore, urgent investigation and treatment are crucial in cases 'atypical' for MS-ON. Following the 1992 Optic Neuritis Treatment Trial, clinical practice has evolved, with short-course high-dose corticosteroids considered safe and effective for most people. Timely recognition of patients who could benefit is critical to avoid irreversible vision loss. This review provides a practical guide and a summary of evidence on the investigation and management of acute optic neuritis. It reflects the knowledge and limitations of current evidence, framed through the neuro-ophthalmic perspective of clinical practice at multiple UK academic centres.
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Optic Neuritis , Humans , Optic Neuritis/diagnosis , Optic Neuritis/drug therapy , Optic Neuritis/therapy , United Kingdom/epidemiology , Acute Disease , Ophthalmologists , Glucocorticoids/therapeutic use , Disease ManagementABSTRACT
BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.
Subject(s)
Disease Progression , Multiple Sclerosis , Tomography, Optical Coherence , Humans , Female , Male , Adult , Middle Aged , Prognosis , Multiple Sclerosis/physiopathology , Multiple Sclerosis/diagnostic imaging , Retina/diagnostic imaging , Retina/pathology , Retina/physiopathology , Severity of Illness IndexABSTRACT
BACKGROUND AND PURPOSE: The eye is a well-established model of brain structure and function, yet region-specific structural correlations between the retina and the brain remain underexplored. Therefore, we aim to explore and describe the relationships between the retinal layer thicknesses and brain magnetic resonance image (MRI)-derived phenotypes in UK Biobank. METHODS: Participants with both quality-controlled optical coherence tomography (OCT) and brain MRI were included in this study. Retinal sublayer thicknesses and total macular thickness were derived from OCT scans. Brain image-derived phenotypes (IDPs) of 153 cortical and subcortical regions were processed from MRI scans. We utilized multivariable linear regression models to examine the association between retinal thickness and brain regional volumes. All analyses were corrected for multiple testing and adjusted for confounders. RESULTS: Data from 6446 participants were included in this study. We identified significant associations between volumetric brain MRI measures of subregions in the occipital lobe (intracalcarine cortex), parietal lobe (postcentral gyrus), cerebellum (lobules VI, VIIb, VIIIa, VIIIb, and IX), and deep brain structures (thalamus, hippocampus, caudate, putamen, pallidum, and accumbens) and the thickness of the innermost retinal sublayers and total macular thickness (all p < 3.3 × 10-5). We did not observe statistically significant associations between brain IDPs and the thickness of the outer retinal sublayers. CONCLUSIONS: Thinner inner and total retinal thicknesses are associated with smaller volumes of specific brain regions. Notably, these relationships extend beyond anatomically established retina-brain connections.
Subject(s)
Brain , Magnetic Resonance Imaging , Phenotype , Retina , Tomography, Optical Coherence , Humans , Male , Female , Retina/diagnostic imaging , Retina/anatomy & histology , Middle Aged , Tomography, Optical Coherence/methods , Brain/diagnostic imaging , Brain/anatomy & histology , Aged , AdultABSTRACT
Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.
Subject(s)
Biomarkers , Intermediate Filaments , Nervous System Diseases , Neurofilament Proteins , Humans , Biomarkers/metabolism , Biomarkers/blood , Nervous System Diseases/diagnosis , Nervous System Diseases/metabolism , Nervous System Diseases/blood , Neurofilament Proteins/blood , Intermediate Filaments/metabolismABSTRACT
Purpose: Periodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone, can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration (AMD), in individuals with no eye disease. Design: Cross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank. Participants: Sixty-seven thousand three hundred eleven UK residents aged 40 to 70 years recruited between 2006 and 2010 underwent retinal imaging. Methods: Macular-centered OCT images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses, adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery. Main Outcome Measures: Photoreceptor layer (PRL) and retinal pigment epithelium-Bruch's membrane (RPE-BM) thicknesses. Results: Among 36 897 participants included in the analysis, 1571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation, and were more likely to be hypertensive, diabetic, and current smokers (all P < 0.001). On average, those with very severe periodontitis were hyperopic (0.05 ± 2.27 diopters) while those unaffected were myopic (-0.29 ± 2.40 diopters, P < 0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 µm, 95% confidence interval [CI], -0.97 to -0.12; P = 0.022) but there was no difference in RPE-BM thickness (0.00 µm, 95% CI, -0.12 to 0.13; P = 0.97). The association between PRL thickness and very severe periodontitis was modified by age (P < 0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60 to 69 years with disease (-1.19 µm, 95% CI, -1.85 to -0.53; P < 0.001) but not among those aged < 60 years. Conclusions: Among those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient AMD. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON; one standard deviation of MS-GRS increased the Hazard of MS 1.3-fold (95% confidence interval 1.07-1.55, P < 0.01). Participants stratified into quartiles of predicted risk developed incident MS at rates varying from 4% (95%CI 0.5-7%, lowest risk quartile) to 41% (95%CI 33-49%, highest risk quartile). The model replicated across two cohorts (Geisinger, USA, and FinnGen, Finland). This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.
Subject(s)
Multiple Sclerosis , Optic Neuritis , Humans , Genetic Risk Score , Multiple Sclerosis/diagnosis , Multiple Sclerosis/genetics , Multiple Sclerosis/complications , Optic Neuritis/diagnosis , Optic Neuritis/genetics , Optic Neuritis/complications , Risk Factors , FinlandABSTRACT
INTRODUCTION: Remyelination failure hampers symptomatic recovery in multiple sclerosis (MS), underlining the importance of developing remyelinating therapies. Optic neuritis is currently the most established method of measuring remyelination in MS trials. Complementary more generalisable methods of measuring remyelination are required to confirm treatment efficacy. Measuring internuclear ophthalmoplegia (INO) with infrared oculography provides such a method. Moreover, this method can be expanded with a test for selecting likely treatment responders by using fampridine. The aim of this trial is to investigate the (long-term) remyelinating effects of clemastine fumarate in patients with MS and INO and to evaluate if treatment response can be predicted using fampridine. METHODS AND ANALYSIS: RESTORE is a single-centre double-blind randomised placebo-controlled trial of clemastine fumarate versus placebo. Prior to clemastine treatment improvement in oculographic features of INO after a single 10 mg dose of fampridine is measured in all participants and used to predict the treatment response to clemastine. Eighty individuals with MS and INO will be 1:1 randomised to 4 mg of clemastine fumarate two times a day for 6 months or equivalent placebo. Our primary outcome is improvement in the Versional Dysconjugacy Index-area under the curve, measured by infrared oculography after 6 months of treatment. Participants are assessed for persistent treatment effects 6, 18 and 30 months after end of treatment. Secondary outcome measures include other oculography parameters including double-step saccades, retinal imaging, visual acuities, physical disability, cognition and patient-reported outcomes. ETHICS AND DISSEMINATION: Clemastine is a registered and very well-established drug with well-known safety and side effects. The protocol was approved by the medical ethical committee of the Amsterdam UMC, location VUMC and the Dutch Central Committee on Research Involving Human Subject. Written informed consent is obtained from all participants. The results will be published in peer-reviewed medical scientific journals. TRIAL REGISTRATION NUMBER: EudraCT: 2021-003677-66, ClinicalTrials.gov: NCT05338450.
Subject(s)
Multiple Sclerosis , Ocular Motility Disorders , Humans , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Clemastine/therapeutic use , 4-Aminopyridine/therapeutic use , Treatment Outcome , Double-Blind Method , Randomized Controlled Trials as TopicABSTRACT
Retinal thickness may serve as a biomarker in Parkinson's disease (PD). In this prospective longitudinal study, we aimed to determine if PD patients present accelerated thinning rate in the parafoveal ganglion cell-inner plexiform layer (pfGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) compared to controls. Additionally, we evaluated the relationship between retinal neurodegeneration and clinical progression in PD. A cohort of 156 PD patients and 72 controls underwent retinal optical coherence tomography, visual, and cognitive assessments between February 2015 and December 2021 in two Spanish tertiary hospitals. The pfGCIPL thinning rate was twice as high in PD (ß [SE] = -0.58 [0.06]) than in controls (ß [SE] = -0.29 [0.06], p < 0.001). In PD, the progression pattern of pfGCIPL atrophy depended on baseline thickness, with slower thinning rates observed in PD patients with pfGCIPL below 89.8 µm. This result was validated with an external dataset from Moorfields Eye Hospital NHS Foundation Trust (AlzEye study). Slow pfGCIPL progressors, characterized by older at baseline, longer disease duration, and worse cognitive and disease stage scores, showed a threefold increase in the rate of cognitive decline (ß [SE] = -0.45 [0.19] points/year, p = 0.021) compared to faster progressors. Furthermore, temporal sector pRNFL thinning was accelerated in PD (ßtime x group [SE] = -0.67 [0.26] µm/year, p = 0.009), demonstrating a close association with cognitive score changes (ß [SE] = 0.11 [0.05], p = 0.052). This study suggests that a slower pattern of pfGCIPL tissue loss in PD is linked to more rapid cognitive decline, whereas changes in temporal pRNFL could track cognitive deterioration.
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PURPOSE: To offer a comprehensive review of the available data regarding non-arteritic anterior ischaemic optic neuropathy and its phenocopies, focusing on the current evidence to support the different existing aetiopathogenic hypotheses for the development of these conditions. CONCLUSIONS AND IMPORTANCE: Due to the limited array of responses of the neural tissue and other retinal structures, different aetiopathogenic mechanisms may result in a similar clinical picture. Moreover, when the insult occurs within a confined space, such as the optic nerve or the optic nerve head, in which different tissues (neural, glial, vascular) are highly interconnected and packed together, determining the primary noxa can be challenging and may lead to misdiagnosis. Anterior ischaemic optic neuropathy is a condition most clinicians will face during their everyday work, and it is important to correctly differentiate among resembling pathologies affecting the optic nerve to avoid unnecessary diagnostic procedures. Combining a good clinical history and multimodal imaging can assist diagnosis in most cases. The key remains to combine demographic data (e.g. age), with ophthalmic data (e.g. refractive error), systemic data (e.g. comorbidities and medication), imaging data (e.g. retinal OCT) with topographic signs (e.g. focal neurology). METHODOLOGY: Papers relevant for this work were obtained from the MEDLINE and Embase databases by using the PubMed search engine. One author (MPMG) performed the search and selected only publications with relevant information about the aetiology, pathogenic mechanisms, risk factors as well as clinical characteristics of phenocopies (such as vitreopapillary traction, intrapapillary haemorrhage with adjacent peripapillary subretinal haemorrhage or diabetic papillopathy) of non-arteritic anterior ischaemic optic neuropathy (NAION). The terms "non-arteritic ischaemic optic neuropathy/NAION", "vitreopapillary traction", "vitreopapillary traction AND non-arteritic ischaemic optic neuropathy/NAION", "posterior vitreous detachment AND non-arteritic ischaemic optic neuropathy/NAION", "central retinal vein occlusion AND non-arteritic ischaemic optic neuropathy/NAION", "disc oedema/disc oedema", "diabetes mellitus AND non-arteritic ischaemic optic neuropathy/NAION" and "diabetic papillopathy" were searched on PubMed. From each of these searches, publications were selected based on their title, obtaining a total of 115 papers. All papers not written in English were then excluded, and those whose abstracts were not deemed relevant for our review, according to the aforementioned criteria. Subsequent scrutiny of the main text of the remaining publications led us (MPMG, AP, ZS) to include references which had not been selected during our first search, as their titles did not contain the previously mentioned MeSH terms, due to their significantly relevant contents for our work. A total of 62 publications were finally consulted for our review. The literature review was last updated on 24-Aug-2022.
Subject(s)
Diabetes Mellitus , Optic Neuropathy, Ischemic , Papilledema , Humans , Optic Neuropathy, Ischemic/diagnosis , Optic Neuropathy, Ischemic/etiology , Diagnosis, Differential , Tomography, Optical Coherence/methods , Papilledema/diagnosis , Edema , Hemorrhage/diagnosisSubject(s)
Guillain-Barre Syndrome , Humans , Guillain-Barre Syndrome/physiopathology , Peripherins , Biomarkers , Axons , Intermediate FilamentsABSTRACT
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.
Subject(s)
Retinal Vessels , Tomography, Optical Coherence , Humans , Consensus , Fluorescein Angiography/methods , Retina/diagnostic imagingABSTRACT
BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.
Subject(s)
Parkinson Disease , Retinal Ganglion Cells , Humans , Female , Adult , Middle Aged , Aged , Male , Parkinson Disease/diagnostic imaging , Parkinson Disease/epidemiology , Tomography, Optical Coherence/methods , Retrospective Studies , Prospective Studies , Cross-Sectional Studies , Nerve Fibers , Retina/diagnostic imagingABSTRACT
Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.
Subject(s)
Dementia , Guillain-Barre Syndrome , Multiple Sclerosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Peripherins/metabolism , Intermediate Filaments , Guillain-Barre Syndrome/pathology , Axons/pathology , Biomarkers , Dementia/pathology , Multiple Sclerosis/pathologyABSTRACT
BACKGROUND/AIMS: The analysis of visual field loss patterns is clinically useful to guide differential diagnosis of visual pathway pathology. This study investigates whether a novel index of macular atrophy patterns can discriminate between chiasmal compression and glaucoma. METHODS: A retrospective series of patients with preoperative chiasmal compression, primary open-angle glaucoma (POAG) and healthy controls. Macular optical coherence tomography (OCT) images were analysed for the macular ganglion cell and inner plexiform layer (mGCIPL) thickness. The nasal hemi-macula was compared with the temporal hemi-macula to derive the macular naso-temporal ratio (mNTR). Differences between groups and diagnostic accuracy were explored with multivariable linear regression and the area under the receiver operating characteristic curve (AUC). RESULTS: We included 111 individuals (31 with chiasmal compression, 30 with POAG and 50 healthy controls). Compared with healthy controls, the mNTR was significantly greater in POAG cases (ß=0.07, 95% CI 0.03 to 0.11, p=0.001) and lower in chiasmal compression cases (ß=-0.12, 95% CI -0.16 to -0.09, p<0.001), even though overall mGCIPL thickness did not discriminate between these pathologies (p=0.36). The mNTR distinguished POAG from chiasmal compression with an AUC of 95.3% (95% CI 90% to 100%). The AUCs when comparing healthy controls to POAG and chiasmal compression were 79.0% (95% CI 68% to 90%) and 89.0% (95% CI 80% to 98%), respectively. CONCLUSIONS: The mNTR can distinguish between chiasmal compression and POAG with high discrimination. This ratio may provide utility over-and-above previously reported sectoral thinning metrics. Incorporation of mNTR into the output of OCT instruments may aid earlier diagnosis of chiasmal compression.