Nuclear Layer Volume Research Articles

Serum glial fibrillary acidic protein and neurofilament light chain in patients with early treated phenylketonuria.

To pave the way for healthy aging in early treated phenylketonuria (ETPKU) patients, a better understanding of the neurological course in this population is needed, requiring easy accessible biomarkers to monitor neurological disease progression in large cohorts. The objective of this pilot study was to investigate the potential of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as blood biomarkers to indicate changes of the central nervous system in ETPKU. In this single-center cross-sectional study, GFAP and NfL concentrations in serum were quantified using the Simoa® multiplex technology in 56 ETPKU patients aged 6–36 years and 16 age matched healthy controls. Correlation analysis and hierarchical linear regression analysis were performed to investigate an association with disease-related biochemical parameters and retinal layers assessed by optical coherence tomography. ETPKU patients did not show significantly higher GFAP concentrations (mean 73 pg/ml) compared to healthy controls (mean 60 pg/ml, p = 0.140). However, individual pediatric and adult ETPKU patients had GFAP concentrations above the healthy control range. In addition, there was a significant association of GFAP concentrations with current plasma tyrosine concentrations (r = −0.482, p = 0.036), a biochemical marker in phenylketonuria, and the retinal inner nuclear layer volume (r = 0.451, p = 0.04). There was no evidence of NfL alterations in our ETPKU cohort. These pilot results encourage multicenter longitudinal studies to further investigate serum GFAP as a complementary tool to better understand and monitor neurological disease progression in ETPKU. Follow-up investigations on aging ETPKU patients are required to elucidate the potential of serum NfL as biomarker.

Machine Learning–Based Automated Detection of Hydroxychloroquine Toxicity and Prediction of Future Toxicity Using Higher-Order OCT Biomarkers

Despite guidelines for hydroxychloroquine (HCQ) toxicity screening, there are clear challenges to accurate detection and interpretation. In the current report, the feasibility of automated machine learning (ML)-based detection of HCQ retinopathy and prediction of progression to toxicity in eyes without preexisting toxicity has been described. Retrospective, longitudinal cohort study. Subjects on HCQ therapy. This was an institutional review board-approved, retrospective, longitudinal image analysis of 388 subjects on HCQ. Multilayer, compartmental, retinal segmentation with ellipsoid zone (EZ) mapping was used to harvest quantitative spectral-domain (SD)-OCT biomarkers. Using a combination of clinical features (i.e., cumulative HCQ dose and the duration of therapy) and quantitative imaging biomarkers (e.g., volumetric EZ integrity and compartmental measurements), ML models were created to detect toxicity and predict progression based on ground-truth OCT-based toxicity readings by 2 masked retina specialists. Furthermore, 10-fold cross-validation was performed. The model performance was visualized using receiver operator curves and calculating the area under the curve (AUC). The corresponding sensitivity and specificity values were evaluated for the feasibility of HCQ toxicity screening and prediction. The prevalence of HCQ toxicity in this cohort of 388 patients was 9.8% (n= 38). Twenty-one eyes progressed to toxicity during follow-up. OCT-based features (i.e., partial EZ attenuation, EZ volume, outer nuclear layer volume, and compartmental thicknesses) and clinical features (i.e., HCQ daily dose, HCQ cumulative dose, and duration of therapy) showed significant differences between the toxic and nontoxic groups. Percentage area with partial EZ attenuation (i.e., percentage of the macula with an EZ-retinal pigment epithelium thickness of ≤ 20 μm) was the most discriminating single feature (toxic, 35.7 ± 46.5%; nontoxic, 1.8 ± 4.4%; P < 0.0001). Using a random forest model, high-performance, automated toxicity detection was achieved, with a mean AUC of 0.97, sensitivity of 95%, and specificity of 91%. Furthermore, the toxicity progression prediction model had a mean AUC of 0.89, with a sensitivity and specificity of 90% and 80%, respectively. This report described the feasibility of high-performance automated classification models that used a combination of clinical and quantitative SD-OCT biomarkers to detect HCQ retinal toxicity and predict progression to toxicity in cases without toxicity. Future work is needed to validate these findings in an independent dataset.

Objective quantification of vitreous haze on optical coherence tomography scans: no evidence for relationship between uveitis and inflammation in multiple sclerosis.

Background and purposeThe occurrence of intermediate uveitis, which is characterized by the presence of vitreous haze (VH), in patients with multiple sclerosis (MS) may be a sign of coexistent inflammatory central nervous system (CNS) disease activity. Using an automated algorithm to quantify VH on optical coherence tomography (OCT) scans, the aim was to investigate whether VH in MS patients is associated with signs of inflammatory CNS disease activity.MethodsVitreous haze was quantified on OCT macular volume scans of 290 MS patients and 85 healthy controls (HCs). The relationship between VH and clinical, retinal OCT and magnetic resonance imaging parameters of inflammatory disease activity was investigated using generalized estimating equations.ResultsMean VH scores did not differ between patients and HCs (P = 0.629). Six patients (2.1%) showed values higher than the highest of the controls by HCs. VH scores did not differ between the different disease types or between eyes with and without a history of optic neuritis (P = 0.132). VH was not associated with inner nuclear layer volume on OCT (P = 0.233), cerebral T2 lesion load on magnetic resonance imaging (P = 0.416) or the development of new relapses (P = 0.205).ConclusionIn this study, OCT‐based automated VH estimation did not detect increased vitreous inflammation in MS patients compared to HCs and did not find an association with CNS inflammatory burden.

Correlation of retinal neurodegeneration with measures of peripheral autonomic neuropathy in type 1 diabetes.

PurposeTo evaluate the relationship of neuroretinal layer thickness with sensitive measures of cardiovascular autonomic neuropathy in diabetic patients with non‐proliferative diabetic retinopathy (NPDR).MethodsTwenty‐seven eyes of 27 patients with type 1 diabetes presenting with mild‐to‐moderate NPDR were compared to 27 healthy control (HC) eyes matched for age and gender. The total macular volume (TMV) and the volumes of individual neurosensory layers in the macula were analysed from spectral domain optical coherence tomography using automated layer segmentation. Cardiovascular autonomic regulation was assessed by short‐term power spectrum analysis of heart rate variability (HRV) before, during and after an orthostatic challenge.ResultsThe patients had an age of 46 ± 12 years and diabetes since 28 ± 9 years. Diastolic and mean arterial pressure was lower in the patients compared to HCs. TMV (r = 0.58, p = 0.002), inner plexiform layer volume (IPLV; r = 0.39, p = 0.047) and inner nuclear layer volume (INLV; r = 0.60, p = 0.001) were associated with reduced recovery of low‐frequency (LF) spectral power of HRV after orthostatic load in diabetic patients but not in HCs. The response of LF spectral power during the orthostatic manoeuvre was blunted in patients compared to HCs (p = 0.02). Diabetes duration was negatively associated with TMV and INLV, whereas IPLV was significantly reduced in eyes with moderate NPDR compared to HCs.ConclusionThe results indicate a correlation between inner retinal tissue loss and diminished autonomic regulation in type 1 diabetic patients with mild‐to‐moderate NPDR. The observed changes can be interpreted as congruent early signs of retinal and systemic neuropathy in diabetes.

Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients With Diabetic Macular Edema.

To investigate the associations between soluble CD14 (sCD14), a cytokine released by microglia and macrophages, and hyperreflective foci (HF) and various characteristics of spectral-domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME). Sixty-nine eyes from 51 patients with DME and 28 eyes from 28 control subjects were studied. sCD14 levels in the aqueous humor (AH) were measured using ELISA before bevacizumab injection (IVB), and the associations between sCD14 and visual acuity, the number of HF, retinal volume, and the DME pattern were assessed. sCD14 levels were higher in DME patients than in the control subjects (29.9 ± 41.6 pg/mL versus 8.1 ± 3.6 pg/mL, P < 0.001). sCD14 levels in diffuse edema were higher than those in focal edema (50.0 ± 65.3 pg/mL versus 19.8 ± 14.7 pg/mL, P = 0.039). The number of HF in the inner retina of patients with diffuse edema was significantly higher than that in patients with focal edema (4.4 ± 2.3 vs. 2.6 ± 2.1, P = 0.001), but no difference was found in the outer retina (5.8 ± 3.4 vs. 5.0 ± 3.9, P = 0.25). According to multivariate analyses, elevated sCD14 levels were associated with an increased inner nuclear layer volume and the total number of HF in all retinal layers on SD-OCT. Reduction of DME following IVB was correlated with reduction in the number of HF in a subset of eyes followed longitudinally in the study (n = 30). DME patients with diffuse edema exhibit higher sCD14 levels in the AH and more HF in the inner retina than patients with focal edema, indicating severe inflammation. The strong correlation between sCD14 and HF in the inner retina suggests that the HF observed on SD-OCT may be due to activated microglia in DME.

Outer Retinal Dysfunction in the Absence of Structural Abnormalities in Multiple Sclerosis.

Recent evidence suggests structural changes distal to the inner retina in multiple sclerosis (MS) patients. The functional correlates of these proposed structural abnormalities remain unclear. We investigated outer retinal function and structure in MS patients, and quantified to what extent outer retinal structure influenced function in these patients. Outer retinal function was assessed using the full-field and multifocal electroretinogram (ERG/MF-ERG), whereas retinal structure was assessed using spectral-domain optical coherence tomography (OCT). Results were compared with preexisting normative data. The relationships between electrophysiology parameters and the OCT values corresponding to the proposed cellular origins of the ERG and MF-ERG were analyzed. Most electrophysiological responses were delayed in MS patients, independently of optic neuritis (ON). Inner retinal thickness and volumes were reduced, and inner nuclear layer volume marginally increased, in eyes with previous ON; all other OCT parameters were normal. OCT results correlated with ERG amplitudes, but not with ERG peak times or any MF-ERG parameters. We recorded outer retinal dysfunction without detectable abnormalities of the corresponding retinal layers in MS patients, not ascribable to retrograde degeneration following ON. The findings complement a growing body of literature reporting primary retinal abnormalities distal to the ganglion cell-inner plexiform layer complex in MS patients, with our data suggesting that this may be a more widespread phenomenon than previously thought. ERG may be of more utility in detecting retinal dysfunction in MS patients than MF-ERG. Analysis of peak times, rather than response amplitudes, is recommended.

Neuroprotection and visual function after optic neuritis.

This article discusses the advantages and pitfalls of testing neuroprotective treatment strategies in patients suffering from optic neuritis. Spectral domain optical coherence tomography now permits for automated segmentation of individual retinal layers. The peripapillary retinal nerve fibre layer (pRNFL) has been used in 13 of the 15 trials reviewed. Twelve trials also made use of electrophysiology. Overestimation of good visual recovery in the past has recently been recognized. Assessment of low contrast visual acuity and colour vision are now mainstream. The availability of highly accurate and robust trial outcome measures has facilitated research on this topic. A single long-term structural outcome measurement of the pRNFL is sufficient. For shorter term, assessments of the ganglion cell/inner plexiform layer and axonal birefringence are promising. Longitudinal blood levels of neurofilament proteins permit to recognize axonal loss at presentation and monitor changes longitudinally. Inner nuclear layer volume changes relate to inflammatory disease activity.Pitfalls are related to the timing of events. Hyperacute recruitment is needed for future trials. The onset of demyelination is not known, which complicates timing of electrophysiological recordings. Optic disc oedema precludes the use of the pRNFL from the affected eye as a baseline variable. The concomitant use of corticosteroids complicates interpretation of trial data.

Retinal glymphatic system: an explanation for transient retinal layer volume changes?

This scientific commentary refers to ‘Retinal inner nuclear layer volume reflects response to immunotherapy in multiple sclerosis’, by Knier et al. (doi:10.1093/brain/aww219) . A recent article in Brain by Gelfand et al. (2012) on the inner nuclear layer (INL) of the retina in multiple sclerosis triggered a lively exchange of Letters to the Editor. With the advent of optical coherence tomography (OCT), a forgotten autopsy observation was restored to the top of the research agenda in multiple sclerosis. Over 150 years ago, severe atrophy of the retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) was shown to be associated with only subtle changes in the INL whilst the outer retinal layers were completely preserved (Muller, 1857). Although Heinrich Muller was cautious in interpreting potential INL changes, he was more convinced about the existence of secondary (retrograde) axonal degeneration. ‘Die sogenannten Korner erschienen etwas kornig, doch war mir sehr zweifelhaft, ob dies als pathologische Veranderung anzusprechen sei, da man Aehnliches auch sonst zu Gesicht bekommt.’ This case was discussed on pages 92–98 and the citation taken from page 93 (Muller, 1857). For the contemporary translation it is important to refer back to the terminology of the time. There were three ‘Kornerschichten’ that correspond to the present day: ‘ganglion cell layer’, ‘inner nuclear layer’ and ‘outer nuclear layer’. Muller was not able to see the GCL and his comment is on the next nuclear layer, the INL: ‘The so called nuclei seemed more grainy, but I am rather doubtful if this should be interpreted as a (specific) pathological finding as one can see similar features in other situations’. Subsequent histological studies of the macaque monkey eye following experimental lesions to the afferent visual pathway provided evidence for retrograde trans-synaptic degeneration reaching the GCL with associated changes in the …

Retinal inner nuclear layer volume reflects response to immunotherapy in multiple sclerosis.

Assessment of inflammatory disease activity during multiple sclerosis is crucial for selecting appropriate disease- modifying therapies. Previous studies suggested that the retinal inner nuclear layer reflects inflammatory disease severity within the central nervous system. In our study, correlations of longitudinal retinal layer changes as measured by retinal optical coherence tomography with ongoing disease activity were evaluated in 108 multiple sclerosis patients without therapy, on first- line therapy, or on second- line therapy. Healthy subjects served as controls. Inner nuclear layer volume at baseline correlated positively with paraclinical disease activity during the subsequent 12 months. Longitudinal thinning of the inner nuclear layer and thickening of total macular volume were associated with reduced inflammatory disease activity. Reduction in inner nuclear layer volume after 1 year indicated efficient control of inflammatory disease activity including ` no evidence of disease activity'. In conclusion, the retinal inner nuclear layer could serve as biomarker to monitor sustained control of autoimmune central nervous system inflammation by therapeutic interventions.

Quantifying visual pathway axonal and myelin loss in multiple sclerosis and neuromyelitis optica.

BackgroundThe optic nerve is frequently injured in multiple sclerosis and neuromyelitis optica, resulting in visual dysfunction, which may be reflected by measures distant from the site of injury.ObjectiveTo determine how retinal nerve fiber layer as a measure of axonal health, and macular volume as a measure of neuronal health are related to changes in myelin water fraction in the optic radiations of multiple sclerosis and neuromyelitis optica participants with and without optic neuritis and compared to healthy controls.Methods12 healthy controls, 42 multiple sclerosis (16 with optic neuritis), and 10 neuromyelitis optica participants (8 with optic neuritis) were included in this study. Optical coherence tomography assessment involved measurements of the segmented macular layers (total macular, ganglion cell layer, inner plexiform layer, and inner nuclear layer volume) and paripapillary retinal nerve fiber layer thickness. The MRI protocol included a 32-echo T2-relaxation GRASE sequence. Average myelin water fraction values were calculated within the optic radiations as a measure of myelin density.ResultsMultiple sclerosis and neuromyelitis optica eyes with optic neuritis history had lower retinal nerve fiber layer thickness, total macular, ganglion cell and inner plexiform layer volumes compared to eyes without optic neuritis history and controls. Inner nuclear layer volume increased in multiple sclerosis with optic neuritis history (mean = 0.99 mm3, SD = 0.06) compared to those without (mean = 0.97 mm3, SD = 0.06; p = 0.003). Mean myelin water fraction in the optic radiations was significantly lower in demyelinating diseases (neuromyelitis optica: mean = 0.098, SD = 0.01, multiple sclerosis with optic neuritis history: mean = 0.096, SD = 0.01, multiple sclerosis without optic neuritis history: mean = 0.098, SD = 0.02; F3,55 = 3.35, p = 0.03) compared to controls. Positive correlations between MRI and optical coherence tomography measures were also apparent (retinal nerve fiber layer thickness and ganglion cell layer thickness: r = 0.25, p = 0.05, total macular volume and inner plexiform layer volume: r = 0.27, p = 0.04).ConclusionsThe relationship between reductions in OCT measures of neuro-axonal health in the anterior visual pathway and MRI-based measures of myelin health in the posterior visual pathway suggests that these measures may be linked through bidirectional axonal degeneration.