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

BACKGROUND AND PURPOSE: The 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. METHODS: Vitreous 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. RESULTS: Mean 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). CONCLUSION: In 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.

Predicting clinical progression in multiple sclerosis after 6 and 12 years.

BACKGROUND AND PURPOSE: To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. METHODS: A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow-up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. RESULTS: Higher 6-year EDSS score was predicted by early EDSS score and whole-brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2  = 0.56). Predictors for 12-year EDSS score included larger EDSS score changes and higher T1-hypointense lesion volumes (adjusted R2  = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole-brain atrophy (adjusted R2  = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1-hypointense lesion volumes (adjusted R2  = 0.14). CONCLUSIONS: Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

Diagnostic accuracy of optical coherence tomography inter-eye percentage difference for optic neuritis in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis-associated optic neuritis (MSON) causes atrophy of the inner retinal layers, which can be quantified by optical coherence tomography. It has been suggested that the inter-eye percentage difference (IEPD) of atrophy may be of diagnostic value in MSON. METHODS: This was a prospective, cross-sectional study in patients with multiple sclerosis and healthy controls (HCs). Spectral-domain optical coherence tomography of both eyes was performed, followed by automated retinal layer segmentation of the peri-papillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (mGCIPL). Receiver operator characteristics curves were plotted and the area under the curve was calculated for group comparisons of the IEPD of the pRNFL and mGCIPL. RESULTS: There were 39 patients with bilateral MSON, 62 patients with unilateral MSON, 106 patients without MSON and 63 HCs. Diagnostic accuracy (area under the curve) of the IEPD was 0.73-0.86 for the pRNFL and 0.75-0.94 for the mGCIPL. The diagnostic sensitivity of the mGCIPL IEPD was 70% with a specificity of 97% for distinguishing unilateral MSON from HCs. For the comparison of bilateral MSON with HCs, sensitivity was 86% with a specificity of 97%. CONCLUSIONS: The IEPD of the pRNFL, and more particularly the IEPD of the mGCIPL, is a useful diagnostic measure for MSON. The IEPD is a dimensionless unit and may therefore contribute to overcome device and proprietary segmentation algorithm limitations.

Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

OBJECTIVE: To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS). METHODS: In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. RESULTS: In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. INTERPRETATION: This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans-synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

A dam for retrograde axonal degeneration in multiple sclerosis?

OBJECTIVE: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS). METHODS: A single-centre study, including patients with long-standing MS and healthy controls. Structural imaging of the brain (MRI) and retina (spectral-domain optical coherence tomography) were used to quantify the extent of atrophy of individual retinal layers and the primary and secondary visual cortex. Generalised estimation equations and multivariable regression analyses were used for comparisons. RESULTS: Following rigorous quality control (OSCAR-IB), data from 549 eyes of 293 subjects (230 MS, 63 healthy controls) were included. Compared with control data, there was a significant amount of atrophy of the inner retinal layers in MS following optic neuritis (ON) and also in absence of ON. For both scenarios, atrophy stopped at the level of the inner nuclear layer. In contrast, there was significant localised atrophy of the primary visual cortex and secondary visual cortex in MS following ON, but not in MS in absence of ON. INTERPRETATION: These data suggest that retrograde (trans-synaptic) axonal degeneration stops at the inner nuclear layer, a neuronal network capable of plasticity. In contrast, there seems to be no neuroplasticity of the primary visual cortex, rendering the structure vulnerable to anterograde (trans-synaptic) degeneration.

Disease course heterogeneity and OCT in multiple sclerosis.

BACKGROUND: The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials. OBJECTIVE: The objective of this paper is to investigate the relationship between disease course heterogeneity and retinal layer thicknesses in MS. METHODS: A total of 230 MS patients and 63 healthy control subjects were included. Spectral-domain OCT scanning of the peripapillary and macular regions was performed, followed by automated eight-layer segmentation. Generalised estimation equations were used for comparisons. Receiver operating characteristic (ROC) curves were calculated for distinguishing a benign from a typical disease course. RESULTS: Primary progressive patients showed relative preservation of inner retinal layers, compared to the relapsing onset MS types. Only in MS eyes without optic neuritis did patients with typical MS show more severe thinning of the inner retinal layers (RNFL to INL) compared to patients with a benign disease course, even after an average disease course of 20 years. CONCLUSION: The thicknesses, particularly of the innermost retinal layers (RNFL, GCC), were significantly related to the heterogeneous disease course in MS. The relative preservation of these layers in primary progressive and benign MS suggests rather limited susceptibility of the retina to neurodegeneration, which may be relevant for future neurodegenerative treatment trials employing OCT as a secondary outcome measure in primary progressive MS.

Impaired saccadic eye movements in multiple sclerosis are related to altered functional connectivity of the oculomotor brain network.

BACKGROUND: Impaired eye movements in multiple sclerosis (MS) are common and could represent a non-invasive and accurate measure of (dys)functioning of interconnected areas within the complex brain network. The aim of this study was to test whether altered saccadic eye movements are related to changes in functional connectivity (FC) in patients with MS. METHODS: Cross-sectional eye movement (pro-saccades and anti-saccades) and magnetoencephalography (MEG) data from the Amsterdam MS cohort were included from 176 MS patients and 33 healthy controls. FC was calculated between all regions of the Brainnetome atlas in six conventional frequency bands. Cognitive function and disability were evaluated by previously validated measures. The relationships between saccadic parameters and both FC and clinical scores in MS patients were analysed using multivariate linear regression models. RESULTS: In MS pro- and anti-saccades were abnormal compared to healthy controls A relationship of saccadic eye movements was found with FC of the oculomotor network, which was stronger for regional than global FC. In general, abnormal eye movements were related to higher delta and theta FC but lower beta FC. Strongest associations were found for pro-saccadic latency and FC of the precuneus (beta band ß = -0.23, p = .006), peak velocity and FC of the parietal eye field (theta band ß = -0.25, p = .005) and gain and FC of the inferior frontal eye field (theta band ß = -0.25, p = .003). Pro-saccadic latency was also strongly associated with disability scores and cognitive dysfunction. CONCLUSIONS: Impaired saccadic eye movements were related to functional connectivity of the oculomotor network and clinical performance in MS. This study also showed that, in addition to global network connectivity, studying regional changes in MEG studies could yield stronger correlations.

Saccadic delay in multiple sclerosis: A quantitative description.

In multiple sclerosis (MS), eye movement disorders are common and can be quantified with infrared video-oculography. A well-known abnormality is internuclear ophthalmoplegia (INO). This study aims to describe saccadic abnormalities beyond INO and investigate their clinical relevance. A validated standardized infrared oculography protocol, DEMoNS, was used for quantifying saccadic eye movements in three different tasks in MS patients and healthy controls. The relationship between the saccadic parameters and disease characteristics was investigated. Furthermore, the association between saccadic parameters and visual functioning was analysed using logistic regression models, adjusted for possible confounders. This cross-sectional study included 218 subjects with MS and 58 healthy controls. The latency of all saccades was longer in MS patients than in healthy controls. This saccadic delay was larger in subjects with a longer disease duration and more disabled subjects. Furthermore, it was significantly related to presence of a lower vision-related quality of life. This study provided a comprehensive overview of performance of MS patients in different saccadic tasks, compared to healthy controls. Saccadic delay in MS patients was present in all saccadic tasks and was related to advancing disease and visual functioning in daily life.

Electrical properties of nanostructured tin oxide surfaces produced by thermal treatments.

Sintering SnO2 powder in air or under an oxygen atmosphere at different temperatures, leads to polycrystalline samples with nanostructured surface as revealed by atomic force microscopy (AFM). The thermal treatments are also responsible for the variation of the surface electrical properties, as studied by scanning spreading resistance microscopy (SSRM) and scanning tunnelling microscopy and spectroscopy (STM-STS). The surface presents a p-conductance, contrary to the n-type characteristic of the bulk, and a band gap lower than the bulk band gap (3.6 eV). The electrical behaviour at the grain boundaries and the role of oxygen are discussed. X-ray photoelectron spectroscopy (XPS) results show a higher presence of oxygen at the boundaries, which generates a shift of the Fermi level position (E(F)-E(V)) towards lower energies.

Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia.

OBJECTIVE: We present an objective and quantitative approach for diagnosing internuclear ophthalmoplegia (INO) in multiple sclerosis (MS). METHODS: A validated standardized infrared oculography protocol (DEMoNS [Demonstrate Eye Movement Networks with Saccades]) was used for quantifying prosaccades in patients with MS and healthy controls (HCs). The versional dysconjugacy index (VDI) was calculated, which describes the ratio between the abducting and adducting eye. The VDI was determined for peak velocity, peak acceleration, peak velocity divided by amplitude, and area under the curve (AUC) of the saccadic trajectory. We calculated the diagnostic accuracy for the several VDI parameters by a receiver operating characteristic analysis comparing HCs and patients with MS. The National Eye Institute Visual Function Questionnaire-25 was used to investigate vision-related quality of life of MS patients with INO. RESULTS: Two hundred ten patients with MS and 58 HCs were included. The highest diagnostic accuracy was achieved by the VDI AUC of 15° horizontal prosaccades. Based on a combined VDI AUC and peak velocity divided by amplitude detection, the prevalence of an INO in MS calculated to 34%. In the INO group, 35.2% of the patients with MS reported any complaints of double vision, compared to 18.4% in the non-INO group (p = 0.010). MS patients with an INO had a lower overall vision-related quality of life (median 89.9, interquartile range 12.8) compared to patients without an INO (median 91.8, interquartile range 9.3, p = 0.011). CONCLUSIONS: This study provides an accurate quantitative and clinically relevant definition of an INO in MS. This infrared oculography-based INO standard will require prospective validation. The high prevalence of INO in MS provides an anatomically well described and accurately quantifiable model for treatment trials in MS.

Saccadic fatigability in the oculomotor system.

BACKGROUND: Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), but challenging to quantify. This prospective study investigated if repeated saccadic eye movements enable measurement of oculomotor fatigability and can reflect on perceived fatigue in MS. METHODS: A standardized infrared oculography protocol (DEMoNS) was used for quantifying saccades in MS patients and healthy controls which included a first and a repeated pro-saccadic task (FPT and RPT). Saccadic peak velocity, latency, gain, area under the curve (AUC) and peak velocity divided by amplitude (Pv/Am) were calculated in both tasks. Perception based fatigue was assessed using the Checklist Individual Strength and the Neurological Fatigue Index (NFI). Linear regression models were used for assessing the relation between saccadic parameters and perceived fatigue. RESULTS: This study included 181 MS patients and 58 healthy controls subjects. From FPT to RPT, there were significant changes in saccadic parameters. Latency of both tasks was significantly related to NFI summary score (FPT: ß = 0.022, p = .049, RPT: ß 0.023, p = .021). These relationships were weakened after adjustment for Expanded Disability Status score (p > .05). There was however no significant group difference in changes in saccadic parameters. CONCLUSIONS: This study presents an objective and reproducible method for measuring saccadic fatigability. Saccadic fatigability was found to be of limited use in MS, and should be tested in conditions affecting ocular muscles or the neuromuscular junction.

Acid sphingomyelinase: No potential as a biomarker for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) lacks reliable biomarkers that reflect disease activity. Recent evidence suggests that an altered sphingolipid metabolism is associated with MS pathogenesis. OBJECTIVE: To explore acid sphingomyelinase (ASM) activity and altered sphingolipid metabolism as potential biomarkers in serum of MS patients, to predict active and progressive disease, and response to disease modifying therapy (DMT). METHODS: Levels of serum ASM activity were longitudinally analyzed in 40 clinically isolated syndrome, 64 relapsing remitting (RR) and 10 primary progressive MS patients, and 22 healthy controls (HC). ASM activity and sphingolipid levels were measured in a different sample of 61 RRMS patients using DMT. RESULTS: A significant difference in ASM activity levels was observed between MS patients and HC (p < 0.001). There was no correlation between ASM activity levels and disease activity, progression or response to DMT. Ceramide (Cer)-C16:0 , Cer-C24:0 and sphingomyelin (SM)-C20:0, SM-C22:0, SM-C24:0 and SM-C24:1 showed a significant increase during fingolimod use. CONCLUSION: Although higher levels in MS patients were found, ASM activity levels do not show potential as a biomarker for predicting disease activity, progression or response to DMT. Two ceramides and four types of sphingomyelin require further investigation as potential markers for treatment response.

Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab.

BACKGROUND: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. OBJECTIVE: To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. METHODS: Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. RESULTS: EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028). CONCLUSION: The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.

A standardized protocol for quantification of saccadic eye movements: DEMoNS.

OBJECTIVE: Quantitative saccadic testing is a non-invasive method of evaluating the neural networks involved in the control of eye movements. The aim of this study is to provide a standardized and reproducible protocol for infrared oculography measurements of eye movements and analysis, which can be applied for various diseases in a multicenter setting. METHODS: Development of a protocol to Demonstrate Eye Movement Networks with Saccades (DEMoNS) using infrared oculography. Automated analysis methods were used to calculate parameters describing the characteristics of the saccadic eye movements. The two measurements of the subjects were compared with descriptive and reproducibility statistics. RESULTS: Infrared oculography measurements of all subjects were performed using the DEMoNS protocol and various saccadic parameters were calculated automatically from 28 subjects. Saccadic parameters such as: peak velocity, latency and saccade pair ratios showed excellent reproducibility (intra-class correlation coefficients > 0.9). Parameters describing performance of more complex tasks showed moderate to good reproducibility (intra-class correlation coefficients 0.63-0.78). CONCLUSIONS: This study provides a standardized and transparent protocol for measuring and analyzing saccadic eye movements in a multicenter setting. The DEMoNS protocol details outcome measures for treatment trial which are of excellent reproducibility. The DEMoNS protocol can be applied to the study of saccadic eye movements in various neurodegenerative and motor diseases.

Retinal hyperaemia-related blood vessel artifacts are relevant to automated OCT layer segmentation.

A frequently observed local measurement artifact with spectral domain OCT is caused by the void signal of the retinal vasculature. This study investigated the effect of suppression of blood vessel artifacts with and without retinal hyperaemia. Spectral domain OCT scans, centred on the optic nerve head, were performed in 46 healthy subjects (92 eyes). Baseline scans were made during rest, while for the follow-up scan, 23 subjects (50 %) performed strenuous physical exercise. Systemic and retinal hyperaemia were quantified. Quantification of retinal nerve fibre layer (RNFL) thickness was performed with and without suppression of retinal blood vessel artifacts. The potential systematic effect on RNFL thickness measurements was analysed using Bland-Altman plots. At baseline (no retinal hyperaemia), there was a systematic difference in RNFL thickness (3.4 µm, limits of agreement -0.9 to 7.7) with higher values if blood vessel artifacts were not suppressed. There was significant retinal hyperaemia in the exercise group (p < 0.0001). Baseline thickness increased from 93.18 to 93.83 µm (p < 0.05) in the exercise group using the algorithm with blood vessel artifact suppression, but no significant changes were observed using the algorithm without blood vessel artifact suppression. Retinal hyperaemia leads to blood vessel artifacts which are relevant to the precision of OCT layer segmentation algorithms. The two algorithms investigated in this study can not be used interchangeably. The algorithm with blood vessel artifact suppression was more sensitive in detecting small changes in RNFL thickness. This may be relevant for the use of OCT in a range of neurodegenerative diseases were only a small degree of retinal layer atrophy have been found so far.

Reflection mode scanning near-field optical microscopy analyses of integrated devices.

Ultra-large-scale integrated devices have been investigated by a reflection mode scanning near-field optical microscope designed for semiconductor analyses. Although it could be found that imaging the reflectivity of metal structures buried underneath thin, optically transparent passivation layers is practicable, shading of the reflected light by the SNOM probe complicated the interpretability of the achieved results. This issue has been overcome by using the SNOM probe as both illumination source and detector, simultaneously. The application of focused ion beam milling to the probes has allowed the increase of the transmittivity of the probes to such an extent that coated fibres could be utilized and the interpretability of the results could be enhanced. Furthermore, the investigated structures are of great interest for an investigation of z-motion artefacts, as the presence of the polished passivation layers allows topographical influences to be distinguished from pure optical contrast.

Spectrally resolved cathodoluminescence analyses in the optical near-field.

By implementing a scanning near-field optical microscope into the specimen chamber of a scanning electron microscope, cathodoluminescence can be locally detected in the optical near-field. The achievable spatial resolution in this set-up is only limited by the size of the aperture in a coated fibre probe and its separation from the sample, rather than by the energy dissipation volume of the primary electrons and diffusion processes of excess carriers inside the specimen. We demonstrate how electronically active defects in polycrystalline diamond can be distinguished and localized with sub-wavelength lateral resolution by spectral filtering of the cathodoluminescence signal.