Diagnosing myasthenia gravis using orthoptic measurements: assessing extraocular muscle fatiguability.

INTRODUCTION: Diagnosing ocular myasthenia gravis (MG) can be challenging because serum antibodies are often not detected. We aimed to explore whether determining extraocular muscle (EOM) weakness using orthoptic measures, including an adapted Hess chart examination, can aid in diagnosing MG. METHODS: We conducted a prospective study among patients with acetylcholine receptor antibody positive MG (20 recently diagnosed, 19 chronic) and 14 seronegative MG patients. We compared orthoptic measures to 19 healthy and 18 disease controls with Graves orbitopathy, chronic progressive external ophthalmoplegia or oculopharyngeal muscular dystrophy. Maximal eye duction angles were measured using a synoptophore. Gaze deviations between eyes were measured using standard Hess chart examination with addition of 1 min persistent gaze to assess MG-associated fatiguability. Receiver operating characteristics curve analysis was performed. RESULTS: For duction angles, the area under the curve (AUC) was 0.73 comparing MG to healthy, and 0.69 comparing to patient controls. For the outer field of the Hess chart, the AUC was 0.89 comparing to healthy and 0.54 to patient controls. For drift, the AUC was 0.93 comparing to healthy and 0.93 to patient controls. The sensitivity and specificity of the presence of drift was 81% and 100%. DISCUSSION: Orthoptic measurements can be used to diagnose MG by quantifying EOM weakness and fatiguability. Drift during persistent gaze on a Hess chart is specific for MG and could be used for diagnostic purposes. The Hess chart examination is widely available, inexpensive and fast. Moreover, orthoptic measurements may be a clinically relevant outcome measure for clinical trials.

MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma.

PURPOSE: MRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound. METHODS: Twenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline. RESULTS: Pre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10-3mm2/s increase 12 months after treatment (p = 0.15). CONCLUSION: MR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

A Comparison of 3 T and 7 T MRI for the Clinical Evaluation of Uveal Melanoma.

BACKGROUND: Magnetic resonance imaging (MRI) is increasingly being used in the diagnosis and treatment planning of uveal melanoma (UM), the most common primary intraocular tumor. Initially, 7 T MRI was primarily used, but more recently these techniques have been translated to 3 T, as it is more commonly available. PURPOSE: Compare the diagnostic performance of 3 T and 7 T MRI of UM. STUDY TYPE: Prospective. POPULATION: Twenty-seven UM patients (19% female). FIELD STRENGTH/SEQUENCE: 3 T: T1- and T2-weighted three-dimensional (3D) spin echo (SE) and multi-slice (MS) SE, 7 T: T1-weighted 3D gradient echo (GE), T2-weighted 3D SE and MS SE, 3 T and 7 T GE dynamic contrast-enhanced. T1 weighted images: acquired before and after Gadolinium (Gd) administration. ASSESSMENT: For all sequences, scan and diagnostic quality was quantified using a 5-point Likert scale. Signal intensities on T1 and T2 relative to choroid and eye muscle respectively were assessed as well as the tumor prominence. Finally, the perfusion time-intensity curves (TICs) were classified as plateau, progressive, or wash-out. STATISTICAL TESTS: Image quality scores were compared between both field strengths using Wilcoxon signed-rank and McNemar tests. Paired t-tests and Bland-Altman were used for comparing tumor prominences. P < 0.05 was considered statistically significant. RESULTS: Image quality was comparable between 3 T and 7 T, for 3DT1, 3DT2, 3DT1Gd (P = 0.86; P = 0.34; P = 0.78, respectively) and measuring tumor dimensions (P = 0.40). 2DT1 and 2DT2 image quality were rated better on 3 T compared to 7 T. Most UM had the same relative signal intensities at 3 T and 7 T on T1 (17/21) and T2 (13/17), and 16/18 diagnostic TICs received the same classification. Tumor prominence measurements were similar between field strengths (95% confidence interval: -0.37 mm to 0.03 mm, P = 0.097). DATA CONCLUSION: Diagnostic performance of the evaluated 3 T protocol proved to be as capable as 7 T, with the addition of 3 T being superior in assessing tumor growth into nearby anatomical structures compared to 7 T. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

MR imaging characteristics of uveal melanoma with histopathological validation.

PURPOSE: To evaluate the magnetic resonance imaging (MRI) characteristics of uveal melanoma (UM), to compare them with fundoscopy and ultrasound (US), and to validate them with histopathology. METHODS: MR images from 42 UM were compared with US and fundoscopy, and on 14 enucleated cases with histopathology. RESULTS: A significant relationship between the signal intensity on T1 and pigmentation on histopathology was found (p=0.024). T1 hyperintense UM were always moderately or strongly pigmented on histopathology, while T1-hypointense UM were either pigmented or non-pigmented. Mean apparent diffusion coefficient (ADC) of the UM was 1.16 ± 0.26 × 10-3 mm2/s. Two-thirds of the UM had a wash-out and the remaining a plateau perfusion time-intensity curve (TIC). MRI was limited in evaluating the basal diameter of flat tumors. US tends to show larger tumor prominence (0.5mm larger, p=0.008) and largest basal diameter (1.4mm larger, p<0.001). MRI was good in diagnosing ciliary body involvement, extrascleral extension, and optic nerve invasion, but limited on identifying scleral invasion. An increase of tumor prominence was associated with lower ADC values (p=0.030) and favored a wash-out TIC (p=0.028). An increase of tumor ADC correlated with a plateau TIC (p=0.011). CONCLUSIONS: The anatomical and functional MRI characteristics of UM were comprehensively assessed. Knowing the MRI characteristics of UM is important in order to confirm the diagnosis and to differentiate UM from other intra-ocular lesions and because it has implications for treatment planning. MRI is a good technique to evaluate UM, being only limited in case of flat tumors or on identifying scleral invasion.

Two-year results after combined phacoemulsification and iris-fixated phakic intraocular lens removal.

PURPOSE: To describe and present results after a technique for cataract surgery combined with explantation of an iris-fixated phakic intraocular lens (IF-pIOL). METHODS: The medical records of all patients, who had undergone cataract surgery combined with IF-pIOL explantation and subsequent implantation of a posterior chamber IOL by the Single Incision Technique (SIT), were reviewed. Data collection included preoperative and postoperative corrected distance visual acuity (CDVA), manifest refraction, and endothelial cell density (ECD) up to a follow-up time of 24 months. RESULTS: Fifty myopic eyes (34 patients) and 9 hyperopic eyes (6 patients) had undergone a SIT procedure mainly because of cataract (67%). Postoperative CDVA improved in both the myopic eyes to 0.16 ± 0.37 logMAR, as in the hyperopic eyes to - 0.10 ± 0.55 logMAR with no eyes having loss of Snellen lines. Mean postoperative spherical equivalent was - 0.34 ± 0.72 D and - 0.10 ± 0.55 D, respectively. ECD loss 6 months after surgery was 5% and remained stable thereafter. CONCLUSION: SIT for combined phacoemulsification and IF-pIOL removal yields good visual and refractive results and is a safe procedure in regard to ECD loss. The technique has advantages over the conventional procedure and is easy to perform.

Eye-specific quantitative dynamic contrast-enhanced MRI analysis for patients with intraocular masses.

OBJECTIVE: Dynamic contrast enhanced (DCE)-MRI is currently not generally used for intraocular masses as lesions are small, have an inhomogeneous T1 and the eye is prone to motion. The aim of this paper is to address these eye-specific challenges, enabling accurate ocular DCE-MRI. MATERIALS & METHODS: DCE-MRI of 19 uveal melanoma (UM) patients was acquired using a fat-suppressed 3D spoiled gradient echo sequence with TWIST (time-resolved angiography with stochastic trajectories sequence). The analysis consisted of a two-step registration method to correct for both head and eye motion. A T1 map was calculated to convert signal intensities to concentrations. Subsequently, the Tofts model was fitted voxel wise to obtain Ktrans and ve. RESULTS: Registration significantly improved the concentration curve quality (p < 0.001). The T1 of melanotic lesions was significantly lower than amelanotic lesions (888 ms vs 1350 ms, p = 0.03). The average achieved B1+ in the lesions was 91%. The average Ktrans was 0.46 min-1 (range 0.13-1.0) and the average ve was 0.22 (range 0.10-0.51). CONCLUSION: Using this eye-specific analysis, DCE of intraocular masses is possible which might aid in the diagnosis, prognosis and follow-up of UM.

The Value of Static Perimetry in the Diagnosis and Follow-up of Negative Dysphotopsia.

SIGNIFICANCE: There is a clinical need for a quantitative test to objectively diagnose negative dysphotopsia, especially because the diagnosis is generally assessed using patients' subjective descriptions. In the search of a clinical test to objectify the shadow experienced in negative dysphotopsia, this study excludes static perimetry as suitable evaluation method. PURPOSE: This study aimed to evaluate the value of static perimetry in the objective assessment and follow-up of negative dysphotopsia. METHODS: Peripheral 60-4 full-threshold visual field tests were performed in 27 patients with negative dysphotopsia and 33 pseudophakic controls. In addition, 11 patients with negative dysphotopsia repeated the test after an intraocular lens exchange. Both the total peripheral visual field and the averaged peripheral visual field from 50 to 60° eccentricity were compared between patients and controls, and pre-operatively and post-operatively in patients who had an intraocular lens exchange. RESULTS: The peripheral visual fields from 30 to 60° did not show significant differences between patients with negative dysphotopsia and pseudophakic controls. Analysis of the peripheral visual field from 50 to 60° showed a median [Q1, Q3] of 20.0 [17.1, 22.5] dB in the negative dysphotopsia group compared with 20.1 [15.5, 21.3] dB in the control group (P = .43). Although 82% of patients treated with an intraocular lens exchange subjectively reported improvement of their negative dysphotopsia complaints post-operatively, there were no significant differences in their total peripheral visual field or averaged peripheral visual field from 50 to 60° (P = .92). CONCLUSIONS: Full-threshold static perimetry with a Goldmann size III stimulus up to 60° eccentricity does not show significant differences between patients with negative dysphotopsia and pseudophakic controls or between measurements before and after intraocular lens exchange. Therefore, this type of static perimetry cannot be used as a quantitative objective test for diagnosis or follow-up of patients with negative dysphotopsia.

Outcome Measures of New Technologies in Uveal Melanoma: Review from the European Vision Institute Special Interest Focus Group Meeting.

Uveal Melanoma (UM) is the most common primary intra-ocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma", addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's wellbeing. This review highlights the meeting's presentations in the context of the published literature.

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2water ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2water values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2water and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm3 (LoA: ± 0.36 cm3 ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm3 ) and MG (0.8 ± 0.2 cm3 ) compared with HC (0.6 ± 0.2 cm3 ). The average T2water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.

Differences between Scheimpflug and optical coherence tomography in determining safety distances in eyes with an iris-fixating phakic intraocular lens.

PURPOSE: To investigate the agreement and reliability of anterior segment optical coherence tomography (AS-OCT) and Scheimpflug imaging in measuring the distance from the anterior edge of an iris-fixated phakic intraocular lens (IF-pIOL) to the corneal endothelium. METHODS: Anterior segment configuration was assessed in a total of 62 eyes of which 25 hyperopic and 37 myopic eyes, all corrected with an IF-pIOL. Measurements were performed by two independent observers using AS-OCT (Visante, Model 1000, Carl Zeiss Meditec Inc.) and Scheimpflug imaging (Pentacam HR, Oculus Optikgerate). The distance from the anterior edge of the pIOL to the endothelium was measured in five different positions using both modalities with their corresponding pIOL software. The measurements as well as the inter- and intra-observer reliability of the two imaging modalities were then compared. RESULTS: Distance measurements for all positions performed by AS-OCT were found to be significantly larger than those performed by Scheimpflug imaging, with mean differences ranging from 0.11 to 0.22 mm. Both instruments exhibited good inter- and intra-observer reliability. CONCLUSION: Anterior pIOL edge to endothelium distance measurements by AS-OCT and Scheimpflug imaging have good intra- and inter-observer reliability. However, as AS-OCT provides larger measurements, these two modalities cannot be used interchangeably. Correction of this difference might be essential for proper decision-making during pre-operative screening for pIOL implantation and post-operative safety monitoring.

T2 relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

PURPOSE: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T2 of the myocytic component (T2water ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T2fat calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T2fat . METHODS: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T2fat estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T2fat calibration methods and T2water estimations. RESULTS: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T2water up to 10 ms. Furthermore, a wrongly calibrated T2fat caused a bias of up to 4 ms in T2water . For the in vivo data, one-component calibration led to a lower T2fat compared with a two-component method, and T2water decreased with increasing fat fractions. CONCLUSION: In vivo data showed a decline in T2water for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T2water from MSE sequences with two-component T2fat calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.

Cartesian MR fingerprinting in the eye at 7T using compressed sensing and matrix completion-based reconstructions.

PURPOSE: To explore the feasibility of MR Fingerprinting (MRF) to rapidly quantify relaxation times in the human eye at 7T, and to provide a data acquisition and processing framework for future tissue characterization in eye tumor patients. METHODS: In this single-element receive coil MRF approach with Cartesian sampling, undersampling is used to shorten scan time and, therefore, to reduce the degree of motion artifacts. For reconstruction, approaches based on compressed sensing (CS) and matrix completion (MC) were used, while their effects on the quality of the MRF parameter maps were studied in simulations and experiments. Average relaxation times in the eye were measured in 6 healthy volunteers. One uveal melanoma patient was included to show the feasibility of MRF in a clinical context. RESULTS: Simulation results showed that an MC-based reconstruction enables large undersampling factors and also results in more accurate parameter maps compared with using CS. Experiments in 6 healthy volunteers used a reduction in scan time from 7:02 to 1:16 min, producing images without visible loss of detail in the parameter maps when using the MC-based reconstruction. Relaxation times from 6 healthy volunteers are in agreement with values obtained from fully sampled scans and values in literature, and parameter maps in a uveal melanoma patient show clear difference in relaxation times between tumor and healthy tissue. CONCLUSION: Cartesian-based MRF is feasible in the eye at 7T. High undersampling factors can be achieved by means of MC, significantly shortening scan time and increasing patient comfort, while also mitigating the risk of motion artifacts.

9.4T and 17.6T MRI of Retinoblastoma: Ex Vivo evaluation of microstructural anatomy and disease extent compared with histopathology.

BACKGROUND: Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. PURPOSE: To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. STUDY TYPE: Prospective case series. POPULATION: Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). FIELD STRENGTH/SEQUENCE: In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. ASSESSMENT: After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). RESULTS: Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 µm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 µm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. DATA CONCLUSION: Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

Automated eye blink detection and correction method for clinical MR eye imaging.

PURPOSE: To implement an on-line monitoring system to detect eye blinks during ocular MRI using field probes, and to reacquire corrupted k-space lines by means of an automatic feedback system integrated with the MR scanner. METHODS: Six healthy subjects were scanned on a 7 Tesla MRI whole-body system using a custom-built receive coil. Subjects were asked to blink multiple times during the MR-scan. The local magnetic field changes were detected with an external fluorine-based field probe which was positioned close to the eye. The eye blink produces a field shift greater than a threshold level, this was communicated in real-time to the MR system which immediately reacquired the motion-corrupted k-space lines. RESULTS: The uncorrected images, using the original motion-corrupted data, showed severe artifacts, whereas the corrected images, using the reacquired data, provided an image quality similar to images acquired without blinks. CONCLUSION: Field probes can successfully detect eye blinks during MRI scans. By automatically reacquiring the eye blink-corrupted data, high quality MR-images of the eye can be acquired. Magn Reson Med 78:165-171, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Clinical evaluation of ultra-high-field MRI for three-dimensional visualisation of tumour size in uveal melanoma patients, with direct relevance to treatment planning.

OBJECTIVES: To assess the tumour dimensions in uveal melanoma patients using 7-T ocular MRI and compare these values with conventional ultrasound imaging to provide improved information for treatment options. MATERIALS AND METHODS: Ten uveal melanoma patients were examined on a 7-T MRI system using a custom-built eye coil and dedicated 3D scan sequences to minimise eye-motion-induced image artefacts. The maximum tumour prominence was estimated from the three-dimensional images and compared with the standard clinical evaluation from 2D ultrasound images. RESULTS: The MRI protocols resulted in high-resolution motion-free images of the eye in which the tumour and surrounding tissues could clearly be discriminated. For eight of the ten patients the MR images showed a slightly different value of tumour prominence (average 1.0 mm difference) compared to the ultrasound measurements, which can be attributed to the oblique cuts through the tumour made by the ultrasound. For two of these patients the more accurate results from the MR images changed the treatment plan, with the smaller tumour dimensions making them eligible for eye-preserving therapy. CONCLUSION: High-field ocular MRI can yield a more accurate measurement of the tumour dimensions than conventional ultrasound, which can result in significant changes in the prescribed treatment.

Correction Method for Optical Scaling of Fundoscopy Images: Development, Validation, and First Implementation.

Purpose: Although fundus photography is extensively used in ophthalmology, refraction prevents accurate distance measurement on fundus images, as the resulting scaling differs between subjects due to varying ocular anatomy. We propose a PARaxial Optical fundus Scaling (PAROS) method to correct for this variation using commonly available clinical data. Methods: The complete optics of the eye and fundus camera were modeled using ray transfer matrix formalism to obtain fundus image magnification. The subject's ocular geometry was personalized using biometry, spherical equivalent of refraction (RSE), keratometry, and/or corneal topography data. The PAROS method was validated using 41 different eye phantoms and subsequently evaluated in 44 healthy phakic subjects (of whom 11 had phakic intraocular lenses [pIOLs]), 29 pseudophakic subjects, and 21 patients with uveal melanoma. Results: Validation of the PAROS method showed small differences between model and actual image magnification (maximum 3.3%). Relative to the average eye, large differences in fundus magnification were observed, ranging from 0.79 to 1.48. Magnification was strongly inversely related to RSE (R2 = 0.67). In phakic subjects, magnification was directly proportional to axial length (R2 = 0.34). The inverse relation was seen in pIOL (R2 = 0.79) and pseudophakic (R2 = 0.12) subjects. RSE was a strong contributor to magnification differences (1%-83%). As this effect is not considered in the commonly used Bennett-Littmann method, statistically significant differences up to 40% (mean absolute 9%) were observed compared to the PAROS method (P < 0.001). Conclusions: The significant differences in fundus image scaling observed among subjects can be accurately accounted for with the PAROS method, enabling more accurate quantitative assessment of fundus photography.

Geometrical accuracy of magnetic resonance imaging for ocular proton therapy planning.

Background & purpose: Magnetic resonance imaging (MRI) is increasingly used in treatment preparation of ocular proton therapy, but its spatial accuracy might be limited by geometric distortions due to susceptibility artefacts. A correct geometry of the MR images is paramount since it defines where the dose will be delivered. In this study, we assessed the geometrical accuracy of ocular MRI. Materials & methods: A dedicated ocular 3 T MRI protocol, with localized shimming and increased gradients, was compared to computed tomography (CT) and X-ray images in a phantom and in 15 uveal melanoma patients. The MRI protocol contained three-dimensional T2-weighted and T1-weighted sequences with an isotropic reconstruction resolution of 0.3-0.4 mm. Tantalum clips were identified by three observers and clip-clip distances were compared between T2-weighted and T1-weighted MRI, CT and X-ray images for the phantom and between MRI and X-ray images for the patients. Results: Interobserver variability was below 0.35 mm for the phantom and 0.30(T1)/0.61(T2) mm in patients. Mean absolute differences between MRI and reference were below 0.27 ± 0.16 mm and 0.32 ± 0.23 mm for the phantom and in patients, respectively. In patients, clip-clip distances were slightly larger on MRI than on X-ray images (mean difference T1: 0.11 ± 0.38 mm, T2: 0.10 ± 0.44 mm). Differences did not increase at larger distances and did not correlate to interobserver variability. Conclusions: A dedicated ocular MRI protocol can produce images of the eye with a geometrical accuracy below half the MRI acquisition voxel (<0.4 mm). Therefore, these images can be used for ocular proton therapy planning, both in the current model-based workflow and in proposed three-dimensional MR-based workflows.

Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition in a zebrafish xenograft model.

Inhibition of VEGF signalling effectively suppresses localized tumour growth but accelerates tumour invasiveness and micrometastasis by unknown mechanisms. To study the dynamic and reciprocal interactions between tumour cells and their microenvironment during these processes, we established a xenograft model by injecting tumour cells into the blood circulation of transparent zebrafish embryos. This reproducibly results in rapid simultaneous formation of a localized tumour and experimental micrometastasis, allowing time-resolved imaging of both processes at single-cell resolution within 1 week. The tumour vasculature was initiated de novo by remodelling of primitive endothelial cells into a functional network. Roles of myeloid cells in critical tumourigenesis steps such as vascularization and invasion were revealed by genetic and pharmaceutical approaches. We discovered that the physiological migration of neutrophils controlled tumour invasion by conditioning the collagen matrix and forming the metastatic niche, as detected by two-photon confocal microscopy and second harmonic generation. Administration of VEGFR inhibitors blocked tumour vascularization and a localized tumour growth but enhanced migration of neutrophils, which in turn promoted tumour invasion and formation of micrometastasis. This demonstrates the in vivo cooperation between VEGF signalling and myeloid cells in metastasis and provides a new mechanism underlying the recent findings that VEGFR targeting can promote tumour invasiveness.

Distinct defects in collagen microarchitecture underlie vessel-wall failure in advanced abdominal aneurysms and aneurysms in Marfan syndrome.

An aneurysm of the aorta is a common pathology characterized by segmental weakening of the artery. Although it is generally accepted that the vessel-wall weakening is caused by an impaired collagen metabolism, a clear association has been demonstrated only for rare syndromes such as the vascular type Ehlers-Danlos syndrome. Here we show that vessel-wall failure in growing aneurysms of patients who have aortic abdominal aneurysm (AAA) or Marfan syndrome is not related to a collagen defect at the molecular level. On the contrary our findings indicate similar (Marfan) or even higher collagen concentrations (AAA) and increased collagen cross-linking in the aneurysms. Using 3D confocal imaging we show that the two conditions are associated with profound defects in collagen microarchitecture. Reconstructions of normal vessel wall show that adventitial collagen fibers are organized in a loose braiding of collagen ribbons. These ribbons encage the vessel, allowing the vessel to dilate easily but preventing overstretching. AAA and aneurysms in Marfan syndrome show dramatically altered collagen architectures with loss of the collagen knitting. Evaluations of the functional characteristics by atomic force microscopy showed that the wall has lost its ability to stretch easily and revealed a second defect: although vascular collagen in normal aortic wall behaves as a coherent network, in AAA and Marfan tissues it does not. As result, mechanical forces loaded on individual fibers are not distributed over the tissue. These studies demonstrate that the mechanical properties of tissue are strongly influenced by collagen microarchitecture and that perturbations in the collagen networks may lead to mechanical failure.