Joël Lefebvre

Patrick Delafontaine-Martel

Philippe Lemieux

Maxime Descoteaux

Laurent Petit

Frédéric Lesage

Localization and imaging of white matter fiber crossings in whole mouse brains using diffusion MRI and serial blockface OCT

Keywords: Whole Brain Imaging, Neurophotonics, Multimodal Imaging, Diffusion MRI, Optical Coherence Tomography, Serial Blockface Histology

To obtain an accurate representation of a brain structural connectivity, diffusion MRI and fiber tracking depend on a good understanding of white matter fiber structures. Although the tracking methods work well when performed in single orientation fiber bundles, most methods are limited in more complex cases, especially to take into account crossing, fanning, and kissing fibers. A recent international fiber tracking challenge concluded that most tracking algorithms generated 4-5 times more false positive tracks than true tracks on average. This was attributed in large part to a lack of knowledge about the fiber crossing geometry. There is thus a dire need to study more complex fiber geometries to improve the tractography algorithms, for example by classifying those geometries into characteristic crossing topologies (e.g., fanning, curving, bottleneck, pure crossing, ...). Here, we propose a multimodal neuroimaging pipeline to identify and acquire fiber crossing areas in whole mouse brains. Our method uses the Allen Mouse Brain connectivity atlas and tractogram analysis using diffusion MRI techniques to identify candidate regions of interests containing fiber crossings based on two predetermined retrograde viral injection site locations. Based on serial OCT acquisitions, we confirmed the location of crossings. Further experiments will validate in detail the structural nature of crossings using retrograde injections of fluorescent tracers and whole mouse brain serial blockface histology. We believe that this new methodological approach will provide indispensable data for the development of a new generation of tractography algorithms that better resolve complex fiber geometries.

INTRODUCTION

To obtain an accurate representation of the brain structural connectivity, diffusion MRI and fiber tracking depend on a good understanding of white matter fiber structures. Although the tracking methods work well when performed in single orientation fiber bundles, most methods are limited in more complex cases, for example in the presence of crossing, fanning, and kissing fibers. A recent international fiber tracking challenge concluded that across groups, most tracking algorithms could detect 90% of the true tracks from synthetic brain data, but that all methods consistently generated 4-5 times more false positive tracks on average. [START_REF] Maier-Hein | The challenge of mapping the human connectome based on diffusion tractography[END_REF] This was attributed in large part to a lack of knowledge about the fiber crossing geometry. There is thus a dire need to study more complex fiber geometries to improve the tractography algorithms, for example by classifying those geometries into characteristic crossing topologies (e.g., fanning, curving, bottleneck, pure crossing, . . . ). Here, we propose a multimodal neuroimaging pipeline to identify and acquire fiber crossing areas in whole mouse brains.

Our imaging pipeline is based on the previously published work. [START_REF] Lefebvre | Whole mouse brain imaging using optical coherence tomography: reconstruction, normalization, segmentation, and comparison with diffusion MRI[END_REF][START_REF] Lefebvre | Fully automated dual-resolution serial optical coherence tomography aimed at diffusion MRI validation in whole mouse brains[END_REF] It combines diffusion MRI and dualresolution OCT to acquire whole mouse brains in a fully automated fashion. Here, we focus on the experimental Further author information: (Send correspondence to lefebvre.joel@uqam.ca) preparation phase of this pipeline. Indeed, due to the high amount of data generated by serial histology and to limit the use of animals, one needs to carefully plan these neuroimaging experiments. Our overarching research goal is to study white matter fiber crossing geometry in order to improve the performance of diffusion MRI-based tractography algorithms in those critical areas. To do so, we first need to identify fiber crossing areas in the mouse brain that will be targeted with a high resolution optical microscope sensitive to white matter. One could use diffusion MRI data, obtained before the ex vivo microscopy acquisition, to identify potential fiber crossing areas. Another approach, which we propose in this paper, is to exploit the extensive Allen Mouse brain connectivity atlas. [START_REF] Oh | A mesoscale connectome of the mouse brain[END_REF]

METHODS

Multimodal imaging pipeline

The multimodal imaging pipeline is separated into three phases. The initial phase is experiment planning. This consists in using existing datasets and past experiments to identify candidate regions of interest (ROIs) in the mouse brain where we might expect fiber crossings. The second phase of the pipeline, which we presented in previous publications, [START_REF] Lefebvre | Whole mouse brain imaging using optical coherence tomography: reconstruction, normalization, segmentation, and comparison with diffusion MRI[END_REF][START_REF] Lefebvre | Fully automated dual-resolution serial optical coherence tomography aimed at diffusion MRI validation in whole mouse brains[END_REF] consists in the actual multimodal acquisition itself. In the previous paper, we used a serial dual-resolution optical coherence tomography (2R-SOCT), combined with diffusion MRI, to image whole mouse brains at high resolution. The third phase consists in data reconstruction and multimodal registration of the OCT and dMRI data. The focus of this conference paper is to present the experimental planning phase that we intend to use to study fiber crossings.

Fiber crossing localization

The Allen Mouse Brain Connectivity Atlas 4, 5 offers data for around 3,000 experiments where a mouse brain was injected with a fluorescent virus which was followed throughout the mouse neurons. This atlas consists in 3D high-resolution map of neural connections in the mouse brain. The axonal projections, originating from various injection sites, were aligned to the Allen Mouse brain common coordinate framework (CCF) to create a neural projection database. This data can be browsed and queried using some of the many modules of the Allen software development kit (SDK). In this paper, we used the neuronal projection paths toward the injection site to identify potential fibers crossing areas. Using the Allen software development kit (SDK), we created a Flask web interface for studying the topology of fibers crossing in mouse brains. This application lets users browse and query experiment data from the Mouse Connectivity Project, as well as looking for potential structures for fiber crossing. The developed platform enables non-programming experts to filter the Allen connectivity Atlas database with a set of search parameters and experimental constraints; this creates an experimental planning map used to assist the microscope operator during the acquisition.

Given two injection site locations our method uses the Allen mouse brain connectivity atlas to identify fiber crossing areas to image. Exploiting retrograde injections from the Allen Mouse brain connectivity dataset, we have selected a list of experiments for which the injection site was in the isocortex of wild-type mice. With this experiment filter, we performed a source search and identified a list of 129 candidate experiments. Then, for each of these experiments we have generated the projection matrix for all the descendant structures of the fiber tracts group in the mouse brain ontological atlas. These amount to 191 fiber structures. They were further separated by hemisphere (left, right, and both), which gives a total of 3 × 191 = 573 structures. Of these, 252 structures did not have any projection signal and were ignored in the analysis. The value within the projection matrix consists in the average fluorescence density within the structure. We defined candidate fiber crossing areas by comparing the projection matrix between multiple retrograde tracer injection experiments. If multiple experiments resulted in high fluorescent expression in the same brain areas, this brain area was selected as a candidate ROIs for imaging.

An additional streamline analysis was performed to better identify the expected crossing geometry (e.g., number of fiber orientations). The streamlines were downloaded from the Allen Institute database and inspected with the MI-Brain software * . The streamline data set was made available through the Neuroinformatics-NL group † . The streamlines were generated from the viral projection maps with a simple marching cube method and they represent the shortest path from any viral projection voxel to the injection site location for each experiment. We performed a Tract Orientation Density Imaging (TODI) analysis [START_REF] Dhollander | Track orientation density imaging (TODI) and track orientation distribution (TOD) based tractography[END_REF] with the viral projection tractograms to obtain fiber orientation distribution function (fODF), which then allowed the use of diffusion MRI methods to evaluate the number of fiber orientations 7 (NuFO) and of apparent fiber density maximum 8 (AFD max).

We combined the information gathered from the Allen connectivity atlas, and from the streamlines analysis and displayed it as a color-coded coronal slice montage (Fig. 1). Simulating an injection experiment, we also displayed two neural projection maps with two different colors, and delineated the expected fiber crossing area with blue overlay. This experimental planning map served as a reference for the microscope operator in the data acquisition phase of the experiment. It was also used to identify 40X OCM mosaics that contained the candidate ROIs.

Figure 1. Viral projections (Left) and associated streamlines (Right) for two injection site locations (Red and Green). The data was obtained from the Allen Institute through its AllenSDK python package and was used to target fiber-crossing areas (blue) to image with our system. Here the primary injection structures are the ectorhinal and visceral cortex areas respectively.

Data Acquisition

We used two sources of data to investigate the fiber crossing localization method. First, we exploited 40X OCM mosaics that were acquired with our previously published fully automated dual-resolution serial OCT system. This system consisted in a motorized sample holder coupled with a vibrating blade. The vibratome sequentially removed small 200 microns layers of agarose embedded brain tissue, and then moved the sample under a 3X objective to acquire a low-resolution mosaic. A coarse image reconstruction was performed on-line and the tissue area was detected using image processing methods. Then the sample was placed automatically under a 40x microscope objective, and 40X optical coherence microscopy (OCM) mosaic acquisitions were performed for this slice. The sequence of vibratome slicing, 3X imaging and 40X imaging was repeated automatically until the whole brain was acquired. With this system, multiple high resolution OCM mosaics were generated in various locations in the mouse brain. Using this procedure, we built a dataset of 345 high resolution mosaics acquired in 6 mouse brains (this data was acquired for another neuroimaging study, and animal ethics protocols were followed). Using this low-res/high-res OCT dataset, we identified 40x OCM mosaics that were acquired within the fiber crossing candidate ROIs identified with the method described in the previous section.

In addition to the 40X OCM mosaics, we also performed new acquisitions in a single mouse brain and targeted four different regions with a 25x OCM system. 9 An 8-month-old mouse's brain has been retrieved after culling via transcardiac PFA injection. For fixation in a matrix of agarose (4%), a custom hook holds the sample steady inside a custom holder used as a mold. The solution of agarose is then heated to 70 degree Celsius until it becomes transparent. The agarose is then poured in the mold to enclose the sample inside the agarose matrix during the cooling. The matrix is then freed from the custom mold and cut with a scalpel at the desired bregma cut. For the imaging, an SD-OCM coupled with a Thorlabs camera via a spectral filter used to locate the area of imaging. To enable 3D imaging, a Newport linear motor stage performs SD-OCM with axial steps of 20 microns, which correspond to the Rayleigh length of the microscope objective (XLPLN-MP 25x, Olympus) at 1310 nm and a PSF of 4 microns of diameter. The OCM stacks were assembled with the Gabor fusion method. [START_REF] Rolland | Gabor-based fusion technique for Optical Coherence Microscopy[END_REF]

RESULTS

As a proof of concept, we selected the two injection experiments that had the highest viral projection density across all fiber tract structures (see Fig. 1). For these, the injections were in the right hemisphere and the four fiber structures exhibiting the largest correlated fluorescence signal, as defined by the product of their respective unionized projection density, were the extreme capsule of the corpus callosum, the amygdala capsule, and both side (left/right hemispheres) of the anterior commissure temporal limb (delineated in blue in Fig. 1).

Figure 2. Serial OCT imaging of a whole brain with our previously published dual-resolution OCT system. [START_REF] Lefebvre | Fully automated dual-resolution serial optical coherence tomography aimed at diffusion MRI validation in whole mouse brains[END_REF] High resolution imaging of identified fiber crossing areas reveals complex fiber crossing geometries. Similar observations were made with diffusion MRI acquisitions in the same mouse brain. The Allen connectivity-derived tractogram was analyzed with the TODI method (Allen TODI) of the dMRI scilpy analysis python package § .

Based on this experimental planning map, we then identified 40x OCM mosaics (Fig. 2). Qualitatively we can see that these regions indeed contain complex fiber geometries. We performed a 2D structure tensor analysis to detect the local principal orientations. [START_REF] Wang | Structure tensor analysis of serial optical coherence scanner images for mapping fiber orientations and tractography in the brain[END_REF] To display the orientation, we use the HSV color coding scheme (hue : angle, saturation : tensor energy, value : image intensity). As can be seen in the Fig. 3, the structure tensor was able to detect the main in-plane orientation of the fiber structures.

We also computed local orientation distribution functions (ODFs) using the extracted orientation from the structure tensor analysis (Fig. 3, bottom row). We used neighborhood size of 64 pixels (corresponding to around 200 microns) and we applied an angular smoothing with a Gaussian kernel (σ = 3). As can be seen, we detect small orientation orientations in tightly packed fiber bundles such as in the anterior commissure. Multiple orientation peaks are observed in areas of fanning geometry.

In addition to automated 40X OCM mosaics, we performed OCT acquisitions in a few regions of mouse brain slice. Those regions were selected by the microscope operator based on the generated experimental planning maps. Those areas are in the corpus callosum, the auditory radiation, and two locations in the endopiriform nucleus (Fig. 4, only the corpus callosum is shown). For the corpus callosum, the assembled OCM volume shows multiple fiber bundles crossings. Upon visual inspection one can see that some fibers overlap others. We are optimistic that this kind of 3D OCM data can be used to distinguish between interleaving, fanning and other crossing geometries. This will be the subject of further investigations.

DISCUSSION

In this paper, we made use of an existing public dataset of mouse brain connectivity to identify brain regions that might contain fiber crossings. With this information, we generated experimental planning maps that were used to assist the microscope operator during acquisition. These maps were compared with 40x mosaics that were acquired automatically with a serial OCT system in a previous study. They were also used to guide 3D OCM stacks acquisitions in new mouse brain slices. With this data, complex white matter fiber geometries were visualized in 2D and in 3D. This proposed fiber crossing localization methodology will be part of a multimodal neuroimaging pipeline combining serial OCT with diffusion MRI.

An advantage of our approach is that it reduces the number of animal experiments that are necessary to target specific brain areas by exploiting the extensive database of injection experiments and neural mappings that were performed by the Allen Institute. In addition to a reduction of animal use, which is one of the aims of animal ethics committees, this use of existing datasets could prove beneficial for small research labs and for small-scale animal brain imaging studies.

The experimental planning maps combines regions of interest overlays and expected neural projections for specific injection locations. This map was shown to be useful to assist a microscope operator. This approach was particularly interesting in the context of remote working where precise and reproducible mouse brain imaging experiments need to be communicated to the limited staff present in the imaging lab. In this study, we used these maps to manually target ROIs with OCM in mouse brain slices, and to identify 40x mosaics within an existing serial OCT dataset. To further automatize serial histology, these experimental planning maps could be integrated in the microscope's control interface and combined with computer vision approach to provide in situ information about the ROIs to target. Also these maps could include other information (e.g., expert delineated targets), and other imaging modalities (e.g., diffusion MRI), thus providing other ways of targeting ROIs.

One limitation of our method is that OCT uses intrinsic contrast of brain tissue, as opposed to the 2-photon fluorescence microscopy used to build the Allen connectivity atlas. OCT is more sensitive to myelinated axons and in-plane fiber bundles, but it also has contrast in other regions such as axially inclined fiber bundles, gray matter and other tissues. Instead, 2-photon fluorescence microscopy combined with injections of retrograde tracers can only visualize the projections of a small subset of infected neurons. A consequence is that the fiber crossing areas identified from the Allen connectivity atlas may not be readily visible in OCT. Furthermore, our fiber crossing localization method identified candidate ROIs by verifying if two injection experiments resulted in strong fluorescence co-expression in the same brain areas. This approach detects fiber crossings regardless of its topology (crossing, interleaved, fanning, collinear, ...). To address these limitations, one could use more than 2 injection sites to identify fiber crossings to better emulate the tissue structures visible with OCT, and one could integrate streamlines analysis to better detect and distinguish between expected crossing topologies.

Regarding the 2D structure tensor analysis to extract the principal local orientation, careful interpretation is required. First of all, the filter response greatly depends on its parameters (i.e., pre-smoothing and neighborhood kernel sizes) and on the local size of the structure being analyzed. For example, using a small pre-smoothing size will extract the orientation of small structures and of large structure boundaries, but will result in apparent isotropic orientations inside large fiber bundles. Also, large neighborhood sizes lead to smoother orientation maps at the expense of loss of spatial information. In addition to this parameter sensitivity, we have observed (with synthetic and real data) that isotropic areas were erroneously described by the structure tensor analysis as containing 2 main orientations instead of a uniform distribution of orientations. We believe that this is due to a poor angular resolution of the structure tensor and to a sensitivity bias toward certain orientations. Regardless of the cause of this bias, which would necessitate further investigation, one does need to be careful when using structure tensor derived metrics to identify fiber crossings.

Finally, we performed a TODI analysis 6 to convert tractograms acquired from the Allen mouse brain connectivity atlas into fiber orientation diffusion functions (fODF). The TODI-derived fODF were then used to estimate the number of fiber orientations (NuFO) and the apparent fiber density maximum (AFD max). This information was provided with the experimental planning maps. While doing this analysis we observed that certain voxels resulted in enormous fiber density. Upon closer inspection, we realized that the streamlines generated by the 3D marching cube algorithm effectively represent a path within the maximum fluorescent intensity from any point in the neural projection toward the injection site. This represents a bias as all the streamlines will cross the same voxels when performed with neural projections containing single axons and other thin structures. To address this one could perform tractogram cleaning, streamline fusions, or other preprocessing methods to avoid concentrating all streamlines in individual voxels. Integrating more thorough tractogram analysis in the experimental planning map would be an interesting approach to distinguish between various fiber crossing area geometries.

CONCLUSION

In this paper we presented a method to identify candidate brain regions containing fiber crossings, which can then be acquired with serial blockface histology or with other imaging modalities. Our method made use of the publicly available Allen mouse brain connectivity atlas to detect brain areas exhibiting fluorescence co-expression between two viral injection experiments. We generated experimental planning maps to assist the microscope operator during the acquisition. Our method was able to target some fiber crossing candidates, even though it lacked discriminability between fiber crossing geometries (such as fanning, interleaving, collinear, etc.). Further work will address this limitation, for example by better analyzing optical modality-derived tractograms and by integrating diffusion MRI data into the experimental planning phase. Future experiments will validate in detail the structural nature of crossings using retrograde injections of fluorescent tracers. We believe that this new methodological approach will provide indispensable data for the development of a new generation of tractography algorithms that better resolve complex fiber geometries. It will empower neuroanatomists and dMRI scientists to ask new questions and to validate the hypotheses used to understand the diffusion signal.

Figure 3 .

 3 Figure 3. 40X OCM mosaics. (Left) 3X OCT brain slices used to automatically detect 40X ROIs. (Top row) Color coded 40x mosaics (the color wheel indicate the local orientation, as estimated with 2D structure tensor). (Bottom row) Local orientation distribution functions for the corresponding mosaics.

Figure 4 .

 4 Figure 4. Montage of an assembled 3D OCM acquired in the corpus callosum. Each image represents a different axial depth within the stack, organized in a row-first order. The data was denoised with a non-local mean filter and the intensity was normalized for each slice separately.

† https://neuroinformatics.nl/

ACKNOWLEDGMENTS

This work was supported by a Québec Bioimaging Network (QBIN) pilot research project grant (35450) and by a FRQNT team research project grant (2021-PR-282231).

We also wish to express our gratitude to all the open science efforts, such as the mouse brain images and the connectivity data shared by the Allen Mouse Brain Institute and by the Neuroinformatics-NL group. Open science democratizes the access to mouse brain data and enables the pursuit of various neuroimaging experiments and novel questions. It is particularly useful in this time of uncertainty related to COVID-19, where many labs and research groups have limited access to animals, imaging facilities and other resources.


Clara Plancher

Cédric Gaucherel

Didier Galop

Thomas Houet

L Marquer

S Sugita

Florence Mazier

A pollen-based land-cover atlas covering the last 200 years of Bassies valley vegetation changes: results from a new spatialization method

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

RESULTS

Landscape Reconstruc�on Algorithm es�mates

Pollen % Vegeta�on % of 20 dominant taxa in a 1 km radius around each site (Fig . 1) for 10 to 20-year �me windows 5 topographic and hydrographic variables 1890-1910 1910-1930 1930-1945 1945-1955 1955-1965 1965-1975 1975-1985 1985-1995 Interval

Land-cover maps

CONCLUSION AND PERSPECTIVES

SITES AND DATASET

Figure 3 :2-

 3 Figure 3 : Examples of pollen-based past land-cover maps

-

  Grasslands declined by more than 50% over 200 years, mainly replaced by heathlands . -Phases of rates of change : (1) 19th century slowdown, (2) stabilisa�on un�l the 1940s, accelera�on in (3) the 1950s and (4) from the 1970s .

Figure 1 :Figure 2 :

 12 Figure 1 : Bassiès pollen sites : 2 small lakes ( ) and 5 bogs ( ) . Red line : Target area for land-cover reconstruc�on 1 8 1 0 1 8 7 0 1 8 9 0 1 9 1 0 1 9 3 0 1 9 4 5 1 9 5 5 1 9 6 5 1 9 7 5 1 9 8 5 1 9 9 5 2 0 0 5 1 8 3 0 1 8 5 0

Figure 4 :

 4 Figure 4 : Rates of land-cover changes between �me windows midpoint


Annie Lannuzel Neurologie

Narcisse Elenga

Pédiatrie De Ch

Cayenne

Nadège Cordel

Dermatologie & Vénérologie

Harold Merle

Pierre-Marie Roger

Chu De Pointe-À -Pitre

/ Abymes

Maturin Tabue Teguo

Cordel-Wattier Nadège

Chu De

Marie-Laure Lalanne-Mistrih

Moana Gelu-Simeon Gastroentérologie

Chu De Pointe-A-Pitre

Véronique Baccini

Hématologie Chu De Pointe-A-Pitre

Professeurs des Universités -Praticiens Hospitaliers (suite)

Maître de Conférences des Universités -Praticiens Hospitaliers

Au Professeur Harold Merle, merci de me faire l'honneur de juger mon travail. Mes collègues ne tarissent pas d'éloges à votre égard, et j'ai un certain regret de ne pas être passée dans votre service.

Au Professeur Maturin Tabue Teguo, merci d'avoir accepté de faire partie de ce jury.

Au Docteur Laurence Beral, merci de m'avoir appris la rigueur et de m'avoir donné la volonté de toujours chercher à faire mieux. Le temps a passé depuis mon premier semestre comme Dona. J'espère être à la hauteur de ton investissement et de tes attentes aujourd'hui. Merci Au Docteur Daena Hobeika, merci de m'avoir appris que l'ophtalmo pédiatrique ce n'est pas l'enfer comme je le pensais au début. Ta patience et ton calme sont exemplaires.

Au Docteur Pierre Sustronck, tu m'as appris énormément de choses que ce soit en Guadeloupe ou à Créteil. Tu as été un super binôme. Mési an pil.

Au Docteur Sadri Chahed, vous m'avez transmis votre passion pour la chirurgie et je vous en suis reconnaissante. Merci de m'avoir donné les outils pour devenir une bonne chirurgienne.

Au Professeur Baram Bodaghi, pour m'avoir accepté dans votre service. Ce semestre d'inflammation fut passionnant.

Au Professeur Eric Souied, d'avoir suscité en moi cette passion pour la rétine médicale.

Merci à vous et à votre brillante équipe de m'avoir appris que la réflexion ne s'arrête pas à : on injecte, on n'injecte pas. Merci de me donner l'opportunité de rejoindre votre service et de pouvoir en apprendre davantage.

Merci aux docteurs Francesca Amoroso, Olivia Zambrowski et au reste de l'équipe de Créteil.

INTRODUCTION

Sympathetic ophthalmia (SO) is a rare bilateral pan-uveitis following scleral infraction either after an accidental penetrating injury or due to multiple retinal surgeries to one eye.

The true incidence of SO reminds difficult to establish and the literature reports are variable, likely owing to the fact that there is no ancillary test. Hence the diagnosis is based on medical history and clinical finding. A large immune and infectious check-up is needed to eliminate a differential diagnosis such as tuberculosis.

In 1982, Gass Erreur ! Source du renvoi introuvable. reported the prevalence of SO at 0.01% following pars plana vitrectomy, and a 0.06% after other penetrating ocular trauma.

SO accounted for approximately 0.3% of the uveitis and the one-year incidence was calculated to be a minimum of 0.03/100,000 population Erreur ! Source du renvoi introuvable.. The rarity of the disease makes it difficult to establish any general consensus.

William

The purpose of this study is to evaluate retrospectively the long-term visual outcome and steroid-sparing related to successive steps of the medico-surgical management of SO.

METHODS AND PATIENTS

This retrospective study, carried out in the ophthalmology department of La Pitié-Salpêtrière hospital, constitutive reference center for rare diseases, reports serial SO seen at the consultation between January 2006 and April 2020.

Inclusion criteria were a bilateral granulomatous pan-uveitis with a context of penetrating injury or intra-ocular surgery, with a negative check-up for infectious or auto-immune diseases and a follow-up for at least 3 years with IS therapy.

The clinical exam included best corrected visual acuity (BCVA) on decimal scale, converted to LogMar, biomicroscopy, tonometry, fundoscopy and analysis of the vitreous. The central foveal thickness (CFT) was obtained automatically by a Spectral Domain OCT (Spectralis ® HRA-OCT device, Heidelberg, Germany) for objective measurements and made by an optometrist that ignored the treatment regimen.

Fundus photographs were performed using Optos ® California, autofluorescence and angiography using a Spectralis ® HRA-OCT device (Heidelberg, Germany) and an Optos ® California (figure 1), and automated flare measurement using a Laser Flare Meter (FC-1000 Kowa, Kowa Company, Japan).

Etiological testing was performed at the screening visit and included blood count, serum ionogram, sedimentation rate, protein electrophoresis, HIV, syphilis, Lyme serology, anti-DNA antibodies, IFN-γ release assay QuantiFERON®, chest scan, tuberculin skin test and brain magnetic resonance imaging. Depending on the clinical findings, the etiological testing was extended with an aqueous humor sampling for herpes virus PCR, bacterial analysis, interleukin 10/6 measurement and other specific tests if necessary.

The primary endpoint was the steroid-sparing, between the admission time for uveitis activity and at the end of follow-up. The secondary endpoints were the BCVA, the anterior chamber cells and the vitreous haze, the anterior flare and the central foveal thickness of the sympathetic eye. were considered statistically significant when p < 0.05.

RESULTS

Thirteen charts were initially reviewed: 1 had short follow up, 2 had differential diagnoses including one case of orbital Malt lymphoma while the contralateral eye was traumatized 34 years earlier and one case of ocular tuberculosis proved histologically. Ten patients with a diagnosis of SO fitted the inclusion criteria. At admission, all patients received topical dexamethasone, systemic prednisone with a daily median dose of 40mg 30-65. One patient already had an IS therapy (Cyclosporine) and one patient had polyvalent immunoglobulin. Three patients underwent enucleation of the exciting eye 6 months prior to their first visit to our center, where 2 of three patients were referred for an uncontrolled inflammatory rebound of their sympathetic eye. All ten patients were referred to our center for steroid-dependence > 20mg/d. After admission, we started IS therapy for all patients. The reported interval between ocular injury and the onset of SO range from 5 days Erreur ! Source du renvoi introuvable. to 66 years Erreur ! Source du renvoi introuvable..

About 65% occurred within 2 weeks to 2 months after the injury and about 90% occurred within a year Erreur ! Source du renvoi introuvable.Erreur ! Source du renvoi introuvable.Erreur ! Source du renvoi introuvable.. Our cases are consistent with these findings. It varies from days to decades in our series. However, for 5 patients it occurred within a year following the scleral accidental or surgical trauma.

The general treatment principle observed is the initial aggressive control of the uveitis with systemic and topical CS followed by long-term step-wise use of CS-sparing immunosuppressive agents in the vast majority Erreur ! Source du renvoi introuvable..

High dose induction for 4 weeks followed by slowly dose tapering has been shown efficient in uveitis macular edema in a prospective way 2526.

Indeed, there are frequent complications with the level and duration of CS therapy that may be required to control inflammation. Glaucoma and cataract are the commonest ocular problems related to periocular or intravitreal CS injections. Cataract has been reported in 20% at 6 months in eyes treated for uveitis with periocular CS injection 27. Its incidence increases with the number of infections. Regarding steroid-induced glaucoma, it has been reported that 23% to 34% of patients with uveitis presented an intraocular pressure elevation over 24 mmHg with intraocular CS injection 2728.

Others systemic side effects include hypertension, diabetes, osteoporosis and vertebral collapse, and may become the limiting factors in disease management.

For this reason, IS therapy is usually started for those with CS-dependence > 7.5 mg/d of prednisone in intend to reduce its dose and duration.

A step-wise escalation of multiple IS is employed when the first-line agent is insufficient as in suggested therapeutic algorithm for uveitic macular edema 293031.

AZA and MMF are selective inhibitors of inosine-5-monophosphate dehydrogenase that is essential during the synthesis de novo of purines. They inhibit both T and B lymphocytes thus causing immunosuppression.

Wand K and al, reported the case of a patient with SO, treated with AZA, who improved his sympathizing eye BCVA from 0.6 to 0.9 logMAR 32.

In Hakin and al. study, the use of IS, such as cyclosporine and AZA, in combination with the CS, allows control of the intraocular inflammation at a much lower CS dose 33.

Tumor necrosis factor (TNF)- is produced by T effector cells and macrophages, themselves activated by myeloid dendritic cells (DCs). In contrast, IFN- is produced by plasmocytes dendritic cells (pDCs), mostly in response to viral infection. This response is necessary to control spread of virus but may also have implications for autoimmunity. 34

The effectiveness of IFN- therapy and of anti-TNF- therapy in control of clinical and experimental autoimmune noninfectious uveitis implies a defect in regulation of autoreactive T-cells. In organ-specific autoimmune uveoretinitis, there may be a defect in pDCs function, Another study reported that IFN-2a therapy had a beneficial effect on infectious UME for 100% of the 5 patients of the study. The results revealed that it was effective in 2 patients (3 eyes), effective dose-dependent in 2 patients, and partly effective in 1 patient 47.

Recently, based on the available evidence, an expert panel recommended that IFX and ADA (but not Etanercept) could be considered first-line immunomodulatory agents for the treatment of ocular manifestations of Behcet disease and in second-line immunomodulatory therapy for children with vision-threatening uveitis secondary to juvenile idiopathic arthritis in whom methotrexate therapy was insufficiently effective or not tolerated. They also recommended anti-TNF- therapy for patients with panuveitis with vision-threatening, corticosteroid-dependent disease who failed first-line immunomodulatory therapies such as antimetabolites or calcineurin inhibitors 48. Unlike conventional IS therapy and other biotherapy, IFN does not increase the infectious and carcinogenic risk that could be of interest in young people. Unfortunately, many side effects limit their use. The most common is the quasi-systematic flu-like syndrome, within hours of the injection. Psychiatric disorders (depression, anxiety, psychosis, suicide) are reported in 4 to 7.5% of patients. We have developed a closed psychological and ophthalmological care, allowing promptly adaptation of the therapeutic, avoiding severe psychological disturbances and preventing treatment discontinuation. The occurrence of cytopenia (mainly leukopenia), and endocrinological disturbances (mainly dysthyroidism) justifies regular monitoring 49.

Removal of the injured eye had been previously suggested at the time of injury, or soon after, in an attempt to prevent the development of SO Erreur ! Source du renvoi introuvable..The postulated role of secondary enucleation of the exciting eye after the onset of symptoms of SO is to reduce the production of inflammatory mediators. It is also unclear whether enucleation of the exciting eye confers any benefit once disease has started in the sympathizing eye. Some feel that enucleation at this stage is valueless Erreur ! Source du renvoi introuvable.50 and should not be performed because the exciting eye may eventually have the better vision, or because the diagnosis of SO may be incorrect.

Others state that enucleation within 2 weeks of onset of sympathetic inflammation is associated with a relatively benign clinical course, and improves visual outcome Erreur ! Source du renvoi introuvable.51.

In our study, 3 patients underwent enucleation, 1 year and 3 years after the outcome of SO.

Two of three were sent to our tertiary for an inflammation rebound in the sympathetic eye following the enucleation.

In case of a painful exciting eye with no perception of light, a retrobulbar injection of mixed alcohol 60% and Xylocaïne 2% could be useful. If needed, a therapeutic contact lens, a scleral cover shell prosthesis or a surgical conjunctival flap can also be proposed.

Therefore, the decision for enucleation should be made very cautiously.

There are a few limitations in our study. It is a small monocentric retrospective series that leads to bias in data collection. Moreover, SO diagnosis is difficult in a late case. Incidence of SO, much of current literature is made up of case reports and small case series.

CONCLUSION

SO is a potentially sight-threatening disease with high rates of visual loss. Multiple combination of immunosuppressive therapy had been tried. IFN- and antimetabolites seemed to be the more effective to control inflammation, to resolve chronic macular edema, and steroid sparing. Enucleation of inciting eye seemed to have been pejorative in uveitis course in that small series. As far as we know, it is the first series of SO treated with IFN- in the literature. A study with a larger sample size is needed to verify this hypothesis. It might be useful for an international consensus to establish and provide clarity in the treatment framework for patients with SO.

  David, merci de me faire l'honneur de présider ce jury. Je vous remercie chaleureusement pour votre disponibilité tout au long de ces années. Vos connaissances et votre savoir-faire autant en chirurgie qu'en médecine m'ont émerveillée et ont suscité chez moi une grande admiration et une recherche perpétuelle de perfectionnement.

  d'avoir été ma chef et mon amie. Au Docteur Christine Fardeau, ma directrice de thèse. Merci pour votre implication sans limite. Vous êtes impressionnante par votre savoir et pour votre amour pour la médecine et en vos patients. Peu de médecins sont à votre niveau. Vous êtes incroyable. Ce fut un réel plaisir de travailler à vos côtés à la Pitié Salpêtrière et sur cet article. Je ne vous remercierai jamais assez. Au Docteur Martin Bonnafous, merci d'avoir été si pédagogue en consultation avec moi. Tes consultations étaient un vrai moment d'apprentissage que ce soit en rétine ou en contactologie. Merci pour ta bonne humeur.

  McKenzie Erreur ! Source du renvoi introuvable. provided the first full clinical description of the disease in 1840. The histopathology was reported in 1905 by Ernst Fuchs as an infiltration of the uveal tract, particularly the choroid, and formation of nodular aggregations beneath the retinal pigment epithelium Erreur ! Source du renvoi introuvable.. Fuchs and Dalen independently described the inflammatory nodular aggregates as "Dalen-Fuchs nodules" Erreur ! Source du renvoi introuvable.. However, much is still to be elucidated about the pathophysiology Erreur ! Source du renvoi introuvable.. The etiology of SO has included two hypotheses: autoimmunity and/or trigger by an infectious agent during antigen exposure. In recent years, studies have emphasized the immune system producing ocular inflammation. That the injured eye, known as the exciting eye, and the contralateral eye, or sympathizing eye, demonstrate similar pathology suggests involvement of an autoimmune response. Rao and al Erreur ! Source du renvoi introuvable. suggest that infraction of the sclera participates in the development of SO by exposing uveo-retinal antigens in the conjunctival lymphatics and thereby induces a subsequent immunopathological response. Different retinal antigens have been suspected, including retinal soluble antigen, rhodopsin, interphotoreceptor retinoid-binding protein, recoverin and melanin antigen Erreur ! Source du renvoi introuvable., but the specific antigen responsible for SO is yet to be found. The visual prognosis for established SO was originally very poor, with only approximately 50% of cases retaining useful vision Erreur ! Source du renvoi introuvable.. The use of systemic corticosteroids (CS) and, more recently, immunosuppressive (IS) drugs has transformed the outlook of this potentially blinding disorder.

  The degree of intraocular inflammation was evaluated according to the Standardization of Uveitis Nomenclature (SUN) Working Group [Erreur ! Source du renvoi introuvable.]. The Nussenblat scale [Erreur ! Source du renvoi introuvable.] was used to evaluate the degree of vitritis. Active anterior segment inflammation corresponded to cell grade 0.5+ or higher or vitreous haze > 1+. Controlled uveitis corresponded to findings of < 0.5+ cell or descriptive terms such as "quiet, quiescent, and no active inflammation".

Figure 1

 1 Figure 1 -a) Fundus photograph and corresponding b) autofluorescence c) fluorescein angiography and d) green indocyanine angiography illustrating chronic choroidal infiltrates (Dallen-Fuchs nodules) in sympathizing eye of patient with sympathetic ophthalmia.

  either intrinsic or extrinsic, with a concomitant reduction in the pDCs' responsiveness to antigen challenge and impaired IFN- production, particularly to viral challenge (CpG). This leads to a secondary defect in T-reg cell activation, with unrestrained autoreactive Th1-cell activation, which if the cross-reactivity matches, leads to autoimmune inflammation. It also explains the responsiveness of patients to IFN- and to anti-TNF- therapy based on low endogenous levels of IFN- in these patients and a cross-regulatory function of TNF- and IFN- 34.

Figure 2

 2 illustrates the effect of immunosuppressive therapy on macular edema for one patient of this study.

Figure 2 -

 2 Figure 2 -Interferon alpha2a effect on macular Edema on a 45 years old patient with sympathetic ophthalmia. Spectral Domain OCT images.a)Macular Edema before any immunosuppressive therapy. Edema persists with azathioprine and adalimumab.b)Reduction of the macular Edema with interferon alpha2a. c)Slow recurrence of the macular Edema 6 weeks after discontinuation of interferon alpha2a.

  Travaillez avec vous était exceptionnel. mon meilleur ami Ludo, tu as toujours été là pour moi. Même à 6h du mat quand j'ai besoin d'un jerrican d'essence. Notre amitié était improbable, et ça ne la rend que plus belle. Tu es un mec bien, vraiment.A Marine, tu es exceptionnelle. Je t'aime fort.

	A Cocobino, my brother from another mother. Tu m'as soutenu pendant mes plus dures
	années en médecine et je t'en remercie. Anguilla est notre madeleine de Proust. J'espère
	que nos enfants auront la même jeunesse que nous.
	A Clémence et Stanley, votre amitié m'est chère.
	A ma famille :
	Vous m'inspirez chaque jour.
	A Laurence, ma personne, tu me nourris, tu essuies mes larmes, tu ries avec moi. Tu as
	toujours été là et je ne veux pas que ça change. Et à Guillaume.
	A François, Barbara, Caro, Kate, Melissa, j'ai eu la plus belle jeunesse possible grâce à
	vous.
	A ma marraine.
	A mes deuxièmes parents les Ramzay.
	A Maurice, tu nous as quitté bien trop tôt.
	A mes cousins, taties et tontons.
	A Antony, tu me tires vers le haut et me pousses à me dépasser chaque fois. Merci d'être là.
	Je n'oublierai jamais ce jour où je t'ai vu et où j'ai su. Meredith a trouvé son Dr Shepherd
	comme diraient certains. Chetaume.
	Vous me manquerez.
	A Naiké, continue de nous éblouir avec ta joie de vivre et ta bonne humeur.
	A ma team Forever Together: Arielle, Roxane, Meryem, Mika, Marvin, Alexis, Badr. Ayoub.

A monsieur Mondésir pour vos fraises Tagada. J'ai hâte de vous entendre dire « Beverly dans mon bureau » en novembre. Vous avez toujours été disponible et à mon écoute. Au Professeur Michel Paques et son équipe, le Docteur Julien Boumendil, le Docteur Julia Meney qui m'ont appris comme personne la chirurgie orbito-palpébrale, le Professeur Isabelle Audo avec qui j'ai passé des heures sur des cas de dystrophies rétiniennes passionnantes, le Docteur Sarah Mrejen qui m'a ébloui par son savoir, sa gentillesse et son humilité. A Sandrine Dargent pour ton franc-parler et ta bonne humeur. Et merci au reste de l'équipe des XV-XX. A Milka, pour notre amitié indéfectible depuis le collège. Merci d'être là pour me temporiser et me remettre sur le droit chemin. Cette année est la tienne, je te souhaite le meilleur et encore félicitation. J'espère que nos projets se concrétiseront, je te veux dans ma vie, au quotidien. Comme dirait Princess Lover, tu es mon soleil dans ce service. A Sophie qui est là dans les bons et les mauvais moments. Persévère, tu seras une super rétinologue chir. A Arnaud, Selim, Nico, vous m'avez bien fait rire durant toutes ces années. A Alex, Remi, Maxence et Martin. Je vous bouscule peut-être un peu mais c'est pour vous rendre meilleurs. Vous avez un potentiel incroyable, je crois en vous. A Malik, Coralie et Gigi. Merci de votre aide à tout instant. A Isa, la meilleure des secrétaires. Je pourrai en écrire des lignes sur vous. Plus que des co-internes, on est devenu des amis, des vrais. Grace à vous j'ai retrouvé la chaleur d'une famille loin de ma Guadeloupe. A A mes parents, je n'aurais pas pu espérer mieux, vous êtes parfaits. Vous m'avez appris tant de choses. Merci pour votre amour et votre soutien indéfectible pendant toutes ces années. Je n'ai pas toujours été facile je le reconnais et je m'en excuse. Vous avez toujours cru en moi et j'espère que vous êtes fiers de moi aujourd'hui. Je vous dois ma réussite. Je vous aime de tout mon coeur.

A Céline et Gabriel, on est tous les 3 si différents mais en même temps si complémentaires.

TABLE DES MATIERES TITRE………………………………………………………………………p.12 RESUME……………………………………………………………………p.13 ABSTRACT………………………………………………………………..p.14 INTRODUCTION…………………………………………………………..p.15 MATERIEL AND METHOD………………………………………………p.16 RESULTS…………………………………………………………………..p.17 DISCUSSION………………………………………………………………p. 21 BIBLIOGRAPHY………………………………………………................p.27 SERMENT D'HIPPOCRATE……………………………………………..p.33 RESUME

	But : Évaluer sur le long terme l'épargne cortisonique liée aux étapes successives de la prise
	en charge médico-chirurgicale de l'ophtalmie sympathique (OS)
	Méthodes : les dossiers médicaux de patients avec OS suivi au moins 3 ans dans un centre
	de référence de maladies rares ont été analysés. On a étudié le facteur déclenchant, les
	symptômes et signes cliniques d'OS, le traitement et l'acuité visuelle.
	Résultats : 10 patients correspondaient aux critères d'inclusion. Le délai médian d'apparition
	de l'OS était de 1,5 ans. A l'admission, la médiane de la meilleure acuité visuelle corrigée et
	de la dose journalière de cortico-dépendance était respectivement de 0,45 LogMar 0,2;0,65
	et 40 mg 30;65. Nous avons retrouvé un oedème maculaire inflammatoire chez 7 patients.
	La durée médiane de suivi des patients était de 14 ans 6,5;25. A la fin du suivi, il n'y avait
	pas d'amélioration significative de la meilleure acuité visuelle corrigée p=0,87 mais une
	diminution significative de la dose médiante journalière de corticostéroïdes à 8 mg 3,5;12,5
	p<0,01. Durant le suivi des patients, le contrôle de l'inflammation et des oedèmes maculaires
	a été possible grâce à l'utilisation d'anti métabolites chez 4/6 patients, d'anti TNF-alpha chez
	0/3 patients, de cyclophosphamide chez 0/1 patient, de cyclosporine chez 0/1 patient,
	d'interféron--2a chez 6/6 patients, d'immunoglobulines polyvalentes chez 0/1 patient,
	d'énucléation chez 0/3 patients.
	Conclusion : L'Interféron--2a et les anti métabolites semblent utiles en cas d'oedème
	maculaire et pour l'épargne cortisonique contrairement à l'énucléation qui apparait péjorative
	dans l'évolution de l'uvéite dans cette petite série de patients.

Table 1 ).

 1 Table1summarizes demographic details and clinical profil of the patients. Age at diagnosis ranged from 7 to 80 years, with a follow-up from 5 years to 29 years. Accidental penetrating injuries concerned youngest patients with a median of 12 years 7;15 than retinal detachment with a median of 51 years 35.5;73.5 p= 0.02. The interval between injury or initial surgery and diagnosis ranged from 1 month to 34 years with a median of 1.5 years 0.26;5.5, with 5 cases developing SO within 1 year of insult (

Table 1 -

 1 Demographic details, clinical profile of 10 patients with sympathetic ophthalmia (SO) At the end of follow up, 4 of 10 patients saw 0.3 LogMAR or greater; two saw 1.0 LogMAR or less. There was no significative improvement for the BCVA, with a median of 0.4 LogMAR 0.1;0.75 p=0.87. We found a significant steroid-sparing with a median dose of 8 mg 3.5;12.5 p<0.01. Table2illustrates the steroid-sparing, visual and inflammatory outcomes of this small series.

	Characteristics
	Age [median (IQR)] in yrs

(digestive disturbance) with MMF, one because the patient did not want to continue the treatment due to asthenia with IFN and one because of a good inflammatory control with 7mg of CS. Table

3

summarizes the various types of IS therapy used in the management of

Table 2 -

 2 Steroid-sparing, visual outcome and inflammation outcomes of 10 patients with sympathetic ophthalmia.

	At inclusion	At the end of	p-Value*
		follow-up

Table 3 -

 3 Treatment of ten patient with sympathetic ophthalmia for more than 3 years

	Patients	Age at	Cause	Immunosuppressive therapy	Systemic steroid (mg)
		diagnosis		strategy
		(years)		(Steroid dependence in mg)
					At	At the end
					inclusion	of follow-up
	1	80	RD	AZA (0)	70	0
	2	55	RD	ADA (20) ; MMF (7) ‡	60	15
	3	46	PI	IFN (8)	50	8
	4	79	Choroidal	CP (30); IFN (10)	70	10
			melanoma
	5	7	PI	Cyclosporine (30); AZA (7)	35	7
	6	15	PI	Ig (25) ; AZA (20) ; IFN (10) ‡	11	15
	7	57	RD	AZA (25) ; ADA (20) ; IFN (10)	40	10
	8	32	RD	IFN (0)	30	0
	9	69	RD	ADA (20); IFN (7) ‡	40	7
	10	47	RD	AZA (8)	25	8

RD: Retinal detachment; PI: penetrating injury; AZA: Azathioprine; ADA: Adalimumab; MMF: Mycophenolate mofetil; CP: cyclophosphamide; IFN: interferon alpha2a; Ig: polyvalent immunoglobulin ‡ discontinuation of immunosuppressive therapy

Table 4 -

 4 Steroid dependence for each treatment for 10 patients with Sympathetic ophthalmia

	Treatments	Number of	Steroid dependence
		patients	[median (IQR)] in mg
	Antimetabolites	6	8 (3,5;22,5)
	Interferon-2a	6	9 (3,5;10)
	Cyclophosphamide	1	30
	Cyclosporine	1	30
	Polyvalent immunoglobulin	1	25
	Adalimumab	3	20 (20;20)

DISCUSSION

In our retrospective monocentric study, we present the different clinical characteristics and long-term management of ten patients with SO.

In our retrospective study, we based our diagnosis on chart review. The difficulty with SO is that it remains a clinical diagnosis with numerous differential diagnoses like idiopathic bilateral uveitis. It is considered as a diagnosis of exclusion. We based our diagnosis on a body of arguments such as the medical history, a large infectious, tumor and autoimmune negative screening, the absent of history of a uveitis prior to the penetrating injury or intraocular surgery according to the literature Erreur !

Source du renvoi introuvable.Erreur ! Source du renvoi introuvable..

  Penetrating trauma used to be described as the most common cause of SO Erreur !

Source du renvoi introuvable.Erreur ! Source du renvoi introuvable.Erreur ! Source du renvoi introuvable.Erreur ! Source du renvoi introuvable

	.. Our findings are
	consistent with more recent studies witch report that the most common cause of SO is after
	surgery Erreur !

Source du renvoi introuvable.Erreur ! Source du renvoi introuvable

  With the advancements in vitreoretinal surgical instruments and training, ophthalmologists are operating on more cases, including complex cases and multiple surgeries or procedures, which would have been given up in the past Erreur ! Source du renvoi introuvable.. SO is usually described as more common in men. This gender predilection has been attributed to the increased exposure to trauma in men Erreur ! Source du renvoi introuvable.. In our study we found more men with SO independently of the cause. It can be explained by the small population of our study.Regarding age, most studies indicate that the age distribution for SO generally follows the average distribution of the general population, some report higher occurrence among children and individuals over 60 years of age, likely arising from increased ocular injury in young age and increased frequency of intraocular surgery in the older population Erreur !

.Erreur ! Source du renvoi introuvable..The authors attributed this decline in trauma-induced SO to the strict industrial safety laws that mandate the use of appropriate personal protective equipment at work. Source du renvoi introuvable.. In this study, we found a higher occurrence among young patients due to penetrating injury and older patients due to intraocular surgery.

  Lopez-Prats et al 35 reported a case of a good inflammation management in SO with ADA. S.Gupta et al 36 reported a case of a 7-year-old diagnosed with SO. They had difficulties to taper CS doses using, in association or successively, cyclosporine, methotrexate and MMF.InDoycheva D, et al 41 study, upon 38 patients treated with MMF, CMT decreased for 12/24 patients with preexisting UME, but 14 patients with no history of UME before treatment, developed one. Other studies are more positive such as the Neri P. et al 42 study showing and improvement of UME at 1 year for 96% of the 19 patients with noninfectious chronic uveitis and ME treated with MMF. Cyclosporine at a nephrotoxic dose (5 and 10 mg/Kg/d), has been described as efficient on UME and has been used in numerous countries for more than 30 years for this purpose 43. In the Schaap-fogler et al 44 study, upon 15 eyes treated with anti-TNF- (IFX or ADA), 13 eyes achieved complete resolution of the UME and 2 showed partial improvement. 27 eyes received conventional treatment (CS,

	methotrexate) and only the combination of systemic CS, cyclosporine, and IFX demonstrated
	a significant improvement in BCVA (p= 0.032).
	Kilmartin et al 39 reported a case of a 3-year-old with SO who presented a complete
	resolution of a ME causing by an inflammatory-induced CNV, and an improvement of BCVA
	in 3 months with cyclosporine 5mg/kg per day. Hiyama et al 40 reported 2 cases of SO with
	serous retinal detachment (SRD). They first initiated cyclosporine but one SRD relapsed and
	the other patient presented side effect of the treatment leading to switch therapy for ADA
	which successfully resolved the SRD.
	AZA, MMF, cyclosporine, methotrexate). The maximal reduction of CMT from baseline
	occurred at 6 months, in the anti-TNF-α group, reaching 262±73 μm (p=0.04). At 12 months,
	the anti-TNF-α group showed a significantly greater reduction in CMT from baseline than the
	conventional-treatment group (304±243 μm vs 57±227 μm, p=0.03). In the Mackensen et al
	study 45, IFN- and beta have shown efficiency in refractory ME. In intermediate uveitis,
	the CFT mean decreased for 206 m with INF (44g), and increased for 47m with MTX
	(20mg/week) at 3 months (p <.0001). The BIRDFERON study 25 showed a similar
	efficiency of systemic CS therapy and INF-2a alone at 4 months. The CFT mean decreased
	by 63m with INF- and by 52 m with systemic CS and increased by 3m without treatment
	at 4 months. Moreover, the CFT mean of the eye with the worst BCVA, dropped by 20 μm in
	the group with systemic CS and by 155 μm in the group with INF- suggesting an interest for
	They finally managed to taper and stop CS by introducing Infliximab (IFX). The randomized refractory uveitic ME. Regarding UME in Behçet disease, the Calvo et al study 46, on 124
	and prospective Visual 1 study 37 included 223 patients with intermediate and posterior patients treated with IFX (64%) and ADA (38%) combined or not with conventional IS drugs,
	non-infectious uveitis, and showed a significative longer delay of relapse of the uveitis for the showed a significative improvement of the CFT, from 420 μm (SD 119.5) at baseline to 271
	patient with ADA versus placebos (24 weeks with ADA versus 13 weeks with placebo). μm (SD 45.6) at month 12 (P < 0.01) with a good control of endo-ocular inflammation and a
	However, no significative effect on ME was found. In JF Arevalo et al 38 retrospective study significative improvement of the BCVA.
	over 25 years,132 patients with Behcet disease-related uveitis were reviewed. 116 patients
	were treated by a various combination of IS therapy (cyclosporine, AZA, IFX, CS,

Conflict of interest: none

Statut de l'article : en cours de soumission pour la revue « Eye » ABSTRACT Objective: to evaluate retrospectively the long-term visual outcome and steroid-sparing related to successive steps of the medico-surgical management of sympathetic ophthalmia (SO).

Methods: medical records of patients with SO, followed in a reference center for rare diseases, for at least 3 years, were reviewed for history of ocular trauma or surgery and subsequent development of SO, presenting symptoms, treatments, and visual outcomes.

Results: Ten patients fitted the inclusion criteria. The median time of SO occurrence was 1,5 years. At admission, median best-corrected visual acuity (BCVA) was 0,45 LogMAR 0,2;0,65, median steroid dependence daily dose was 40 mg 30;65, and inflammatory macular edema was present in 7/10 eyes. The median time of follow up was 14 years 6,5;25.

At the end of follow-up, there were no significative improvement for the BCVA with a median of 0,4 LogMAR 0,1;0,75 p=0,87. However, the median daily prednisone dose was significantly decreased to 8 mg 3,5;12,5 p<0,01. At six months on prednisone associated to immunosuppressive drugs, inflammation and macular edema control was assessed using antimetabolites in 4/6 treatments, anti TNF-alpha in 0/3 treatments, cyclophosphamide in 0/1 treatment, cyclosporine in 0/1 treatment, interferon--2a in 6/6 treatments, polyvalent immunoglobulin in 0/1 treatment, enucleation in 0/3 treatments. Conclusion: Interferon--2a and antimetabolites seemed to be useful in case of macular edema and in steroid sparing unlike enucleation which appeared to be pejorative in uveitis course in that small series. KEYS WORDS: sympathetic ophthalmia, uveitis, immunosuppressive therapy, macular edema, retinal vasculitis, interferon