A high frequency of retinitis pigmentosa (RP) is found in Northern Sweden. In an inventory of autosomal recessive RP patients in Västerbotten County, a great number of cases with a unique phenotype was noticed, denoted Bothnia Dystrophy (BD). The aim of the study was to describe the phenotype, to determine the chromosomal location, and to identify the gene. Patients typically show night blindness from early childhood. Symptoms of defect macular function with a decrease of visual acuity can appear in early adulthood. The retinal fundus shows irregular white spots in a central, and parafoveal pattern along the arcades. Centrally areolar maculopathy develops and round circular atrophies are observed in the periphery. The disease was shown to be associated with a missense mutation in the RLBP1 gene resulting in an amino acid substitution (R234W) in the cellular retinaldehyde-binding protein (CRALBP). The R234W mutation was found in a homozygous state in 61 patients affected with BD. Ten patients were heterozygous for the R234W mutation, and presented a similar phenotype. No additional mutations in the coding sequence or exon-intron junctions were found. CRALBP is localised in retinal pigment epithelium (RPE), and Müller cells of the retina. In the RPE, CRALBP functions as a carrier protein for endogenous retinoids. Dark adaptometry and electrophysiologic testing showed an initial loss of rod function followed by a progressive reduction of the cone responses in older ages. A compromised rod function, dysfunction of the Müller cells, and indications of a disturbed function of the inner retina were found. With prolonged dark adaptation, a gradual increase in retinal sensitivity to light and an improvement of the ERG components occurred. The findings indicate a prolonged synthesis of photopigments, retardation of the visual process in the retinal pigment epithelium and a loss of retinal cells probably starting at a relative early age in BD. To evaluate the subjective visual function in BD patients, a battery of objective tests of visual function and composite score of the 25-item NEI-Visual Function Questionnaire (VFQ-25) were analyzed. We found that weighted distance logMAR visual acuity (WVA), had the strongest association with subjective visual function, and that there was a considerable loss of subjective and objective visual function with increasing age in BD patients. The prevalence of BD is as high as 1:3600 in Västerbotten County. The possibility that recycling of retinoids localized in the RPE might be impaired in BD might give future therapeutic possibilities. Due to the large and clinically well-characterized set of patients with this disease, they constitute a suitable study group.

L'émergence de l'ophtalmologie en tant que spécialité pointue est récente, contemporaine de l'aire de la révolution technologique. Cette discipline ne s'exerce qu'en présence de dispositifs médicaux et ses spécificités sont aussi liées aux particularités de l'organe responsable de la fonction visuelle. Mais justifient-elles un traitement particulier de la responsabilité de l'ophtalmologiste ? Médicale, chirurgicale et fonctionnelle cette discipline embrasse de nombreux champs de la responsabilité médicale. Les réponses en vue de la réparation du dommage produit, sont examinées au regard de la causalité qu'une perte de chance relativise fréquemment. Le fait originel obéit aux qualifications habituelles, mais l'incidence du défaut des produits prend un relief particulier au côté de la faute, de l'aléa et de l'infection nosocomiale. Les frontières des qualifications évoluent dans le temps et participent outre une certaine ambiguïté, à alimenter les procédures. Le contexte d'exercice et le développement du consumérisme modifient la jurisprudence. Ils sont à l'origine de la loi du 4 mars 2002, tournant de la relation médecin malade, qui assoie les récents revirements de jurisprudence, notamment sur le plan de l'information. Elle créé les commissions de conciliation et d'indemnisation qui transcendent les voies judiciaires et administratives sans les supprimer. Ouvertes aux préjudices visuels, les critères de gravité liés tant à leur accès et qu'à la solidarité nationale renforcent les tensions autour de l'oeil par un seul fait arithmétique. En fait, ces différentes instances ne tiennent pas compte du particularisme de l'exercice mais intègrent leur raisonnement en droit commun. / The ophtalmology has very old history; it's recently appeared like a speciality because of the technological revolution. The specificities of the discipline are applied only with medical devices and are connected with the peculiarities of this organ ; the eye is manager of the visual function. But do they justify a particular treatment of the ophtalmologist responsibility? It's a medical, surgical and functional discipline which opens so many medical responsibilities. Answers to repair the ophthalmologist intervention damage are examined face to causality, the loose of lucky often reduce it. The original fact obeys to the usual qualifications, but the incidence of the default product is particular next to the fault, the hazard and the hospital-borne infection. Qualifications limit differ with the time and play with a certain ambiguity to create so many process for the ophthalmologist. The practicing context and the consumer society development m odify the case law which doesn't miss and are of the origin of an Act. The recent cases laws completes changes, particular for patient information, are to the origin of the Act of 4 March 2002 and show a modification of the patient doctor relation. The Act creates reconciliation and compensation board which transcend judicial and administrative ways without deleting them. Those last one are open to the visual damages. The seriousness criteria linked to access and national solidarity increase problems around the eye by a only arithmetical fact. In my opinion, these different authorities don't take care about the particularism of exercise but integrate their arguments into common law.

As disturbed binocular functions in small children may lead to severe amblyopia it is of interest to detect it as early as possible. Most tests for binocular functions, however, demand active cooperation and may be unreliable in children up to 4-5 years of age. This study therefore aims to employ visual evoked potentials (VEP) to enable the examiner to evaluate the binocular function in a subject without need of active cooperation from the subject. Initially we studied the relation of suprathreshold contrast to the latency of the transient pattern VEP (tpVEP). Although suprathreshold contrast independently influenced the tpVEP latency, interindividual variation was too large to suggest tpVEP as a possible method for objectively measuring contrast sensitivity in a subject. The tpVEP latency in normal and microstrabismic adult subjects was examined. It was significantly shorter with binocular viewing in normals, but not in the microstrabismic group. Contrast sensitivity and tpVEP latency was examined in adults, both with normal binocularity and with microstrabismus, using both luminance (black-and-white) contrast and colour contrast patterns. The tpVEP latency to colour contrast, like that to luminance contrast, is shorter in normal subjects who view the stimulus binocularly. Interindividual variation or overlap between the normal and microstrabismic groups did not improve with colour contrast. The most significant features of the tpVEP are amplitude and latency. Depending on stimulus conditions, the response may show variations in configuration, amplitude and, to a lesser degree, latency. To decrease the influence of such variations steady-state VEP (ssVEP) can be used. The stimulus is presented in a fast repetitive manner, yielding a VEP response shaped as a continuous curve. The frequency components of this curve can be analysed using Fast Fourier Analysis. Fast Fourier analysis of ssVEP in children aged 8-15 years with normal binocularity and with microstrabismus showed that the power of the second harmonic (the double frequency of stimulus frequency) of the response with binocular viewing was larger than with monocular viewing, both in normals and microstrabismic subjects. For higher stimulus frequencies, microstrabismic subjects showed a significantly lower power of the second harmonic compared with subjects with normal binocularity, when the stimulus was presented binocularly. Finally, Fast Fourier analysed ssVEP in pre-school children aged 4-5 years was studied. A normal group was compared with a group with microstrabismus and a group with significant amblyopia. Amblyopic subjects had significant interocular differences in the first harmonic. We confirmed the significant difference found between microstrabismic subjects and subjects with normal binocularity regarding the second harmonic’s power with higher temporal frequency binocular stimulation, although at a slightly lower frequency than for older children. A low power of the second harmonic in the ssVEP to a binocular stimulus with high temporal frequency is a strong indicator of disturbed binocular function. / För att förhindra amblyopi (ensidig synsvaghet) hos barn är det viktigt att upptäcka störningar i samsynsfunktionerna så tidigt som möjligt. Samsynstester kräver dock aktiv medverkan och kan ge osäkra resultat hos barn upp till 4-5 års ålder. Den här avhandlingen studerar möjligheterna att utifrån tidsmässiga (temporala) egenskaper hos visual evoked potentials (VEP) undersöka samsynsfunktioner objektivt, utan att den undersökte behöver medverka aktivt. Första delstudien visar att ett synstimulus kontrastnivå i relation till kontrastkänslighetströskeln oberoende påverkar latensen i VEP, men variationer mellan individer gör metoden olämplig som objektiv kontrastkänslighetstest. Andra delstudien jämför latensen i VEP hos individer med normal samsyn med den hos personer med mikroskelning. Stimulering av båda ögonen gav signifikant kortare latens än stimulering av ett öga hos normala, men inte hos mikroskelare. I den tredje delstudien jämfördes känslighet för luminanskontrast och färgkontrast hos individer med normal samsyn och personer med mikroskelning. Både luminansmönster (svart-vita) och färgkontrastmönster upptäcktes vid lägre kontrast om båda ögonen stimulerades istället för ett i taget hos normalseende. Mikroskelare uppfattade mönstren sämre med båda ögonen än med ett öga (det dominanta). Latensen i VEP mättes i båda grupperna för både luminans- och färgkontrastmönster. Båda typerna av kontrast gav förkortning av latensen när båda ögonen stimulerades vid normal samsyn, men denna förkortning uteblev hos mikroskelare. Både luminans- och färgkontrast gav för varierande resultat för att utnyttja metoden för objektiv undersökning av samsynen. Fourier-analys innebär att en kurvform delas upp i sinuskurvor med olika frekvens, amplitud och fas. Om ett stimulus växlar hastigt får man ett steady-state VEP (ssVEP), dvs en kontinuerligt vågformad VEP-kurva, som kan delas upp i delsinuskurvor med Fourieranalys. Detta gör att man särskilt kan studera frekvenser som är relaterade till stimuleringsfrekvensen, till exempel grundton och övertoner (multipler av grundtonsfrekvensen). Barn 8-15 år gamla, med normal samsyn och med mikroskelning undersöktes med ssVEP i det fjärde delarbetet. Den första övertonen (= ”second harmonic”) var statistiskt signifikant svagare hos mikroskelare jämfört med normala individer, när stimuleringsfrekvensen var hög. Det femte och sista delarbetet undersökte ssVEP hos 4-5 år gamla förskolebarn på motsvarande sätt. I denna studie deltog också en grupp barn med amblyopi (synsvaghet) på ena ögat. På en något lägre stimuleringsfrekvens bekräftades den svagare första övertonen hos barnen med mikroskelning jämfört med barnen med normal samsyn. De amblyopa barnen visade tydligast förändringar vid lägre stimuleringsfrekvenser och i ssVEP:s grundtonsfrekvens (= ”first harmonic” eller ”fundamental harmonic”). Resultaten i de olika grupperna är så pass åtskilda att metoden verkar lämpa sig för objektiv undersökning av samsynsfunktioner, i det att en svag första överton i binokulärt ssVEP utlöst av hög stimuleringsfrekvens inger en stark misstanke om störd samsyn, medan en stor skillnad i grundtonens styrka i höger respektive vänster ögas ssVEP tyder på amblyopi.

Background: In order to perform cataract surgery, adequate dilatation of the pupil is essential. This is traditionally achieved by preoperative topical mydriatic eye-drops, commonly cyclopentolate and phenylephrine. This routine has several disadvantages. First, the slow penetration through the cornea delays the onset of mydriasis. Second, the limited bioavailability of topically administered substances with significant systemic absorption may increase the risk for systemic side effects. Third, even if good mydriasis is achieved initially with topical mydriatics (TM), the effect tends to wear off during surgery. In relation to cataract surgery a transient postoperative corneal oedema is sometimes noted, indicating effects on the corneal endothelial pump function. These effects have been ascribed to ultrasonic or mechanical trauma from the phacoemulsification procedure. Corneal endothelial cell loss (ECL) is a commonly studied variable, not least because it is associated with the long-term risk for corneal decompensation. But, there has been a debate whether postoperative corneal swelling after phacoemulsification cataract surgery correlates to ECL. Aims: To evaluate an alternative mydriatic regimen for phacoemulsification cataract surgery: intracameral injection of mydriatics mixed with lidocaine (ICM). Additionally, to determine the correlation between early transient postoperative corneal oedema and permanent ECL after phacoemulsification cataract surgery. Methods: Pupil dilatation with ICM (150 µl of lidocaine 1%, phenylephrine 1.5%, and cyclopentolate 0.1%) was compared to TM (phenylephrine 10% and cyclopentolate 1%) prior to cataract surgery. Additionally, two ICM-groups were randomized to receive either 0.6 µg/ml epinephrine added to the irrigating balanced salt solution or no epinephrine in the irrigation solution. Furthermore, two randomized ICM-groups, with or without cyclopentolate, were analyzed. The patients planned for cataract surgery were examined with ultrasonic pachymetry, specular microscope endothelial photography and Orbscan II slit-scan tomography pre- and postoperatively. Results: With ICM, mydriasis reached 95 ± 3% of its final value within 20 seconds. In the ICM-group, the pupils were smaller than in the TM-group (mean 6.7 ± 1.0 mm versus 7.7 ± 1.0 mm, P<.001), but did not contract intraoperatively as the TM pupils did. Conversely, with ICM the pupil sizes generally increased during the cataract procedures. This increase was significantly greater without epinephrine in the irrigating solution (13 ± 19% versus 4 ± 14%; p = 0.02). No significant differences in pupil sizes were observed between the patients who were given ICM with or without cyclopentolate. The central corneal swelling at the first postoperative day was strongly correlated to the central ECL at 3 months, R2 = 0.785, P < 0.001. Conclusions: ICM is a rapid and safe alternative to TM in phacoemulsification cataract surgery. An irrigating solution without epinephrine can safely be used with ICM. Cyclopentolate, administrated intracamerally, has no immediate additive mydriatic effect to intracameral lidocaine combined with phenylephrine. The degree of permanent corneal endothelial damage in cataract surgery is reflected in the degree of early postoperative corneal swelling.

There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.

Le diagnostic des rétinopathies pigmentaires pose différents problèmes, au niveau clinique comme au niveau moléculaire. En premier lieu, il s'agit de maladies rares, la faible prévalence de chaque pathologie à l'échelle de la population mondiale rend difficile leur étude. En second lieu, la caractérisation phénotypique de ces maladies est délicate car les symptômes qui en découlent s'avèrent très similaires. De manière liée, l'œil et le processus de la vision s'avèrent complexes et impliquent les produits d'expression de nombreux gènes. Ainsi, bien que les rétinopathies soient majoritairement monogénique et respectent le modèle d'hérédité mendélienne, les causes génétiques des maladies sont variées. Sur la base de ce double constat, nous proposons deux approches méthodologiques complémentaires menant à une meilleure compréhension de ce groupe de pathologies. Une première approche a pour finalité l'acquisition du jeu exhaustif des gènes impliqués. Les travaux portent sur l'exploitation des puces de génotypage. Nous effectuons une étude de liaison génétique entre les variations ponctuelles et les pathologies. Une seconde approche porte sur la représentation des connaissances associées aux phénotypes cliniques. Un composant ontologique est construit afin d'expliciter les savoirs nécessaires au diagnostic. Les données collectées sur le long terme par les experts sont étiquetées au travers de termes organisés au sein d'un thésaurus dédié. Les profils cliniques des patients et des maladies sont manipulés sous forme de collections de caractéristiques et comparés au moyen d'une mesure de similarité adaptée. L'objectif est alors de proposer un système d'aide au diagnostic. / Diagnosis of retinitis pigmentosa could be difficult regarding both to clinics or molecular issues. Firstly, there are rare diseases, so the prevalence of each pathology in the world population is very low. Secondly, the symptoms of diseases are very similar, so their phenotypic characterization is hard. Moreover, the eye and the visual process are complex and numerous genes' products are implicated. Although retinopathies are mainly monogenic and mendelian inherited diseases, the polymorphisms involved in these diseases are very diverse.These both observations lead us to develop two complementary methodological approaches in a view to better understand the retinopathies.The first approach aims to identify all the genes involved in the diseases using genotyping chips. For this purpose, we studied genetic linkage between single nucleotide variations and pathologies. The second approach leads to the representation of clinical knowledge. An ontological compound was built to make explicit the knowledge involved in the process of diagnosis. The data previously collected by experts were labeled by terms that were organized in a specific thesaurus. The clinic profiles of the patients and diseases were handled as features collections and were compared by similarity calculations. The goal of this work is to build a knowledge-based system for diagnosis.

Le chien présente de nombreuses maladies génétiques dont les rétinopathies auxquelles je me suis intéressée. Historiquement, l’homme a appliqué aux chiens une sélection artificielle extrêmement forte, créant ainsi près de 400 races répondant à des besoins spécifiques. En uniformisant ainsi de nombreux traits phénotypiques et comportementaux, l’homme a sélectionné les allèles recherchés mais a également concentré involontairement des allèles délétères responsables de maladies génétiques. Ces maladies étant pour beaucoup cliniquement et génétiquement similaires aux maladies humaines, le chien constitue alors un modèle de choix pour en rechercher les bases génétiques et développer de nouvelles thérapies pour un bénéfice mutuel pour l’homme et le chien. J’ai travaillé sur l’Atrophie Progressive de la Rétine (APR) dans deux races avec le concours du Dr Gilles Chaudieu et des clubs de race : le border collie et le berger picard. Concernant l’APR du border collie, les analyses réalisées avant mon arrivée avaient identifié un locus de 20Mb sur le chromosome X. J’ai tout d’abord mis à jour les données épidémiologiques et cliniques d’environ 500 chiens et poursuivi la collecte de prélèvements. Une analyse de liaison génétique pangénomique sur 130 chiens m’a permis de confirmer le mode de transmission et le locus. J’ai ensuite conduis plusieurs analyses génétiques (« homozygosity mapping », analyses des génotypes, séquençage de gènes candidats) sans pour autant réduire le locus ni identifier de mutation causale. Dans ce contexte et grâce à l’avènement des nouvelles technologies de séquençage, j’ai choisi de séquencer le génome complet de trois chiens atteints et deux porteurs apparentés. Ce travail m’a permis d’identifier 117variants dont 9 dans le locus d’intérêt, mais aucun dans des régions codantes. Je me suis donc focalisée sur les variants de régions régulatrices pour 13 gènes candidats. De plus, j’ai identifié cinq variants structuraux, encore en cours d’étude. Concernant l’APR du berger picard, nous avons relancé le projet par la collecte de prélèvements et la réalisation d’un pedigree de 154 chiens. Ce travail a amené à une collaboration tripartite internationale par le séquençage de deux chiens atteints et deux indemnes d’APR, dont les analyses sont en cours. Cette thèse m’a permis d’aborder la génétique d’une maladie génétique rare chez l’homme grâce à un modèle spontané original ; et même si ce travail n’a pas abouti à l’identification de mutations à ce jour, ces APR restent de bons modèles génétique et thérapeutique pour les rétinites pigmentaires humaines. / Dogs are affected by numerous genetic diseases including retinopathies, the subject of my thesis. Historically, humans have exerted a very strong artificial selection to dogs, thus creating some 400 breeds to perform specific tasks or to harbour specific traits. By such an homogenisation of phenotypic and behavioural traits, humans have selected desired alleles but also concentrated undesired deleterious alleles responsible of genetic diseases. These diseases are clinically and genetically similar to human genetic diseases, making dogs a model of choice to search for the genetic bases of such genetic diseases and to develop new therapies for a mutual benefit for dogs and humans. I worked on Progressive Retinal Atrophies (PRA) in two breeds, thanks to the contribution of the veterinary ophthalmologist Dr. Gilles Chaudieu and the breed clubs of border collies and berger picard. Concerning the border collie PRA, genetic analyses performed before my thesis allowed the identification of a locus of 20Mb on the X chromosome. I first completed and supplemented the epidemiological and clinical data for about 500 dogs and continued the sample and data collection. A first genetic linkage analysis on 130 dogs allowed to confirm the transmission mode and the locus. I then performed several genetic analyses (« homozigosity mapping », genotypes analyses, candidate gene sequencing) without significantly reducing the locus,neither finding the causal mutation, unfortunately. In this context and thanks to the development of new sequencing technologies, I chose to sequence the entire genome of three PRA affected border collies and two unaffected related dogs. This work allowed the identification of 117variants, 9 in the locus but none in coding regions. I thus focused my research on genetic variants from potential regulatory regions for 13 candidate genes. In addition, I identified five structural variants. The analysis of these variants is still ongoing. Concerning the berger picard PRA, we have re-initiated the project by collecting samples and designing a large pedigree of 154 dogs. This workled to an international collaboration by the sequencing of the entire genomes of 2 affected and 2 unaffected bergers picards for which the statistical analyses are ongoing. This thesis allowed me to work on the genetics of rare diseases in humans with a spontaneous and original animal model and even if thiswork has not yet reached the identification of the mutations, these two PRAs in these two breeds remain good genetic and therapeutic models for human RP RetinitisPigmentosa.

The object of this thesis is the design of eye measuring equipment, concretely autorefractometer. The proposed solution is based on innovative reorganization parts of this machine. The thesis is based on complex analysis of ophtalmology history, technical data and design of current autorefractometers. The design report contains the identified problems, variant design concepts and final solution. The design report accompained a product mock-up in 1:1 scale.

Les procédures chirurgicales intraoculaires sont des procédures difficiles par la précision qu’elles demandent, on parle de microchirurgie, mais aussi par la difficulté et la faible qualité de visualisation des tissus à traiter. En effet, dans la plupart des procédures intraoculaires le chirurgien utilise uniquement un microscope ophtalmologique qui ne permet la visualisation des tissus que par la pupille du patient et offre une perception limitée de la profondeur. La Tomographie en Cohérence Optique (OCT) fournit des images en profondeur des tissus sains de manière non invasive, elle est utilisée couramment en diagnostic ophtalmologique et est de plus en plus utilisée intra-opérativement. Dans cette thèse nous allons présenter deux systèmes OCT intra-opératifs qui visent à assister les chirurgiens sur deux procédures intraoculaires, la vitrectomie et l’injection sous-rétinienne. Pour ces deux projets nous avons utilisé le matériel chirurgical utilisé cliniquement pour plusieurs raisons : s’assurer d’utiliser des outils adéquats (dimensions, efficacité, sécurité) pour la procédure, garder des outils que les chirurgiens utilisent régulièrement et avec lesquels ils sont familiers et limiter les coûts de développement. Pour le système OCT nous avons utilisé des sondes OCT en fibre optique car elles sont flexibles, bon marché et de petit diamètre. Leur focalisation peut également être modifiée dépendamment de l’application avec une fibre optique GRIN à leur extrémité pour augmenter le signal OCT. Nous avons ainsi attaché à ces outils chirurgicaux des sondes OCT en fibre optique. Pour le projet portant sur les injections sous-rétiniennes il a fallu dans un premier temps développer des sondes OCT avec des diamètres plus petits que ceux existant. Pour ce faire nous avons développé une méthode permettant de réduire le diamètre des sondes avec de l’acide fluorhydrique et grâce à un design permettant de conserver les propriétés optiques des sondes. Ce travail est présenté dans le premier article. Le second article présente un système permettant de guider les injections sous-rétiniennes. L’injection sous-rétinienne est une intervention chirurgicale de haute précision visant à restaurer et/ou préserver la vision des patients souffrant de maladies rétiniennes. Néanmoins, l’injection sous-rétinienne reste à la limite des capacités physiologiques humaines en raison des tremblements de la main et peut être compromise par le reflux du médicament si l’injection n’est pas assez profonde dans la rétine. Nous avons développé un système pour guider l’injection avec un micromanipulateur et donner des informations précises sur la profondeur au chirurgien avec l’OCT intra-opératif. Après avoir miniaturisé une sonde OCT en fibre optique avec la méthode présentée dans l’article 1 nous avons pu l’insérer dans une canule utilisée cliniquement. La sonde couplée à un système OCT que nous avons développé acquiert un signal A-scan qui va permettre de connaitre la distance entre la canule et la rétine mais aussi de sélectionner la profondeur de l’injection dans les couches rétiniennes. La canule est attachée à un micromanipulateur qui assure son déplacement dans l’œil. Une image M-scan est construite avec le signal OCT et le chirurgien peut directement sélectionner sur l’image la profondeur de l’injection. Nous avons développé l’interface sur Labview. Après avoir sélectionné la cible de l’injection le programme de guidage va déplacer la canule et injecter le volume adéquat grâce à une pompe contrôlable. Nous avons validé notre système de guidage sur des yeux de porcs ex-vivo. Sur 40 injections 38 présentaient un décollement rétinien ciblé et localisé, preuve de la réussie de l’injection rétinienne ce qui représente un taux de succès de 95% (CI : 83.1 – 99.4). Nous avons aussi grâce à un algorithme de traitement de l’image calculé le volume présent sous la rétine après l’injection que nous avons comparé au volume injecté. Nous avons ainsi trouvé que 75% du volume initialement injecté se retrouve bien sous la rétine. Le troisième article présente un système permettant d’arrêter automatiquement le vitrecteur lors d’une vitrectomie pour réduire les dommages accidentels sur la rétine. La survenue de déchirures rétiniennes iatrogèniques dans la vitrectomie par la pars plane est une complication qui compromet l’efficacité globale de la chirurgie. Un certain nombre de déchirures rétiniennes iatrogènes se produisent lorsque la rétine est coupée accidentellement par le vitrecteur. Nous avons développé un vitrecteur intelligent capable de détecter en temps réel une coupure rétinienne accidentelle et de désactiver rapidement la machine de vitrectomie pour les prévenir. Ce vitrecteur intelligent est composé d’une sonde OCT attachée au vitrecteur et va avoir comme rôle de détecter si le vitrecteur aspire la rétine et va endommager ces tissus sains. La sonde OCT agit comme un détecteur de présence devant l’ouverture du vitrecteur, ceci en comparant un signal de référence avec le signal en direct. Cette comparaison de signal OCT va commander un bras robotique pour actionner la pédale d’arrêt du vitrecteur. Ainsi le chirurgien n’a pas besoin d’interpréter un signal, la décision d’arrêt du vitrecteur dû à la présence de la rétine est prise automatiquement. Ceci va permettre de réduire grandement, de 300 ms à 29 ms, le délai de la prise de décision d’arrêt du vitrecteur précédemment limité par le temps de réaction du chirurgien. Nous avons développé les sondes OCT, le système OCT ainsi que l’algorithme d’arrêt automatique de ce système. Nous avons validé sur des yeux porcins in-vivo, deux chirurgiens ont utilisé notre système en essayant d’endommager les tissus rétiniens. 70% (CI : 56.39 – 82.02) des tentatives de dommages rétiniens des chirurgiens furent atténuées ou empêchées par notre système. Ce projet a abouti au dépôt d’un brevet ("Smart Vitrector", Provisional patent application, US 63109040). / Intraocular surgical procedures are difficult procedures because of the precision they require, they are often referred as microsurgery, but also by the little information available to the surgeon. In most intraocular procedures the surgeon only uses an ophthalmic microscope which allows visualization of tissue just through the patient’s pupil and offers limited depth perception. Optical Coherence Tomography (OCT) provides in-depth images of healthy tissue in a non-invasive manner, is commonly used in ophthalmologic diagnostics, and is increasingly used intraoperatively. In this thesis we will present two intraoperative OCT systems that aim to assist surgeons with two intraocular procedures, vitrectomy and subretinal injection. For these two projects we used the surgical equipment used clinically for several reasons : to make sure to use adequate tools (dimensions, efficiency, safety) for the procedure, to keep tools that surgeons use regularly and with which they are familiar and limit development costs. For the OCT system we used fiber optic OCT probes as they are flexible, cheap and small in diameter. Their focus can also be modified, depending the application, with a GRIN fiber at their tip to increase the OCT signal. We have attached optical fiber OCT probes to these surgical tools. For the subretinal injections project it was first necessary to develop OCT probes with smaller diameters than existing ones. To do this, we have developed a method to reduce the diameter of the probes with hydrofluoric acid and a design to maintain the optical properties of the probes. This work is presented in the first article. The second article presents a system for guiding subretinal injections. Subretinal injection of drugs is a challenging surgical intervention aiming to restore and/or preserve the vision of patients suffering from retinal diseases. Nevertheless, the subretinal injection remains at the edge of human physiological capacity because of hand tremor and can be mitigated by drug reflux if the injection is not deep enough in the retina. We developed a system to guide the injection with a micromanipulator and give precise depth information to the surgeon with intraoperative OCT. To do so we first miniaturized an optical fiber OCT probe with the method presented in article 1, we were able to insert it into a cannula used clinically. The probe coupled to an OCT system that we have developed acquires an A-scan signal which enables to know the distance between the cannula and the retina but also to select the depth of the injection into the retinal layers. The cannula is attached to a micromanipulator that moves it inside the eye. An M-scan image is built with the OCT signal and the surgeon can directly select on the image the depth of the injection. We developed the interface on Labview. After selecting the injection target, the guidance program will move the cannula and inject the appropriate volume using a controllable pump.We have validated our guidance system on pig eyes ex-vivo. Out of 40 injections, 38 presented a retinal detachment, proof of a successful retinal injection, which represents a success rate of 95% (CI : 83.1 – 99.4). Thanks to an image processing algorithm, we also calculated the bleb volume under the retina after the injection, which we compared to the initial injected volume. We have found that 75% of the injected volume ends in the subretinal space. The third article presents for automatically stopping the vitrector during a vitrectomy. The occurrence of iatrogenic retinal breaks in pars plana vitrectomy is a complication that compromises the overall efficacy of the surgery. A subset of iatrogenic retinal break occurs when the retina is cut accidentally by the vitrector. We developed a smart vitrector that can detect in real-time potential accidental retinal cut and activate promptly a vitrectomy machine to prevent them. To do so an OCT probe is attached to the vitrector and will have the role of detecting if the vitrector sucks the retina and will damage these healthy tissues. The OCT probe acts as a presence detector in front of the vitrector opening, by comparing a reference signal with the live signal. This OCT signal comparison will control a robotic arm to operate the vitrector stop pedal. Thus, the surgeon does not need to interpret a signal, the decision to stop the vitrector due to the presence of the retina is taken automatically. This will greatly reduce, from 300 ms to 29 ms, the delay to stop the vitrector previously limited by the reaction time of the surgeon. We have developed the OCT probes, the OCT system, and the automatic shutdown algorithm for this system. We validated our system on in-vivo porcine eyes, two surgeons used the modified vitrector trying to damage retinal tissue. 70% (CI : 56.39 – 82.02) of surgeons’ retinal damage attempts were mitigated or prevented by our system. This project resulted in a patent ("Smart Vitrector", Provisional patent application, US 63109040).

<p>Glaucoma is a common disease in the elderly population. Open-angle glaucoma (OAG) is the predominant form of glaucoma. Chronic simple glaucoma and capsular glaucoma, characterized by the occurrence of pseudoexfoliation in the anterior eye segment, are the most frequent types of OAG. The purpose of the present thesis was to study the epidemiology of OAG in the municipality of Tierp, whose population has a high exposure to pseudoexfoliation.</p><p>In a case-finding study, the prevalence of known cases of OAG by December 31, 1983 was estimated to 1.4% in people ≥45 years of age. Sixty-three percent of all cases had capsular glaucoma. Patients with advanced glaucoma were older, had had the disease for longer, had higher mean initial intraocular pressure, and had more extensive visual field defects at the time of diagnosis.</p><p>A population survey of people 65–74 years of age was conducted in 1984–86. The prevalence of OAG was 5.3%. Pseudoexfoliation was found in 17%, being more common in females. Pseudoexfoliation was associated with OAG only in people previously diagnosed with the disease (odds ratio = 16). In cases detected at the survey, an intraocular pressure ≥20 mmHg was a serious risk factor of having OAG (odds ratio = 9.7).</p><p>In a 5-year follow-up study of participants in the population survey, increased intraocular pressure and pseudoexfoliation were recognized as independent risk factors for the development of OAG (standardized risk ratios = 3.4 and 9.8, respectively). Interaction between increased intraocular pressure and pseudoexfoliation was indicated. By May 2006, the incidence of OAG was estimated to 7.1 per 1,000 person-years. The incidence of capsular glaucoma was more than twice that of chronic simple glaucoma.</p><p>The prevalence and incidence of OAG was higher than that reported from other studies conducted on Caucasian populations. The probable explanation for this finding is exposure to pseudoexfoliation.</p>