Ischaemic stroke after exposure to aflibercept: interaction with vitamin K antagonist and/or direct pharmacodynamic effect?

WHAT IS KNOWN AND OBJECTIVE: Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of vascular endothelium, and their inhibition led to the development of a number of drugs used for malignancies or exudative neo-vascular age-related macular degeneration (AMD). CASE SUMMARY: We report a case of ischemic stroke in an 87-year-old woman having received intravitreal aflibercept, a new anti-VEGF for AMD. She had been treated with ranibizumab since 2007. In 2013, ranibizumab was replaced with aflibercept, followed by a decrease in the International Normalized Ratio, complicated by a stroke a few days later. The rechallenge was positive. WHAT IS NEW AND CONCLUSION: A potential time-dependent interaction between aflibercept and VKA antagonist and/or a direct effect of aflibercept may have contributed to the occurrence of the ischaemic stroke. Currently available data suggest some pharmacokinetic and pharmacodynamic effects of aflibercept by explaining its pro-thrombotic profile.

Prospective assessment of peripapillary microvasculature using optical coherence tomography angiography in para-optic intracranial and sinonasal tumors treated with proton therapy.

PURPOSE: Radiation-induced optic neuropathy (RION) is rare but may lead to blindness. The mechanisms by which this occurs include endothelial and neuronal damage, but RION has been assessed very little in the case of extraocular tumors treated with high-energy proton therapy, the use of which is expanding worldwide. We assessed peripapillary microvascular changes by optical coherence tomography angiography (OCT-A) in patients undergoing high-energy proton therapy for para-optic intracranial or head and neck tumors. MATERIALS AND METHODS: In this prospective institutional review board approved study, patients receiving>40Gy_RBE maximal PBT dose to their optic nerve between 2018 and 2020 underwent quantitative OCT-A analyses. ImageJ software was used to assess changes in the peripapillary superficial vascular complex (SVC) using vascular area density (VAD), vessel length density (VLD) and fractal dimension (FDsk). Uni- and multivariate analyses were performed. RESULTS: Of 47 patients (78 eyes) with 29±6 months of follow-up (range 18-42), 29 patients (61.7%) had previously undergone surgery and 18 (32.1%) had microvascular abnormalities prior to proton therapy. Total radiotherapy dose was the most relevant factor in decreased peripapillary microvasculature. Duration of follow-up was associated with lower VAD (P=0.005) and mean retinal nerve fiber layer (RNFLm) thickness also decreased. There was no significant correlation between OCT-A changes and mean visual defect. CONCLUSION: Peripapillary microvasculature changes may occur from tumor compression or surgery and proton therapy for extraocular tumors. OCT-A may provide quantitative and mechanistic insights into RION before the occurrence of clinical symptoms.

[High energy proton therapy for extraocular tumors, neurotrophic keratitis and functional consequence: A series of 3 cases]. / Protonthérapie haute énergie des tumeurs extra-oculaires, kératite neurotrophique et conséquence fonctionnelle : une série de 3 cas.

INTRODUCTION: High energy proton therapy (HEP) is a form of radiation therapy using protons for extraocular tumors. Its ballistic properties are theoretically advantageous, but the real impact on the surrounding ocular tissues during cerebral and ENT irradiation is poorly documented. We describe three consecutive patients with corneal damage following such irradiation. MATERIALS/METHODS: Post-proton therapy neurotrophic keratitis (NK) is defined as corneal hypo/anesthesia responsible for an alteration of corneal trophicity and graded according to the Mackie classification, in terms of a prospective ophthalmological follow-up protocol for all patients with extraocular tumors treated with HEP. RESULTS: Among 193 patients treated with HEP between 2018 and 2021 for extraocular tumors, three patients developed severe neurotrophic keratitis, i.e. 1.6% of treated patients. According to the Mackie classification, the three patients showed grade 3 NK less than one year after the conclusion of their HEP. These three patients underwent amniotic membrane grafting. They were placed on autologous serum eye drops. Two of the three patients had to be eviscerated. The dose to the cornea was greater than 50 Gray (Gy)_Relative biological effectiveness (RBE) in the three cases. DISCUSSION: The diagnosis and etiological origin of neurotrophic keratitis are often difficult to establish. In these cases, the imputability of radiation therapy, proton therapy in our cases, in the development of neurotrophic keratitis was plausible based on the dosimetry of the patients, all of whom had anterior tumors with a poor prognosis requiring high tumoricidal doses. CONCLUSION: Further studies to establish the impact of proton therapy on corneal sensitivity are necessary. However, this feedback and the multidisciplinary management of tumors can help to limit the risk of some complications of radiation therapy. Early diagnosis allows for appropriate management and could possibly minimize the anatomical and functional ocular complications of neurotrophic keratitis.

[Recurrence of palpebral basal cell carcinoma according to histological margins]. / Récidive des carcinomes basocellulaires palpébraux selon les marges histologiques.

BACKGROUND: Basal cell carcinomas (BCCs) represent 90% of malignant tumors of the eyelids, which can be locally invasive and destructive. The observation of histological safety margins (MHS) allows for the prevention of recurrence while maintaining a fair compromise between aesthetics and functionality. However, to date, there is no consensus or national recommendations concerning the MHS to be observed according to the various histological subtypes of BCCs. METHODS: Through a retrospective analysis of patient records and corresponding excisional slides, we studied the 6-year recurrence rate of 98 patients who underwent surgery for palpebral BCC. RESULTS: MHS were mostly absent in the excisional specimens of recurrent BCCs and significantly more narrow than in non-recurrent BCCs, on average over 2mm. CONCLUSION: The results of our study suggest that an average MHS greater than 2mm prevents most recurrences.

Radiotherapy of sinonasal cancers.

We present the update of the recommendations of the French society of radiotherapy and oncology on the indications and the technical methods of carrying out radiotherapy of sinonasal cancers. Sinonasal cancers (nasal fossae and sinus) account for 3 to 5% of all cancers of the head and neck. They include carcinomas, mucosal melanomas, sarcomas and lymphomas. The management of sinonasal cancers is multidisciplinary but less standardized than that of squamous cell carcinomas of the upper aerodigestive tract. As such, patients with sinonasal tumors can benefit from the expertise of the French expertise network for rare ENT cancers (Refcor). Knowledge of sinonasal tumour characteristics (histology, grade, risk of lymph node involvement, molecular characterization, type of surgery) is critical to the determination of target volumes. An update of multidisciplinary indications and recommendations for radiotherapy in terms of techniques, target volumes and radiotherapy fractionation of the French society of radiotherapy and oncology (SFRO) was reported in this manuscript.

[Management of ocular toxoplasmosis in France: Results of a modified Delphi study]. / Prise en charge de la toxoplasmose oculaire en France : résultats d'une étude Delphi modifiée.

OBJECTIVE: To evaluate diagnostic and therapeutic practices and then establish a consensus on the management of ocular toxoplasmosis in France through a Delphi study. MATERIALS AND METHODS: Twenty-three French experts in ocular toxoplasmosis were invited to respond to a modified Delphi study conducted online, in the form of two questionnaires, in an attempt to establish a consensus on the diagnosis and management of this pathology. The threshold for identical responses to reach consensus was set at 70 %. RESULTS: The responses of 19 experts out of the 23 selected were obtained on the first questionnaire and 16 experts on the second. The main elements agreed upon by the experts were to treat patients with a decrease in visual acuity or an infectious focus within the posterior pole, to treat peripheral lesions only in the presence of significant inflammation, the prescription of first-line treatment with pyrimethamine-azithromycin, the use of corticosteroid therapy after a period of 24 to 48hours, the prophylaxis of frequent recurrences (more than 2 episodes per year) with trimethoprim-sulfamethoxazole as well as the implementation of prophylactic treatment of recurrences in immunocompromised patients. On the other hand, no consensus emerged with regard to the examinations to be carried out for the etiological diagnosis (anterior chamber paracentesis, fluorescein angiography, serology, etc.), second-line treatment (in the case of failure of first-line treatment), or treatment of peripheral foci. CONCLUSION: This study lays the foundations for possible randomized scientific studies to be conducted to clarify the management of ocular toxoplasmosis, on the one hand to confirm consensual clinical practices and on the other hand to guide practices for which no formal consensus has been demonstrated.

Matrix metalloproteinase 14 overexpression reduces corneal scarring.

Once a corneal scar develops, surgical management remains the only option for visual rehabilitation. Corneal transplantation is the definitive treatment for a corneal scar. In addition to the challenges posed by graft rejections and other postoperative complications, the lack of high-quality donor corneas can limit the benefits possible with keratoplasty. The purpose of our study was to evaluate a new therapeutic strategy for treating corneal scarring by targeting collagen deposition. We overexpressed a fibril collagenase (matrix metalloproteinase 14 (MMP14)) to prevent collagen deposition in the scar tissue. We demonstrated that a single and simple direct injection of recombinant adeno-associated virus-based vector expressing murine MMP14 can modulate gene expression of murine stromal keratocytes. This tool opens new possibilities with regard to treatment. In a mouse model of corneal full-thickness incision, we observed that MMP14 overexpression reduced corneal opacity and expression of the major genes involved in corneal scarring, especially type III collagen and α-smooth muscle actin. These results represent proof of concept that gene transfer of MMP14 can reduce scar formation, which could have therapeutic applications after corneal trauma.

[Combined vitrectomy-lensectomy surgery with bag-in-the-lens or lens in the bag implantation: comparison of final visual acuity]. / Chirurgie combinée vitrectomie et phakoéxérèse avec implantation bag-in-the-lens (BIL) ou de sac : comparaison de l'acuité visuelle finale.

INTRODUCTION: Combined vitrectomy-lensectomy surgery is a safe and effective procedure. Nevertheless, it is frequently complicated by posterior capsule opacification and the formation of posterior synechiae. These complications can be avoided by placing a "bag in the lens" (BIL) implant. The objective of this study is to compare the visual acuity gain (VA) after combined vitrectomy-lensectomy surgery between a group implanted with the BIL technique and a group with implantation in the bag (LIB). MATERIAL AND METHODS: We included in the study all vitrectomy-lensectomy procedures for epiretinal membrane and vitreomacular traction performed between May 2013 and July 2016 at the Hospital and University Center of Caen. We compared the VA gain between the BIL group and the LIB group six months after surgery. RESULTS: A total of 33 patients were included in the study, consisting of 28 eyes in the BIL group and 8 eyes in the LIB group. The mean VA gain in the BIL group was -0.52 LogMAR (P<0.0001) and -0.56 LogMAR (P=0.0047) for the LIB group. The difference between the two groups was not significant (P=0.74). CONCLUSION: The use of the BIL technique during vitrectomy-lensectomy allows visual recovery as good as implantation within the capsular bag. In addition, this implant has the advantage of significantly reducing the occurrence of posterior synechiae and preventing anterior and posterior capsular proliferation.

[Postural changes in patients with visual deficits]. / Étude des atteintes posturales chez les patients déficients visuels.

INTRODUCTION: Balance is an active system allowing the body to maintain individual stability despite external stimuli. It relies on many senses which provide data to compensate for external variations such as visual information. It is thus necessary that the senses be in good condition and transmit accurate data. We wished to study postural adaptations made by visually impaired people. MATERIAL AND METHODS: We performed a prospective study of patients with macular degeneration with visual acuity less than 20/40, glaucoma with a mean visual field defect less 12 decibels, and a control population. All subjects underwent a dynamic equilibrium test on a stabilometric platform with Win-Posturo software. We assessed their postural profile in various situations : eyes open, eyes closed, balance, anteroposterior displacement and lateral displacement. RESULTS: The first group consisted of 16 patients with age macular degeneration (AMD), the second of 17 patients with glaucoma and the third of 18 control subjects. In static equilibrium, for the parameter "length vs. surface area," all groups had an improvement in their performance with eyes open (P=0.05). There was a significant difference between the subject and control groups (P<0.01). In addition, subjects in the group with peripheral visual impairment had significantly greater tendency to lean forward. In dynamic equilibrium, we did not demonstrate any significant difference between the groups. DISCUSSION: In static equilibrium, patients with poor peripheral vision have better quality somatosensory compensation, but they have a tendency to lean forward, which increases the risk of falling forward. For the three groups, the tests showed that the subjects are vision-dependent, which implies that somatosensory compensation could be developed to limit this dependency. In dynamic equilibrium, the subjects in the disease groups perform significantly worse than the controls. All the visually impaired have a more developed somatosensory mechanism than the controls. The subjects in the first and third groups have the same postural profile, they are vision-dependent. Subjects in the second group have an instability and change in their postural strategy, increasing the risk of falling. Visual acuity has a lesser impact on the risk of falling than the visual field. CONCLUSION: Comparing postural responses in these different situations, it appears that postural profiles are modified in the case of visual disability, although the postural profile of the group with central visual loss is similar to that of the controls. Retinal involvement, whether central or peripheral, leads to postural imbalance that may result in falls in certain cases. To limit the prevalence of these falls, it would be interesting to address visually impaired patients by examination and postural rehabilitation to decrease the effects of this visual impairment.

[Comparison of two surgical techniques for the treatment of superior oblique palsy]. / Comparaison de deux techniques chirurgicales dans le traitement de la paralysie du muscle oblique supérieur.

AIM: To compare two surgical techniques for the treatment of superior oblique palsy. PATIENTS AND METHODS: Retrospective study involving 32 patients operated on at the Rouen Teaching Hospital for superior oblique palsy. Group 1 patients were treated by surgical reinforcement of the superior oblique muscle and group 2 patients were treated by surgical loosening (or weakening) of the antagonist muscles. One-year follow-up explored head tilt, diplopia, vertical deviation and cyclotorsion. RESULTS: Functional results (presence of diplopia or stiff neck) were positive in both groups but better in group 1. Only 12.5% of patients required a second operation. Cyclotorsion amounted to less than 2% in group 1 and was still greater than 8% in group 2; on the other hand, vertical deviation had improved more in group 2, where it decreased to 2.1 diopters versus 3.1 in group 1. DISCUSSION: and conclusion: Only reinforcing the superior oblique adequately corrects cyclotorsion, which is the main cause of asthenopia and diplopia, despite an often insufficient height correction that is otherwise clinically well tolerated. We suggest reinforcing the superior oblique as a first intent rather than weakening hyperactive muscles, and in case of excessive postoperative height, we would carry out additional treatment of one of the hyperactive muscles later.

Subretinal fluid in primary rhegmatogenous retinal detachment: physiopathology and composition.

During retinal detachment, subretinal fluid is present, whose composition and physiopathology are still little known. Under normal conditions, osmotic and oncotic pressures help keep the retina in place, but the main retinal attachment force is provided by active transport in the pigment epithelium. Subretinal fluid composition varies according to detachment duration; total protein concentration in subretinal fluid increases with time. In addition, all proteins are qualitatively modified. The detached retina loses its oxygen supply, and it then uses the anaerobic pathway to degrade glucose. Thus, long-duration retinal detachments feature increased lactic acid and dextrose concentrations. Phospholipids are also increased in subretinal fluid, reflecting retinal degradation. This review presents data on the physiopathology and composition of the subretinal fluid in retinal detachments.

Comparison after 10 years of two 100-patient cohorts operated on for eviscerations or enucleations.

PURPOSE: To compare the indications, surgical techniques, and operative outcome between two 100-patient populations operated on for evisceration or enucleation with a 10-year interval. METHODS: This retrospective study involved 100 patients operated on between 1987 and 1990 (Group 1) compared with another 100 patients operated on between 1996 and 2000 (Group 2). Group 1 included 64 males and 36 females, mean age 49 years; Group 2 included 60 males and 40 females, mean age 53. RESULTS: In Group 1, 19 eviscerations were performed, versus 55 in Group 2. In both groups, half of the indications for surgery were a painful blind eye. In Group 1, endophthalmia (23%) came second, whereas it was trauma (15%) in Group 2. Sixty-eight patients were implanted in Group 1 (silicone spheres 69%) versus 86 in Group 2 (hydroxyapatite spheres 69%). Twenty spheres (20%) were rejected in Group 1 versus 7% in Group 2. DISCUSSION AND CONCLUSIONS: The proportion of eviscerations increased in 10 years. The number of endophthalmitis-related operations decreased and trauma-related operations increased. The number of implantations increased with hydroxyapatite as the first choice material instead of silicone. This most likely contributed to reducing the number of rejections.