Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature.

We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.

Clinical Outcomes in AYAs (Adolescents and Young Adults) Treated with Proton Therapy for Uveal Melanoma: A Comparative Matching Study with Elder Adults.

OBJECTIVE: The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). MATERIAL AND METHODS: A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15-39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. RESULTS: Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). CONCLUSION: While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general.

MRI and FUNDUS image fusion for improved ocular biometry in Ocular Proton Therapy.

INTRODUCTION: Ocular biometry in Ocular Proton Therapy (OPT) currently relies on a generic geometrical eye model built by referencing surgically implanted markers. An alternative approach based on image fusion of volumetric Magnetic Resonance Imaging (MRI) and panoramic fundus photography was investigated. MATERIALS AND METHODS: Eighteen non-consecutive uveal melanoma (UM) patients, who consented for an MRI and had their tumour base visible on panoramic fundus photography, were included in this comparative analysis. Through generating digitally-reconstructed projections from MRI images using the Lambert azimuthal equal-area projection, 2D-3D image fusion between fundus photography and an eye model delineated on MRI scans was achieved and allowed for a novel definition of the target base (MRI + FCTV). MRI + FCTV was compared with MRI-only delineation (MRIGTV) and the conventional (EyePlan) target definition (EPCTV). RESULTS: The combined use of fundus photography and MRI to define tumour volumes reduced the average discrepancies by almost 65% with respect to the MRI only tumour definitions when comparing with the conventionally planned EPCTV. With the proposed method, shallow sub-retinal tumour infiltration, otherwise invisible on MRI, can be included in the target volume definition. Moreover, a novel definition of the fovea location improves the accuracy and personalisation of the 3D eye model. CONCLUSION: MRI and fundus image fusion overcomes some of the limitations of ophthalmological MRI for tumour volume definition in OPT. This novel eye tumour modelling method might improve treatment planning personalisation, allowing to better anticipate which patients could benefit from prophylactic treatment protocols for radiation induced maculopathy.

Valsalva-Induced Spontaneous Suprachoroidal Hemorrhage: A Case Report and Review of the Literature.

We report a rare case of spontaneous suprachoroidal hemorrhage and present a systematic review of the literature using PubMed/Medline databases. Patients that developed a spontaneous suprachoroidal hemorrhage with a history of previous intraocular surgery were excluded. An 82-year-old male patient with no known ocular pathologies or surgical history was referred with acute ocular pain and decreased vision in the right eye (BCVA: 0.6 with hyperopic correction) following a Valsalva maneuver. General history included chronic heart failure and coronary artery disease, treated with anticoagulant and antihypertensive drugs. Dilated fundus examination revealed a posterior red-brown choroidal mass, with a thickness of 1.5 mm on B-scan ultrasonography. The lesion was not visible on fluorescein or indocyanine green angiography and was located under the choroid on B-scan optical coherence tomography. The diagnosis of a spontaneous suprachoroidal hemorrhage was evoked, and the patient was observed. Five months later, BCVA was 1.0 uncorrected, with a normal-appearing fundus. In a literature review, eight cases of spontaneous suprachoroidal hemorrhage following an episode of increased intrathoracic pressure were identified, including our patient. M/F ratio was 1 : 1, with a median age of 66.5 years. All cases presented systemic pathologies. All cases presented with a unilateral suprachoroidal hemorrhage. Only 2/8 patients had ocular comorbidities. Complications requiring treatment were noted in 4/8 cases, including 2 cases that resulted in the loss of the vision following an acute angle-closure glaucoma. Spontaneous resolution of the hemorrhage was observed in the other 4 patients. In 6/8 cases, vision recovered over a mean period of 10 weeks. In conclusion, spontaneous suprachoroidal hemorrhage following a Valsalva maneuver in eyes with no history of ocular surgery or trauma is rare, and has been associated with advanced age, cardiovascular disease and asthma. In severe cases (2/8) the eye was lost, while most cases (6/8) recovered, presenting a good visual outcome.

Clinical Outcomes after International Referral of Uveal Melanoma Patients for Proton Therapy.

OBJECTIVE: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. MATERIALS AND METHODS: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. RESULTS: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. CONCLUSION: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.

EIGHTEEN-MONTH RESULTS OF INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ON VISION AND MICROCIRCULATION IN RADIATION MACULOPATHY.

PURPOSE: To evaluate 18 months' results of a strict anti-vascular endothelial growth factor protocol for radiation maculopathy following proton therapy in choroidal melanoma. METHODS: Retrospective, comparative, nonrandomized study of 74 radiation maculopathy patients presenting macular lipid deposits, hemorrhages, microaneurysms, cystoid edema, nerve layer infarction, telangiectasia, or capillary nonperfusion. The study group included 52 consecutive patients injected with intravitreal anti-vascular endothelial growth factors (bevacizumab/ranibizumab: 46/6) every two months for the first and every 3 months for the second year, with minimum 12 months' follow-up. The control group consisted of 22 patients having declined this treatment. Best-corrected visual acuity, spectral domain-optical coherence tomography and optical coherence tomography angiography were recorded at baseline, 6, 12, and 18 months. The foveal avascular zone and capillary density were measured at the superficial capillary plexus. RESULTS: Radiation maculopathy was diagnosed at 2 years (1.5-3.5) after proton therapy. Best-corrected visual acuity at baseline, 12 and 18 months improved in the study group from 0.45, 0.3 to 0.2 logarithm of the minimum angle of resolution, but decreased in the control group from 0.5, 0.9 to 1.0 logarithm of the minimum angle of resolution respectively (P < 0.001 at 12 months). Simultaneously, foveal avascular zone enlargement was less in the study (from 0.377, 0.665 to 0.744 mm2) than control group (from 0.436, 1.463 to 2.638 mm2) (P = 0.05 at 12 months). CMT (280 and 276 µm) and capillary density (37% and 38%, at baseline, respectively) did not evolve significantly different. CONCLUSION: Intravitreal anti-vascular endothelial growth factors, every 2 months for the first and every 3 months for the second year, slow down, over up to 18 months, vision loss and anatomical degradation in radiation maculopathy following proton therapy for choroidal melanoma.

Good long-term visual outcomes of parapapillary choroidal melanoma patients treated with proton therapy: a comparative study.

PURPOSE: To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years. METHODS: This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years. RESULTS: Mean follow-up was 120.8 ± 48.8 months (54.0-295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the "good visual outcome" (GVO) group, while the remaining 246 (79%) constituted the "poor visual outcome" (PVO) group, subdivided into 70 (22%) with a VA of 0.3-1.0 logMAR (0.1-0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (< 0.1 decimal). On multivariate analysis, older age (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P < 0.03), volume of the optic disc and macula receiving 50% of dose (30 CGE) (P = 0.02 and P < 0.001, respectively) were independent negative predictors of GVO. CONCLUSIONS: Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

Genomic and transcriptomic landscape of conjunctival melanoma.

Conjunctival melanoma (CJM) is a rare but potentially lethal and highly-recurrent cancer of the eye. Similar to cutaneous melanoma (CM), it originates from melanocytes. Unlike CM, however, CJM is relatively poorly characterized from a genomic point of view. To fill this knowledge gap and gain insight into the genomic nature of CJM, we performed whole-exome (WES) or whole-genome sequencing (WGS) of tumor-normal tissue pairs in 14 affected individuals, as well as RNA sequencing in a subset of 11 tumor tissues. Our results show that, similarly to CM, CJM is also characterized by a very high mutation load, composed of approximately 500 somatic mutations in exonic regions. This, as well as the presence of a UV light-induced mutational signature, are clear signs of the role of sunlight in CJM tumorigenesis. In addition, the genomic classification of CM proposed by TCGA seems to be well-applicable to CJM, with the presence of four typical subclasses defined on the basis of the most frequently mutated genes: BRAF, NF1, RAS, and triple wild-type. In line with these results, transcriptomic analyses revealed similarities with CM as well, namely the presence of a transcriptomic subtype enriched for immune genes and a subtype enriched for genes associated with keratins and epithelial functions. Finally, in seven tumors we detected somatic mutations in ACSS3, a possible new candidate oncogene. Transfected conjunctival melanoma cells overexpressing mutant ACSS3 showed higher proliferative activity, supporting the direct involvement of this gene in the tumorigenesis of CJM. Altogether, our results provide the first unbiased and complete genomic and transcriptomic classification of CJM.

Occult Spontaneous Ocular Perforation Presenting as Conjunctival Chemosis in a Patient with Marfan's Syndrome.

We report a case of occult spontaneous ocular perforation presenting as conjunctival chemosis in a patient with Marfan's syndrome (MFS). A 38-year-old female with MFS presented with bilateral conjunctival chemosis since 6 months. Best-corrected visual acuity was 20/20 in both eyes. On slit-lamp examination, a diffuse conjunctival chemosis was observed in both eyes without any signs of ocular hypotony (decreased visual acuity, low intraocular pressure, shallow anterior chamber, pupil distortion, hypotony maculopathy, and chorioretinal folds). Anterior-segment optical coherence tomography revealed a corneoscleral fistula at the left nasal limbus, without any similar finding in the right eye. A scleral patch was performed at the site of the perforation. At 3 month's follow-up, the left chemosis had regressed, with a stable best-corrected visual acuity in both eyes. However, on ultrasound biomicroscopy, another fistula at the right superior limbus was found, and the patient was referred for treatment with a scleral patch. In conclusion, conjunctival chemosis in a patient with MFS should raise the suspicion of an occult spontaneous ocular perforation.

Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition.

Purpose: To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells. Methods: The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining. Results: A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested. Conclusions: The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.