Novel Variant IMPDH1 c.134A>G, p.(Tyr45Cys): Phenotype-Genotype Correlation Revealed Likely Benign Clinical Significance.

Pathogenic variants in IMPDH1 are associated with autosomal dominant retinitis pigmentosa 10 (RP10), and Leber congenital amaurosis 11. This case report of a 13-year-old girl with Down's syndrome and keratoglobus is aimed at linking the novel variant IMPDH1 c.134A>G, p.(Tyr45Cys), a variant of uncertain significance, to a clinical phenotype and to provide grounds for the objective assignment of its benign features. RP10 is characterized by the early onset and rapid progression of ocular symptoms, beginning with nyctalopia in childhood, accompanied by typical RP fundus changes. As evidenced via thorough clinical examination and testing, none of the RP10 characteristics were present in our patient. On the contrary, our patient who was heterozygous for IMPDH1 c.134A>G, p.(Tyr45Cys) showed no signs of peripheral retinal dystrophy, and did not manifest any disease characteristics typical of the IMPDH1 gene mutation. Consequently, we conclude that the variant did not contribute to the phenotype. According to standards and guidelines for the interpretation of sequence variants, IMPDH1 c.134A>G, p.(Tyr45Cys) revealed likely benign features.

Pathogenicity reclassification of the RPE65 c.1580A>G (p.His527Arg) - a case report.

BACKGROUND: It is of utmost importance to define the molecular diagnosis of patients with retinitis pigmentosa (RP) due to existing targeted therapeutic option: voretigene neparvovec.We provide clinical evidence for pathogenicity reclassification of variants of uncertain significance (VUSs) RPE65 c.1580A>G (p.His527Arg). MATERIALS AND METHODS: A case report of a 10-year-old boy with progressive vision loss. The patient manifested disease highly suggestive of RPE65 retinal dystrophy: nyctalopia, fairly good central vision, severely depressed full-field electroretinography responses and complete loss of peripheral fundus aut ofluorescence. RESULTS: Invitae Inherited Retinal Disorders Panel identified likely pathogenic mutation RPE65 c.499G>T (p.Asp167Tyr) and RPE65 c.1580A>G (p.His527Arg), variant of uncertain significance. Segregation analysis confirmed that these variants are in trans. CONCLUSIONS: We conclude that the variant RPE65 c.1580A>G (p.His527Arg) has contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as pathogenic. Therefore, patients with this specific variant in homozygous or compound heterozygous form would likely benefit from genetic treatment based on recombinant adeno-associated virus vector, providing a working RPE65 gene to act in place of a mutated RPE65 gene.

The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal Dystrophy

RPE65, an abundant membrane-associated protein present in the retinal pigment epithelium (RPE), is a vital retinoid isomerase necessary for regenerating 11-cis-retinaldehyde from all-trans retinol in the visual cycle. In patients with inherited retinal dystrophy (IRD), precise genetic diagnosis is an indispensable approach as it is required to establish eligibility for the genetic treatment of RPE65-associated IRDs. This case report aims to report the specific phenotype−genotype correlation of the first patient with a homozygous missense variant RPE65 c.499G>T, p. (Asp167Tyr). We report a case of a 66-year-old male who demonstrated a unique phenotype manifesting less severe functional vision deterioration in childhood and adolescence, and extensive nummular pigment clusters. The underlying causes of the differences in the typical bone spicule and atypical nummular pigment clumping are unknown, but suggest that the variant itself influenced the rate of photoreceptor death. Functional studies are needed to define whether the substitution of aspartate impairs the folding of the tertiary RPE65 structure only and does not lead to the complete abolishment of chromophore production, thus explaining the less severe phenotype in adolescence.

Long-Term Functional Hyperemia after Uncomplicated Phacoemulsification: Benefits beyond Restoring Vision.

The purpose of the study was to investigate the long-term effects of uncomplicated phacoemulsification on macular perfusion using optical coherence tomography angiography (OCTA) in healthy aging subjects. OCTA was performed before phacoemulsification and 1 week, 1 month, 3 months, and 6 months after. Superficial vascular complex (formed of nerve fiber layer vascular plexus and superficial vascular plexus), deep vascular complex (formed of intermediate capillary plexus and deep capillary plexus), as well as choriocapillaris (CC) and large choroidal blood vessels were recorded. Significant changes of vascular parameters in 95 eyes of 95 patients reached plateau 1 week after surgery and remained stable up to 6 months, occurring in all retinal layers but not in choroid and CC. Statistically significant increases in retinal vessels area, vessels percentage area, total number of junctions, junctions density, and total and average vessels length were found, followed by the total number of end points and mean lacunarity decline, proving an increase in blood supply. The study confirmed that uncomplicated phacoemulsification leads to a long-term increase in macular retinal perfusion. The results might ease the decision regarding timing for cataract surgery as long-term perfusion benefits can be achieved. Furthermore, study results provide a normative database of retinal and choroidal vasculature in healthy aging patients.

RPE65 c.353G>A, p.(Arg118Lys): A Novel Point Mutation Associated with Retinitis Pigmentosa and Macular Atrophy

Precise genetic diagnosis in RPE65-mediated retinitis pigmentosa (RP) is necessary to establish eligibility for genetic treatment with voretigene neparvovec: a recombinant adeno-associated viral vector providing a functional RPE65 gene. This case report aims to report a novel RP-related point mutation RPE65 c.353G>A, p.(Arg118Lys), a variant of uncertain significance associated with a severe clinical presentation and the striking phenotypic feature of complete macular atrophy. We report the case of a 40-year-old male with inherited retinal dystrophy, all features typical for the RPE65-associated RP, and marked macular atrophy. Genetic testing identified that the patient was a compound heterozygote in trans form with two heterozygous variants: RPE65 c.499G>T, p.(Asp167Tyr) and RPE65 c.353G>A, p.(Arg118Lys). Furthermore, short-wavelength and near-infrared autofluorescence patterns exhibited deficiencies specific to mutations in the visual cycle genes. To the best of our knowledge, RPE65 c.353G>A, p.(Arg118Lys) is the first described point mutation on this locus, among all other reported insertional mutations, currently classified as likely benign and of uncertain significance. We concluded that this variant contributed to the pathological phenotype, demonstrating its significance clearly to be reclassified as likely pathogenic. This being the case, patients with this specific variant in homozygous or compound heterozygous form would be likely candidates for genetic treatment with voretigene neparvovec.

Thyroid peroxidase antibodies may induce demyelination and oculomotor neuromyotonia in the absence of thyroid eye disease.

INTRODUCTION: The first report of oculomotor neuromyotonia (ONM) in a child induced by thyroid peroxidase antibodies (anti-TPO) in the absence of thyroid eye disease (TED). CASE: 14-year-old girl complained of left eye (LE) paroxysmal upper lid fluttering and ptosis precipitated by hyperventilation or sustained left gaze. On sustained left gaze, right eye (RE) upper lid retraction and LE upper lid fluttering with ptosis ensued. RESULTS: Diagnostic work-up revealed markedly elevated anti-TPO (> 600 IU/ml) and no TED. Brain MRI was normal with no signs of tortuous vessels presenting focal demyelination. We hypothesized that anti-TPO directly induced demyelination and set the ground for right ONM with ephaptic transmission between neurons supplying right medial rectus and levator muscle. CONCLUSIONS: Plethora of theories try to decode the ONM. TED associated ONM is not reported in children but is the second most common cause of ONM in adults, advocated to be of compressive origin. Conversely, this case holds true for cross talk hypothesis. All extraocular muscles must be tested to determine the triggering one. ONM should not be overlooked due to its positive response to carbamazepine.

Rare case of nasal cavity chondrosarcoma presenting only with unilateral decreased vision.

Chondrosarcomas comprise a heterogeneous group of malignant lesions characterized by production of cartilage matrix. Sinonasal involvement is extremely rare, with nasal congestion and obstruction being the leading symptoms. We present a rare case of large chondrosarcoma of the nasal cavity and paranasal sinuses, primarily presenting with ocular symptoms.

The New Face of the Switch Flap in the Reconstruction of a Large Upper Eyelid Defect.

Reconstruction of a large defect after the removal of a massive malignant upper lid tumor is still a challenge in oculoplastic surgery. Our method of choice is Mustardé switch flap. Due to the lack of Mohs micrographic surgery and frozen section technique as well as waiting time of two weeks for histopathological results, we made modifications enabling us to reexcise in case of positive margins: the width of the pedicle of the flap was 7 mm allowing the length of the flap to be increased if needed, the lids were closed with temporary lateral tarsorrhaphy to protect the eye, and the lower lid is finally reconstructed in the second stage of the procedure. In three patients with malignant upper lid tumors, this method of reconstruction proved to be safe and effective with favorable long-term results.

Macular perfusion normative data acquired with optical coherence tomography angiography in healthy four-year-old Caucasian children.

BACKGROUND: The purpose of this cross-sectional study involving healthy emmetropic four-year-old Caucasian children was to provide a macular perfusion normative database acquired with optical coherence tomography angiography (OCTA). One eye of each examinee underwent OCTA imaging. The following parameters were analyzed using AngioTool Image J software: vessels area (VA), vessels density (VD), total number of junctions (TNJ), junctions density (JD), total vessel length (TVL), average vessel length (AVL), total number of endpoints (TNEP), lacunarity (L), vessel diameter index (VDI), tortuosity (T) and foveal avascular zone (FAZ). Average central macular thickness (CMT) and average central macular volume (CMV) were measured. RESULT: Sixty-two eyes of 62 children of average age 50.4 ± 3.8 months were examined. VA, VD, and T increased from the inner towards the outer layers of the retina. The intermediate capillary plexus had the highest JD and TNEP and narrowest FAZ. Retinal sexual differentiation was supported with higher values of the retinal VA, VDI and TNEP, and chorioretinal VA, VDI and L in males. The choriocapillaris presented with the highest VD, AVL, and T and the lowest L and TNEP. CONCLUSION: The study provides the first detailed normative database of the macular vascular network in the youngest uniform cohort of emmetropic four-year-old children.

Ultrasound Biomicroscopy Documented Anterior Uveal Melanoma Regression after Ruthenium-106 Plaque Therapy.

INTRODUCTION: Ultrasound biomicroscopy (UBM) is the only widely used method for the evaluation of anterior uveal melanoma (AUM). OBJECTIVE: Documentation of regression of AUM treated with ruthenium-106 (Ru-106) plaque types CCB and CCC using UBM. METHODS: This single institution-based retrospective case series involved 10 Caucasian patients with AUM followed after brachytherapy with UBM from January 2014 until February 2019. The largest prominence of the tumor perpendicular to the sclera or the cornea (including scleral/corneal thickness) (D) and the largest basal dimension (B) were measured in millimeters with UBM for all patients prior to the brachytherapy and at 4-month interval follow-up. Tumor regression was calculated as a percentage of decrease in the initial D and B values. RESULTS: The study involved 10 patients with a mean age of 64.4 years (yr) (range 46-80 yr). D ranged from 1.82 to 5.5 mm (median 2.99 mm) and B from 2.32 to 12.38 mm (median 4.18 mm). The apical radiation dose in all patients was 100 Gy. The median follow-up was 42.02 months. Regression for D was 21.11 ± 13.66%, 31.09 ± 14.66%, and 34.92 ± 19.86% at 1st, 2nd, and 3rd year of the follow-up, respectively, while for B it was 21.58 ± 16.05%, 28.98 ± 17.71%, and 32.06 ± 18.96%, respectively. Tumor recurrence was documented in 2/10 patients. CONCLUSION: The major regression of AUM, treated with Ru-106 plaque types CCB and CCC, was documented in the first 2 years after brachytherapy in our study group. In the following years, only minimal regression was documented that warns of the need for close monitoring and active search for local recurrences.

Central retinal artery and vein occlusion as a complication of persistent hyaloid artery - a case report.

BACKGROUND: In this case report, we present for the first time central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) as a complication of persistent hyaloid artery (PHA). CASE PRESENTATION: In August 2019, a six-year-old male patient manifested right eye (RE) excessive tearing, conjunctival injection and pain. On examination, RE demonstrated light perception and intraocular pressure of 36 mmHg. The diagnoses of neovascular glaucoma, CRVO and CRAO were established as affirmed with fluorescein angiography (FA). PHA was not reported. Extensive work-up and family history were unremarkable. The child was born on term after uncomplicated twin pregnancy. In December 2019, he was referred to our Centre. Transillumination revealed fully dilated, non-reactive RE pupil, clear lens and tubular remnant of HA containing blood cells in its lumen freely rotating in the anterior vitreous. CONCLUSIONS: PHA results from failure of apoptosis during gestation. It can easily be observed during the red reflex screening at neonatal wards. We hypothesized that PHA twisting led to torsion of the residual primordial common bulb, branching off to HA and CRA with CRAO occurring first. The consequential CRVO presumably advanced by venous stasis due to decrease in arterial inflow. Liquid vitreous appears as early as 4 years of age enabling PHA to whirl more freely. Thus, in case of PHA, we advocate FA to be performed and if connection with retinal artery is proven, parents should be informed on the possible devastating complications and prompt surgical treatment should be considered.

A Retrospective Data Review Confirms That Topical Preservative-Free Hydrocortisone Improves Inflammation in Dry Eye Disease.

BACKGROUND: Inflammation is among the most important mechanisms in the pathogenesis of dry eye disease (DED), triggering the vicious circle of the disease. Reducing inflammation is an important target in dry eye disease treatment. Hydrocortisone is a low-potency corticosteroid with a low ocular penetration potential. AIM: To document the effect of topical preservative-free hydrocortisone 0.335% (PFH, Softacort®, Laboratoires Théa, France) on DED. METHODS: Retrospective data review of patients with mild to moderate DED, treated with PFH for 15 days. Clinical evaluations at Days 0 and 15 included the assessment of the central precorneal tear film thickness (CPTFT), fluorescein tear breakup time, Schirmer test, corneal grading staining (Oxford schema), ocular surface disease index (OSDI) spatial distribution of the precorneal tear film thickness, intraocular pressure (IOP) and local tolerance. RESULTS: Data from 13 women and 2 men were collected. Mean age±SD was 51±5 years for women and 53±4 years for men. Clinical signs and symptoms significantly (all p<0.05) improved after 15 days of treatment. A significant positive correlation between the percentage of change in left eye CPTFT and that in the contralateral eye CPTFT was observed (p=0.003) as well as for both eyes and the left eye FTBUT (p=0.03). For the percentage of change in OSDI, the only significant correlation was with the percentage of change in right eye and FTBUT (p=0.03). IOP remained unchanged. No adverse events were recorded. CONCLUSION: This retrospective data review confirms that topical PFH twice daily for 2 weeks significantly improves clinical signs and symptoms in patients with mild to moderate DED with no safety issues.

Physical Incompatibility between Vancomycin and Viscoelastic Mimicking Acute Endophthalmitis: The First Report.

This is the first documentation of vancomycin precipitation with viscoelastic in the anterior chamber of the eye. A 34-year-old white male underwent uneventful penetrating keratoplasty. Intracameral instillation of 1 mg/0.1 mL of vancomycin followed no attempts of meticulous viscoelastic irrigation. Six hours later thick white material in the anterior chamber was sedimented. The following criteria excluded the diagnosis of endophthalmitis and TASS: clear and transparent anterior chamber and vitreous body, the absence of ciliary injection and corneal oedema, and unremarkable laboratory tests' results. This iatrogenic complication mimicking endophthalmitis does not require any specific management and should be acknowledged in guidelines for prevention and treatment of endophthalmitis. The objective of this paper is to alert colleagues to this iatrogenic complication of vancomycin mimicking endophthalmitis. Whether this condition should be labelled as positive or negative demands further investigation. As vancomycin is a time-dependent antibiotic, it is possible that this precipitate could serve as a slowly releasing drug depot and viscoelastic as a vehicle for precipitation. This being the case, investigation is needed to analyse its potential to precipitate with another dispersive and cohesive viscoelasticity.

Dermis-Fat Graft for Correction of Recurrent Severe Upper Eyelid Retraction in Graves' Orbitopathy.

Dermis-fat graft has been proven as a useful replacement tissue for eyelid and orbit reconstruction, but there is no evidence in the literature that it can be used for correction of upper eyelid retraction. This is the first report that presents two cases (four eyelids) of dermis-fat graft usage as a spacer in the treatment of severe recurrent upper eyelid retraction due to Graves' orbitopathy. Improvement was achieved with minimum complications, patient symptoms were reduced, and the results were stable almost three years after the procedure.

Single-Stage Orbital Socket Reconstruction Using the Oversized Dermis Fat Graft and the 22 mm Silicone Orbital Implant after an Extended Enucleation.

We would like to present a surgical technique of orbital socket reconstruction using oversized dermis fat graft and 22 mm silicone orbital implant in a single-stage after extended enucleation in two patients with massive local recurrence of anteriorly located choroidal melanoma previously treated with endoresection. Orbital tissues en bloc were removed leaving conjunctival lining only at the fornices. Simultaneously, the 22 mm silicone sphere was implanted deeply into the orbit and covered with the oversized dermis fat graft of 30 mm in height and 35 mm in length with 20 mm of the fat thickness. The graft was sutured to the residual forniceal conjunctiva with interrupted 6/0 absorbable sutures overlapping conjunctiva with the graft edge for 2 mm to facilitate the epithelization. Epithelization was completed in two months, leaving well-formed fornices with good fitting of the prosthesis. The key point of orbital socket reconstruction after extended enucleation is to restore conjunctival lining prior to volume. Thus, whenever facing a massive volume and conjunctival lining loss, simultaneous insertion of the 22 mm silicone sphere deep into the orbit combined with oversized dermis fat graft is, in our opinion, the method of choice. It proved to be safe and effective with favourable long-term results.

Ultrasound reliability in detection of retinal tear in acute symptomatic posterior vitreous detachment with vitreous hemorrhage.

Cross-sectional study of 75 consecutive patients presenting with acute symptomatic posterior vitreous detachment (ASPVD) and vitreous hemorrhage was conducted at University Eye Clinic, University Hospital "Sveti Duh", Zagreb, Croatia. To check ultrasound reliability in detecting retinal tears in patients with ASPVD, transpalpebral ultrasound of the eye and the orbit was performed followed by fundus examination initially and in 6wk period. In 13 (17%) patients membranous lesion with ultrasound characteristics of retinal tear was detected. Ophthalmoscopy confirmed the diagnosis in 8/13 patients. In 62/75 patients neither ultrasound nor clinical examination revealed retinal tear. Sensitivity of ultrasound examination was 100%, specificity 92%, positive predictive value 62% and negative predictive value 100%. Ultrasound proved to be a reliable and accurate method for detection of retinal tears in ASPVD. Given the high sensitivity and negative predictive value, negative result on B-scan ultrasound excludes the probability of the retinal tear with a high degree of certainty.

Histopathological changes in involutional lower eyelid entropion: the tarsus is thickened!

OBJECTIVE: Evaluation of histopathological changes in lower eyelid involutional entropion. DESIGN: Case-control, comparative study at a single institution. PARTICIPANTS: A total of 20 consecutive patients with previously untreated involutional lower eyelid entropion and 20 matching patients with lateral lower eyelid basal cell carcinoma (BCC). METHODS: Patients with involutional entropion were operated using our modified surgical method, and patients with BCC underwent full-thickness pentagonal excision with 3-mm surgical margins. Histopathological analysis of the full-thickness eyelid specimens of both groups included measurements of tarsal thickness and height, thickness of the pretarsal orbicularis oculi muscle, diameter of muscle fibres, and qualitative changes in lower eyelid retractor attachment. RESULTS: The tarsus was significantly thicker in the entropion group (p = 0.006). The mean tarsal thickness was 1.40 ± 0.32 mm, whereas in the BCC group it was 1.16 ± 0.19 mm. There was no statistically significant difference in the tarsal height and the thickness of the pretarsal orbicularis oculi muscle between the 2 groups. In the entropion group, 60% of the lids had total and 35% partial dehiscence of the retractor, whereas in the BCC group, dehiscence was found in only 45% of the lids. The difference was statistically significant (p = 0.002). CONCLUSIONS: To the best of our knowledge, this is the first histopathological study documenting thickening of the tarsus in involutional lower eyelid entropion. Moreover, dehiscence of the lower eyelid retractor was proven histopathologically in 95% of the entropic lids. With this in mind, correction of vertical instability should be mandatory in involutional lower eyelid entropion repair.