RESUMEN
Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up to 80% of European FECD cases have been attributed to expansion of a non-coding CTG repeat element (termed CTG18.1) located within the ubiquitously expressed transcription factor encoding gene, TCF4. The non-coding nature of the repeat and the transcriptomic complexity of TCF4 have made it extremely challenging to experimentally decipher the molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven molecular components of disease within primary patient-derived corneal endothelial cells (CECs), generated from a large cohort of individuals with CTG18.1-expanded (Exp+) and CTG 18.1-independent (Exp-) FECD. We employ long-read, short-read, and spatial transcriptomic techniques to interrogate expansion-specific transcriptomic biomarkers. Interrogation of long-read sequencing and alternative splicing analysis of short-read transcriptomic data together reveals the global extent of altered splicing occurring within Exp+ FECD, and unique transcripts associated with CTG18.1-expansions. Similarly, differential gene expression analysis highlights the total transcriptomic consequences of Exp+ FECD within CECs. Furthermore, differential exon usage, pathway enrichment and spatial transcriptomics reveal TCF4 isoform ratio skewing solely in Exp+ FECD with potential downstream functional consequences. Lastly, exome data from 134 Exp- FECD cases identified rare (minor allele frequency <0.005) and potentially deleterious (CADD>15) TCF4 variants in 7/134 FECD Exp- cases, suggesting that TCF4 variants independent of CTG18.1 may increase FECD risk. In summary, our study supports the hypothesis that at least two distinct pathogenic mechanisms, RNA toxicity and TCF4 isoform-specific dysregulation, both underpin the pathophysiology of FECD. We anticipate these data will inform and guide the development of translational interventions for this common triplet-repeat mediated disease.
Asunto(s)
Distrofia Endotelial de Fuchs , Factor de Transcripción 4 , Expansión de Repetición de Trinucleótido , Humanos , Masculino , Empalme Alternativo/genética , Células Endoteliales/metabolismo , Endotelio Corneal/metabolismo , Endotelio Corneal/patología , Distrofia Endotelial de Fuchs/genética , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Transcriptoma/genética , Expansión de Repetición de Trinucleótido/genética , FemeninoRESUMEN
Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.
Asunto(s)
Distrofia Endotelial de Fuchs/genética , Predisposición Genética a la Enfermedad , Oligonucleótidos Antisentido/farmacología , Factor de Transcripción 4/genética , Expansión de Repetición de Trinucleótido/genética , Anciano , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Estudios de Cohortes , Células Endoteliales/metabolismo , Endotelio Corneal/patología , Femenino , Distrofia Endotelial de Fuchs/patología , Humanos , Masculino , Ratones Endogámicos C57BL , Especificidad de Órganos , Precursores del ARN/genética , Procesamiento Postranscripcional del ARN , Factores de Empalme de ARN/metabolismo , ARN Mensajero/metabolismo , Factores de RiesgoRESUMEN
PURPOSE: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC). METHODS: Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4-18 years with AKC treated with topical CsA 1 mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects. RESULTS: The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1-4) during the 12 months prior to CsA to 1 (IQR 0-3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p < 0.01). In the 12-month period following initiation of CsA 1 mg/ml with concomitant prescription of tCS (n = 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3-6) to 3 (IQR 2-5; Wilcoxon p < 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%). CONCLUSIONS: Off-label use of commercial preparations of CsA 1 mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation.
Asunto(s)
Conjuntivitis Alérgica , Exantema , Queratoconjuntivitis , Humanos , Niño , Adolescente , Ciclosporina , Inmunosupresores/uso terapéutico , Estudios de Cohortes , Administración Tópica , Queratoconjuntivitis/diagnóstico , Queratoconjuntivitis/tratamiento farmacológico , Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/tratamiento farmacológico , Glucocorticoides , Soluciones Oftálmicas/uso terapéutico , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Resultado del TratamientoRESUMEN
PURPOSE: To characterise the phenotype and genotype of concurrent keratoconus and Fuchs endothelial corneal dystrophy (KC + FECD). METHODS: We recruited 20 patients with concurrent KC + FECD for a retrospective observational case series from the United Kingdom and the Czech Republic. We compared eight parameters of corneal shape (Pentacam, Oculus) with two groups of age-matched controls who had either isolated keratoconus (KC) or isolated FECD. We genotyped probands for an intronic triplet TCF4 repeat expansion (CTG18.1) and the ZEB1 variant c.1920G >T p.(Gln640His). RESULTS: The median age at diagnosis of patients with KC + FECD was 54 (interquartile range 46 to 66) years, with no evidence of KC progression (median follow-up 84 months, range 12 to 120 months). The mean (standard deviation (SD)) of the minimum corneal thickness, 493 (62.7) µm, was greater than eyes with KC, 458 (51.1) µm, but less than eyes with FECD, 590 (55.6) µm. Seven other parameters of corneal shape were more like KC than FECD. Seven (35%) probands with KC + FECD had a TCF4 repeat expansion of ≥50 compared to five controls with isolated FECD. The average of the largest TCF4 expansion in cases with KC + FECD (46 repeats, SD 36 repeats) was similar to the age-matched controls with isolated FECD (36 repeats, SD 28 repeats; p = 0.299). No patient with KC + FECD harboured the ZEB1 variant. CONCLUSIONS: The KC + FECD phenotype is consistent with KC but with superimposed stromal swelling from endothelial disease. The proportion of cases with a TCF4 expansion is similar in concurrent KC + FECD and age-matched controls with isolated FECD.
Asunto(s)
Distrofia Endotelial de Fuchs , Queratocono , Humanos , Distrofia Endotelial de Fuchs/complicaciones , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factor de Transcripción 4/genética , Estudios Retrospectivos , Queratocono/complicaciones , Queratocono/diagnóstico , Queratocono/genética , Factores de Transcripción/genética , Genotipo , FenotipoRESUMEN
PURPOSE: To describe the risk factors, management, and outcome of delayed Descemet membrane (DM) detachment after penetrating keratoplasty (PK) for keratoconus. METHODS: We report 7 eyes from 6 cases and combine these data with 7 previous case reports identified by a search of PubMed. RESULTS: DM detachment occurred at a median of 25 years (range, 7-33 years) after PK. One individual had bilateral detachments. There was typically a mild ocular discomfort accompanied in some cases by a rapid onset of visual blur. Cases were often treated for allograft rejection before a DM detachment was suspected and confirmed by optical coherence tomography. Detachments were limited to the donor tissue in 11 eyes, but a DM break was identified at the time of onset in only 4 eyes. Thinning of the host corneal rim with ectasia was reported in 8 eyes (57%). In 3 eyes, the detachment resolved spontaneously, but in 2 eyes, a detachment was still present at 12 months. Gas tamponade to reattach the DM was performed in 9 eyes and was effective in 4 eyes. Five eyes underwent a repeat PK or endothelial keratoplasty. Histology showed fibroblastic proliferation on the stromal surface of the folded DM. CONCLUSIONS: The cause for DM detachment many years after PK is unknown, although progressive thinning of the host cornea and secondary graft ectasia may be implicated. Gas tamponade can be effective, but a repeat keratoplasty might be necessary. DM detachment should be included in the differential diagnosis for late-onset corneal edema after PK.
Asunto(s)
Lámina Limitante Posterior/lesiones , Queratocono/cirugía , Queratoplastia Penetrante/efectos adversos , Rotura/etiología , Adulto , Lámina Limitante Posterior/diagnóstico por imagen , Lámina Limitante Posterior/patología , Endotaponamiento , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Rotura/diagnóstico por imagen , Rotura/terapia , Hexafluoruro de Azufre/administración & dosificación , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: We describe the case of a 41-year-old male that underwent laser in situ keratomileusis (LASIK) complicated by Urrets-Zavalia syndrome with interface fluid syndrome and epithelial ingrowth. OBSERVATION: The patient presented at our institution with headache and blurred vision three weeks after a right microkeratome-assisted LASIK procedure. On examination, the visual acuity was hand movements and the intraocular pressure (IOP) was 45â¯mmHg with fluid in the flap interface, a fixed pupil in moderate mydriasis, iris transillumination and cells in the anterior chamber. A Baerveldt tube implant was necessary to control the IOP. After three months, the corrected visual acuity was 20/40 with normal IOP and an early cataract. CONCLUSION AND IMPORTANCE: To our knowledge this is the first report of a case of combined Urrets-Zavalia syndrome and interface fluid syndrome after LASIK. We speculate that steroid induced ocular hypertension was the primary cause.
RESUMEN
Brittle cornea syndrome (BCS1 OMIM #229200, BCS2 #614170) is a rare autosomal recessive condition characterised by diffuse thinning and fragility of the cornea. Affected individuals are at risk of globe rupture and blindness after relatively minor eye trauma. We describe a 9-year-old girl with BCS1, already blind in one eye following trauma, who had a 14 mm diameter corneoscleral onlay graft to her contralateral eye to reduce gross irregular corneal astigmatism and potentially to reduce further risk from accidental injury. Although there was a significant initial improvement in the unaided visual acuity, there was subsequent visual loss from secondary glaucoma. In addition, despite the onlay graft, an acute corneal hydrops developed approximately 2 years following surgery, suggesting that in BCS1, corneal tissue degeneration or resorption continues despite external support. Finally, because secondary glaucoma is not a feature of BCS1, we speculate that the onlay graft may have reduced aqueous outflow by compression of the thinned sclera.
Asunto(s)
Trasplante de Córnea/métodos , Anomalías del Ojo/cirugía , Inestabilidad de la Articulación/congénito , Esclerótica/trasplante , Anomalías Cutáneas/cirugía , Preescolar , Anomalías del Ojo/complicaciones , Anomalías del Ojo/genética , Femenino , Glaucoma/complicaciones , Humanos , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/cirugía , Rotura/prevención & control , Anomalías Cutáneas/complicaciones , Anomalías Cutáneas/genética , Tomografía de Coherencia Óptica , Agudeza VisualRESUMEN
OBJECTIVE: To describe conjunctival epithelial overgrowth of the cornea after surgery for glaucoma. METHODS: This is a retrospective case series (setting: Moorfields Eye Hospital). Fourteen eyes of 13 patients with suspected limbal stem cell deficiency (LSCD) and corneal conjunctivalization after glaucoma drainage surgery. Conjunctivalization was defined as corneal epithelium that demonstrated late stain after topical application of fluorescein. Patient demographics, clinical features, potential risk factors, treatment, and final visual acuity were recorded. Main outcome measures were potential risk factors for conjunctivalization, complications, and response to treatment. RESULTS: Eleven eyes had multiple procedures involving the limbus, and in 11 eyes mitomycin C (MMC) or 5 fluorouracil had been used as an adjunct to reduce fibrosis. Affected eyes typically had a segment of late stain with fluorescein based at the site of previous glaucoma surgery, but in one eye there was total loss of the corneal epithelial phenotype. All eyes previously had topical treatment for their glaucoma but only 2 had an ocular surface disease associated with LSCD. Most cases were asymptomatic, but in 3 eyes there was visual loss when the abnormal phenotype crossed the visual axis. In these 3 eyes there was recurrent epithelial breakdown, often at the interface between the 2 epithelial phenotypes. In one individual, these symptoms resolved after limbal epithelial transfer from the unaffected contralateral eye. CONCLUSIONS: Glaucoma drainage surgery can damage the adjacent corneal limbal epithelial stem cell population. This can be associated with recurrent epithelial breakdown and reduced vision. If there is visual loss, limbal epithelial transplantation is a potential treatment option.
Asunto(s)
Enfermedades de la Córnea/etiología , Cirugía Filtrante/efectos adversos , Glaucoma/cirugía , Limbo de la Córnea/patología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades de la Córnea/diagnóstico , Epitelio Corneal/patología , Femenino , Estudios de Seguimiento , Humanos , Enfermedad Iatrogénica , Limbo de la Córnea/lesiones , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: To compare the early postoperative hypotony rates and intraocular pressure (IOP) in two groups of eyes using either 23-gauge (23G) or 25-gauge (25G) needle in the creation of the anterior chamber entry tract for Baerveldt tube. The primary outcome measure was incidence of hypotony, and secondary outcome measures included comparison of mean IOP and other early complications. MATERIALS AND METHODS: Ours was a retrospective case review of consecutive patients who underwent 350 mm2 Baerveldt implantation in two units over a 2-year period. Data including IOP and complications were collected at 1 day, 1 week, and 1 month following surgery from patients' notes. Statistical analysis between groups was determined using the unpaired 2-tailed f-test for continuous variables and chi-squared test for categorical variables. Statistical significance was defined at the 0.05 level. RESULTS: A total of 58 eyes of 58 patients were included in this study. Preoperative mean IOP in the 25G group was significantly higher (26.4 ± 6.8 mm Hg) when compared with the 23G group (21.6 ± 4.0 mm Hg) (p = 0.002). The mean postoperative IOP remained significantly higher in the 25G group at day 1 (p=0.004), week 1 (p = 0.008), but not at month 1 (p = 0.744). Four patients in the 23G group had hypotony within 1 month postsurgery compared with no cases in the 25G group (chi-squared test p = 0.038). CONCLUSION: There was a significantly higher risk of early hypotony and lower IOP in the larger 23G group at days 1 and 7, although the IOP was similar in both groups by 1 month. CLINICAL SIGNIFICANCE: After all glaucoma drainage device (GDD) tube implantation, regardless of which needle is used to create the tract, the entry site should always be checked with 2% fluorescein drop and 10.0 nylon suture is used with or without autologous Tenon's tissue to close any leakage.How to cite this article: Lim KS, Garg A, Cheng J, Muthusamy K, Beltran-Agullo L, Barton K. Comparison of Short-term Postoperative Hypotony Rates of 23-gauge vs 25-gauge Needles in Formation of the Scleral Tract for Baerveldt Tube Insertion into the Anterior Chamber. J Curr Glaucoma Pract 2018;12(1):36-39.
RESUMEN
PURPOSE: To determine whether patients historically diagnosed with bilateral superior oblique paresis (BSOP) categorized into (1) immediate-onset and (2) gradual-onset torsional diplopia groups are also distinguishable on the basis of patterns of subjective misalignment in various directions of gaze, consistent with the gradual-onset group being caused by sensory extorsion rather than by BSOP. METHODS: The medical records of all patients diagnosed with BSOP, V-pattern esotropia, or V-pattern exotropia between 1978 and 2009 were retrospectively reviewed. Those patients with torsional diplopia were classified into immediate- or gradual-onset diplopia groups. The torsional misalignments measured by Lancaster red-green plots were compared, and the surgical outcomes were evaluated. RESULTS: Of 38 patients identified, 27 had immediate-onset and 11 gradual-onset diplopia. There was a statistically significant difference in the increase in extorsion from up- to downgaze between the immediate- versus gradual-onset group (17.8° versus -1.5°, P < 0.001). Patients in the immediate-onset group fared significantly better with bilateral Harada-Ito procedures than with bilateral inferior oblique-weakening procedures (P = 0.02), whereas patients in the gradual-onset group fared equally well with either procedure (P = 0.72). CONCLUSIONS: Extorsion in upgaze is largely absent in patients with immediate-onset BSOP but is present in both up- and downgaze in patients with gradual-onset sensory extorsion. Lancaster red-green testing aids in distinguishing these two groups. The bilateral Harada-Ito procedure is a better procedure for true BSOP, whereas a bilateral inferior oblique-weakening procedure may be preferred for patients with sensory extorsion.
Asunto(s)
Diplopía/diagnóstico , Oftalmoplejía/diagnóstico , Enfermedades del Nervio Troclear/diagnóstico , Adolescente , Adulto , Anciano , Técnicas de Diagnóstico Oftalmológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Penetrating injuries from non-venomous snakebites are, thankfully, rare. They are, however, sight-threatening and the recent trend for using non-venomous snakes as props in the entertainment industry is increasing exposure of this hazard to people with no animal handling training. We report a case of a penetrating corneal injury in a 35 year old woman following a bite from a snake she had been given to hold for a photograph opportunity. The injury was repaired surgically and she had a good visual outcome, largely due to very good fortune in the site and nature of the injury. This case highlights the danger of exposing untrained handlers to snakes in the entertainment industry.
Asunto(s)
Boidae , Córnea/cirugía , Lesiones de la Cornea , Mordeduras de Serpientes/complicaciones , Mordeduras de Serpientes/cirugía , Heridas Penetrantes/etiología , Heridas Penetrantes/cirugía , Adulto , Animales , Femenino , Humanos , Enfermedades Raras , Mordeduras de Serpientes/diagnóstico , Resultado del Tratamiento , Heridas Penetrantes/diagnósticoRESUMEN
This article summarizes the ocular pathology that can be seen in conjunction with renal disease. Both the eye and the kidney can be the target of systemic disease processes, but the eye can also be affected as a consequence of either renal disease or its treatment.