WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

Virtual visits at the Helsinki Head and Neck Center during the COVID-19 pandemic: patient safety incidents and the experiences of patients and staff.

BACKGROUND: During the COVID-19 pandemic, health care had to find new ways to care for patients while reducing infection transmission. The role of telemedicine role has grown exponentially. METHODS: A questionnaire on experiences and satisfaction was sent to the staff of the Head and Neck Center of Helsinki University Hospital and to otorhinolaryngology patients treated remotely between March and June 2020. Additionally, patient safety incident reports were examined for incidents involving virtual visits. RESULTS: Staff (response rate 30.6%, (n = 116)) opinions seemed to be quite polarized. In general, staff felt virtual visits were useful for select groups of patients and certain situations, and beneficial in addition to face-to-face visits, not instead of them. Patients (response rate 11.7%, (n = 77)) gave positive feedback on virtual visits, with savings in time (average 89 min), distance travelled (average 31.4 km) and travel expenses (average 13.84€). CONCLUSIONS: While telemedicine was implemented during the COVID-19 pandemic to ensure patient treatment, its usefulness after the pandemic must be examined. Evaluation of treatment pathways is critical to ensure that quality of care is upheld while new treatment protocols are introduced. Telemedicine offers the opportunity to save environmental, temporal, and monetary resources. Nonetheless, the appropriate use of telemedicine is essential, and clinicians must be offered the option to examine and treat patients face-to-face.

Foveal thickness and its association with visual acuity in adults born preterm with very low birth weight: A two-country birth cohort study.

PURPOSE: To explore foveal and parafoveal thickness in adults born preterm with very low birth weight (VLBW) and its association with best-corrected visual acuity (BCVA) and gestational age (GA) compared to adults born at term. METHODS: In a joint study of the Helsinki Study of Very Low Birth Weight Adults (Finland) and the NTNU Low Birth Weight Life study (Norway), 106 VLBW and 143 term-born controls were examined with spectral-domain optical coherence tomography and BCVA at age 31-43 years. Thickness of retinal layers was segmented in the foveal and parafoveal areas of the macula. RESULTS: The total retinal thickness in the foveal area was thicker in VLBW adults compared with controls; mean (SD): 292.5 µm (28.2) and 272.4 µm (20.2); p < 0.001, and thinner in the parafoveal areas of the macula. These findings could be explained by a thicker inner retinal layer in the foveal area found in VLBW adults compared with controls (mean difference 20.4 µm; CI: 15.0 to 25.9), where a thicker fovea was associated with lower GA, but not BCVA. CONCLUSION: Adults born preterm with VLBW had a thicker retina in the foveal area than controls and this was associated with GA, but not with BCVA. These changes seem to be related to a thicker inner retinal layer in VLBW adults. The findings imply that signs of macular underdevelopment are still present in adulthood, but not necessarily related to reduced visual function.

Visual function in adults born preterm with very low birth weight-A two-country birth cohort study.

PURPOSE: The purpose of the study was to investigate visual function and vision-related general health in adults that were born preterm with very low birth weight (VLBW: birth weight < 1500 g) in their 30s-40s. METHODS: We recruited 137 adults born preterm with VLBW and 158 term-born controls aged 31-43 years from two birth cohorts: the Helsinki Study of Very Low Birth Weight Adults (Finland) and the NTNU Low Birth Weight in a Lifetime Perspective study (Norway). We used neonatal data and measured refraction, best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, contrast sensitivity, visual fields, intraocular pressure (IOP), self-reported vision-targeted health status with the National Eye Institute Visual Function Questionnaire-25. RESULTS: VLBW adults had a lower BCVA ETDRS score than controls: mean (SD) better eye 86.7 (13.4) versus 90.2 (4.4), p = 0.02; mean (SD) worse eye 82.3 (14.9) versus 87.6 (4.6), p = 0.003. VLBW adults also had lower contrast sensitivity thresholds in several spatial frequencies and scored lower than controls in eight out of the 12 subscales of self-reported vision-targeted health status. Refraction, visual fields and IOP were similar between groups. Two VLBW participants were blind. None had been treated for retinopathy of prematurity. CONCLUSION: We suggest that lower visual function and vision-related health represent life-long consequences of prematurity and VLBW in the studied 31- to 43-year-old cohort. The underlying mechanisms remain to be determined.

Natural history and biomarkers of retinal dystrophy caused by the biallelic TULP1 variant c.148delG.

PURPOSE: To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby-like protein 1 (TULP1) gene. METHODS: A retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral-domain optical coherence tomography (SD-OCT) were assessed. A meta-analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference. RESULTS: The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra-foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD-OCT images. The horizontal width of the foveal EZ showed significant regression with the best-corrected visual acuity (BCVA) of the eye (p < 0.0001, R2  = 0.541, F = 26.0), the age of the patient (p < 0.0001, R2  = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R2  = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants. CONCLUSIONS: This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL-ONL layers could serve as biomarkers of the disease stage.

Analysis of glaucoma genes in Finnish patients with juvenile open-angle glaucoma.

PURPOSE: To identify germline variants in myocilin (MYOC) and other known monogenic glaucoma genes in Finnish patients with juvenile open-angle glaucoma (JOAG). METHODS: Finnish patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland, were enrolled. We sequenced all exonic regions and flanking splice sites of MYOC for five patients and one healthy relative using Sanger sequencing. In 48 patients, we performed exome sequencing to identify variants also in 28 other glaucoma-related genes. RESULTS: Fifty-three individuals with JOAG from 50 pedigrees, and one healthy relative, participated. The mean age at diagnosis was 30.8 years [SD 7.6; range 11 to 39]. Five probands had probably pathogenic variants in MYOC: c.1102C>T p.(Gln368Ter), c.1109C>T p.(Pro370Leu), c.1130C>T p.(Thr377Met), c.1132G>A p.(Asp378Asn) and c.1456C>T p.(Leu486Phe). Four of these patients had a family history of dominantly inherited JOAG. The frequency of MYOC variants was 10% (5 of 50 families). One patient and his mother with JOAG had a novel loss-of-function variant in the FOXC1 gene, c.366G>A p.(Trp122Ter). A patient with sporadic JOAG had a homozygous likely pathogenic variant in the LTBP2 gene, c.3938G>A p.(Cys1313Tyr). The genetic variants explained 14% (7 out of 50 families; 95% CI, 6%-23%) of JOAG in our cohort. CONCLUSIONS: The frequency of pathogenic variants in previously known glaucoma-associated genes is low in Finnish patients with JOAG. Because of the distinct genetic background of Finns, it might be possible to identify novel glaucoma genes through our JOAG series in the future.

Childhood-Onset Leber Hereditary Optic Neuropathy-Clinical and Prognostic Insights.

PURPOSE: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease. DESIGN: Retrospective cohort study. METHODS: We retrospectively included 2 cohorts of patients with LHON with onset of visual loss before the age of 12 years from Italy and the United Kingdom. Ophthalmologic evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing, and optical coherence tomography, was considered. Patients were classified based on both the age of onset and the pattern of visual loss. RESULTS: A total of 68 patients were stratified based on the age of onset of visual loss: group 1 (<3 years): 14 patients (20.6%); group 2 (≥3 to <9 years): 27 patients (39.7%); and group 3 (≥9 to ≤12 years): 27 patients (39.7%). Patients in group 2 achieved a better visual outcome than those in group 3. Patients in groups 1 and 2 had better mean deviation on visual field testing than those in group 3. The mean ganglion cell layer thickness on optical coherence tomography in group 2 was higher than those in groups 1 and 3. Patients were also categorized based on the pattern of visual loss as follows: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%). CONCLUSIONS: Children who lose vision from LHON before the age of 9 years have a better visual prognosis than those who become affected in later years, likely representing a "form frustre" of the disease.

Anterior segment optical coherence tomography in congenital corneal opacities.

PURPOSE: To evaluate the clinical usefulness of anterior segment (AS) optical coherence tomography (OCT) in diagnosis and follow-up of children with congenital corneal opacities. DESIGN: Noncomparative case series. PARTICIPANTS: Seven consecutive patients with bilateral congenital corneal opacity between 2 days and 2.5 years of age. METHODS: In addition to basic outpatient examination, eyes were imaged using AS OCT. Anterior segment structures and corneal thicknesses were evaluated from the images. Three children also underwent evaluation under anesthesia, including measurement of corneal thickness with ultrasound pachymetry. MAIN OUTCOME MEASURES: Evaluation of the type and severity of the congenital corneal opacity based on the findings in AS OCT. RESULTS: Thirteen of the 14 eyes could be imaged using AS OCT. The youngest patient studied was only 2 days old. Three distinct phenotypes were found based on the AS OCT findings. Three patients with iridocorneal adhesions were deduced to have type 1 Peters' anomaly, and 2 patients with lenticulocorneal adhesions were deduced to have type 2 Peters' anomaly. The 2 youngest patients had complete corneal opacity with features of corneal staphyloma and marked changes in the AS structures during the first months of life. CONCLUSIONS: Anterior segment OCT was a valuable method in the diagnosis and follow-up of patients with congenital corneal opacities. As a fast and noncontact technique, it was applicable even for neonates. It allowed early characterization of the type and the extent of the AS disorder. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Refined staging for chorioretinopathy in long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency.

OBJECTIVE: Neonatal screening and earlier diagnosis have improved the prognosis of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency, which causes a need to refine the staging of the pigmentary chorioretinopathy and thus improve monitoring and comparability of patients under dietary therapy. METHODS: Seven children with LCHAD deficiency caused by homozygous G1528C mutation attended sequential fundus photography for stage 2 chorioretinopathy in 1997­2006. After arranging 21 pairs of fund us photographs according to the severity of the fundus changes,the images best representing 3 different grades of pigmentary deposits (P1­P3) and retinal pigment epithelial(RPE) atrophy (A1­A3) were chosen as reference photographs.To evaluate the substaging, 29 pairs of photographs were graded according to the reference photographs. RESULTS: In the assessment of pigmentary deposits, the 3 ophthalmologists agreed in 41% and differed by a single substage in 45% of instances (combined weighted ĸ statistic was 0.38, indicating moderate agreement). In pairwise comparisons,the weighted ĸ statistic ranged from 0.31 to 0.56 (agreement, 71­81%). In the assessment of RPE atrophy, all 3 raters agreed in 17% and 2 raters in 70% of instances (combined ĸ statistic 0.018, indicating poor agreement). DISCUSSION: Despite variation in imaging techniques and limitations in the visual assessment of fundus photographs, the agreement obtained in grading the pigmentary deposits was comparable to that reported for photographic grading of retinopathy of prematurity. We recommend photographic documentation and substaging based on reference photographs in the follow-up of LCHAD retinopathy. The refined staging allows a more detailed assessment on the progression of the retinopathy and optimization of the therapeutic protocols in individual patients and between centres using different therapeutic protocols.

Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3.

PURPOSE: To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and the geographic distribution of their ancestors. DESIGN: A prospective cross-sectional study. METHODS: This study took place in a tertiary referral center with a cohort of 84 Finnish patients (55% female) from 25 families with the pathogenic nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) variant c.61G>C. Observation procedures and main outcome measures were Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality of life, treatment, and comorbidities. RESULTS: The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%, 46/60) experienced their first attack between age 6 and 20 years. Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent (48/60) reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred in 75% (45/60) and 91% (55/60) during and after the attack, respectively, for a median of 10 days (range, 1 day-2 months). Forty-seven percent (39/60) had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks. CONCLUSIONS: Symptoms and signs of KFH are restricted to the anterior segment of the eye and vary widely between individuals. We recommend scleral contact lenses as the first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage.

WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression.

OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON). DESIGN: Multicenter cohort study. METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. MAIN OUTCOME MEASURES: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile. RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON.

In Vivo Corneal Confocal Microscopy and Histopathology of Keratitis Fugax Hereditaria From a Pathogenic Variant in NLRP3.

PURPOSE: To apply in vivo corneal confocal microscopy (IVCM) to study the pathogenesis of keratitis (keratoendotheliitis) fugax hereditaria, an autosomal dominant cryopyrin-associated periodic keratitis, associated with the c.61G>C pathogenic variant in the NLRP3 gene, in its acute and chronic phase, and to report histopathologic findings after penetrating keratoplasty. DESIGN: This was an observational case series. METHODS: The study population included 6 patients during an acute attack, 18 patients in the chronic phase, and 1 patient who underwent penetrating keratoplasty. Interventions included Sanger sequencing for the NLRP3 variant c.61C>G, a clinical examination, corneal photography, IVCM, light microscopy, and immunohistochemistry. Our primary outcome measures included IVCM and histopathologic findings. RESULTS: During the acute attack, hyperreflective cellular structures consistent with inflammatory cells transiently occupied the anterior to middle layers of the corneal stroma. Other corneal layers were unremarkable. With recurring attacks, central oval stromal opacities accumulated. IVCM revealed that they contained long, hyperreflective, needle-shaped structures in the extracellular matrix. Using light microscopy, the anterior half of the stroma displayed thin and finely vacuolated lamellae, and keratocytes throughout the stroma were immunopositive for syndecan. CONCLUSIONS: The acute attacks and chronic stromal deposits mainly involve the anterior to middle layers of the corneal stroma, and the disease is primarily a keratitis rather than a keratoendotheliitis. IVCM shows that inflammatory cells invade only the stroma during an acute attack. IVCM and light microscopic findings suggest that the central corneal opacities represent gradual deposition of extracellular lipids. The disease could make a good in vivo model to study activation of the NLRP3 inflammasome in cryopyrin-associated periodic syndromes.

Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene.

PURPOSE: To describe the phenotype and the genetic defect in keratoendotheliitis fugax hereditaria, an autosomal dominant keratitis that periodically affects the corneal endothelium and stroma, leading in some patients to opacities and decreased visual acuity. DESIGN: Cross-sectional, hospital-based study. METHODS: Patient Population: Thirty affected and 7 unaffected subjects from 7 families, and 4 sporadic patients from Finland. OBSERVATION PROCEDURES: Ophthalmic examination and photography, corneal topography, specular microscopy, and optical coherence tomography in 34 patients, whole exome sequencing in 10 patients, and Sanger sequencing in 34 patients. MAIN OUTCOME MEASURES: Clinical phenotype, disease-causing genetic variants. RESULTS: Unilateral attacks of keratoendotheliitis typically occurred 1-6 times a year (median, 2.5), starting at a median age of 11 years (range, 5-28 years), and lasted for 1-2 days. The attacks were characterized by cornea pseudoguttata and haze in the posterior corneal stroma, sometimes with a mild anterior chamber reaction, and got milder and less frequent in middle age. Seventeen (50%) patients had bilateral stromal opacities. The disease was inherited as an autosomal dominant trait. A likely pathogenic variant c.61G>C in the NLRP3 gene, encoding cryopyrin, was detected in all 34 tested patients and segregated with the disease. This variant is present in both Finnish and non-Finnish European populations at a frequency of about 0.02% and 0.01%, respectively. CONCLUSION: Keratoendotheliitis fugax hereditaria is an autoinflammatory cryopyrin-associated periodic syndrome caused by a missense mutation c.61G>C in exon 1 of NLRP3 in Finnish patients. It is additionally expected to occur in other populations of European descent.

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses.

Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. Methods: We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. Results: Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log10 unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. Conclusions: Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.

Childhood-onset Leber hereditary optic neuropathy.

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.

Indications and outcomes of keratoplasties in children during a 40-year period.

PURPOSE: To report the indications and the outcomes of keratoplasties in children over four decades. METHODS: A retrospective cohort study of patients aged 16 years or younger who underwent keratoplasty in the Helsinki University Eye Hospital during 1968-2011. Diagnosis, preoperative status, age at the time of surgery, surgical technique, complications and follow-up time were registered. Main outcome measures were visual acuity and graft survival as assessed by Kaplan-Meier analysis. The independent role of risk factors on outcomes was evaluated by Cox multivariate regression analysis. RESULTS: Forty-eight keratoplasties, 42 penetrating and six lamellar, were performed in 44 eyes of 39 children at the age of 4.5 months to 16 years (median, 12 years). Five patients had bilateral grafts, and five grafts were regrafts. The indication for keratoplasty was injury for 13 grafts, non-traumatic acquired corneal opacities for 11, keratoconus for eight, corneal dystrophy for seven, congenital corneal opacities for six and aniridia for three grafts. The cumulative proportion of clear grafts was 46% at 5 years postoperatively, and the median follow-up time of clear grafts was 5.1 years (range, 0.4-29 years) for 41 penetrating allografts (PKP). Simultaneous intraocular surgery at the time of grafting [hazard ratio (HR) 9.7], corneal vascularization (HR 8.1) and regrafting (HR 5.4) were the main independent risk factors for graft failure in this PKP cohort. The cumulative proportion of clear grafts was 84% at 5 years in the absence of any of these risk factors. PKP for keratoconus and corneal dystrophy yielded clear grafts in 83% of the eyes, and a visual acuity ≥0.3 (Snellen) in 75% of the eyes. Seventeen of the 20 graft failures were due to rejection. CONCLUSIONS: Favourable graft survival was obtained in primary keratoplasties for non-vascularized corneal opacities performed without any other simultaneous intraocular surgery. Visual outcome was favourable in keratoconus and corneal dystrophies and poor in most eyes with injury.

Potential Effect of Tumor Necrosis Factor Inhibitors on Trabeculectomy With Mitomycin C for Patients With Juvenile Idiopathic Arthritis-Related Uveitic Glaucoma: A Retrospective Analysis.

IMPORTANCE: The majority of patients with juvenile idiopathic arthritis-related uveitic glaucoma require surgery to control intraocular pressure. Trabeculectomy with mitomycin C (MMC) is a major treatment option, although both chronic inflammation and young age increase risk of filtration failure. Factors that potentially protect from filtration failure are important to identify. OBJECTIVE: To evaluate the potential effect of treatment with tumor necrosis factor (TNF) inhibitor on the success of an MMC-augmented trabeculectomy for patients with juvenile idiopathic arthritis-related uveitic glaucoma. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective observational study with a median follow-up of 7.9 years at the Department of Ophthalmology, Helsinki University Hospital, in Helsinki, Finland, 29 eyes of 29 consecutive patients (3.1-20.4 years of age) underwent an MMC-augmented primary trabeculectomy during the period from April 1996 to January 2014. Fifteen patients were treated with systemic TNF inhibitors at the time of their trabeculectomy to control their uveitis, arthritis, or both. No changes were made to the antirheumatic therapy preoperatively. MAIN OUTCOMES AND MEASURES: Successful trabeculectomies, determined by Kaplan-Meier analysis, in which patients have intraocular pressure of 21 mm Hg or lower without antiglaucomatous medications or further glaucoma procedures. RESULTS: The success rate of trabeculectomy for patients who were treated with TNF inhibitors was 73% (95% CI, 44%-89%) at 1, 5, and 10 years after surgery, whereas the success rates of trabeculectomy for patients who were not treated with TNF inhibitors were 57%, 16%, and 0% at 1, 5, and 10 years after surgery, respectively (P = .01). The trabeculectomies of patients who were treated with TNF inhibitors were successful for a median of 3.2 years (95% CI, 0.3-9.9 years), whereas the trabeculectomies of patients who were not treated with TNF inhibitors were successful for a median of 1.2 years (95% CI, 0.6-3.6 years) (P = .14). Nine eyes of 9 patients had previously undergone cyclodestruction, intraocular surgery, or both (ie, prior ocular surgery). The effect of TNF was observed especially in the eyes of patients who had not undergone prior ocular surgery (at 5 years: 83% success rate for patients who had not undergone prior ocular surgery vs 19% success rate for patients who had). A difference in the overall success rate between patients who had and patients who had not had prior surgery was not identified. CONCLUSIONS AND RELEVANCE: Our retrospective data suggest that better control of intraocular pressure was achieved in the eyes of patients with juvenile idiopathic arthritis-related uveitis glaucoma who were treated with TNF inhibitors at the time of their MMC-augmented primary trabeculectomy. The retrospective design of the present study suggests that our data can be used for the planning of future studies but not for making treatment decisions.