Non-Invasive Recording of Ocular-Following Responses in Children: A Promising Tool for Stereo Deficiency Evaluation.

Background: The ability to merge the two retinal images to perceive depth (stereopsis) plays an important role in human vision. Its proper development requires binocular alignment and good visual acuity in both eyes during childhood. Because treatments are more effective when applied early, early diagnosis is important. Unfortunately, assessing stereo deficiencies in infants and young children remains challenging. Recently, it has been shown that ocular-following responses (OFRs; reflexive, short-latency eye movements induced by the sudden motion of a large textured pattern) are sensitive to changes in interocular correlation, making them potentially useful for stereo deficiency assessments. To test this hypothesis, we measured OFRs elicited by dichoptic stimulation in children with normal and compromised stereopsis (due to amblyopia). Methods: Two groups of six children (age- and sex-matched: 3M/3F aged 7-12 yo), one with compromised stereopsis and one with normal stereopsis, were included. OFRs were recorded using a custom high-resolution video eye-tracking system. The relative differences between eye displacement induced by correlated stimuli (up-correlated-down-correlated) and anticorrelated (up-anticorrelated-down-anticorrelated) were compared. Results: We found significant differences between OFRs induced by two dichoptic conditions (correlated and anticorrelated stimuli) in most children with normal stereopsis, whereas no differences were observed in children with compromised stereopsis, indicating a lack of disparity detectors. Conclusions: OFRs might thus be exploited as a diagnostic tool for the objective identification of stereo deficiencies in children. This might lead to improved early diagnosis and treatment outcomes for conditions like amblyopia and strabismus.

Two cases of unilateral limbal Vernal keratoconjunctivitis in the same family: first case report.

This case report describes two cases of unilateral limbal Vernal keratoconjunctivitis (VKC) in the same family. To our knowledge, these are the first two reported cases of unilateral limbal VKC. VKC is a chronic inflammatory disease that typically affects both eyes, with unilateral cases being rare and previously only reported in the tarsal form. Our first case involved a 12-year-old girl with a history of allergic asthma, who had been experiencing conjunctivitis in her right eye since the age of 7. Upon examination, she was diagnosed with unilateral limbal VKC and treated with 1% cyclosporine eye drops with a significant improvement observed at the one and three-month follow-ups. Her 7-year-old brother was also examined and found to have unilateral limbal VKC in his right eye, although it was milder and not associated with allergic pathogenesis. Therefore, in this case, a treatment with hydrocortisone eye drops was started leading to an immediate reduction of the itching. In both cases an IgE-mediated mechanism is less likely because of the monolateral eye involvement, the complete absence of nasal symptoms, the lack of correlation between symptoms and any pollen season, and the negative prick skin test in one of the two siblings. Both cases suggest that unilateral VKC may occur even in the limbal form and that genetic mechanisms may contribute to the inflammatory reaction in VKC. This report highlights the need for further studies to explain the occurrence of unilateral VKC cases and reminds clinicians to consider the possibility of unilateral limbal VKC in pediatric patients.

Ocular-following responses in school-age children.

Ocular following eye movements have provided insights into how the visual system of humans and monkeys processes motion. Recently, it has been shown that they also reliably reveal stereoanomalies, and, thus, might have clinical applications. Their translation from research to clinical setting has however been hindered by their small size, which makes them difficult to record, and by a lack of data about their properties in sizable populations. Notably, they have so far only been recorded in adults. We recorded ocular following responses (OFRs)-defined as the change in eye position in the 80-160 ms time window following the motion onset of a large textured stimulus-in 14 school-age children (6 to 13 years old, 9 males and 5 females), under recording conditions that closely mimic a clinical setting. The OFRs were acquired non-invasively by a custom developed high-resolution video-oculography system, described in this study. With the developed system we were able to non-invasively detect OFRs in all children in short recording sessions. Across subjects, we observed a large variability in the magnitude of the movements (by a factor of 4); OFR magnitude was however not correlated with age. A power analysis indicates that even considerably smaller movements could be detected. We conclude that the ocular following system is well developed by age six, and OFRs can be recorded non-invasively in young children in a clinical setting.

Essential Infantile Esotropia: A Course of Treatment From Our Experience.

Background: Essential infantile esotropia (EIE) is the most common type of childhood esotropia. Although its classical approach is surgical, less invasive techniques have been proposed as an adjunct or alternative to traditional surgery. Among them, chemodenervation with botulinum toxin (BT) has been investigated, showing variable and sometimes conflicting results. Objectives: To compare the outcomes of bilateral BT injection and traditional surgery in a pediatric population with EIE in order to optimize and standardize the therapeutic approach. Other purposes are to evaluate whether early intervention may prevent the onset of vertical ocular deviation (which is part of the clinical picture of EIE) and/or influence the development of fine stereopsis, and also to assess changes in refractive status over time among the enrolled population. Methods: A retrospective consecutive cohort study was conducted in 86 children aged 0-48 months who underwent correction of EIE. The primary intervention in naïve subjects was either bilateral BT injection (36 subjects, "BT group") or strabismus surgery (50 subjects, "surgery group"). Results: Overall, BT chemodenervation (one or two injections) was effective in 13 (36.1%) subjects. With regard to residual deviation angle, the outcomes at least 5 years after the last intervention were overlapping in children receiving initial treatment with either injection or surgery; however, the success rate of primary intervention in the surgery group was higher, and the average number of interventions necessary to achieve orthotropia was smaller. Both early treatment with chemodenervation and surgery at a later age were not found to prevent the onset of vertical ocular deviation, whereas, surprisingly, the percentage of subjects developing fine stereopsis was higher in the surgery group. Finally, with regard to the change in refractive status over time, most of the subjects increased their initial hyperopia, whereas 10% became myopic. Conclusions: Our data suggest that a single bilateral BT injection by age 2 years should be considered as the first-line treatment of EIE without vertical component; whereas, traditional surgery should be considered as the first-line treatment for all other cases and in subjects unresponsive to primary single BT injection.

Minimally-Invasive Surgical Approach to Congenital Dacryostenosis: Proposal for a New Protocol.

Background: Congenital dacryostenosis is one of the most common ophthalmological disorders in infants, with a high spontaneous resolution rate. In patients unresponsive to conservative treatment, the first-line approach is lacrimal drainage system probing, thought there is no clear consensus on optimal timing of surgery. The optimal treatment of patients unresponsive to primary probing is also controversial. Objectives: The aim of this study is to assess the optimal timing of probing in children with congenital dacryostenosis. Other purposes are to evaluate the efficacy of repeated probing and dacryointubation in patients unresponsive to the initial surgery without evident lacrimal outflow dysgenesis, and to determine the epidemiology of these maldevelopments. Methods: A retrospective consecutive cohort study was conducted in 625 eyes of 457 patients aged 7-48 months who underwent surgery for dacryostenosis. Patients were divided into 4 cohorts according to the timing of surgery. Data were analyzed using Fisher's test. Results: The success rate of primary probing was high, without significant differences between cohorts. One-third of recurrences were related to maldevelopments, the other two-thirds were treated with a second probing or dacryointubation, with high success rates, that did not significantly differ between the procedures. All cases unresponsive to the second surgery were resolved with dacryointubation. Conclusions: Probing is highly effective and its outcome is not affected by timing of surgery. Nevertheless, we advocate for early intervention, in order to identify possible maldevelopments, which require more invasive management. In patients unresponsive to primary probing, without evident maldevelopments, repeated probing should still be considered as the first-line approach, since it's less invasive but similarly effective to dacryointubation.

Strabismus surgery in Angelman syndrome: More than ocular alignment.

PURPOSE: To report and evaluate strabismus surgery in children with Angelman syndrome, in order to optimize and standardize surgical approach. Other purposes are to understand the possible relation between ocular findings and motor ability, and between improvement in ocular alignment and changes in motor skills in this population. DESIGN: Observational cross-sectional study. METHODS: Medical records of pediatric patients with Angelman syndrome, who underwent strabismus surgery, were investigated. Collected data included: genotype, gender, age at the time of surgery, refractive error, pre-operative strabismus, surgical procedure, surgical outcome, gross and fine motor development assessment pre- and post-operatively. RESULTS: Seventeen subjects, aged 3-15 years, were investigated. Fourteen patients were exotropic, three esotropic. Most patients presented astigmatism. Considering the exaggerated response to standard amounts of surgery and the risk of consecutive strabismus on long term follow-up reported by previous studies in children with developmental delay, a reduction of the amount of strabismus surgery was applied. Post-operatively, all patients presented with a significative reduction of the baseline deviation angle, with all esotropic patients and 7 exotropic patients (59%) achieving orthotropia. The surgical outcomes were variable according to the type and the amount of baseline strabismus, but no case presented with exaggerated surgical response. At baseline, patients showed important delays in all motor abilities, and, post-operatively, presented a significant improvement in walking and fine motor tasks. Pre- and post-operative motor abilities were negatively correlated to astigmatism, anisometropia, and amount of deviation. CONCLUSIONS: According to our data, the standard nomograms for strabismus surgery may be successfully applied in subjects with Angelman syndrome and exotropia. Our data suggest that the reduction of the deviation angle improves motor skills in strabismic pediatric patients with Angelman syndrome.

Optic Nerve Sheath Diameter Ultrasound: Optic Nerve Growth Curve and Its Application to Detect Intracranial Hypertension in Children.

PURPOSE: First, to create an optic nerve growth curve from normal optic nerve sheath diameter (ONSD) values measured by using B-scan ultrasonography in subjects 0-18 years of age. Second, to identify age-appropriate cutoff values of ONSD to be used in the diagnosis of intracranial hypertension (IHT). DESIGN: Prospective cross-sectional study. METHODS: B-scan ocular ultrasonography was performed on both eyes of 215 subjects 0-18 years of age, divided into 3 groups: 165 healthy children, 29 children with IHT (all >4 years of age), and 21 children with optic disc drusen (ODD). RESULTS: There were no statistically significant differences in between the ONSDs of healthy children and those in subjects with ODD. An optic nerve growth curve was created by using ONSDs measured in healthy subjects 0-18 years of age, using the equation: ONSD = ln [33.15] - (-0.18 × ln [children's age]). The curve showed a progressive increase of ONSD up to 10 years of age, and it remained constant until the age of 18. For this reason, 2 different cutoff values were calculated for age groups 4-10 and 11-18. Values were 4.10 mm and 4.4 mm, respectively, with a 100.0% sensitivity and a specificity ranging from 83.9% to 98.8%. A sensitivity of 28.6% was reached for the population of subjects 4-18 years of age with a threshold value of 5 mm, as used in published reports. CONCLUSIONS: The ONSD continued to enlarge gradually until the age of 10. Therefore, 2 different cutoff values for the age groups 4-10 and 11-18 were calculated, considering the ONSDs of subjects 11-18 years of age overlapping with those of adults. No patients with IHT <4 years old were found. Further studies are needed to evaluate the correct cutoff values for these ages.

PSIP1/LEDGF: a new gene likely involved in sensorineural progressive hearing loss.

Hereditary Hearing Loss (HHL) is an extremely heterogeneous disorder. Approximately 30 out of 80 known HHL genes are associated with autosomal dominant forms. Here, we identified PSIP1/LEDGF (isoform p75) as a novel strong candidate gene involved in dominant HHL. Using exome sequencing we found a frameshift deletion (c.1554_1555del leading to p.E518Dfs*2) in an Italian pedigree affected by sensorineural mild-to-moderate HHL but also showing a variable eye phenotype (i.e. uveitis, optic neuropathy). This deletion led to a premature stop codon (p.T519X) with truncation of the last 12 amino acids. PSIP1 was recently described as a transcriptional co-activator regulated by miR-135b in vestibular hair cells of the mouse inner ear as well as a possible protector against photoreceptor degeneration. Here, we demonstrate that it is ubiquitously expressed in the mouse inner ear. The PSIP1 mutation is associated with a peculiar audiometric slope toward the high frequencies. These findings indicate that PSIP1 likely plays an important role in HHL.

Saccadic alterations in severe developmental dyslexia.

It is not sure if persons with dyslexia have ocular motor deficits in addition to their deficits in rapid visual information processing. A 15-year-old boy afflicted by severe dyslexia was submitted to saccadic eye movement recording. Neurological and ophthalmic examinations were normal apart from the presence of an esophoria for near and slightly longer latencies of pattern visual evoked potentials. Subclinical saccadic alterations were present, which could be at the basis of the reading pathology: (1) low velocities (and larger durations) of the adducting saccades of the left eye with undershooting and long-lasting postsaccadic onward drift, typical of the internuclear ophthalmoplegia; (2) saccades interrupted in mid-flight and fixation instability, which are present in cases of brainstem premotor disturbances.

A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family.

Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC.

A singular case of congenital self-healing histiocytosis with skin, liver and atypical eye involvement.

PURPOSE: To describe a rare case of congenital self-healing Langerhans cell histiocytosis (CSHLCH) presenting with atypical eye involvement. DESIGN: Case report. METHODS: A female newborn presented with purpuric lesions over the trunk, limbs, and face. Liver ultrasonography revealed hypoechogenic lesions with blurred borders. Biomicroscopy showed right posterior synechiae with fibrinoid deposits on the lens. At 7 months she presented with right acute glaucoma. RESULTS: Biomicroscopy showed the presence of inflammatory pseudo-membrane covering the anterior surface of the lens, iris, and iridocorneal angle. Ab externo trabeculotomy was performed; access to the anterior chamber with capsulorrhexis forceps permitted a peeling of the pseudo-membrane with normalization of the intraocular pressure. Histologic examination of the membrane revealed an inflammatory tissue with CD1a and S-100 positive histiocytic cells. CONCLUSIONS: This is the first case of CSHLCH describing acute glaucoma secondary to a pseudo-inflammatory membrane with typical histiocytic cells, occluding the iridocorneal angle.

Congenital aplasia of the optic chiasm and esophageal atresia: a case report.

INTRODUCTION: The complete absence of the chiasm (chiasmal aplasia) is a rare clinical condition. Hypoplasia of the optic nerve and congenital nystagmus are almost invariably associated characteristics. Microphthalmos or anophthalmos are common features in chiasmal aplasia, while central nervous system abnormalities are less frequent. Esophageal atresia can be isolated or syndromic. In syndromic cases, it is frequently associated with cardiac, limb, renal or vertebral malformations and anal atresia. More rarely, esophageal atresia can be part of anophthalmia-esophageal-genital syndrome, which comprises anophthalmia or microphthalmia, genital abnormalities, vertebral defects and cerebral malformations. Here, a previously unreported case of chiasmal aplasia presenting without microphthalmos and associated with esophageal atresia is described. CASE PRESENTATION: Aplasia of the optic chiasm was identified in a Caucasian Italian 8-month-old boy with esophageal atresia. An ultrasound examination carried out at 21 weeks' gestation revealed polyhydramnios. Intrauterine growth retardation, esophageal atresia and a small atrial-septal defect were subsequently detected at 28 weeks' gestation. Repair of the esophageal atresia was carried out shortly after birth. A jejunostomy was carried out at four months to facilitate enteral feeding. The child was subsequently noted to be visually inattentive and to be neurodevelopmentally delayed. Magnetic resonance imaging revealed chiasmal aplasia. No other midline brain defects were found. His karyotype was normal. CONCLUSION: If achiasmia is a spectrum, our patient seems to depict the most severe form, since he appears to have an extremely severe visual impairment. This is in contrast to most of the cases described in the literature, where patients maintain good--or at least useful-- visual function. To the best of our knowledge, the association of optic nerve hypoplasia, complete chiasmal aplasia, esophageal atresia and atrial-septal defect, choanal atresia, hypertelorism and psychomotor retardation has never been described before.

Ophthalmic findings in Angelman syndrome.

PURPOSE: To provide detailed information about opthalmological findings in a group of patients with Angelman syndrome (AS). METHODS: Consecutive patients with a genetically confirmed diagnosis of AS were submitted to ophthalmic and orthoptic examinations. Strabismus, visual acuity, cycloplegic refraction, and iris and fundus pigmentation were evaluated. Parents were also examined to compare the extent of fundus pigmentation. RESULTS: A total of 34 patients were identified, representing 3 genetic classes: deletion, uniparental disomy, and mutation. Ametropia >1 D was present in 97% of cases: myopia in 9%, hyperopia in 76%, and astigmatism in 94%. Myopia and anisometropia were found only in the genetic deletion group. Strabismus, most frequently exotropia, was found in 24 patients (75%). Ocular hypopigmentation was observed in 18 subjects (53%), with choroidal involvement in 3 cases and isolated iris involvement in 4. Hypopigmentation was observed in all of the 3 genetic classes. CONCLUSIONS: Ophthalmic alterations in AS were observed more frequently than has been previously reported, except for ocular hypopigmentation, which was observed less frequently.

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

Paediatric Behçet's disease presenting with recurrent papillitis and episcleritis: a case report.

INTRODUCTION: Behçet's disease is a chronic multisystem vasculitis characterized by mucocutaneous, articular, neurological, gastrointestinal and ophthalmological lesions. Ocular involvement is mainly represented by recurrent uveitis, especially posterior uveitis; however, iridocyclitis, retinal and choroidal vasculitis, optic neuritis and retinal vascular occlusion can also occur. CASE PRESENTATION: A 12-year-old Caucasian boy with a history of recurrent buccal aphthosis and nonspecific gastrointestinal symptoms was admitted to our hospital with blurred vision associated with acute episcleritis and papillitis. The patient's pathergy test was positive, suggesting a diagnosis of Behçet's disease. Corticosteroid and cyclosporine therapy was started, but further episodes were noted in both eyes. The patient was then switched to intravenous infliximab, with complete resolution of the inflammation after the second infusion. CONCLUSION: Episcleritis and papillitis should be added to the list of uncommon manifestations of pediatric Behçet's disease. Infliximab is an effective, new therapeutic approach for Behçet's disease that is refractory to the conventional corticosteroid and immunosuppressive therapy.

Corneal curvature and thickness development in premature infants.

PURPOSE: Analysis of postnatal changes in central corneal thickness (CCT) and corneal curvature (CC) in premature infants, their relation, and their possible influence on eye growth and intraocular pressure (IOP) evaluation. METHODS: CCT and CC were assessed in both eyes of 56 premature infants, born at 24 to 32 weeks of gestational age (GA), and then two or three times at post-conceptional ages (PCAs) of 28 to 42 weeks. RESULTS: CC changed from 65.83 diopters at 28 weeks of PCA to 49.38 diopters at 42 weeks of PCA. CCT decreased from 794 to 559 µm at the same ages. The reductions of these two corneal parameters seem to be related to each other and begin immediately after birth. CONCLUSION: In light of the few data available in the literature, these data provide more certainty about the CCT values of premature infants. The importance of CCT and CC fast variations after premature birth concerns both the knowledge of anterior segment development and the correct evaluation of IOP in immature eyes; the influence of these two parameters on the methods of IOP evaluation could be more remarkable at the lowest PCAs.

Eye movement impairment recovery in a Gaucher patient treated with miglustat.

In Gaucher Disease (GD) the enzyme (imiglucerase) replacement therapy (ERT) is not able to stop the progression of the neurological involvement, while the substrate reduction therapy (SRT), performed by N-Butyldeoxynojirimycin (miglustat), is an alternative that should be evaluated. Two sisters, presenting the same genotype (R353G/R353G), were diagnosed as suffering from GD; one of them later developed neurological alterations identified by quantitative saccadic eye movements analysis. The aim of the study was to quantitatively measure the miglustat effects in this GD neurological patient. Eye movement analysis during subsequent controls was performed by estimating the characteristic parameters of saccadic main sequence. The study demonstrates that the SRT alone can be effective in GD3. Moreover, it confirms that quantitative eye movement analysis is able to precociously identify also slight neurological alterations, permitting more accurate GD classification.

Central corneal thickness in children with growth hormone deficiency.

PURPOSE: To evaluate central corneal thickness (CCT), intraocular pressure (IOP) and eye refraction in patients with congenital growth hormone (GH) deficiency. METHODS: Retrospective case series. Forty-five patients with growth defect treated with recombinant GH and 45 healthy children underwent ophthalmological examination, including CCT measurements, applanation tonometry and cycloplaegic refraction. RESULTS: The average CCT in the GH deficiency group was 570.6µm [standard deviation (SD) 37.4]. In the control group, it was 546.0 (SD 24.9). The average IOP in the GH deficiency group was 18.2mmHg (SD 3.4). In the control group, it was 14.6 (SD 2.0). The mean refractive error (spherical equivalent) in the GH deficiency group was 0.59D (SD 1.9). In the control group, it was 0.11 (SD 2.1). CONCLUSION: GH and insulin-like growth factor 1 are involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera. Children with congenital GH deficiency or insensitivity have a mean hyperopic defect related to a shorter axial length. A number of studies have demonstrated that CCT in newborns is significantly greater than in adults; a decrease in CCT is closely correlated with an increase in corneal diameter. This finding suggests that the growth of the eye, with possible remodelling and stretching of collagen fibres, may play an important role in the reduction of corneal thickness in the first years of life. Therefore, we conclude that a greater CCT can represent a sign of a delayed growth of the eye in patients with GH deficiency. Finally, our study confirms the influence of corneal thickness on IOP measures, and the prevalence of hyperopia among children with growth defect.