Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling. METHODS: We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs. RESULTS: We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expression profile. CONCLUSION: These data indicate that the MAPK pathway may be pivotal to the transition from AK to cSCC, thus representing a potential target for cSCC prevention. In addition, transcriptome differences identified between cSCC subtypes have important implications for future development of targeted therapies for this malignancy.

Longitudinal changes in the spherical equivalent refractive error of children with accommodative esotropia.

AIM: To assess the longitudinal changes in the spherical equivalent (SE) refractive errors of children with accommodative esotropia as a function of the age when glasses were prescribed. METHODS: Refractive errors were followed longitudinally for 126 children with accommodative esotropia for a mean of 4.4 (SD 2.5) years. Cycloplegic refractions were performed using an autorefractor for older children and retinoscopy for younger children. The refractive data were analysed for three groups of children based on their age at the time spectacles were prescribed. RESULTS: The initial SE refractive error was age dependent (<2 years, 5.1 (1.9) D; 2-<4 years, 4.2 (1.9) D; 4-8 years, 3.8 (1.7) D). Children in all age groups had an initial increase in their SE refractive error, followed by a later decrease; however, the greatest decrease occurred in the patients in the oldest age group. The SE refractive error peaked 1 year after spectacles were prescribed for the children 4-8 years of age versus 6 years after spectacles were prescribed for the children less than 2 years of age. CONCLUSION: Longitudinal changes in SE refractive error for children with accommodative esotropia vary as a function of their age when spectacle wear is initiated.

Cryptic cerebral visual impairment in children.

AIM: To review the medical records of seven children with a delayed diagnosis of cerebral visual impairment. METHODS: The charts of a consecutive series of children examined in a university based ophthalmology clinic with a delayed diagnosis of cerebral visual impairment were reviewed. Their neuroimaging studies were evaluated by a paediatric neuroradiologist. RESULTS: The seven patients ranged in age from 2 years to 10 years at the time of presentation and had acuities ranging from 20/40 to 20/400. Their visual fields ranged from full visual fields to homonymous hemianopias. Neuroimaging findings ranged from subtle occipital lobe abnormalities to obvious cerebral volume loss. CONCLUSIONS: Cerebral visual impairment can be cryptic in children with mild visual impairment. Neuroimaging studies and visual field testing can help to differentiate this condition from other causes of visual impairment.

Associated systemic and ocular disorders in patients with congenital unilateral cataracts: the Infant Aphakia Treatment Study experience.

PurposeFive-year prospective data on children enrolled in the Infant Aphakia Treatment Study (IATS) provided an opportunity to explore ocular and systemic associations in patients with a unilateral congenital cataract.MethodsInfants <7 months of age with a unilateral cataract were eligible for IATS screening. We reviewed data pertaining to the exclusion of patients as well as data collected on standardized study forms used at any time for documentation of ocular or systemic disorders.ResultsOverall, 227 infants were referred for possible enrollment. Of these, 10 had insignificant cataracts and 32 refused to participate. Of those excluded, 3 were premature, 27 had significant ocular disease (usually persistent fetal vasculature (PFV) or corneal diameter <9 mm), and 4 had systemic disorders. An additional 26 were excluded at the time of the first EUA, most often because of PFV or variants thereof. On follow-up, in the 114 enrolled patients, the following disorders were diagnosed: Stickler syndrome (1), mitochondrial disease (1), autism (1), and presumed congenital rubella syndrome (1). No patient developed a cataract in the fellow eye.DiscussionSome conditions that can feature unilateral cataracts are diagnosed at birth or very early in life, but others may be diagnosed at varying periods thereafter. PFV and its variants are the most common associated ocular findings in about a quarter of cases of unilateral congenital cataracts.ConclusionAlthough patients with a unilateral cataract may have significant associated abnormalities in the affected eye, most commonly PFV and its variants, the prevalence of associated significant systemic disease is quite low.

Factors associated with stereopsis and a good visual acuity outcome among children in the Infant Aphakia Treatment Study.

PurposeTo identify factors associated with stereopsis in children with good visual acuity after unilateral congenital cataract surgery in the Infant Aphakia Treatment Study.Patients and methodsInfants with a unilateral congenital cataract (n=114) were randomized to IOL implantation or contact lens correction after cataract surgery. At age 4.5 years, a masked examiner assessed HOTV acuity and stereopsis. Adherence to patching was assessed using 48-h recall telephone interviews and 7-day diaries throughout the first 5 years of life. Ocular motility was evaluated at age 5 years. Baseline, postoperative, and adherence findings were compared between patients with 20/40 or better acuity in their treated eyes with or without stereopsis.ResultsThirty (27%) of 112 patients who were evaluated at age 4.5 years had 20/40 or better acuity in their treated eye. Stereopsis was present on one or more tests in 15 of these 30 (50%) children. Baseline characteristics and postoperative findings did not differ between patients with or without stereopsis. Children with stereopsis were more likely to be orthotropic at distance (P=0.003) and were patched for fewer hours per day throughout the first 5 years of life and the difference increased over time (P<0.001). On average children with stereopsis were patched for 3.4 h/day during the first year of life and patching steadily decreased to 1.8 h/day by age 4 years.ConclusionAmong children with good vision following unilateral congenital cataract surgery, orthophoria and fewer hours of patching, particularly during years 2, 3, and 4, are associated with some evidence of stereopsis.

Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients: a randomized safety and efficacy study.

PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).ConclusionsDifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.

Downregulation occurs normally in cultured Epstein-Barr virus-transformed lymphocytes from patients with extreme insulin resistance. Discrepancy between downregulation in vivo and in vitro.

Levels of fasting plasma insulin are generally inversely correlated with 125I-insulin binding to circulating blood cells. In disease states associated with hyperinsulinemia (e.g., obesity and non-insulin-dependent diabetes mellitus), 125I-insulin binding is usually low. In contrast, 125I-insulin binding to circulating cells may be normal in patients with certain forms of extreme insulin resistance despite marked hyperinsulinemia. To explain this paradox, it has been proposed that postbinding defects in insulin action may give rise to defects in downregulation. We have employed cultured Epstein-Barr virus (EBV)-transformed lymphocytes from eight patients with extreme insulin resistance to address the question of whether there is a defect in the downregulation process in vitro. In this cell type, insulin leads to a decrease in the number of insulin receptors on the cell surface by accelerating the rate of degradation of insulin receptors. We could not detect any abnormality in in vitro down-regulation with cultured EBV-transformed lymphocytes from insulin-resistant patients. The apparent discrepancy between the in vivo and in vitro studies raises the possibility that some factor in the patient's internal milieu may prevent insulin-induced downregulation. An alternative possible explanation might be that the mechanism of downregulation in vitro differs from the mechanism whereby receptor number is regulated in vivo in insulin's target cells.

Isolated congenital hemianopia caused by prenatal injury to the optic radiation.

Isolated congenital hemianopias are typically caused by developmental abnormalities of the occipital lobe cortex. We describe two patients with an incidental partial hemianopia associated with unilateral periventricular leukomalacia that was acquired prenatally. Magnetic resonance imaging scans suggest a late second or early third trimester unilateral cerebral ischemic event.

Retinal disease masquerading as spasmus nutans.

Two children with congenital stationary night blindness were originally diagnosed as having spasmus nutans. Both children had the typical features of spasmus nutans including asymmetric nystagmus, head shaking, and torticollis. The diagnosis of congenital stationary night blindness was established only after each child underwent electroretinography. The nystagmus associated with retinal disease can mimic many of the features of spasmus nutans. Children suspected of having spasmus nutans should undergo complete ophthalmologic examination and electroretinography if they are myopic.

Botulinum toxin treatment of supranuclear ocular motility disorders.

We treated one patient with bilateral internuclear ophthalmoplegia and another with skew deviation with extraocular muscle botulinum toxin injection. Both patients had pre-injection symptomatic diplopia in primary position, one for 1 month and the other for 12 months. Resolution of diplopia and complete and permanent binocular fusion in primary position was obtained within 3 to 4 days in both cases.

Acuity and contrast sensitivity in monkeys after neonatal intraocular lens implantation with and without part-time occlusion of the fellow eye.

PURPOSE: The authors used a monkey model to evaluate intraocular lenses (IOLs) for the treatment of infantile cataract in humans. Specifically, they sought to assess the effectiveness of IOLs, with and without occlusion therapy, in preventing amblyopia. METHODS: A diffuser contact lens was placed on one eye each of 11 neonatal monkeys to simulate an infantile cataract. A unilateral lensectomy, combined with the implantation of an IOL, was performed on the same eye 1 to 2 weeks after birth. Clear contact lenses were used to adjust the optical correction of the pseudophakic eyes to a near point, and opaque lenses were used to maintain daily part-time (70%) occlusion of the fellow eyes of half the subjects. Behavioral methods were used to assess grating acuity, optotype acuity (Landolt C), and contrast sensitivity. RESULTS: In five of the animals, complications that developed in the eye with the implant were severe enough to interfere with visual function. The authors present only behavioral outcomes obtained before or in the absence of surgical complications. In monkeys that underwent daily 70% occlusion, grating acuity in the pseudophakic eyes eventually matured to normal adult levels. Grating acuity was significantly poorer in animals with no occlusion therapy. Even in animals with normal grating acuity, assessments of optotype acuity revealed amblyopic deficits; contrast sensitivity was impaired as well at middle and low spatial frequencies. CONCLUSIONS: The current study demonstrates that if there are no complications secondary to surgery, normal grating acuity can be obtained in neonatal monkey eyes that undergo IOL implantation, optical correction of the pseudophakic eye to a near point, and 70% occlusion of the fellow eye. However, these good outcomes for grating acuity cannot be attained without occlusion therapy. In addition, optotype acuity and sensitivity to contrast always are impaired.

Pseudophakia retards axial elongation in neonatal monkey eyes.

PURPOSE: To evaluate the affect of removing the crystalline lens and implanting an intraocular lens on the axial elongation of a neonatal eye. METHODS: Monocular lensectomy coupled with the implantation of a monofocal or multifocal intraocular lens was performed on 21 neonatal rhesus monkeys. Fellow eyes were randomized to part-time occlusion therapy or no treatment. Longitudinal axial elongation of the pseudophakic eyes was then compared to that of the fellow eyes, to the eyes of 19 monkeys made monocularly aphakic as neonates, and to the eyes of 39 normal monkeys. RESULTS: At 5 weeks of age, aphakic and pseudophakic eyes were significantly shorter than their fellow eyes (P < 0.01). After 1 year of follow-up, the mean axial lengths of the pseudophakic and aphakic eyes were 2.0 +/- 0.2 mm and 2.3 +/- 0.2 mm, respectively, shorter than their fellow eyes. This axial length difference persisted through a second year of follow-up. The difference between the mean axial lengths of the aphakic and pseudophakic eyes was not significant (P > 0.10). Part-time occlusion of the fellow eyes did not affect axial elongation. CONCLUSIONS: Removing the crystalline lens and implanting an intraocular lens in a neonatal monkey eye retards its axial elongation.

Visual outcome after contact lens and intraocular lens correction of neonatal monocular aphakia in monkeys.

PURPOSE: A monkey model was used to evaluate intraocular lenses (IOLs) and extended-wear contact lenses (EWCLs) for the optical treatment of infantile aphakia in humans. Specifically, the relative effectiveness of EWCLs used alone and IOLs used in combination with EWCLs in preventing amblyopia was assessed. METHODS: A total of 33 rhesus monkeys was studied in this project, 24 assigned to experimental treatment groups and 9 to normal controls. Contact lenses made from a diffusing material or dyed opaque were placed on one eye at birth to simulate an infantile cataract. A unilateral lensectomy was then performed on the same eye within 2.5 weeks after birth. In 15 monkeys this was combined with implantation of an IOL. The eyes were left aphakic in the remaining 9 animals. EWCLs were used to adjust the optical correction of both aphakic and pseudophakic eyes to a near point (3-5 D). Opaque lenses were used to maintain daily part-time (approximately 70%) occlusion of the fellow eye. The primary outcome measure was grating acuity assessed with behavioral methods. Some animals were also assessed for acuity with sweep visually evoked potentials (VEPs) and for optotype acuity (Landolt C) with behavioral methods. RESULTS: Two of the animals with IOLs developed complications in the eye that precluded completion of the behavioral assessment protocol. Only behavioral outcomes obtained before or in the absence of surgical complications are presented. There was a developmental delay in the maturation of grating acuity in both eyes of both treatment groups. Normal adult levels of grating acuity were eventually achieved in the group treated with IOLs combined with EWCLs. Grating acuity was significantly poorer than normal in aphakic eyes treated only with EWCLs. Comparison of the two treatment groups revealed that pseudophakic eyes treated with multifocal IOLs had significantly better gating acuity than aphakic eyes. Assessments of optotype acuity and sweep VEP acuity revealed amblyopic deficits in both pseudophakic and aphakic eyes. CONCLUSIONS: Given an absence of serious postoperative complications, neonatal correction of aphakia with IOLs combined with EWCLs can lead to normal grating acuity in a primate model. Correction with EWCLs alone was not sufficient to produce normal grating acuity. Multifocal IOL treatments combined with EWCL provided a significantly better outcome than EWCL methods alone. However, neither IOL nor EWCL methods were able to prevent amblyopia as evaluated using behavioral testing with optotypes or with sweep VEPs.

Neonatal lensectomy and intraocular lens implantation: effects in rhesus monkeys.

PURPOSE: To compare the effects of a lensectomy with and without intraocular lens (IOL) implantation on a neonatal rhesus monkey eye. METHODS: A lensectomy and anterior vitrectomy was performed on 75 monkeys during the first 16 days of life; 21 of these monkeys also had an IOL implanted into the posterior chamber. The eyes were examined at regular intervals using biomicroscopy, applanation tonometry, and ophthalmoscopy. RESULTS: The pseudophakic monkeys were studied until they were 92.5 +/- 5.8 weeks of age and the aphakic monkeys until they were 80.4 +/- 5.7 weeks of age. Pupillary membranes (100% versus 55.5%; P < 0.01) and lens regeneration into the pupillary aperture (28.6% versus 5.6%; P = 0.02) occurred more often in the pseudophakic than the aphakic eyes. As a result, the pseudophakic eyes required more reoperations than the aphakic eyes to keep the visual axis clear (P < 0.01). There was not a significant difference in the incidence of ocular hypertension between the pseudophakic and aphakic eyes (9.5% versus 12.7%; P = 0.34). Pupillary capture of the IOL optic occurred in 52% and haptic breakage in 33% of the pseudophakic eyes. All of the eyes with broken haptics had a prominent Soemmerring's ring varying in maximum thickness from 0.6 to 2 mm. Nine of the haptics from the seven eyes with broken IOLs had eroded into the iris, two into the ciliary body, and one into the anterior chamber. CONCLUSIONS: Implanting an IOL into a neonatal monkey eye after a lensectomy and anterior vitrectomy increases the likelihood of a reoperation being necessary. Haptics frequently erode into the iris and ciliary body and may break because of stress placed on the optic-haptic junction by forward movement of the IOL.

Concordance and recessive inheritance of Leber congenital amaurosis.

Pedigrees were obtained on 43 patients with confirmed Leber congenital amaurosis, a rare form of blindness caused by congenital dysfunction of the retina. All of the pedigrees were consistent with autosomal recessive inheritance and the segregation frequency using classical segregation analysis was 0.24 +/- 0.07. Six of the 7 affected sib pairs were concordant in regards to systemic abnormalities. Despite previous reports that Leber congenital amaurosis can be inherited either as an autosomal dominant or recessive condition, our findings support only an autosomal recessive inheritance of this disorder.

The effect of age on the retardation of axial elongation following a lensectomy in infant monkeys.

OBJECTIVE: To determine the effect of age on the retardation of axial elongation in neonatal monkey eyes following the extraction of the crystalline lens. METHODS: A monocular lensectomy was performed on 4 rhesus monkeys when they were 4 days, 2 weeks, 7.5 months, and 1 year of age. Longitudinal measurements of axial lengths and keratometry readings were made. RESULTS: The aphakic eye was 1.7 mm shorter than the unmanipulated fellow eye in the monkey undergoing surgery at 4 days of age and 1.1 mm shorter in the monkey undergoing surgery at 2 weeks of age. However, the aphakic eyes were only 0.2 mm and 0.1 mm shorter than their unmanipulated fellow eyes, respectively, in the monkeys undergoing surgery at 7.5 months and 1 year of age. CONCLUSIONS: The retardation of axial elongation following a lensectomy in infantile monkey eyes is age dependent. Little effect is observed in monkeys aged 7.5 months or older.

Serous retinal detachments in thrombotic thrombocytopenic purpura.

Serous retinal detachments are a rare ocular complication of thrombotic thrombocytopenic purpura (TTP), with only six previous case reports in the literature. We have recently observed two patients with relapsing TTP who developed bilateral serous retinal detachments during acute exacerbations of their disease. In contrast to all but one of the previously described patients, both of our patients survived the episode during which retinal detachments occurred. Hypertension appears to contribute to the development of retinal detachments in TTP, and vigorous efforts at blood pressure control are indicated. Serous retinal detachments may be a more frequent component of chronic relapsing TTP than has been suspected.

Optic nerve sheath and retinal hemorrhages associated with the shaken baby syndrome.

A 13-month-old child with the pathognomonic findings of the shaken baby syndrome died secondary to cerebellar herniation. Pathologic examination disclosed extensive intraocular, optic nerve sheath, and intracranial hemorrhages, despite a paucity of external signs of trauma. Many of the hemorrhages were old, suggesting that the child had experienced multiple episodes of trauma. Hemorrhages of the optic nerve sheaths have not been previously reported with the shaken baby syndrome but probably accompany this condition frequently. Our patient's ocular hemorrhages may have resulted from a sudden rise in intracranial pressure.

Joubert syndrome.

Joubert syndrome is an autosomal recessive condition in which there is a variable combination of central nervous system defects with a distinctive congenital retinal dystrophy, ocular motor abnormalities, and respiratory abnormalities in early infancy. The retinal dystrophy has been previously classified as a variant of Leber's congenital amaurosis. We report electrophysiologic and eye movement findings in a series of seven consecutive children with Joubert syndrome. Unlike patients with Leber's congenital amaurosis, all but one of these children had preserved flash and pattern-reversal visual evoked potentials. Six of the seven children had abnormalities of smooth pursuit, optokinetic nystagmus, and saccades. Six of the children had nystagmus: three had a pendular torsional nystagmus and three had a form of see-saw nystagmus. An alternating hyperdeviation was present in five of the patients, two of whom also had a tonic deviation of their eyes laterally. All seven patients had cerebellar vermis hypoplasia on a magnetic resonance imaging scan. Developmentally delayed children with an absent or highly attenuated electroretinogram should be investigated for Joubert syndrome.

Ocular manifestations of the congenital varicella syndrome.

Three children developed the congenital varicella syndrome following a maternal varicella infection during the second trimester of pregnancy. Systemic findings included a bulbar palsy, mild hemiparesis, cicatricial skin lesions, developmental delay, and learning difficulties. Ocular findings included chorioretinitis, atrophy and hypoplasia of the optic discs, a congenital cataract, and Horner's syndrome. Electroretinograms and pattern-reversal visual-evoked potentials recorded from the four eyes with chorioretinitis were attenuated and degraded. Two of the children had been misdiagnosed as having congenital toxoplasmosis. Chorioretinal scars probably occur more frequently with the congenital varicella syndrome than has been previously recognized and should be included in the differential diagnosis of congenital chorioretinal scars. Hypoplasia of the optic disc may develop after an intrauterine varicella infection during the 16th week of gestation. Children with the congenital varicella syndrome should be examined by an ophthalmologist to exclude ocular abnormalities. These abnormalities are often subtle and difficult to diagnose correctly.