Shows a child with congenital corneal anesthesia due to aplasia of the trigeminal nerve. (a) shows the child at presentation with a neurotrophic ulcer and hypopyon. (b) shows the corneal neurotization procedure at the point where the sural nerve is divided into its component fascicles which are then passed under the conjunctiva to the limbus.(c) shows an integrated intraoperative OCT of one of the fascicles under the conjunctiva about 3 months after the surgery (white arrow)
Classification for congenital corneal opacities. All conditions in red have a poor prognosis for corneal transplant
Shows a child with congenital corneal opacities. The right eye (a and c) shows no keratolenticular adhesions but does show iridocorneal adhesions. The thick white arrow is showing a formed anterior chamber. The left eye shows a clearing centrally but this is due to thinning of the cornea and a keratolenticular adhesion (thin white arrows b and d)
The image shows pre-selective endothelial removal (a), then a few weeks later (b) and then a few months later (c). There is remarkable clearing of the opacity and emphasizes the need for deep phenotyping in these cases so that the correct treatment can be used; e.g. selective endothelial removal could not be used in the eye shown in (b). Courtesy of Professor J Mehta
Shows a child with Bardet Biedl syndrome with retinal dystrophy. The fundus autofluorescence shows hyper fluorescence around the macula (black arrow) while the fundus picture shows marked attenuation of the arterioles (white arrow) without any bony spicule pigmentation
Collagen cross linking (CXL) has been developed to increase the biomechanical rigidity of an ectatic cornea (keratoconus). Initially the application of this technique was in progressive keratoconus in adults but as our understanding of the technique and its applications has improved, its use in children has spread. In children the presence of keratoconus alone is enough to offer CXL. While arguments about epithelium on or epithelium off rage in the literature, evidence to date suggests that long-term stability is better achieved with epithelium off using the Dresden protocol in children.
Shows a child with traumatic corneal scar (a black arrow) and traumatic cataract . In order to perform a corneal transplant, cataract removal and primary lens implantation, the integrated intraoperative OCT (i2OCT) was used to cut the keratolenticular adhesion (a, b—thin white arrow) using the simultaneous OCT view in the binoculars of the operative microscope (b, c—thick white arrow shows the microscissors and the dashed white arrow in (b) shows the keratolenticular adhesion cut
CXL induces and enhances cross-linking between collagen fibrils. Riboflavin causes photo-sensitisation and UV-A creates cross-linking by generating oxidative products in the presence of oxygen [12]. This process increases the corneal biomechanical strength arresting the progression of biomechanical weakening (ectasia).
Paediatric keratoconus is more aggressive even at presentation with an aggravated progression compared to adults % [13] with a seven-fold increased risk of requiring a penetrating keratoplasty compared to adults [14, 15]. Studies that include no children with allergic eye disease show stabilization of progression with no requirement of any further intervention [14, 16]. In those studies where patients had allergic eye disease [17] 20% of eyes that were followed beyond 4 years showed reversal of keratometric flattening with minimal drop in visual acuity; This regression of cross linking effect in a small subset of patients was thought to be due to persistent eye rubbing due to allergic eye disease.
In patients of keratoconus older than 15 years, an objective study of quality of life using NEI-VFQ 25 questionnaire by Cingu et al. has shown better quality of life and decreased anxiety related traits 1 year following cross linking [18].
Studies have demonstrated both statistically and clinically that CXL with the Dresden protocol arrests the progression of keratoconus, while causing corneal flattening, variable visual improvement and significantly decreases the requirement of keratoplasty for keratoconus and improves quality of life [16–23].
CXL is associated with minimal sight threatening complications which include infectious keratitis (0.0017%), sterile infiltrates, limbal stem cell damage and an anterior stromal haze not affecting vision with long-term studies showing a regression of CXL effect or failure of up to 8–10% [23–25].
Studies have shown significant progression of the disease in non-cross-linked eyes. Progression is especially higher and rapid in paediatric keratoconus eyes affecting vision significantly and leading to contact lens intolerance and eventually acute hydrops [18, 26, 27].
Other options in moderate to severe keratoconus management include Intra corneal ring segments (Intacs®) and keratoplasty. Intacs, though can partially rehabilitate vision and delay keratoplasty, is associated with poor outcomes with higher grades of keratoconus and has reported risk of extrusion or need for removal [28, 29], which increases the number of procedures, especially in paediatric patients. Pediatric keratoplasty has a higher risk of infections, graft rejection and difficult visual rehabilitation compared to adult keratoplasties [19].
Accelerated CXL (KXL) significantly reduces irradiation time and use of pulsed UV delivery has circumvented the problem of O2 delivery. Long term comparative studies with 48 months follow up in paediatric and adult populations have proven safety and efficacy in halting progression compared to Dresden protocol. Further better outcomes are reported with KXL when Riboflavin with HPMC is used instead of Photrexa viscous [30].
Customised KXL with graded energy delivery to different zones of the cornea with maximum energy at the cone has proven safety and better flattening of cone and visual gain with lesser keratocyte damage in corneal periphery compared to conventional technique [30].
For thinner corneas (less than 400 μm), epi-on trans epithelial CXL, though was initially reported to be inferior to conventional epi-off method, is now showing promise on safety and efficacy with use of modified Riboflavin with other agents as EDTA and use of Iontophoresis for Riboflavin delivery [30].
Pediatric Cataract
No field in pediatric ophthalmology has advanced at as fast a rate than the area of pediatric cataract surgery surgically. Key studies globally have contributed to a better understanding of surgical outcomes, techniques and decision making for intervention. In the past 5 years.
There have been outcomes of randomized controlled trials (RCT), an individual metanalysis and a Delphi consensus statement, reflecting the integration of real-world evidence, real world data with basic scientific rigor [31–34].
The infant Aphakia Treatment study was the first RCT to be published in the area of pediatric cataract surgery, and specifically looked at unilateral cataract in infants. The conclusion drawn from this study, which has had some criticisms in methodology, were that at 5 year follow up IOL implantation resulted in greater number of re-operations with no difference in vision between the two groups (aphakic corrected with Contact lenses or IOL implantation group corrected with glasses). These conclusions hold true for unilateral cataract [31].
Bilateral cataracts are a different type of disease and extrapolations from IATS to applications in bilateral congenital cataract are misleading and misguided. Recently a group in India performed a randomized controlled trial for bilateral congenital cataracts and have shown that the reoperation rates between aphakic and IOL groups were the same and the visual outcomes in the bilateral group with IOL rending to be better than those in the control group [32].
Sixty children (120 eyes) up to 2 years of age undergoing bilateral congenital cataract surgery were randomized to aphakia (n = 30), or primary IOL implantation (pseudophakia) (n = 30). A single surgeon performed all the surgeries with identical surgical technique. All patients were followed up regularly for 5 years. The median age of the patients at time of surgery was 5.11 months (aphakia group) and 6.01 months (pseudophakia group). At 5 year follow up the incidence of glaucoma was about the same (16% aphakic and 13.8% pseudophakic). The incidence of posterior synechiae was significantly higher in the pseudophakia group and visual axis opacification requiring surgery was seen in 8% of the aphakes and 10.3% of the pseudophakes. Mean logMAR visual acuity at 5 years follow-up was 0.59 ± 0.33 and 0.5 ± 0.23. However, more eyes in the pseudophakic group started giving documentable vision earlier in their postoperative follow-ups than the aphakic group [32].
This is understandable for two reasons: firstly almost ALL unilateral cataracts (truly unilateral) are due to some form of persistent fetal vasculature (PFV) and secondly, the IATS included several surgeons (some of whom had small volumes of surgery for pediatric cataract) while the RCT for bilateral disease was performed by a single center high volume pediatric cataract surgeon.
In the only individual metanalysis performed on infant cataract surgery [33], having analyzed 486 eyes the authors concluded that surgery before 4 weeks of age and multiple reoperations increased the risk of glaucoma development while placement of an IOL protected against glaucoma. This last is still controversial; reasons why this should be so, are likely hidden by the fact that each of the surgeons who participated in this metanalysis were experienced high volume cataract surgeons, who had specific indications to abort placement of IOL in even those eyes where parents had been counseled that an IOL would be placed. This of course is real-world evidence. Conducting RCTs for surgical techniques may not be appropriate when the factors that influence a surgeon’s decision to place one are not taken into account. In fact some authors suggest that RCTs in such circumstances are in fact dangerous for the participants.
A Delphi process led consensus was reported for management of pediatric cataract [34]. The process consisted of three rounds of anonymous electronic questionnaires followed by a face-to-face meeting, followed by a fourth anonymous electronic questionnaire. The executive committee created questions to be used for the electronic questionnaires. Questions were designed to have unit-based, multiple choice or true–false answers. The questionnaire included issues related to the preoperative, intraoperative and postoperative management of pediatric cataract. Consensus based on 85% of panelists being in agreement for electronic questionnaires or 80% for the face-to-face meeting, and near consensus based on 70%. Sixteen international pediatric cataract participated. Consensus or near consensus was reached for 85/108 (78.7%) questions and non-consensus for the remaining 23 (21.3%) questions.
The first Delphi consensus statement was more valuable in determining where consensus could not be reached rather than where it could. To this end the following remain areas of controversy. There was no consensus on certain topics such as the use of hydrodissection in cases where a pre-existing posterior capsule defect is not suspected, the best formula to use while calculating IOL power and the minimum age for primary IOL implantation.
Surgical techniques for pediatric capsule management continue to improve. While femtosecond laser has been used to describe excellent centration and precision of both anterior and posterior rhexis in children [35, 36], the expense of the procedure has prohibited its widespread use. The zeptosecond capsulotomy device [37] has gained some interest but its use in small eyes is questionable. The Two incision push pull technique continues to gain favor and allows sizing of the anterior and posterior capsulorhexis in pediatric cataract surgery [38]. Continuing this need for precisely sizing the anterior and posterior rhexis, a foldable capsulorhexis ring has been developed specifically for use with the bag-in the lens (BIL). This IOL is designed with a groove around the optic, into which the anterior capsule and posterior capsule fit after capsulorhexes are performed. The beauty of this lens is that the lens epithelial cells are captured and cannot proliferate, resulting in clear visual axes [39].
The use of multifocal implants in children continues to be reported but studies fail to measure contrast sensitivity in children who have had diffractive mutifocal IOLs placed. Without this outcome measure the use of diffractive multifocal IOLs is controversial [40].
The most important and perhaps controversial development has been the report of using a new surgical technique which results in regeneration of the lens itself. This group [41] showed in donor eyes that the younger the patient the greater the ability for LEC’s to reproliferate; this is a clinical fact well known to pediatric cataract surgeons. They then showed that the mere act of injury to the capsule would result in a seven-fold increase in LEC proliferation regardless of age. Based on a series of in vitro experiments, followed by surgeries on rabbit and then macaque monkey eyes they described a surgical technique whereby a small peripheral capsule opening was made and the lens fibers removed with as little damage to the proliferating anterior lens epithelial cells. This technique resulted in a regrowth of the lens fibers over a period of several weeks in the animal eyes. This technique was repeated in 24 eyes (12 cases) with congenital cataract in human children and compared to standard cataract surgery in 25 cases (50 eyes) with congenital cataract. The results published show regeneration of the lens using the newer technique over 3–5 months. There are of course many unanswered questions such as, how did an opaque lens regenerate into a clear one and during the period of regeneration how was amblyopia prevented? That said this concept is potentially disruptive if it can be replicated once the unanswered questions are clarified.
Refractive Error
Myopia, commonly called near-sightedness, is the most common human eye disorder in the world, affecting 85–90% of young adults in some Asian countries such as Singapore and Taiwan, and between 25 and 50% of older adults in the United States and Europe. Unlike Western populations where the prevalence of myopia is low (<5%) in children aged 8 years or younger, in Asian children there is a significantly higher prevalence of myopia, affecting 9–15% of preschool children, 24.7% of 7-year-olds, 31.3% of 8-year-olds, and 49.7% of 9-year-old primary school children in Singapore [42]. In 12 year-old children, the prevalence of myopia is 62.0% in Singapore and 49.7% in Guangzhou, China compared with 20.0% in the United States, 11.9% in Australia, 9.7% in urban India and 16.5% in Nepal [43].
The economic cost of myopia is estimated at an annual US$268 billion worldwide. Not only is there a socio-economic burden, there is a significant increased odds ratios for myopic maculopathy, retinal detachment, cataracts, and glaucoma, even for low and moderate levels of myopia and these odds ratios increase further with higher levels of myopia [44].
Evidence supports heritability of the nonsyndromic forms of myopia, especially for high-grade myopia (−5 D or higher) and Genome-wide association studies (GWAS) have identified >20 associated loci for myopia. However, the majority of recent studies show that the boom in myopia prevalence reported in different populations is related mostly to environmental factors, including excess in near work especially in young age and low light exposure, especially as outdoor activity.
There has been much interest recently to try and retard myopic progression of childhood. Some interventions that have been used in the past appear not to work. For example under-correction of myopia either increases or has no effect on myopia progression. Under correction does not slow myopia progression and should no longer be advocated [45].
While there is some evidence that bifocal lenses may reduce myopia progression there is some that suggests that they do not [45, 46]. Older studies (PALS, COMET, CLAMP) have shown minimal myopia retardation effect on myopia using traditional contact lenses [45–48].
In overnight orthokeratology the patient wears reverse geometry contact lenses overnight to temporarily flatten the cornea and provide clear vision during the day without any glasses or contact lenses. Reduction in myopia (up to −6 D) is achieved by central corneal epithelial thinning, midperipheral epithelial, and stromal thickening. Unfortunately, more than one hundred cases of severe microbial keratitis related to orthokeratology have been reported since 2001. Randomized clinical trials of orthokeratology myopia control demonstrated significantly slower axial elongation in children wearing orthokeratology lenses than children wearing single vision spectacles. Orthokeratology contact lenses can be used to correct central refractive error while leaving peripheral myopic blur, which may act as a putative cue to slow the progression of myopia. Overall, ortho-k results in an approximately 40% reduction in the progression of myopia. There is no good controlled long term study demonstrating sustained myopia control effect and there is no washout data [49, 50].
While there is accumulating evidence for the role of the peripheral retina in the development of refractive errors [51] with initial human studies involving mainly Caucasians suggesting an association between relative peripheral hyperopia and axial myopia, the Peripheral Refraction in Preschool Children (PREP) Study of Singaporean Chinese children and Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) study showed that relative peripheral hyperopia had little consistent influence on the risk of myopia onset, myopia progression, or axial elongation [52]. Even human clinical trials with treatment strategies aimed at reducing the peripheral retinal hyperopic defocus, there were no statistically significant differences in the rates of myopia progression between children who wore one of three novel spectacle lenses that decreased relative peripheral hyperopia and those who wore the conventional single-vision spectacle lenses. However, for children aged 6–12 years whose parents are myopic, one of the three spectacle lenses was found to reduce the progression of myopia significantly when higher rates of progression were evident [53, 54].
There has been a tremendous amount of interest in the use of topical atropine. Atropine blocks muscarinic receptors non-selectively. Muscarinic receptors are found in human ciliary muscle, retina and sclera. Although the exact mechanism of atropine in myopia control is not known, it is believed that atropine acts directly or indirectly on the retina or scleral, inhibiting thinning or stretching of the scleral, and thereby eye growth. This was also shown that atropine acts via non-accomodative way. Studies have shown some clinical effect on slowing the progression of myopia in children. The Atropine for the Treatment of Myopia studies (ATOM 1 and 2) were randomized, double-masked, placebo-controlled trials each involving 400 Singapore children. The ATOM1 study suggested 1% atropine eyedrops nightly in one eye over a 2-year period slowed myopic progression by 77% and reduced the axial length elongation (mean axial length increase of 0.39 mm in controls versus no growth in atropine group). The ATOM2 study demonstrated a dose-related response with 0.5%, 0.1% and 0.01% atropine slowing myopia progression by an estimated 75%, 70% and 60% with SE changes of 0.30D,0.38D and 0.48D, respectively over 2-years. However, when atropine was stopped, there was an inverse increase in myopia, with rebound being greater in the children previously on higher doses. This resulted in myopia progression being significantly lower in children previously assigned to the 0.01% group at 36 months compared with that in the 0.1 and 0.5% groups. Younger children and those with greater myopic progression in year 1 were more likely to require re-treatment. By the end of 5 years, myopia progression remained lowest in the 0.01% group. It was estimated that, overall, atropine 0.01% slowed myopia progression by at least 50%. The efficacy of lower dose atropine is corroborated by Taiwanese cohort studies. However, there may be children who are poor responders to atropine. In ATOM1, 12.1% of children (younger, with higher myopia, and greater tendency of myopic progression) had myopia progression of more than 0.5D after 1 year of treatment with atropine 1%. Atropine 0.01% caused minimal pupil dilation (0.8 mm), minimal loss of accommodation (2–3 D), and no near visual loss compared with higher doses. Children on atropine 0.01% did not need progressive additional lenses, and they did not need photochromatic lenses because of photophobia [55–58].
Finally, there have been many studies showing that outdoor activity, what was shown to be exposition to natural light, decreased the onset of myopia and neutralized the effect of parental myopia and near-distance work. The role of outdoor activity to myopia progression is not as clear since different studies shown conflicting results. The recent interventional studies showed effectiveness in reducing the myopia onset after increasing outdoor activity time in school. The notion that at least 2 h daylight exposure can be preventive against myopic progression of childhood has gained favour and in some countries is influencing the design of classrooms to increase daylight exposure while indoors [59–62].
Molecular Genetics
There is of course always something new in the field of molecular genetics but in terms of overarching concepts the two that are the most important and relatively new are nonsense suppression therapy and ciliopathies.
Nonsense mutations are single base pair substitutions in the DNA that create one of three stop codon sequences, UAA, UAG, or UGA, called premature termination codons (PTC). These types of mutations often result in truncated protein products which may be subject to nonsense-mediated mRNA decay (NMD). NMD is an evolutionarily-conserved surveillance pathway designed to eliminate abnormal mRNA transcripts before abnormally truncated proteins can be synthesized [63, 64]. Interference in the NMD pathway may stabilize abnormal transcripts, promote “read-through” of PTCs, and increase the amount of functioning protein [65].
“Read-through” is the misreading of stop codon during translation, allowing an amino acid to be incorporated into the growing polypeptide [66, 67] and occurs at a frequency of less than 0.1% at normally positioned stop codons and less than 1% at PTCs [66–70]. Nonsense suppression therapy (NST) is promotion of read-through and is potentially very impactful since nonsense mutations account for about 30% of ocular genetic disease [71].
Ataluren is classified as an orphan drug by the European Medicines Agency and U.S. Food and Drug Administration for treatment of Duchenne Muscular Dystrophy and cystic fibrosis as a form of NST [72–76]. Despite its successes, the in vivo and in vitro effectiveness of ataluren has been questioned and the potential complication of action on non-targeted genes and stop codons has been raised [71, 77, 78].
In ophthalmology ataluren has been used to treat aniridia [79]. Aniridia is a congenital, progressive, panocular condition characterized by partial or complete absence of iris, nystagmus, corneal opacification, glaucoma, cataract, and foveal hypoplasia. The condition is due to mutations in the PAX6 gene, which plays a central role in early ocular development of the cornea, iris, lens, and retina [80, 81].
Using a mouse model of aniridia with a naturally occurring nonsense mutation, notated Gly194Term, in PAX6, Gregory-Evans et al. administered daily subcutaneous injections of ataluren (30 μg/g) from postnatal days 4 to 14 [79]. In untreated mice, the baseline ocular phenotype included a thickened cornea connected to a lenticular stalk and a thickened retina with abnormal infolding. By day 14, the phenotype progressed to globe distortion, further retinal infolding, and an abnormally small lens. In ataluren-treated mice, the retinal infolding was corrected and the lens was 70% larger compared to controls. Functional improvements were also apparent by postnatal day 60 when measured by electroretinography (ERG), where untreated mice had non-recordable ERG tracings at and treated mice had relatively substantial ERG responses. Of note, the ERG responses in treated mice were improved but not normalized. Anterior segment examinations revealed an abnormally thick corneal stroma with epithelial thinning, which was not statistically different from untreated mice. Extending injections to postnatal day 60 did not significantly improve the corneal phenotype. The authors concluded that systemic injection may limit delivery to the cornea and that improvement in the corneal phenotype may be also be limited as other PAX6-independent factors contribute to anterior segment development and would not be responsive to ataluren. Modification of the study for topical delivery rescued the corneal abnormalities, demonstrated a greater reversal of lens and retina defects compared to systemic injection, and improved retinal function by ERG and behavioral optokinetic tracking. This study was the first to demonstrate that an abnormal ocular phenotype could be subject to remodeling and rescue of a near-normal or normal phenotype after birth in an animal model. These remarkable research outcomes have led to the design and implementation of an ongoing clinical trial of ataluren in children and adults with aniridia (NCT02647359).
To date, research of the read-through efficacy of aminoglycosides or ataluren in cell and animal models has included aniridia, ocular coloboma, Usher Syndrome Type 1C, choroideremia, and various forms of retinitis pigmentosa [82–84]. Given the frequency of nonsense mutations in certain ocular disorders and the optimized delivery system of ataluren that can penetrate both anterior and posterior segment tissues, the success of nonsense suppression therapy with ataluren has the potential to be extended and positively impact the phenotype of patients.
For optimal patient management and consideration for the ongoing clinical trial, patients with aniridia should have a comprehensive testing including PAX6 sequencing and PAX6/WT1 deletion/duplication studies. PAX6 sequencing will allow detection of intragenic mutations, including nonsense mutations that would establish the patient’s eligibility for the clinical trial of ataluren, and PAX6/WT1 deletion/duplication studies are essential to rule out involvement of the nearby WT1 gene that increases the risk for Wilms Tumor to 45–57% [85, 86]. In the case of WT1 involvement or in the absence of any PAX6 analyses, children with aniridia should undergo renal ultrasound every 3 months until age 8 years when the development of Wilms Tumor is rare. Late-onset Wilms Tumor, delayed involvement of the contralateral kidney, and high incidence of renal failure with or without a history of Wilms Tumor justifies a low threshold for ultrasonography, kidney function tests, and nephrology referral [86–89].
Cilia are highly conserved organelles that exist and function as either motile or non-motile structures. Motile cilia are primarily found in the ventricles, middle ear, respiratory tract, and fallopian tubes, where they protrude from the cellular surface and move in a coordinated, wave-like motion [90–93]. A dysfunction of motile cilia result in certain diseases in these tissues, such as hydrocephalus, airway disease, and infertility, or cause a broader effect such as situs inversus totalis [90–92]. Non-motile, or primary, cilia are expressed in nearly every cell type and therefore have the potential to result in multisystem dysfunction [91, 93].
The motile and non-motile cilia are structurally similar in that they are both anchored by a basal body and have a projection, referred to as the axoneme. The axonemes contain nine paired microtubule structures, where the motile cilia have an additional, central pair of microtubules. These microtubule configurations are referred to as 9 + 0 for non-motile cilia and 9 + 2 for motile cilia [94]. Within the cilia, there are hundreds of proteins responsible for its functions. The synthesis of these proteins does not occur within the cilium; rather, they are transported through a process referred to as intraflagellar transport (IFT). IFT is achieved through complexes within the base and along the cilium, which are essential for the protein trafficking to form and maintain cilia [95, 96].
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Mechanosensation . External stimuli including fluid flow, osmotic pressure, heat shock, touch, and extracellular movement can impact primary cilia [97–100]. In response, signaling inside the cilium result in changes in length and stiffness which alter how the cilia interact with their immediate environment. The mechanical properties and relation to disease are most understood in the setting of cystic kidney diseases including polycystic kidney disease and nephronophthisis. The relevant proteins (referred to as cystoproteins), have been localized to the cilia and centrioles and are mislocalized or absent in models in animal models of cystic kidney diseases [101–104]. Studies have demonstrated the mechanical role of cilia in these diseases, where bending of kidney epithelial cilia initiates a calcium-mediated response that subsequently affects several signaling pathways related to cell proliferation and cystogenesis [104]. As an example, mutations in NPHP1 account for approximately 20% of cases nephronophthisis, resulting in cyst formation and subsequent renal failure [105, 106].
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