October 20, 2017 - HYNES Conference

AM: Genetics in Pediatric Eye Diseases – Clinical Implications

Genetics in ophthalmology- practical relevance and examples from inherited retinal disorders
Jason Comander

Certain ophthalmic genetic disorders have traditionally had no treatments available, limiting the practical need for identification and diagnostic testing.  However, advances in gene therapy are beginning to make an appearance in the clinic; for example one form of Leber Congenital Amaurosis, a gene therapy drug is under review for approval by the FDA.  Genetic conditions with ongoing human clinical trials include a number of retinal disorders (certain forms of retinitis pigmentosa, achromatopsia, juvenile retinoschisis, Stargardt disease, Usher syndrome, etc.) and Leber Hereditary Optic Neuropathy.  Practical tips for diagnosing and referring patients with suspected genetic disorders include: understanding the implications of a positive family history or lack thereof; typical presentations / questions for history taking; and typical exam findings.  With some simple knowledge, every ophthalmologist can be equipped to identify patients who might be eligible for the newest generation of genetic treatments.

Advances in the genetics of strabismus – will this change clinical care?
Mary Whitman

Strabismus can be divided into paralytic forms, in which one or both eyes cannot move fully, and non-paralytic forms, in which both eyes have full range of motion.  Although less common, the paralytic forms of strabismus often display Mendelian inheritance patterns, and multiple causative genes have been identified. Non-paralytic “common” strabismus represents the vast majority of strabismus cases, and displays complex inheritance.  Although there have been some reports linking strabismus to certain genetic regions, causative genes have not yet been identified. Among patients for whom a genetic diagnosis has been found, it is starting to affect clinical care. For ocular care, treatment of both strabismus and ptosis can be tailored based on molecular diagnosis. In addition, certain genetic mutations are associated with additional conditions, and timely referrals and screening can lead to earlier treatments.Strabismus can be divided into paralytic forms, in which one or both eyes cannot move fully, and non-paralytic forms, in which both eyes have full range of motion.  Although less common, the paralytic forms of strabismus often display Mendelian inheritance patterns, and multiple causative genes have been identified. Non-paralytic “common” strabismus represents the vast majority of strabismus cases, and displays complex inheritance.  Although there have been some reports linking strabismus to certain genetic regions, causative genes have not yet been identified. Among patients for whom a genetic diagnosis has been found, it is starting to affect clinical care. For ocular care, treatment of both strabismus and ptosis can be tailored based on molecular diagnosis. In addition, certain genetic mutations are associated with additional conditions, and timely referrals and screening can lead to earlier treatments.

Pediatric genetic disorders of lens
Bharti Gangwani

Pediatric genetic disorders of lens include cataractous as well as  non-cataractous anomalies. Approximately 50% of childhood cataracts are caused by genetic mutations. The cataracts could be isolated or can be associated with ocular or systemic (and metabolic) anomalies.  It is important to obtain a comprehensive history, and perform a detailed ophthalmic and systemic examination in children with bilateral cataracts. The patients with systemic findings should be referred to the geneticists. Non-cataractous anomalies are less common and include lens coloboma, lenticonus, microspherophakia, and dislocation of lens (ectopia lentis). The genetic diagnosis helps the families to better understand the disorder and develop realistic expectations as to the course of their child’s disorder and an understanding regarding future risk in siblings and off springs. Recent advances in genetic testing, including the next generation sequencing, can provide an underlying diagnosis in about 70% isolated congenital cataracts and 63% of those with syndromic congenital cataracts.

Genetics testing in the ophthalmology clinic: the benefits, limitations and challenges
Emily Place

Major advances in the field of genetics and specifically molecular genetic testing is impacting all areas of medicine including ophthalmology.  Such advances have improved our abilities to provide an accurate and definitive diagnosis of ocular disease.  Given these advances, patients and families have many questions for their eye care clinicians about the availability and utility of genetic testing. There a number of factors for clinicians to consider when exploring the topic of genetic testing with patients including testing method, appropriateness of testing for the patient, implications of the results on clinical care as well as the implications for at risk family members.  Discussing the strengths and limitations of genetic testing with patients and families is key to patients making informed decisions about testing.

Gene Therapy for Pediatric Genetic Blindness
Arlene Drack

Introduction: Leber congenital amaurosis (LCA) is a leading cause of congenital blindness with at least 19 causative genes. A gene therapy (SPK-RPE65) for LCA caused by RPE65 gene mutations recently completed a Phase 3 trial.  Many other gene therapy trials for pediatric ocular disorders are in earlier phases.

Methods: 31 patients with CLIA laboratory-confirmed RPE65-mediated LCA were enrolled at two centers. 21 participants were randomized to the intervention group; 10 were randomized to 1 year of observation before crossover. Subretinal injection of SPK-RPE65 in a 300 uL volume was delivered to one eye, followed by the contralateral eye within 18 days. Efficacy measures included mobility testing (MT), full-field light sensitivity threshold (FST), and visual acuity (VA).  Review of gene therapy trials recruiting patients was obtained from www.clinicaltrials.gov and other sites.

Results: The trial met its primary endpoint (p=0.001), demonstrating improvement of functional vision in the intervention group compared to the control group, as measured by bilateral MT change score between baseline and 1 year.  FST improved significantly in the intervention group compared to the control group (p<0.001).  MT change score for the assigned first eye was significantly better than controls (p=0.001). VA was not statistically different from controls (p=0.17).  There were no serious adverse events (AEs) related to SPK-RPE65 or deleterious immune responses. Procedure-related AEs included transient elevated IOP (4), cataract (3), retinal tear (2), and inflammation (2).  Patients randomized to no treatment for a year did not improve on testing during this time, but did improve after they were treated following one year of observation.  Results have been stable for 2 years in the initial treatment group and for one year in the second group treated.  Many other gene therapy trials for pediatric eye disorders are underway.

Discussion: SPK-RPE65 resulted in statistically significant improvement in functional vision and visual function measured by MT and FST, respectively. AEs were typical for subretinal surgery and not related to vector or immune response.  Parents of children with genetic eye disorders may benefit from knowing about research trials, and how to check on eligibilty of their children.

Conclusion:  Children with nystagmus and/or poor vision require genetic testing, since subretinal gene therapy improves visual function in RPE65-mediated disease, and other gene therapy clinical trials for different disorders are underway.

Pediatric Vitreoretinopathies: Genetic Considerations
Yoshihiro Yonekawa

Pediatric vitreoretinopathies are relatively rare, but can be devastating diagnoses. Examples include retinopathy of prematurity (ROP), familial exudative vitreoretinopathy (FEVR), Norrie disease, persistent fetal vasculature (PFV), Coats' disease, incontinentia pigmenti, and retinal detachment associated with Stickler syndrome and Marfan syndrome. Children usually do not present with classic textbook findings. Imaging studies coupled with genetic testing are useful in establishing the correct diagnosis, and therefore the optimal treatment plan. Genetic testing also allows the dignosis and surveillance of systemic co-morbidities, and screening of family members. 

Therapy for congenital optic neuropathies: fact vs. fiction
Crandall Peeler

Congenital optic disc anomalies are responsible for 15% of severe visual impairment in children1.  Optic nerve hypoplasia (ONH) is the most common abnormality and is the leading ocular cause of blindness in children in North America and Europe2.  While treatment is available for the endocrinopathies often associated with ONH, there is currently no FDA-approved therapy for vision loss stemming from the optic nerve dysfunction.  The treatment landscape is similarly stark for other congenital disc anomalies, including coloboma and morning glory discs.  Catering to ONH patients seeking visual improvement, medical clinics outside the United States advertise stem cell injections into the cerebrospinal fluid.  The aim of this talk is to discuss the available evidence and safety concerns surrounding stem cell therapy for congenital optic neuropathies.

The Work Up of Nystagmus in the Molecular Genetic Era
Arlene Drack

Drack, Bertsch, Floyd, Kehoe, Pfeifer


Introduction:Infantile nystagmus has many causes, some life threatening. We determined the most common diagnoses in order to develop a testing algorithm.


Retrospective chart review. Exclusion criteria were no nystagmus, acquired after 6 months, or lack of examination. Data collected: pediatric eye examination findings, ancillary testing, order of testing, referral, and final diagnoses.  Final diagnosis was defined as meeting published clinical criteria and/or confirmed by diagnostic testing. Patients with a diagnosis not meeting the definition were “unknown.”  Patients with incomplete testing were “incomplete.”  Patients with multiple plausible etiologies were “multifactorial.” Patients with negative complete workup were “motor.” 

Results:284 charts were identified; 202 met inclusion criteria.  The 3 most common causes were Albinism(19%), Leber Congenital Amaurosis(LCA)(14%) and Non-LCA retinal dystrophy (13%).  Anatomic retinal disorders comprised 10%, motor another 10%.   The most common first test was MRI (74/202) with a diagnostic yield of 16%.  For 28 MRI-first patients, nystagmus alone was the indication; for 46 MRI-first patients other neurologic signs were present.  0/28 nystagmus-only patients had a diagnostic MRI while 14/46 (30%) with neurologic signs did.  Yield of ERG as first test was 56%, OCT 55%, and molecular genetic testing 47%. 90% of patients had an etiology identified.

 A testing algorithm is needed.

Conclusion:The most common causes of infantile nystagmus were retinal disorders (56%), however the most common first test was brain MRI.  For patients without other neurologic stigmata complete pediatric eye examination, ERG, OCT and molecular genetic testing had a higher yield than MRI scan.  If MRI is not diagnostic, a complete ophthalmologic workup should be pursued.

PM: Optimizing Outcomes in Cataract Surgery

Optimizing the Ocular Surface for Cataract Surgery
Helen K. Wu

Cataract surgery is known to induce dry eye, as well as exacerbate preexisting ocular surface disease.  Over half of prospective cataract surgery patients may present with signs of dry eye.  After cataract surgery, dry eye may be worsened due to a combination of factors, including damage to the corneal nerves, toxicity from preserved drops, goblet cell loss, meibomian gland dysfunction, and ocular inflammation.  While a compromised ocular surface may lead to decreased quality of vision and patient dissatisfaction, it may also predispose to such risk factors as infection and corneal melting.  It is thus imperative to recognize and treat preoperatively the signs and symptoms of ocular surface disease, so as to assure optimal outcomes.  The diagnosis of ocular surface disease may be made using a variety of tests, often including patient symptom questionnaires, tear break up time, Schirmer testing, conjunctival staining, and tear film osmolarity.  Many treatments are available, and the clinical signs should guide the choice of treatment options.  A stepwise approach utilizing artificial tears, anti-inflammatory agents, punctal occlusion, treatment of blepharitis and meibomian dysfunction with lid hygiene and antibiotics, oral omega-3 fatty acids and autologous serum tears may be utilized.  Systemic immunosuppressant agents may be necessary in patients with severe preexisting ocular surface disease and underlying systemic autoimmune and inflammatory disorders.

Cataract Surgery in the Presence of Ocular Surface Disease (a.k.a. Leveling the Playing Field)
Lorenzo Cervantes

Patients with eyes with both compromised ocular surfaces and cataracts demand special consideration to optimize their outcomes after cataract surgery. This presentation provides considerations for common conditions that can greatly affect patient expectations, preoperative measurements, and overall quality of vision. Common pathology includes pterygia, corneal scars, epithelial dystrophies, Salzmann nodules, and neoplasias. Strategies for improved cataract surgery outcomes with these comorbidities include patient education and expectation management, and ocular surface optimization techniques such as lesion excision, epithelial debridement, superficial keratectomy, and photherapeutic keratectomy. Photographs and video will be used to demonstrate pathology and these techniques.

Best outcomes in the presence of pseudoexfoliation
Nicoletta A. Fynn-Thompson

Pseudoexfoliation (PXF) is an age-related condition causing deposition of fibrillar material on structures in the anterior segment. This material accumulates on the zonular fibers, the anterior lens capsule and the pupillary margin potentially leading to poor pupillary dilation, zonular instability and elevated intraocular pressure.  It has been shown that cataracts occur at an increased frequency in eyes with PXF. It is, therefore, prudent to pay special attention to these complex surgical cases.

Cataract surgeons must be cognitive of the increased complexity of cataract surgery in eyes with PXF. We shall highlight the important aspects of preoperative evaluation and the potential intraoperative complications in these eyes. Specifically, management of small pupils, zonular weakness and intraocular lens selection during phacoemulsification will be reviewed. Intraoperative techniques and adjunctive devices to achieve optimal post-operative outcomes will be presented.

What to do when the capsule ruptures?
Rosa Braga-Mele

This talk will review pearls on how to recognize when the posterior capsule ruptures during cataract surgery. It will address the best way to respond both in the immediate period and then how best to approach the tear/rupture both in the face of nuclear fragments or without them. It will review best approaches for vitrectomy and/or use of intracameral steroids to aid in surgery to minimize complications and help optimize outcomes.

Management of Patients with Contact Lenses or Keratoconus
Deborah S. Jacobs

      There are an estimated 41 million contact lens wearers in the United States, 7% of whom wear  rigid gas permeable (RGP) lenses, Some of these patients will require cataract surgery each year.  Contact lens wear can contribute to corneal warpage.  Guidelines for duration of contact lens "holiday" for different types of contact lens  prior to biometry for predictable  IOL power calculations will be presented.

      Refractive surgeons of a certain age are aware that patients accustomed to RGP ocrrection of corneal astigmatism may be disappointed by the results of refractive surgery.  Likewise, patients with corneal  astigmatism who are dissatisfied with toric soft contact lenses may be dissatisfied with toric IOLs. Guidelines for the use of toric IOLs in patients with keratoconus will be presented.  Patients with toric IOL who require RGP correction of residual refractive error will need  astigmatism correction in the RGP contact lens (a "bitoric" lens) or spectacle correction over their toric IOL/RGP combo.   This is a disappointing outcome for patient who  has opted for  a toric IOL.

      In patients who are likely to require  RGP correction of astigmatism post-op, one must consider that a corneal or scleral  RGP lens will neutralize corneal power.  In advanced keratoconus, best results will be obtained when the preop spherical equivalent, AND NOT EMMETROPIA,  is selected  as the desired post-op refractive error.  The  habitual contact lens, or one that is only slightly modified,  will work post-operatively. Coming up with a satisfactory corneal  RGP or scleral contact lens fit can be problematic when high plus power is required for an IOL selected for emmetropia in a patient with a steep cornea.  High plus contributes to mechanical instability and/or hypoxic compression over a cone.

      Remember, patients who are contact lens dependent do best with residual myopia post-op.  When in doubt always put more power in the IOL!


Update on IOL Calculations
Roberto Pineda II

Over the last decade, IOL power calculations have become a focal point of cataract surgery. In 1977, the state-of-the-art for estimating IOL power for emmetropia was to simply add +19.0 D to the pre-cataractous refraction. A decade later, being within ±1.00 D of the target refraction was still considered a reasonable standard. The standard for accuracy for normal eyes was more recently addressed in the United Kingdom in the 2006 study: "Benchmark standards for refractive outcomes after NHS cataract surgery." The authors concluded that the "benchmark" standard for refractive outcomes for normal eyes after cataract surgery should be within ±0.50 D for 55% of cases and within ±1.00 D for 85% of cases.1 Today, by carefully optimizing individual component parts of IOL power calculations, combined with advanced surgical techniques it is possible to be within ±0.50 D for better than 70 percent of surgeries and ±1.00 D for better than 90% of surgeries.2 As surgeons have moved to minimally invasive cataract surgery, using premium IOLs and femtosecond lasers, achieving specific postop refraction is as important as cataract surgery itself. Currently, thirty percent of  pts will need glasses or more surgery to address residual refractive error. Cataract surgeons need to maximize accuracy and minimize postoperative refractive misses in order to improve patients’ satisfaction and decrease money spent on additional surgical procedures to refine the postoperative refraction. This talk will review the current trends in IOL calculations  and technology to enhance refractive outcomes after cataract surgery.

Peri-operative management of cataracts with uveitis
Rebecca Hunter

Cataract development is a common complication of patients with uveitis. This can be a result of the primary inflammatory disease itself or as sequelae of treatment with corticosteroids, which remains the most commonly used treatment modality for inflammatory eye disease. Regardless of cause, it remains to be a major cause of vision loss in these patients and occurs in up to 70% of all patients with uveitis.  Cataract surgery in the setting of uveitis adds additional perioperative challenges and risks that are not regularly encountered in patients with age related senile cataracts. Studies have shown that these challenges can be improved with preoperative control of inflammation. Strict preoperative control of inflammation is of significant importance in uveitic eyes undergoing intraocular surgery. However, despite excellent inflammatory control, specific intraoperative challenges are still encountered based on prior inflammatory episodes including anterior and posterior synechiae, inadequate pupil dilation and zonular instability. Even in the event of uncomplicated cataract surgery, there is a considerable increase in postoperative complication rates in these patients given higher risk of recurrent inflammation and cystoid macular edema. Due to these challenges, studies have shown that outcomes of cataract surgery in uveitic eyes suggest poorer visual outcomes.  However with recent studies, various management and treatment strategies have been shown to improve success rates of cataract surgery in patients with uveitis. In this discussion I will review the studies and recommendations for perioperative management that have improved long term outcomes of cataract surgery in this unique patient population. 

Pearls and Pitfalls of premium IOL cataract surgery.
Rosa Braga-Mele

This talk will review the following:

  • preoperative tests and assessments for the premium IOL cataract surgery
  • looking for corneal surface disease, best practices for treatment and when to proceed with premium surgery
  • looking for retinal disease
  • which IOL to match with patients
  • counselling and chair time
  • phaco/femto surgery tips to optimize outcomes

Best Cataract Surgery Outcomes in Patients with Retinal Disease
David Jeng

Pre-existing retinal disease may affect the visual outcomes for patients undergoing cataract surgery.  A detailed retinal exam is essential to rule out undiagnosed retinal disease prior to surgery.  Once these retinal conditions have been identified, patients should be made aware of the potential effect on visual prognosis.  Proper pre- and post-operative management may prevent visual complications of common retinal diseases, such as diabetic retinopathy, retinal vein occlusions, age-related macular degeneration, and macular puckers.  Lastly, specific intra-operative techniques may be helpful in the management of these retinal conditions in the future.