Pediatric physicians discuss risks, benefits of emerging technology

Embracing new technologies, already popularized among adult patients, is not a straightforward choice for pediatric ophthalmologists. Although there are many potential benefits to consider, there are also safety and ethical concerns raised by increased and sometimes unpredictable risks, as well as lack of evidence from trials specifically designed for children.

“The first basic problem of testing technologies in pediatric patients is that we have at least two age groups: below and above 7 years of age. We have to take into account the different anatomy and the different immunological response,” Sreepathi Doddery, MD, head of pediatric ophthalmology at Dr. Agarwal’s Eye Hospital, Bangalore, India, said.

The emotional and ethical concerns of parents, who may be reluctant to sign a consent on behalf of their children, are an additional problem, particularly when the testing of new drugs and new devices is involved.

Image: Doddery S

“Parents need and are entitled to complete and detailed information and when it comes to potential side effects, most of which are not yet studied specifically in children – they may refuse to sign,” Doddery said.

Additionally, regular follow-up is difficult in developing countries.

“This is a big issue when potential long-term side effects are involved,” he said.

Ophthalmologists are also constrained by safety concerns due to the lack of knowledge of potential adverse effects. Considering the sensitivity of the pediatric eye and the legal issues associated with side effects, not many eye specialists or clinics will be interested in conducting trials, according to Doddery.

“Some side effects may take years to show. In adults, these may not be significant, but in children there may be lifelong consequences,” Geoffrey Lam, MD, an associate professor of pediatric ophthalmology at the Princess Margaret Hospital for Children, Western Australia, said. “The whole body system is still immature, so any new technologies may affect it in an unfavorable, unpredictable way.”

In addition, he said, children may not be able to communicate that they are experiencing problems.

“The famous Hippocrates oath, ‘First, do no harm,’ becomes dominant in the pediatric treatment. It is known that any organ in a state of organogenesis, any immature tissue, is more susceptible to various influences and more aggressively reacts to them,” Nadiya Bobrova, MD, PhD, a pediatric ophthalmologist at the Filatov Institute of Eye Diseases and Tissue Therapy, Odessa, Ukraine, said.

The child, she emphasized, “is not a small adult.” Along with tissue immaturity, the pediatric age is characterized by high permeability barrier properties, inadequate neuronal regulatory mechanisms, low activity of specific and non-specific immunity, easy generalization of infectious processes and specific reactivity state and metabolic processes.

“These factors may explain why the pediatric ophthalmologist is not a leader in new technologies and begins to apply them only after testing has been extensively carried out in adult patients,” Bobrova said.

Off-label use

In the absence of specific studies, clinicians resort to off-label use of technologies.

“Most of what we do, including many of the drugs that we routinely administer in children, is off-label. Pediatric-patented technologies are very few. Theoretically, we should not even treat congenital glaucoma with drops, as none of the available drugs are licensed for children,” Michele Fortunato, MD, of Bambino Gesù Pediatric Hospital in Rome, Italy, said.

Doses are usually presented as milligram per kilogram, but in the absence of specific testing, this is not always a reliable method. Pharmacokinetic responses are substantially different in children as compared with adults and change with growth and maturation.

“Off-label means untested, so dosage, duration [and] even mode of application might not have been established. We are potentially exposing the child to unknown risks, and yet we need to accept these potential risks when the treatment is necessary,” Lam said.

Because off-label usage is unproven in children, risk of litigation is high, even after years have passed, he said.

Furthermore, justifying off-label use becomes very awkward with parents, according to Fortunato.

“They read on patient information leaflets that the meds we prescribed should not be used in children. It requires a great deal of trust in their physician,” he said.

“When we propose novel surgical procedures, [parents] go back home, Google, don’t find anything and are puzzled,” Samer Hamada, MD, consultant at Great Ormond Street Hospital, London, and Queen Victoria Hospital, East Grinstead, UK, said. “When I propose lamellar keratoplasty, they find no data and ask why I don’t do penetrating keratoplasty.”

Problems also come from the fact that most of the technologies now used for adults in an ambulatory setting require general anesthesia in an OR when applied to children.

“We are aware that not only surgery but also the follow-up examinations require general anesthesia. This, plus the need for prolonged use of steroids in the postoperative period, makes us cautious and rather conservative when it comes to trying new procedures,” Fortunato said. “[However], I believe children can benefit as much as adults, and even more, from some of the latest innovations.”

Multifocal IOLs

Doddery uses toric and multifocal IOLs in pediatric patients. In his experience, the best candidates are children aged older than 6 years.

“At this age, primary posterior curvilinear capsulorrhexis and anterior vitrectomy are not required, which leads to better IOL stability and centration,” he said.

Progressive myopic shift is one of the long-term issues associated with the use of premium IOLs, but it is less frequently encountered when the patients are above the age of 6 years.

“In all cases, however, myopic shift is an issue that needs to be discussed with parents. They must be aware that adjustments may be needed in adult age, and of the options we can offer. Bioptics work out well in such cases,” Doddery said.

Fortunato is an advocate of premium IOLs in pediatric eyes. Twenty four years of experience have led him to conclude that they should be considered as first choice.

“They are the only option that preserves accommodation and, therefore, the full visual function of a young eye,” he said.

Fortunato has found that children adapt better and more rapidly than adults to multifocality. The plasticity of the brain and visual function are at their peak for development, allowing for greater and more natural acceptance of multifocal optics.

“Adults have a memory of the previous situation, and neuroadaptation may be slow or even impossible. The typical adult problems, such as double vision, dysphotopsia and blurred vision, are never found in children,” he said.

Diffractive multifocal IOLs with a +4 near add are currently his first choice, leading to an approximate +3.25 add at the spectacle plane.

Fortunato has had the chance to observe some of his multifocal-implanted pediatric patients into adulthood and said that good vision is maintained over time.

“Some of the implants were done in infants and have worked wonderfully all along. Of course, the younger the child, the higher the margin of error; not only the axial length, but also the corneal curvature undergoes progressive changes, and you have to take both parameters into account,” he said. “One rule is that the younger the child, the more the undercorrection needs to be to avoid the risk of significant myopia at ocular maturity. There are formulas, and experience teaches you how to deal with the many variables in individual patients.”

Out of approximately 1,800 children, Fortunato has performed multifocal IOL exchange in fewer than 10 cases.

“Results are rewarding in terms of visual acuity, and IOL power calculation can be tackled successfully,” Doddery said.

Accommodative IOLs, he said, are not suited for pediatric patients.

Femtosecond lasers for cataract

Femtosecond laser-assisted cataract surgery has the potential to make a challenging surgery easier and more predictable in children, according to several surgeons.

“It is promising as far as obtaining a precise anterior and posterior capsulorrhexis. However, we need to test it further in adults. Large case series are needed for Asian eyes, which have specific characteristics,” Doddery said.

The size and centration of both the anterior and posterior capsulotomy are mandatory for good results; however, due to the extreme elasticity of a child’s capsule, manual capsulorrhexis is a difficult step, often leading to capsule tears and unpredictably large diameter, according to Burkhard Dick, MD, PhD, head of the University Eye Clinic in Bochum, Germany.

In 2012, Dick performed the first worldwide cases of pediatric femtosecond laser-assisted cataract surgery using the Catalys system (OptiMedica/Abbot Medical Optics). Sixteen children, of whom the youngest was only 2 weeks old, have since been operated on with success and no complications.

“In all femtosecond laser manuals, pediatric cataract is listed as a contraindication, and legal implications had, therefore, to be considered,” Dick said. “We obtained from a local ethics committee permission to perform the procedure off-label, with a specific protocol and a separate informed consent from the parents.”

Specific insurance plans were also needed for off-label use of the technology.

“We were able to regularly start with our pediatric procedures in March 2012,” Dick said.

Anterior and posterior capsulotomy are the only steps where the femtosecond laser has advantages in pediatric eyes, according to Dick. The soft nucleus only needs aspiration and there seems to be no real benefit in performing the incision with laser rather than manually.

“Capsulotomy comes out just perfect. You have to target the capsulotomy diameter a little bit smaller to obtain the size you want, but this is about the only aspect,” Dick said.

Posterior capsulotomy, perfectly coinciding in size and position with the anterior, can be performed straight through or preferably after puncturing the capsule and injecting an ophthalmic viscosurgical device to push back the anterior hyaloids membrane.

“With the hyaloid membrane far away, the posterior capsule is more or less convex to the surface and is detected as if it was the anterior capsule. You redock and start the laser again,” Dick said.

This procedure allows the surgeon to keep the hyaloid and anterior vitreous intact.

“Aphakic correction with contact lenses is to be preferred before the age of 2 years because of the high rate of axial growth,” Dick said. “An IOL should, however, be implanted before the child begins to go to school. BIL, which requires no vitreous disruption, is a good option and is facilitated by the femtosecond laser.”

Pediatric femtosecond laser-assisted cataract surgery requires special settings. The laser should be placed in the OR next to the microscope to allow for the entire procedure to be performed on the same bed under sterile conditions.

“This technique has great potential to increase safety, predictability and accuracy of congenital cataract. Infants and children are in fact the real winners of the femto technology — those who can benefit more from the procedure,” Dick said.

New options in cross-linking

Keratoconus typically begins in the second decade of life. Corneal collagen cross-linking (CXL) is an option that has proven effective, and its safety in pediatric patients has been investigated in several studies. New developments, such as a transepithelial procedure and an accelerated procedure, have the potential advantages of less invasiveness and shorter treatment time in pediatric patients.

“I routinely offer the option of doing the epithelium-on procedure. It takes away some of the safety concerns of parents. Children like it. There is no pain; you don’t touch the eye, just put a drop, evaluate by optical coherence tomography if there is sufficient riboflavin penetration and sit the child under the lamp. You can turn it into game play,” Hamada said.

The epithelium-off method has demonstrated more effectiveness, with a 3.5% to 15% failure rate in literature compared to the 30% of the transepithelial approach.

“If patients are young, I tell parents that the transepithelial procedure has a higher failure rate and might need to be performed a second time. I talk about pros and cons and leave the choice to them. I also consider individual cases. If the child is cooperative, I suggest they should consider the epi-off procedure,” he said.

Epithelium-on with epithelial puncture is a good compromise in many cases, according to Hamada. Only the affected area is disrupted, healing is fast and failure rate is around 7% in his hands.

“Complication rates are very low, around 1%. We hardly see any permanent haze; 6% to 7% have haze in the first month due to keratocyte activity. Some might have it for 3 months, but it clears eventually. We have not seen any scars or infections. It is pretty safe,” he said.

With very thin corneas, Hamada uses hypo-osmolar riboflavin solution to induce tissue swelling, making sure that the cornea is at least 400 µm before the procedure starts.

With transepithelial CXL, Fortunato recently started using iontophoresis, a noninvasive technique that applies a small amount of electric current to enhance riboflavin penetration into the tissue.

“We have a good range of options, and now that most of the limitations and safety concerns have been dispelled, we can do CXL as it should be done — as early as possible,” he said.

However, since the long-term potential damaging effect of cross-linking on the corneal endothelium and retina are not fully clear, it should be used in children with caution, according to Bobrova.

“Corneal thickness, presence of herpes keratitis, as well as atopic keratitis and vernal catarrh, should be evaluated and all technical options should be used,” she said.

Doddery prefers the epithelium-off procedure under general anesthesia, even if the child appears to be cooperative, and recommended that the procedure not be performed in children younger than 8 years.

“The visual system is still developing and the procedure may interfere with it. Also, the collagen in the corneal tissue has not achieved stability,” he said.

Overall, before the age of 8 years, keratoconus does not normally show much evidence of progression and performing CXL prematurely may not be ideal, he said.

Anti-VEGF therapy

Patient information leaflets and drug reference books clearly report that anti-VEGF drugs are not approved in children. Used off-label, they are proving beneficial in treating pediatric choroidal and corneal neovascularization secondary to a variety of etiologies. However, concerns remain about systemic side effects.

“Long-term ophthalmic results are still unproven. There is still concern on potential long-term complications on the brain, heart and even reproductive organs,” Lam said.

“It’s a good concept but to be delivered cautiously,” Doddery said. “Though it has shown a promising response in zone 3 and zone 2 ROP, if detected early, the longstanding systemic and ocular side effects are yet to be studied. Cardiac side effects are also an incognita. It becomes even more complicated when the child has associated cardiac anomaly.”

VEGF is an important and necessary protein in the human body and is highly required for the development of the brain, kidney and lungs and liver, according to Doddery.

“In addition, we don’t have large series to compare with laser,” he said.

Bobrova has used intravitreal injection of Avastin (bevacizumab, Genentech/Roche) to treat persistent fetal vasculature in an infant.

“A single injection resulted in almost complete reduction of persistent fetal vessels, though visual acuity remained lower than in the other eye,” she said.

Fortunato said that anti-VEGFs find an application in all the secondary forms of angiomatosis, such as Coats’ disease, with or without laser therapy.

Hamada uses bevacizumab to treat new corneal vessels in blepharokeratoconjunctivitis or corneal neovascularization following transplantation. The drug is injected subconjunctivally at the same dose used intravitreally, 1 mm away from the limbus, at the root of the new vessels.

“Blood vessels have to be cauterized first with fine needle diathermy, and bevacizumab works on preventing newly formed blood vessels that are the ones that cause problems,” Hamada said.

After receiving the treatment, children are followed closely and reinjected if there are signs of reactivation.

“A minimum of two injections at 4- to 6-week intervals are usually administered, and then can be repeated as-needed,” Hamada said. “Outcomes depend on the extent of neovascularization and are usually poorer if the new vessels are on a corneal graft.”

Blepharokeratoconjunctivitis is an aggressive disease that may lead to corneal melt or perforation. Anti-VEGF treatment is effective and has lower toxicity than corticosteroids, mitomycin C or cyclosporine.

“We’ll have to wait for long-term results, and we must also optimize the treatment schedule,” Hamada said.

Advantages of OCT

OCT, one of the milestone developments of recent years, also has numerous applications in pediatric ophthalmology. Several OCT systems are now portable and can be used in both the sitting and supine position. Deep sedation is not always necessary, as the high-speed acquisition allows imaging in young children with a low attention span or intermittent fixation.

“For a long time, the use of OCT in children was thought to be a luxury and unnecessary. However, its use in children has now been firmly established. It is extremely useful as a diagnostic tool for looking at the retina, optic nerve and even anterior segment,” Lam said. “Some of the new OCT machines are very fast and, in some cooperative children, even in cases as young as 3 or 4 years old, good images can be obtained.”

“We have it in the OR. You don’t know how useful it is until you get it,” Fortunato said. “You can do a detailed ocular fundus examination, and if you do anterior segment surgery or glaucoma surgery, you can examine the anterior chamber in detail so that you know exactly where to enter and how to perform your maneuvers without damaging the iris or crystalline lens. In infants, you may have unpredictable situations, like a chamber that is not yet completely formed, and OCT makes everything visible.”

“The anterior segment OCT is equally important,” Bobrova said. “It greatly helps in the diagnosis and follow-up of complex congenital anterior segment defects with corneal leucomas and helps in determining the surgical treatment.” – by Michela Cimberle

References:

Arora R, et al. J Refract Surg. 2012;doi:10.3928/1081597X-20121011-02.

Azad R, et al. Indian J Ophthalmol. 2011;doi:10.4103/0301-4738.86305.

Caporossi A, et al. Cornea. 2012;31(3):227-231.

Cauduro RS, et al. J Ophthalmol. 2012;doi:10.1155/2012/313120.

Darlow BA, et al. Br J Ophthalmol. 2009;doi:10.1136/bjo.2008.156208.

Dick HB, et al. J Cataract Refract Surg. 2013;doi:10.1016/j.jcrs.2013.02.032.

Filippi L, et al. BMC Pediatr. 2010;doi:10.1186/1471-2431-10-83.

Hamada S, et al. Ophthalmology. 2006;doi:10.1016/j.ophtha.2006.03.057.

Hård AL, et al. Acta Paediatr. 2011;doi:10.1111/j.1651-2227.2011.02330.x.

Jacobi PC, et al. Ophthalmology. 2001;doi:10.1016/S0161-6420(01)00595-4.

Magli A, et al. Cornea. 2013;doi:10.1097/ICO.0b013e31826cf32d.

Mititelu M, et al. J Pediatr Ophthalmol Strabismus. 2012;doi:10.3928/01913913-20120821-03.

Prescott CR, et al. Semin Ophthalmol. 2012;doi:10.3109/08820538.2012.708805.

Vasavada AR, et al. J Cataract Refract Surg. 2011;doi:10.1016/j.jcrs.2010.10.036.

Wilson ME, et al. Trans Am Ophthalmol Soc. 2009;107:120-124.

For more information:

Nadiya Bobrova, MD, PhD, can be reached at the Filatov Institute of Eye Diseases and Tissue Therapy, Frantsuzkyi Boulevard 49/51 Odesa, Ukraine 65061; email: filatovbobrova@mail.ru.

H. Burkhard Dick, MD, can be reached at Center for Vision Science, Ruhr University Eye Hospital, In der Schornau 23 – 25, DE-44892 Bochum, Germany; phone: +49-234-2993101; fax: +49-234-2993109; email: burkhard.dick@kk-bochum.de.

Sreepathi Doddery, MD, can be reached at Dr. Agarwal’s Eye Hospital, Bannerghatta Road, Bangalore, 560076 Karnataka, India; email: sreeps77@yahoo.com.

Michele Fortunato, MD, can be reached at Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio, 4-00165 Roma, Italy; +39-06-39742614; email: micfortunato@hotmail.com.

Samer Hamada, MD, can be reached at Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK; email: corneacare1@gmail.com.

Geoffrey Lam, MD, can be reached at 8 / 20 Churchill Avenue, Subiaco, WA 6008, Australia; +61-8-9380-9977; email: geofflam@wasquint.com.au.

Disclosures: Dick is a member of the medical advisory board of OptiMedica. The other doctors have no relevant financial disclosures.

 

 

Should anti-VEGF therapy be considered as an alternative to laser in the management of ROP?

Never change a winning horse, but ...

The success rate for laser therapy of retinopathy of prematurity is approximately 90%, and 90% success is terrific for a sight-threatening disease afflicting small babies who have their whole lives before them.

Why use Avastin (bevacizumab, Genentech/Roche) then? There are many concerns regarding the possible ocular and systemic side effects of this medication employed for a newborn.

However, laser therapy requires experience and practice. Excellent treatment results are true for specialized centers but not so true for non-specialized centers. This is confirmed by the national ROP survey from Sweden, which shows a retreatment rate of 30% with laser. In addition, we are now dealing with extremely premature newborns, from 22 to 24 gestational weeks.

At our university hospital, we treated all ROP newborns with laser and had almost no complications. We were convinced that this was the perfect therapy. This changed when we treated very prematurely neonates with zone I ROP. For the first time, we had recurrences. One child had initially zone I, stage 3, was completely laser treated and then progressed to stage 3+; no comorbidities. The only therapeutic option was intravitreal bevacizumab. We spoke with the parents and the neonatologists, performed the injection and in both, ROP regressed completely. Laser was no longer the winning horse.

Since then, we treat newborns with zone I ROP with intravitreal bevacizumab and we are happy that the BEAT-ROP study supports our treatment regimen. The BEAT-ROP study demonstrated that the complication rate is much higher after laser than after intravitreal bevacizumab. In addition, extensive visual field defects are avoided.

To make a long story short: Anti-VEGF should be considered as a first-line therapy in zone I ROP and as a second-line therapy for zone II ROP.

 

References:

Early for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 2003;doi: 10.1001/archopht.121.12.1684.

Austeng D, et al. Br J Ophthalmol. 2010;doi:10.1136/bjo.2009.170704.

Mintz-Hittner HA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1007374.

Ulrich Spandau, MD, is the head of Ocular Surgery, University Hospital of Uppsala, Sweden. Disclosure: Spandau has no relevant financial disclosures.

A cautious attitude is recommended

Anti-VEGFs have been extensively used to antagonize VEGF in various retinal diseases, and it is no wonder that they have found their way into ROP, as well; however, it has not yet been established whether they should have a definite role. We are at a crossroads and should still be cautious about their usage.

First of all, ROP follows an unpredictable course and has an unpredictable response to treatment. It is something like a Grand Master playing chess with a very few clues to the opponents.

Various studies have proven that the disease responds to laser effectively, with good anatomical and functional outcomes. Laser, as a therapeutic modality, is safe and noninvasive. It can be delivered without intubating the infant and is universally accepted as a standard treatment option. However, we have cases, mostly advanced/severe cases of ROP, which do not respond to laser. In such cases, the use of anti-VEGFs could be reconsidered.

Recently there has been a lot of discussion on anti-VEGFs as first-line therapy, particularly after the article published in 2011 by Mintz-Hittner et al. However, the study clearly showed a significant treatment effect only in advanced, zone I ROP. Anti-VEGF indication cannot be universalized.

Another potential drawback of anti-VEGF therapy is that it takes a long time to vascularize the retina. Therefore, a longer follow-up is needed for these infants as compared to laser therapy. Recurrences have been seen, and this is a concern for both parents and ophthalmologists.

Issues related to intravitreal injection in infants are another deterrent to the universal use of these agents. Over and above all, systemic absorption and side effects remain open questions. Other issues relate to study protocol, design and the severe adverse events.

In light of the above and also of our experience, we do acknowledge the advances in science and believe that anti-VEGFs do have a role in ROP, and more so in advanced stages. However, we need further studies before we can have a plausible answer on their indications.

 

Reference:

Mintz-Hittner HA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1007374.

Rajvardhan Azad, MD, is the head of R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India. Disclosure: Azad has no relevant financial disclosures.