The use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of posterior segment pathologies is increasing. One feared complication of intravitreal injection is an iatrogenic injury to the crystalline lens, which has been reported in adults.1,2 It may sometimes be detected during the procedure or mostly during cataract surgery later in the form of quiescent posterior capsular defects.1–3 Implications of such injuries to the cataract surgeon are well reported for the adult population.3,4
The use of anti-VEGF agents is being increasingly adopted as a treatment option for retinopathy of prematurity (ROP) in addition to conventional laser and vitrectomy. Although anti-VEGF agents are not approved by the U.S. Food and Drug Administration for treatment-requiring ROP, their off-label use is rapidly gaining popularity for the treatment of small zone I treatment-requiring ROP with good results.5
Pediatric patients with regressed ROP may present with visually significant cataract later in life.6 Anterior segment ischemia after extensive laser treatment is presumed to predispose to cataract formation.7 Iatrogenic needle injury to the lens during intravitreal anti-VEGF injection is rarely reported in pediatric patients.6 We describe three cases of ROP with cataract occurring due to inadvertent posterior capsular dehiscence following intravitreal anti-VEGF injection.
Patients and Methods
A retrospective record review of patients presenting to the ROP clinic of a tertiary eye care center over a period of 1 year (June 2017 to May 2018) with crystalline lens injury following intravitreal anti-VEGF injection was performed. The study adhered to the tenets of the Declaration of Helsinki. A formal institute ethics committee approval was obtained (IEC-527/05.10.18).
The demography, disease classification, and treatment details of the cases were reviewed. The indication for, setting, and method of intravitreal injection were noted. The preoperative ultrasound biomicroscopy (UBM) (35-MHz VuMAX; Sonomed Escalon, New York, NY) details of the lens posterior capsule and intraoperative still photographs were studied for the morphology of cataract and the characteristics of posterior capsular defect wherever available. The follow-up outcomes noted were the stability of the intraocular lens (IOL), clarity of visual axis, and Cardiff visual acuity wherever available. Fundus images (RetCam 3 wide-field imaging; Clarity Medical Systems, Inc., Pleasanton, CA) were reviewed for the regression of the disease.
A total of three cases of ROP with crystalline lens injury following anti-VEGF injection were referred to our center during the study period. The individual case details are as follows.
A 2-year-old boy was referred to our tertiary care center for the management of bilateral lamellar cataract. The child was born of a cesarean section at 28 weeks' gestation with a birth weight of 1,000 grams. Intravitreal injection of ranibizumab was given elsewhere in both eyes under topical anesthesia in the neonatal intensive care unit (NICU) at 36 weeks' post-menstrual age for zone I stage 3 ROP with plus disease. ROP regressed and lamellar cataract was noted in both eyes on follow-up at 3 months. However, the referral records did not mention the serial follow-up condition.
On examination, the Cardiff visual acuity done at a 50 cm distance was 20/200 Snellen equivalent in both eyes. On torch light examination, there was subtle right convergent squint with horizontal jerky nystagmus in both eyes. Direct and consensual pupillary reaction was brisk in both eyes. Lamellar cataract was noted in both eyes that obscured the fundal glow on distant direct ophthalmoscopy. B-scan ultrasonography of the posterior segment was unremarkable in both eyes.
Sequential cataract surgery (right eye followed by left eye) was planned under general anesthesia in view of the visually significant cataract. A dilated fundus examination revealed regressed ROP in both eyes with peripheral laser scars in the left eye. On A-scan ultrasonography, the axial length was 21.89 mm in the right eye and 22.10 mm in the left eye. Automated keratometry readings of the right eye were 44.12 45.62 × 112/52.
The intraoperative still image of the right eye shows a lamellar cataract (Figure 1A). After performing anterior capsulorrhexis and hydrodissection in the right eye, bimanual lens aspiration was done. On near completion of the aspiration, a preexisting posterior capsular defect was noted from 7 to 10 clock hours, extending closer to the lens equator. The defect had a well-defined thick and partially folded fibrotic edge (Figure 1B). Vitreous prolapse was noted through the defect. Limited anterior vitrectomy was done, and a multi-piece 22-diopter IOL (considering the modified SRK2 IOL formula and 10% undercorrection according to age) was placed in the sulcus because in-the-bag placement was precluded by the peripheral nature of the capsular defect. Routine postoperative treatment comprising topical steroid, antibiotic, and cycloplegic was prescribed.
Intraoperative photograph of the right eye (surgeon's view) of case 1. (A) A lamellar or zonular cataract can be noted with no obvious visible posterior capsular abnormality. (B) Following bimanual aspiration, an eccentric irregular posterior capsular defect (yellow arrow) is seen with a thick fibrosed edge with partial folding of the margin.
Owing to a lower respiratory tract infection, the child could not undergo left eye surgery under general anesthesia for 1 month. The left eye did not have a posterior capsular defect, and a foldable IOL was placed in the bag after lens aspiration and posterior capsulorrhexis. At the last follow-up visit at 3 months postoperatively, the anterior chamber was quiet with a stable IOL in both eyes. Cardiff visual acuity done at a 50 cm distance was 20/60 Snellen equivalent with refractive correction in both eyes.
A 9-month-old female infant presented with a complaint of inward deviation of the right eye for the past 3 months. She was born preterm at 30 weeks' gestation with a birth weight of 1,040 grams. Bilateral intravitreal bevacizumab injection was given at 37 weeks' gestation under topical anesthesia in the NICU for bilateral zone II stage 3 ROP.
The patient had left eye esotropia with a dense posterior subcapsular cataract in the visual axis. The anterior segment of the right eye seemed unremarkable. Examination under anesthesia was performed before cataract surgery in the left eye. The axial length (A-scan ultrasonography) was 19.54 mm in the right eye and 19.99 mm in the left eye. Automated keratometry readings were 43.50 45.25 × 175/85 in the right eye and 38.62 42.00 × 175/85 in the left eye. The intraoperative still image of the left eye shows a dense central cataract (Figure 2A). UBM was suggestive of a central posterior capsular defect with herniation of the lens matter into the anterior vitreous (Figure 2B). Fundus examination revealed regressed ROP with complete retinal vascularization in both eyes, although the media was not clear due to cataract in the left eye.
Imaging of case 2. (A) Intraoperative photograph of the left eye (surgeon's view) shows a dense central cataract with a fine lamellar component. (B) Ultrasound biomicroscopy shows a central posterior capsular defect (white arrow) with herniation of lens matter into the anterior vitreous. (C) Following bimanual aspiration, a central oval posterior capsular defect (yellow arrow) can be seen. (D) RetCam (Clarity Medical Systems, Inc., Pleasanton, CA) image at final follow-up shows a clear visual axis, normal posterior pole, and bright reflex from the edge of the intraocular lens.
Left eye bimanual lens aspiration was performed. A central large oval posterior capsular defect was noted with fibrosis of the margins (Figure 2C). A central circular posterior capsulorrhexis was performed incorporating the capsular defect with the help of Utrata forceps. Limited anterior vitrectomy was done, and a multi-piece IOL (22.5 diopters after 20% undercorrection) was put in the capsular bag. The patient received refractive correction on follow-up. At the last follow-up visit at 6 months postoperatively, the IOL was stable and the visual axis remained clear (Figure 2D).
This male infant was the twin of case 2. The birth weight was 980 grams. Bilateral intravitreal bevacizumab injection was given at 37 weeks' gestation under topical anesthesia in the NICU for both eyes with zone II, stage 3 ROP.
The patient had left eye pseudo-esotropia and right eye posterior subcapsular cataract in the visual axis. The axial length (A-scan ultrasonography) was 20.37 mm in the right eye and 20.33 mm in the left eye. Automated keratometry readings were 42.25 46.50 × 15/105 in the right eye and 44.75 46.75 × 17/107 in the left eye. Fundus examination revealed regressed ROP with complete retinal vascularization in both eyes. The intraoperative still image of the right eye shows a dense central cataract (Figure 3A). UBM was suggestive of an eccentric posterior capsular defect with herniation of the lens matter into the anterior vitreous (Figure 3B). Right eye surgery was performed as per the details of case 2. A multi-piece IOL (22.5 diopters after 15% undercorrection) was put in the sulcus, owing to the large eccentric posterior capsular defect (Figure 3C). The patient received refractive correction on follow-up. At the last follow-up visit at 6 months, the IOL was stable and the visual axis remained clear (Figure 3D).
Imaging of case 3. (A) Intraoperative photograph of the right eye (surgeon's view) shows a dense central cataract with a fine lamellar component. (B) Ultrasound biomicroscopy shows an eccentric posterior capsular defect (white arrow) with herniation of lens matter into the anterior vitreous. (C) Following bimanual aspiration, an eccentric oval posterior capsular defect (yellow arrow) can be seen. (D) RetCam (Clarity Medical Systems, Inc., Pleasanton, CA) image at final follow-up shows a clear visual axis, normal posterior pole, and bright reflex from the edge of the intraocular lens.
Apart from the injection procedure being performed under topical anesthesia, the referral records of all three patients did not mention the technique of intravitreal injection (quadrant of the injection, distance of injection site from the limbus, and the needle dimensions).
Subclinical or clinical lenticular injuries after intravitreal injection have been reported in up to 0.07% eyes in the adult population.1 Inadvertent posterior capsular damage with the needle can result in cataract formation. Capsular breach may remain quiescent, only to be noticed later during cataract surgery. Previous intravitreal therapy is significantly associated with a higher likelihood of posterior capsular rupture and lens matter dislocation during cataract surgery.2
Cataract development has been reported in association with ROP with and without treatment.6,8 The etiology of cataract development is unclear with a possible role of anterior segment ischemia and inflammation with laser and anti-VEGF treatment. Nguyen and Yen6 reported visually significant cataract requiring surgery to develop 2.9 to 6.2 years after laser or anti-VEGF treatment in patients with ROP.
Recently, intravitreal anti-VEGF treatment for ROP has gained popularity over laser treatment due to the ease of the procedure and superior results in zone I disease while ensuring better visual fields and lesser myopia. The complications during cataract surgery in children who have received an anti-VEGF injection for ROP are scarcely reported.6 In their case series on cataract surgery in patients treated for ROP, Nguyen and Yen reported a single case of isolated posterior capsular injury consistent with needle entry noted during the time of cataract surgery.6
The development of the eye and ciliary body depends on the pars plana width, which needs to be carefully accounted for while planning the entry for the intravitreal injection.9 Given the complex and difficult assessment of pars plana width in neonates and especially preterm infants, extrapolating the guidelines of sclerotomy placement for pediatric pars plana vitrectomy surgery to intravitreal injections in preterm infants is perhaps not safe.
In the absence of a universal protocol for intravitreal injection in the preterm neonatal population, intravitreal injection in these eyes needs to be performed with extreme caution. Iatrogenic retinal breaks and contralateral retinal injury can occur in preterm infants following intravitreal injections due to an underdeveloped pars plana and small antero-posterior globe diameter. The larger size of the crystalline lens in these preterm eyes requires the angle of entry of the needle during intravitreal injection to be parallel to the visual axis to avoid lens injury.6
Administering intravitreal injection in inappropriate clinical settings in an awake infant can be a potential risk for the development of cataract in pre-term infants, further compounding the morbidity of these already compromised eyes. Most intravitreal injections in preterm infants with ROP in both developing and developed countries are given under topical anesthesia in the nursery or NICU without microscope assistance. These infants are at high risk for iatrogenic lenticular injuries.10 Factors presumed to lead to lenticular injury in such infants include a thicker lens as compared to the axial length with proximity of the needle path to the lens, awake unrestrained movements of the infant, unaided injection procedure due to the lack of a microscope facility in the nursery or NICU and an inexperienced surgeon not well versed with anatomy, and injection distance from the limbus and ideal direction (relatively parallel to the visual axis) of the injection.6,10
Because lamellar or zonular cataract is a common morphological type of pediatric cataract that occurs bilaterally and gradually progresses in density,11 the bilateral symmetrical nature of cataract in case 1 did not prompt us to suspect a preexisting posterior capsular dehiscence preoperatively. Also, the defect may have been hidden from the edge of cortical lamellae temporally in a mid-dilated pupil before starting surgery. The first case had bilateral cataract, yet the damage to the posterior capsule was noted in only the right eye. It is possible that the cataract was not a result of the superimposed trauma from the needle injury and was a coincident occurrence in case 1. Regardless of whether the cataract occurs following needle injury or not, surgeons should be extra cautious and keep the possibility of lens injury/capsular defect in mind while performing cataract surgery in children with a history of intravitreal injection.
Careful attention to the technique of intravitreal injection in preterm infants with ROP can avoid the potential for lens damage.10 The injection procedure should be done by an experienced surgeon under a microscope in an operation room setting with a wire speculum in place under sterile aseptic precautions. The infant should be provided adequate analgesia coverage and should be quiet or restrained by an assistant. The pupil should be well dilated if possible with a combination of pediatric tropicamide and phenylephrine. The drug should be administered at a distance of 1 to 1.5 mm from the limbus (measured with a caliper) depending on the age of the infant10,12 in the most exposed quadrant with a 30-gauge needle over a 1-cc syringe, which allows for better control. The eye is better stabilized by a forceps at the limbus in the vicinity of the injection site by the surgeon with the non-dominant hand. The needle should be inserted parallel to the visual axis and the needle tip should be visualized in the vitreous cavity while the plunger is pushed, preferably by an assistant. Safe needle removal is as essential as the injection, with proper stabilization and ocular massage at the end to prevent drug egress.
These patients need to be observed closely for the development of cataract. A thorough preoperative evaluation of the posterior capsule is warranted in patients undergoing cataract surgery with a history of intravitreal injection. Because pediatric patients are not cooperative for preoperative slit-lamp examination and imaging, examination under anesthesia before starting surgery remains a crucial step. A careful fully dilated retro-illumination examination under the microscope is necessary to identify any subtle needle track injury. UBM can be of great advantage because it provides a high magnification view of the posterior capsule and anterior vitreous in the presence of a dense cataract.13 Surgical planning needs attention in certain aspects to reduce the chance of capsular tear extension and loss of lens fragments into the vitreous cavity.3,4 These include avoidance of hydrodissection, bimanual irrigation-aspiration rather than a coaxial system, low vacuum and aspiration parameters, use of a viscodispersive agent to tamponade vitreous in the area of posterior capsular injury, limited anterior vitrectomy, and placement of a secure posterior chamber IOL, preferably in the ciliary sulcus with optic capture.
Due to the increasing use intravitreal anti-VEGF agents for the treatment of ROP, the possibility of lens injury needs to be kept in mind and evaluated in all children undergoing cataract surgery with a history of intravitreal injection, irrespective of the morphological type of cataract.
- Meyer CH, Rodrigues EB, Michels S, et al. Incidence of damage to the crystalline lens during intravitreal injections. J Ocul Pharmacol Ther. 2010;26:491–495. doi:10.1089/jop.2010.0045 [CrossRef]
- Lee AY, Day AC, Egan C, et al. Previous intravitreal therapy is associated with increased risk of posterior capsule rupture during cataract surgery. Ophthalmology. 2016;123:1252–1256. doi:10.1016/j.ophtha.2016.02.014 [CrossRef]
- Erdogan G, Gunay BO, Unlu C, Gunay M, Ergin A. Management of iatrogenic crystalline lens injury occurred during intravitreal injection. Int Ophthalmol. 2016;36:527–530. doi:10.1007/s10792-015-0156-5 [CrossRef]
- Saeed MU, Prasad S. Management of cataract caused by inadvertent capsule penetration during intravitreal injection of ranibizumab. J Cataract Refract Surg. 2009;35:1857–1859. doi:10.1016/j.jcrs.2009.05.050 [CrossRef]
- Mintz-Hittner HA, Kennedy KA, Chuang AZBEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Nguyen H, Yen KG. Outcome of cataract surgery in patients treated for retinopathy of prematurity. Open J Ophthalmol. 2017;07:293. doi:10.4236/ojoph.2017.74038 [CrossRef]
- Chandra P, Khokhar S, Kumar A. Bilateral total cataract after laser treatment of aggressive posterior retinopathy of prematurity. Indian Pediatr. 2016;53(suppl 2):S157–S158.
- Davitt BV, Christiansen SP, Hardy RJ, Tung B, Good WV. Incidence of cataract development by 6 months' corrected age in the Early Treatment for Retinopathy of Prematurity study. J AAPOS. 2013;17:49–53. doi:10.1016/j.jaapos.2012.10.011 [CrossRef]
- Hairston RJ, Maguire AM, Vitale S, Green WR. Morphometric analysis of pars plana development in humans. Retina. 1997;17:135–138. doi:10.1097/00006982-199703000-00009 [CrossRef]
- Wright LM, Vrcek IM, Scribbick FW, Chang EY, Harper CA. Technique for infant intravitreal injection in treatment of retinopathy of prematurity. Retina. 2017;37:2188–2190. doi:10.1097/IAE.0000000000001561 [CrossRef]
- Tartarella MB, Britez-Colombi GF, Milhomem S, Lopes MC, Fortes Filho JB. Pediatric cataracts: clinical aspects, frequency of strabismus and chronological, etiological, and morphological features. Arq Bras Oftalmol. 2014;77:143–147. doi:10.5935/0004-2749.20140037 [CrossRef]
- Lemley CA, Han DP. An age-based method for planning sclerotomy placement during pediatric vitrectomy: a 12-year experience. Trans Am Ophthalmol Soc. 2007;105:86–91.
- Kucukevcilioglu M, Hurmeric V, Ceylan OM. Preoperative detection of posterior capsule tear with ultrasound biomicroscopy in traumatic cataract. J Cataract Refract Surg. 2013;39:289–291. doi:10.1016/j.jcrs.2012.11.017 [CrossRef]