HPI
A 16-year-old non-verbal male with a history of retinopathy of prematurity (ROP) (born at 24 weeks, 1 lb 1 oz) presented to the clinic with a 2-week history of a red left eye as reported by his mother. The patient indicated irritation by rolling his eyes around. His mother reported that he often squints and winces when exposed to light. No other ocular concerns reported.

Past Ocular History
Retinopathy of prematurity (stage 4A), bilateral optic atrophy, exotropia.

Ocular Medications
None

Past Medical History
Prematurity 24 weeks (1 lb 1 oz)
Cerebral Palsy
Microcephaly
Global developmental delays
Cystic encephalomalacia
Periventricular leukomalacia
Ventriculomegaly
Wheelchair bound
H/o grade 4 intraventricular hemorrhage
H/o necrotizing enterocolitis with intestinal resection
Seizure disorder
Presence of intrathecal baclofen pump
History of tracheostomy
Mild chronic lung disease of prematurity
Obstructive sleep apnea
Laryngomalacia
G-tube placement
GERD, S/P laparoscopic Nissen fundoplication
Chronic hepatitis
Neuromuscular scoliosis
Chronic pain disorder

Surgical History
S/P Panretinal Photocoagulation (PRP) both eyes (OU)

Past Family Ocular History
Non-contributory

Social History
Lives at home with parents and siblings
Attends school (10th grade)

Medications
Fluticasone
Ipratropium-albuterol
Linaclotide
Magnesium oxide
Melatonin
Montelukast
Ondansetron
Phenobarbital
Phytonadione
Rifaximin
Trazodone
Triamcinolone cream
Ursodiol
Acetaminophen
Albuterol
Baclofen
Bisacodyl
Calcium citrate
Zyrtec
Cholecalciferol
Clonidine
Diazepam
Esomeprazole
Famotidine

Allergies
No known drug allergies

ROS
Per HPI, otherwise negative

Ocular Exam

Visual Acuity (cc)
OD: Inconsistent blinks to light using an indirect ophthalmoscope at the brightest setting
OS: Inconsistent blinks to light using an indirect ophthalmoscope at the brightest setting

IOP (iCare tonometry)
OD: 15, 9 mmHg
OS: 51, 53, 41, 54 mmHg

Pupils
OD: 4.5 mm in dark; 3.5 mm in light; round, sluggish, no afferent pupillary defect (APD)
OS: 5.5 mm in dark; 5 mm in light; round, minimal reaction, no obvious APD

Extraocular Movements
OU: Roving eye movements with nystagmus. Ductions grossly full to volitional movements.

Confrontational Visual Fields (Toys)
Unable to test (UTT) due to delay

Slit Lamp:

	OD	OS
External	Normal	Normal
Lids and Lashes	Normal	Normal
Conjunctiva/Sclera	White and quiet	Bulbar conjunctival injection
Cornea	Clear	Mild haze
Anterior Chamber	Deep and quiet	Deep
Iris	Round and sluggish	Round and minimally reactive
Lens	Clear	Clear
Anterior Vitreous	Normal	Normal

Dilated Fundus Examination:

	OD	OS
Disc	Pallor/atrophy	Pallor/atrophy
Macula	Normal	Normal
Vessels	Prominent vascular attenuation, notable temporally	Prominent vascular attenuation, notable temporally
Periphery	PRP scars nasally and temporally	Brief view of PRP temporally

Imaging/additional tests:
RETCAM Fundus Photography – image of right eye followed by left eye
 

RETCAM fundus photos of the left eye reveal mild haze of the vitreous, complete pallor of the optic nerve, mottled macula, attenuated vessels, and 360 laser with temporal peripheral vitreoretinal traction with retinal elevation, but no retinal detachment.

RETCAM

 

RETCAM photos of the anterior segment shows normal appearing anterior segment of the right eye and perilimbal injection of the left eye.

Ultrasound (B-scan)
The B-scan ultrasound of the left eye showed temporal retinal elevation.

Ultrasound biomicroscopy (UBM)

Ultrasound biomicroscopy of the left eye reveals open angle with no obvious narrowing or closure.

Fluorescein angiography (FA) – all images of left eye
 
Fluorescein angiography of right eye shows no neovascularization of the retina or iris. Left eye showed iris neovascularization in the temporal pupillary border and showed temporal retinal neovascularization.

Diagnosis and discussion

Diagnosis
Neovascular glaucoma (NVG) of the left eye due to sequelae of ROP

Differential diagnoses
Differential diagnoses for this presentation include, but are not limited to, uveitis, acute angle-closure glaucoma, chronic angle-closure glaucoma, and retinal detachment.¹

Uveitis
While uveitis may have iris vessels present, it also exhibits other features, such as cell and flare in the anterior chamber and keratic precipitates on the cornea, which are not seen in this case.

Acute angle closure glaucoma/Chronic angle closure glaucoma
Both these diagnoses and NVG can result in a blockage of the anterior angle and thus impede the drainage aqueous fluid; however, acute angle closure glaucoma typically lacks neovascularization or retinal pathology and would have a narrow/closed angle on exam or UBM.

Retinal detachment
Chronic retinal detachment can lead to inflammation and elevated intraocular pressure by several different mechanisms but is less likely in this case given no actual detachment seen on fundus exam or fundus photography.

Definition
ROP is an eye disease that occurs in premature babies born at 30 weeks or earlier and/or weighing less than 1500 grams. Blood vessels in the retina start to develop around the optic nerve at 16 weeks of gestation. By 8 months, the blood vessels have developed around the nasal aspect of the retina. By 9-10 months, the blood vessels have also developed in the temporal aspect, completing their growth.⁶ In patients with ROP, the retinal blood vessels have not had sufficient time to develop normally, resulting in regions of retinal ischemia.⁶ The hypoxia experienced by these ischemic regions triggers the production of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which in turn stimulates the formation of new blood vessels within the eye to compensate for the hypoxic condition.^6-9 These pro-angiogenic factors can eventually outbalance anti-angiogenic factors and migrate from the posterior chamber to the anterior region of the eye causing abnormal, weak, and leaky blood vessel growth in various regions of the eye including the retina, iris (NVI), and anterior chamber angle of the eye, which can lead to neovascular glaucoma.^6-9

Neovascular glaucoma (NVG) is a secondary glaucoma caused by conditions that lead to ocular ischemia, and can result in severe damage to the optic nerve and irreversible vision loss.² The three most common conditions that can cause neovascular glaucoma include diabetic retinopathy, central retinal vein occlusion, and ocular ischemic syndrome.^{2-5, 9} Although these are the three most common conditions, this patient case highlights a rare but important condition that can lead to NVG: ROP. The progression of neovascular glaucoma from these underlying conditions occurs in a spectrum of stages, each reflecting increasing disease severity. The first stage of neovascular glaucoma, also known as rubeosis iridis, occurs when neovascularization of the iris (NVI) is present, with or without neovascularization of the angle (NVA), and eye pressure remains normal.¹³ The second stage of neovascular glaucoma occurs when NVI and NVA are present, IOP is high, but the angle of the eye remains open.¹³ Eventually, with enough abnormal vascularization within the anterior chamber, a fibrovascular meshwork develops. This meshwork may contract and pull the iris forward, thereby entirely blocking the anterior chamber angle. This is known as the third and final stage of neovascular glaucoma, also referred to as secondary angle-closure glaucoma.¹³ During this stage, eye pressure can become significantly elevated (50 mmHg or higher), which is an ocular emergency.²

Examination
Neovascular glaucoma is a clinical diagnosis made by examining the patient with a slit lamp and gonioscopy, as well as utilizing ancillary imaging techniques, which may include fluorescein angiography, ultrasound (A-scan, B-scan, and UBM), OCT, and fundus photography.^3-5,7,13 Patients may be asymptomatic during the early stages of NVG; however, during later stages, they may present with various symptoms, including a red eye, tearing, ocular pain, decreased vision, light sensitivity, seeing halos around lights, and/or nausea and vomiting.²

Diagnostics
For providers, the core diagnostic criteria to assess on exam are neovascularization of the iris, angle, and/or elsewhere, elevated IOP (40 mmHg or higher), and evidence of ischemic retinal disease via fundus exam and/or fluorescein angiography. Neovascularization of the iris in the pupillary margin is often the first sign of NVG.^2-5,13 Other signs that may be present include corneal edema, conjunctival injection, peripheral anterior synechiae, hyphema, and a mid-dilated pupil with poor reaction to light.² There are key features to look for when conducting ancillary tests.¹³ Features based on type of test conducted are listed below:

• Fluorescein angiography: abnormal neovascularization in the iris and/or retina
• Ultrasound (B-scan): may reveal whether a retinal traction or detachment is present
• Ultrasound biomicroscopy (UBM): may reveal the presence or absence of anterior angle narrowing and/or closure

In addition to the slit lamp exam and imaging, it’s also important to obtain a detailed patient history to assess whether patients have any risk factors for developing NVG.¹⁰

Treatment
The treatment of NVG varies based on the stage of disease; however, prevention is key, and therefore, it is important to screen high-risk patients, such as those who have diabetic retinopathy or vascular disorders, which may lead to a central retinal vein occlusion, and/or ocular ischemic syndrome.¹¹ If these conditions are present, it’s essential to treat any underlying systemic disease to prevent the development of NVG.^9,11 Once NVG is diagnosed, the two primary goals for treatment are first, controlling IOP, and second, controlling ischemia-driven neovascularization.^11,13

Options to lower IOP:
There are various classes of IOP-lowering agents that can be used to target different structures within the eye. The most important classes of medications for the treatment of NVG involve decreasing the production of aqueous humor by the ciliary body. These drug classes are beta-blockers (ie. Timolol), alpha-agonists (ie. Brimonidine), and carbonic anhydrase inhibitors (ie. Dorzolamide). Systemic medications such as oral or IV acetazolamide (ie. Diamox) and/or oral mannitol can also be used to lower IOP if needed.²

Options to control ischemia-driven neovascularization:
The source that drives abnormal neovascularization of the eye is ischemic retinal tissue. Panretinal cyclophotocoagulation (PRP) is a laser procedure commonly used to ablate ischemic retinal tissue, thereby reducing the production of pro-angiogenic factors such as VEGF.^5,11,13 PRP is frequently performed in premature babies with moderate to severe stages of retinopathy of prematurity. Additionally, intravitreal anti-VEGF injections are used. These agents have been shown to improve retinal conditions associated with ischemia.^5,11,13

Options to treat refractory NVG:
For patients with refractory NVG, various options exist. One option to consider for patients with poor or no vision is Diode Laser Photocoagulation (DLPC). The DLPC is an effective laser treatment for refractory NVG that utilizes red to near-infrared lasers to deliver energy to the ciliary body. This process causes the ciliary body to shrink, resulting in a reduction of fluid production and a decrease in eye pressure.^5,11,13 Following the laser, the eye is usually treated with a topical antibiotic, steroid, and cycloplegic. Alternatively, surgical options such as a tube shunt implantation or trabeculectomy may be considered.^4,5,11,13

1. What are the three most common conditions that result in neovascular glaucoma?
a. Diabetes, hypertension, and hyperlipidemia
b. Diabetes, age-related macular degeneration, and ocular ischemic syndrome
c. Diabetes, ocular ischemic syndrome, and central retinal vein occlusion
d. Diabetes, ocular ischemic syndrome, and central retinal artery occlusion

2. Name the condition that can result in neovascular glaucoma amongst premature babies.
a. Retinopathy of prematurity
b. Low birth weight
c. Potter’s syndrome
d. Pre-eclampsia

3. What are the three classes of drugs that can be used to decrease aqueous production in patients with neovascular glaucoma?
a. Alpha agonists, beta agonists, carbonic-anhydrase inhibitors
b. Alpha antagonists, beta agonists, carbonic-anhydrase activators
c. Alpha agonists, beta blockers, carbonic anhydrase inhibitors
d. Alpha antagonists, beta antagonists, carbonic-anhydrase inhibitors

1. What are the three most common conditions that result in neovascular glaucoma?
c. Diabetes, ocular ischemic syndrome, and central retinal vein occlusion

2. Name the condition that can result in neovascular glaucoma amongst premature babies.
a. Retinopathy of prematurity

3. What are the three classes of drugs that can be used to decrease aqueous production in patients with neovascular glaucoma?
c. Alpha agonists, beta blockers, carbonic anhydrase inhibitors

 

References
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Havens, S. J., & Gulati, V. (2016). Neovascular Glaucoma. Developments in ophthalmology, 55, 196–204.https://doi.org/10.1159/000431196

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Smith L. E. (2003). Pathogenesis of retinopathy of prematurity. Seminars in neonatology : SN, 8(6), 469–473.https://doi.org/10.1016/S1084-2756(03)00119-

Tang, Y., Shi, Y., & Fan, Z. (2023). The mechanism and therapeutic strategies for neovascular glaucoma secondary to diabetic retinopathy. Frontiers in endocrinology, 14, 1102361. https://doi.org/10.3389/fendo.2023.1102361

Mott, M. (2023). When babies with ROP grow up. American Academy of Ophthalmology Eyenet Magazine. https://www.aao.org/eyenet/article/when-babies-with-rop-grow-up

Olmos, L. C., & Lee, R. K. (2011). Medical and surgical treatment of neovascular glaucoma. International ophthalmology clinics, 51(3), 27–36. https://doi.org/10.1097/IIO.0b013e31821e5960

Pérez-Gutiérrez, L., & Ferrara, N. (2023). Biology and therapeutic targeting of vascular endothelial growth factor A. Nature reviews. Molecular cell biology, 24(11), 816–834. https://doi.org/10.1038/s41580-023-00631-w

Olmos, L. C., Sayed, M. S., Moraczewski, A. L., Gedde, S. J., Rosenfeld, P. J., Shi, W., Feuer, W. J., & Lee, R. K. (2016). Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab. Eye (London, England), 30(3),463–472. https://doi.org/10.1038/eye.2015.259

Senthil, S., Dada, T., Das, T., Kaushik, S., Puthuran, G. V., Philip, R., Rani, P. K., Rao, H., Singla, S., & Vijaya, L. (2021). Neovascular glaucoma - A review. Indian journal of ophthalmology, 69(3), 525–534. https://doi.org/10.4103/ijo.IJO_1591_20