Experts’ opinion – Case 4

In addition to answering the questions posed to our members, our Experts were also asked the following questions :
1) Assuming the decision was made to opt for Anti-VEGF treatment :
a) How many would you give?
b) How safe do you feel it is in young patients (considering more than one may be needed)?
c) How would you titrate the endpoint (subjective vs objective)?
2) Assuming the decision was made to perform surgery; do you feel the results are encouraging?
3) Can leaving the condition untreated (under Poor socio-economic conditions) pose an ethical problem?

Dr. Ankoor Shah

Dr. Yoshihiro Yonekawa

Dr. Ankoor Shah & Dr. Yoshihiro Yonekawa have sent us a joint opinion : In reviewing the history and imaging, this 6-year-old girl has a subfoveal type 2 choroidal neovascular membrane (CNVM) with overlying intraretinal fluid. However, the activity of the CNVM should first be assessed with fluorescein angiography (FA). Intraretinal fluid seen on optical coherence tomography (OCT) may be degenerative cystoid changes, in which case observation may be recommended. The FA will also allow us to better visualize a choroidal rupture that is likely in this setting. If a CNVM is found with active leakage on FA (as opposed to staining), anti-vascular endothelial growth factor (VEGF) agents are the treatment of choice. Anti-VEGF treatment has superior efficacy without the local side effects of steroids (glaucoma and cataract). Intravitreal anti-VEGF treatment is administered either in clinic or during examinations under anesthesia (EUA), depending on the cooperation of the child. The injection in a 6-year-old should be 3.0 to 3.5 mm posterior to the limbus, and povidone iodine 5% solution should always be used with one drop before and after the injection to the location of injection.

We recommend reassessing with repeat clinical evaluation and OCT imaging to determine the treatment response in one month. In our experience, traumatic CNVM due to physical breaks in Bruch’s membrane (such as in myopic CNVM) respond relatively well without requiring too many injections. This is in contrast to a “hot” eye that is primarily VEGF driven, such as in retinal vein occlusions and diabetic macular edema. “Treat-and-extend” anti-VEGF therapy is currently the most popular injection paradigm in the United States for treating macular diseases in adults, where injections are provided every visit, but the intervals are gradually extended as long as disease activity is quiescent. However, in this patient, we would employ a “PRN” paradigm (injections as needed) because we anticipate a relatively favourable response. In addition, the majority of 6-year-old patients will also require EUAs, making treat-and-extend logistically challenging with unnecessary exposure to general anaesthesia in comparison to PRN treatments.

In the United States, most practitioners will use bevacizumab, because payors will not allow ranibizumab and aflibercept for this patient’s condition. Research protocols may allow use of ranibizumab, which has been shown to provide the least systemic exposure. However in a 6-year-old, our concern for systemic effects is much less compared to that in a premature infant being treated for retinopathy of prematurity. If the CNVM is refractory to frequent bevacizumab treatment, switching anti-VEGF agents has been shown to be effective in adult maculopathies. Switching to, or incorporating, intravitreal steroid treatment is also a possibility. However, our next step would be half fluence photodynamic therapy (PDT). It works well, usually with sustained effects. Prior to intravitreal agents and PDT, thermal laser was commonly employed. This would not be advisable in this patient because the lesion is subfoveal, and it will create a scotoma that will expand over the many years that the child has ahead of her. Finally, submacular surgery is not out of the question, because this is a type 2 CNVM (between the retinal pigment epithelium [RPE] and retina), as opposed to type 1 CNVM (underneath the RPE). Type 2 CNVMs potentially do very well after surgical removal, but this is a last resort in this day and age of more efficacious and less invasive treatment modalities.

Second, we recommend checking intraocular pressure. We have found that ~50% of children with closed-globe injuries at our institution suffer angle recession. This needs to be monitored over time.

Third, one must address whether there may be some component of amblyopic vision loss. Although this girl is 6-years-old, it is possible. The refraction is not given, but the case presentation does mention that correction of her refractive error did not improve the vision. However, there may be a slight hyperopic shift in the refractive state of the left eye (if we assume that the refraction was likely equal between the two eyes prior to injury) given the elevation of the fovea, and this may lead to amblyopia in addition to the underlying pathology. Thus, prescribing the refractive correction for full-time wear is recommended even if there is no improvement of vision in the office. Further, we recommend initiating patching therapy for two hours a day if possible and continuing this therapy for at least 3-6 months to see if there is any improvement. As the CNVM is treated, we recommend rechecking the refraction to ensure that the refractive state of the eye has not changed over time.

Fourth, polycarbonate spectacles should be worn at all times for this young girl as a protection for the sound right eye. She now lacks fine stereopsis and may suppress the vision in her affected eye making her prone to injuries.

Last, the ethics of this situation are likely variable depending on the socio-economic conditions in the home region of this child. The condition is not life or death, but if there is an untreated, active CNVM further central vision loss may ensue without treatment. As such, it would be best to treat in this case. However, the most important intervention in our opinion is the polycarbonate glasses worn at all times to protect the sound right eye. There is good evidence to show that people with monocular vision loss are at a higher risk of injury to the fellow eye. Vision loss in the fellow, uninjured eye may lead to permanent vision impairment, and there is evidence that people with vision impairment, especially in lower socioeconomic social situations, are significantly impaired and are a significant socioeconomic burden to the family/community structure.

 

Dr. Shuan Dai

Dr. Shuan Dai feels that this 6 year old child with left traumatic maculopathy has Epiretinal membrane with vitreous macular drag, Macular scarring, Cystoid macular edema & Choroidal neovascular membrane & that they are the major causes for the child’s reduced vision.

The late presentation and chronicity of the maculopathy may limit treatment efficacy, however I believe some visual improvement is achievable if the appropriate treatment is given.

Below are his answers to our questions. 1) What would you do in such a case :

a) Would you Leave the Condition Untreated / As it is? : Though it sounds like a reasonable choice given the chronicity, I would elect to treat in light of the higher chance we may gain significant visual improvement.

b) Would you Use Anti-VEGF? : Yes, I would use intravitreal avastin as the treatment of choice.

c) Would you Perform Surgery? : I wouldn’t in the first instance and it is possible release of vitreous macular traction & peeling epiretinal membrane may be necessary later on if there is significant image distortion.

d) Would you Administer an Intravitreal Steroid? : I wouldn’t, given the significant risk of causing cataract and potential secondary steroid glaucoma associated to intravitreal steroid use.

2) Assuming the decision was made to opt for Anti-VEGF treatment:

a) How many would you give? : In my experience it may take 2-3 injections to settle the macular edema and choroidal neovascular membrane. I would inject 0.625mg intravitreal avastin then follow the child monthly, and repeat injection if necessary pending on response to treatment. In cases with chronic macular changes such as this case it may take more than one injection to see the response.

b) How safe do you feel they are in young patients (considering more than one may be needed)? : There are concerns of potential systemic side effects in neural development for new-borns receiving intravitrel avastin injection for ROP though to date there is no proven adverse event reported. I don’t think there is significant systemic risk in a 6 year old though the risk of potential damage to the ocular structures, such as damage to the lens during injection deserves careful attention. These can be avoided by directing the injection needle toward the optic nerve during the injection.

c) How would you titrate the endpoint (subjective vs objective)? : I anticipate this child may need 3-4 injections to achieve resolution of the macular edema and choroidal neovascular membrane if the child responded to the avastin injection. I will use objective assessment performing macular OCT, and discontinue treatment once OCT showed resolution of macular edema and choroidal neovascular membrane. I don’t think the status of the epiretinal membrane will improve much though.

3) Assuming the decision was made to perform surgery; do you feel the results are encouraging? : Unless the macular edema and choroidal neovascular membrane are treated adequately I don’t think surgical peeling (presume that is the surgical procedure) of the epiretinal membrane & release of vitreous macular traction will be of significant benefit, further it may be complicated by inducing cataract formation.

4) Can leaving the condition untreated (under Poor socio-economic conditions) pose an ethical problem?  : Obviously not the preferred choice here, however “no intervetion” is s an option.

 

Dr. Vincent Daien

Dr. Vincent Daien’s replies were as follows :

1) What would you do in such a case :

a) Would you leave the condition untreated / as it is? : No, the lesion may be still active on the OCT that shows an intra-retinal exudation. An angiography using oral fluorescein may help to confirm whether the CNV lesion is active or not.

b) Would you Use Anti-VEGF? : Yes, it will be the best option to try one intravitreal injection of anti-VEGF.

c) Would you Perform Surgery? : There is no justification to perform a surgery in this patient.

d) Would you Administer an Intravitreal Steroid? : No, the evidence to treat CNV with steroid is low. Moreover, using steroid, there is a risk to induce an intra-ocular pressure rise or a cataract.

2) Assuming the decision was made to opt for Anti-VEGF treatment:

a) How many would you give? : The literature about post-traumatic CNV is weak. There is no standard protocol in the situation of post traumatic CNV in adult nor there are in children. I suggest following a pro re nata approach with visits every months and re-injection of anti-VEGF if the CNV lesion is still active. Previous case series showed that fewer injections of anti-VEGF agents seem to be required to stabilize CNVs in children compared with adults. The reason might be the better health of the RPE pump in younger subjects than in adults.

b) How safe do you feel they are in young patients (considering more than one may be needed)? : The use of anti-VEGF agents in the pediatric population is controversial because of the safety concerns about blocking VEGF in the systemic circulation of a growing child. Several studies documented the use of intravitreal anti-VEGF agents for retinopathy of prematurity, Coats’ disease, familial exudative vitreoretinopathy, and CNV lesion in children. These studies reported no ocular or systemic adverse events for the duration of follow-up (ranging from 6 to 12 months). However, their statistical power to assess the safety of anti-VEGF drugs was too low to conclude about the risk of systemic side effects. Ranibizumab instead of bevacizumab may lower systemic exposure, given its much shorter serum half-life and as found in several animal studies. Of interest, in the paediatric oncology literature the systemic use of much larger doses of anti-VEGF agents for prolonged periods for the management of refractory pediatric solitary tumours is well tolerated by most children with only few side effects. Full information consent should be given to the family about this concern.

c) How would you titrate the endpoint (subjective vs objective)? : Primary endpoint will be the visual acuity change after intravitreal therapy. It should be associated with a regression of intraretinal exudation and of the CNV membrane.

3) Assuming the decision was made to perform surgery; do you feel the results are encouraging? : No.

4) Can leaving the condition untreated (under Poor socio-economic conditions) pose an ethical problem? : Yes; I think at least one intravitreal injection of anti-VEGF should be tried to improve the sight of this children. CNV active lesions can grow and damage a larger area of the retina.<.p>

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