Another Case of Atypical ROP

I have been overly busy with family for thanksgiving and then surgery and clinic, therefore, I have not posted much. However, since atypical ROP is on my mind, I have to discuss one of the children I saw in the office today although I will not have photographs until next week.

A 46 week PMA patient ex-premature infant born at 1556 gms and I believe that the gestational age was 34 weeks. He was noted to have morning glory syndrome in the right eye (65% sure). The question that brought him to my office was about the location of the macula and my sense of the visual potential.

Indeed, it was a beautiful example of morning glory with a deeply excavated peripapillary zone and a bit of "glial" tissue on the cup area. The big surprise was that while the normal left eye was fully vascularized to the ora serrata, the right eye had Stage 2 ROP in Zone 2 without plus disease. I hope to have photographs next week, but wanted to include this case of atypical ROP.

This case joins a group dysmorphic babies that have atypical ROP. I suggest screening for dysmorphic babies up to 2000 gms.

Elevated Optic Nerve in 16-month old

It was the day before Thanksgiving and I had 10 EUAs scheduled. The anesthesiologist were gracious (suffered silently) as we fell far behind schedule.

One of the highlights of today's EUA session was a 16 months- old boy with poor vision in the right eye. The child had an MRI and MRA before my exam and they were reported as no tumor. I have not yet seen them. I did retcam photos and angiography.

Figure 1A: Shows the zone of the optic nerve. The optic nerve is obscured by elevated retina with fibrous tissue central and pleats of retina extending temporally. Hyperpigmentation along the base
Figure 1B: Elevated retina is seen overlying the disc area and fibrous tissue is seen extending from the central zone temporally in a zone of retina folds. Although there are many retinal vessels centrally they are of normal to decreased caliber and straightened.
Figure 1C: Shows the temporal extent of the fibrous tissue that is at the crest of a retina fold.

Figure 2A: Shows the Fluorescein angiogram early frame with severely altered vascular pattern. Nonetheless the vessel patten still respects the median vascular raphe.

Figure 2 B: The angiogram shows the transit phase. in the temporal periphery there is an area of non-perfusion. There is also a looping pattern typically seen near the ora serrata
Figure 2 C: Shows the late frame with subretinal pooling .

The differential diagnosis at presentation was. I guess that was the reason for the MRI and MRA. The parent said they would send me a copy and I will add it to this post when I get it.

1. Morning Glory Syndrome with serous retinal detachment


2. Optic Nerve Glioma

In fact the picture is classic for a combined hamartoma of the retina and RPE (CHRRPE). This is the presentation of the peripapillary form and looks very different from the posterior or peripheral forms. In general there is a large range of appearances. Hamartomas are disorganized tissues from the site. This hamartoma includes glial, vascular, retina and RPE. The positive features are:

1. Retina Detachment
2. Pigment at base (RPE tissue)
   
3. Fibrous tissue associated with retina traction with dendritiform shape (glial tissue)
   
4. Optic nerve head obscured by retina
5. Dragging of the vascularized retina centrally (small vessels)
   
6. Loss of the macula

1. 
   Figure3: Shows another CHRRPE with somewhat more obvious features. The dense fibrous tissue, the retinal elevation and dragging, the retinal pleats and the straightening of the vessels. The FA shows that the retinal detachment occurs from the fibrous traction on the macula.

Figure 4A Shows a morning glory disc shows a central fibrous (glial tissue obscuring the normally yellow-pink rim of neural tissue. The vessels emanate from below the glial tissue and extend radially without the usual posterior branching. The vessels are not symmetric around the center; the arcades vessels are seen temporally. An annulus of white subretinal tissue may represent sclera and this is surrounded by an annulus of choroid without RPE.

Figure 4B: Shows greater detail and the fovea and a retina pleat can be seen temporally. Morning Glory is a coloboma in which there is an ectasia with prolapse of tissue into the ectasia.

The overlap features

1. The radial vessels like morning glory syndrome
2. The glial tisssue like both morning glory
3. The elevated tissue like glioma
   
4. Highly Vascular over disc area liked optic nerve glioma
   

Psuedo-papilledema? In a 4 years-old boy

Figure 1: Shows right optic nerve head that appears hyperemic, no cup, elevated nasally more than temporally with a light reflex nasally and dilated retinal vessels. Disc margins are somewhat blurred nasally
Figure 2: Right eye posterior pole dilated and tortuous retinal vessels.Figure 3 shows left eye disc and macula. The disc elevation is mainly nasal as one follows the vessels follow the contour of the nasal edge. The surface is hyperemic without a cup there is a nasal light reflex. No edema, hemorrhages, or obscured vessels

Friday, I saw a child that according to the mother was referred because of "a leaking blood vessel and just had an MRI yesterday." The 4 years-old boy was quite hysterical during dilation and seemed likely to be a challenge for the eye exam. In an adult, I might have called the referring physician first, however, the patient was ready and so was I. I figured more delay and fatigue would lead to greater grumpiness and less cooperation. Moreover, I was likely to figure out the problem if I just looked.

In fact, our hero, had a natural bob and weave, but was otherwise easily engaged and fairly cooperative at the exam. The finding on ophthalmoscopy with the 28 D lens were more impressive than the photos, with the advantage of axial magnification the optic nerve looked more elevated and the blood vessels appeared more dilated and tortuous. The optic nerves and the peripapillary area did not seem particularly edematous, there were no hemorrhages and the vessels were not obscured by nerve fiber layer tissue. There were no exudates or cotton wool patches.

The photographs really made the diagnosis because it stopped the rapid movement. I was surprised that the photographer did so well.

The eyes reminded me of a recent Down Syndrome child and the pseudo-papilledema is well described in the literature for them. I performed an b-scan looking for disc drusen and found nothing remotely suspicious. Having done my best, I told the mother that I would call the referring physician and check out the MRI and give her the report.

She was assertive and wanted to know what the worst case scenario was. Not a pleasant question. I told her that there was a small risk of a brain tumor, but that I was at least 90% certain the finding was a normal variant. I told her that I hoped she could stay optimistic until we got the MRI report to eliminate the possibility.

I got the MRI report, soon after they left, and it was normal. The pediatric ophthalmologist had referred because of the elevated disks and recent intermittent breakdown into esotropia, and a report of an episode with loss of vision. There was no 6th nerve weakness.

The photography really helped the diagnosis, The disk elevation showed no signs of edema, but I still think that the hyperemia is impressive and uncertainty remains. In a cranky child and bad view the details these discs are certainly in the gray zone between normal and abnormal.

Is it pseudo-papilledema or an early case of papilledema? If I didn't have the MRI or CT I would have wanted follow-up photographs in a week and a month.

In general, in the suspicious elevated disk there are a number of options:

1. A good exam
2. A good photograph
3. A repeated exam to eliminate the early finding.
   
4. An exam under anesthesia
5. An exam with angiography
6. A spiral CT
7. A sedated MRI.

What is the appropriate threshold for these options? I guess a good photograph goes a long way. The spiral CT can usually be done without sedation or anesthesia ? The MRI certainly gives the best information about the brain. The EUA with angiography is the best information about the retinas. I think that much of the approach depends on the child's ability to cooperate and the Ophthalmologist's confidence. Nothing is guaranteed and the question is relative risk of examination versus the disease.

Atypical ROP?

Figure: The contrast of the photograph was enhanced. The temporal vessels are straightened and there is a folding across the foveal zone. Peripherally, there is confluent laser and pink fibrovascular tissue. On indirect there was retinal elevation at the base of the fibrovascular proliferation.

Is this atypical ROP? Yes or No?

This girl was born at 37 weeks 3543 gms by c-section because of severe anemia from bleeding in utero. Was examined for ROP and treated with laser. She was referred for continued activity after complete laser treatment. I watched her for 5 weeks when she developed a 4A detachment and a macular pucker. At surgery the macula was folded by the pucker that was very adherent and after persistent meticulous effort was released and removed. The retina attached. The patient had no rash or seizures.

I performed fluorescein angiography on both parents looking for evidence of FEVR, or Norrie carrier state. Both parents were perfectly normal to the ora serrata.

The macular pucker is my second case in "ROP", but the extent of disease was much less here.

This atypical ROP could be called prematurity exacerbated retinopathy. It probably represents a sub-clinical sporadic FEVR abnormality that we have not yet detected. She would have detached had she not been accidentally screened.

Treatment Decisions

This table is a simple prop for thinking about treatment as opposed to observation. It could also be used to think about two competing interventions: intervention 1 and intervention 2. Along the x-axis (horizontal) in this table is the stage of the disease. The stage increases as one moves to the right as does the risk of unfavorable outcome with observation.

Treatment should be performed anywhere beyond the intersection of the outcome lines. At this point treatment improves the patient outcome (or reduces the unfavorable outcome on this chart). This can be seen only at the fifth stage when the red line crosses above the blue. The major hidden concept is that dead is dead, and it doesn't matter materially, if the patient is dead from the disease or the treatment.

This is a good model when there is good data and it is divisible into good and bad outcomes along a single dimension, but this is frequently not the case.

In the real world the loss of vision in the observation group may have a different time of onset relative to treatment. This model would require a third dimension: time. (eg;MPS subfoveal CNVM). Then one might calculate the area under the curves over time.

Frequently, the outcomes due to treatment complications are qualitatively different from the observation outcomes. For example in using Lucentis for ARMD, how does one factor an increased stroke rate against improvement in acuity measured with the number of letters. Quality of life may allow some bridging between qualitatively different categories. However, I am not always comfortable with valuation techniques.

Another situation is the decision for vitrectomy in vasculopathic diabetics with Vitreous Hemorrhage or TRD. On one side is blindness, on the other side blindness, but also of phthsis and pain requiring enucleation from surgical failure, and even loss of intellectual function and death from anesthesia.

Perhaps the even more difficult are treatments that may harbor very late complications like radiation in Retinoblastoma or chemotherapy.

The Bottom Line:
I try to simplify the analysis to this type of table as much as possible in order to clarify my treatment decisions. At the same time, I track the likely errors in my assumptions for data, complications, qualitative differences etc. Therefore, Instead of treating just beyond the intersection of the two outcome lines, I usually prefer a larger gap between the lines because the data is often biased and limited (I am particularly skeptical about all data from people or companies with money on the table, book smart geniuses, and different patient populations until it conforms with my personal observation) . In prophylaxis for retinal detachment I like a gap of 10%. On the other hand, in some diseases like Zome 1 ROP, I would treat close to the intersection because non-treatment has a very bad outcome and the progression of disease a very fast.

What is the new Atypical ROP ?

Dr. Azad sent me an invitation to write a chapter on atypical ROP. I asked him about his intent and this was the response.

Dear Mike,
Thanks for accepting to write the chapter. The Scope of the chapter includes differential diseases and atpycal ROP excluding AP ROP. This topic is regarding the acute phase.

with best wishes,

Raj

Prof. (Dr.) Rajvardhan Azad, MD, FRCSed, FAMS
Hony. General Secretary
All India Ophthalmological Society (AIOS)
Professor of Ophthalmology
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.I.I.M.S., New Delhi-29(India)

I have about two weeks to write this chapter and think that I will do some of the work on the blog. It would be great to have input about this. Initially, I was disappointed about not having AP-ROP, but in fact that is already out there. (I should start to post my APROP collection for public viewing. It is not all flat neovacularization by any means. Later.)

Now I am excited to discuss my observations in the new atypical ROP. ROP of course is a dynamic disease. We solve one problem and another layer or group becomes the new focus.
Starting the outline on the new atypical disease it is probably useful to review the context of ROP

Part A Differential Diagnoses

1. differential of peripheral avascular retina
2. differential of infantile traction retina detachment,
3. differential of plus disease

Part B atypical cases and groups

1. Unusual ROP behavior: progression despite lack of plus disease
2. The septic, NEC patient that does not respond to laser
3. ROP and dysmorphia
4. Combined diseases
5. Extremely rare presentations (beyond AP-ROP)

I am very open and interested about other categories of cases that do not hit me just now. Please send your thought. If you have a great photo or case that you can send that will be great. India is an incredible big and populous country. This is a special opportunity to contribute.

Persistent Fetal Vascular Syndrome (PFVS)

Figure 1A: Shows the stalk extending anteriorly from the apex of the tent-shape detachment in the simple posterior form of PFVS
Figure 1B: Shows a typical tent-shaped retinal detachment seen in PFVS. The apex occurs in an area of vascularized retina.
Figure 2. Shows a falciform fold in a child with FEVR and peripheral fibrovascular proliferation. The apex of the detachment is peripheral at the junction of vascular and avascular retina and the retina is pulled up into a falciform fold. On the crest is a retinal vessel that functions as the retinal skeleton. No stalk is seen.

Today, I did an EUA and laser on an approximately 10 mm eye with a severe configuration of PFVS. The initial vitrectomy was 2 weeks ago and it looks good but I am worried so I added treatment. There is no macula visible. ( I couldn't photograph because of the anterior fibrosis obscured the view)The eye is doing better than I expected, but the final result is still uncertain because although the retina is largely attached. There is a fold going superiorly off the disc to the ciliary body.

I am using the term PFVS because of my debt to Morton Goldberg who hired me at UIC when I was a young and naive graduate from retina fellowship. PFVS is a good term, but I also like Persistent Hyperplastic Primary Vitreous (PHPV) label. In particular, I like the hyperplastic because fibrous overgrowth and traction plays a central role in the cases that come my way. Between primary vitreous or fetal vasculature, fetal vasculature is definitely more accessible. I have read a good deal of embryology and still forget the meaning of primary vitreous. But it refers to the hyaloid vasculature. I wish we called it persistent and hyperplastic fetal vasculature. In any case this condition is a congenital anomaly that extends from trivial to devastating. Usually, the degree of microphthalmia and the extent of the retrolential fibrosis and traction will track with the severity of the anomaly.

This case is of special interest to me because it was not like the photograph above and seemed like a challenge to my understanding of falciform folds that I have taught my fellows and lectured on recently in Japan. In general, the detachment of ROP, FEVR, Norrie etc arises from traction peripherally related to fibrovascular proliferation that grows because of a peripheral avascular zone. The crest of the fold has retinal blood vessels going up toward the peripheral traction Figure 2. In distinction the classic retinal detachment in PFVS is more tent like than falciform and has a stalk that goes centrally from the apex of the retinal detachment Figure 1A and 1B.

Today's patient had a major retrolental fibrous proliferation with obvious fetal vasculature and no avascular zone the detachment was wing shaped and its apex was involved with the retrolental mass. There was a short stalk, however when you look at the crest of the fold there were vessels that extended out to the peripheral retrolental mass.

After considering the configuration it mainly shows that severe traction causes a change in the configuration from tent-shape to wing-shape. Looking back at figure 1B I can imagine nascent wings that elevate, extend and thin out as the stalk is pulled into the retrolental mass.

Enough for today, I would like to discuss the retina configuration of toxocara canis and hope that I get the video system at LGH up and running.

Late Retinopathy of Prematurity

Today, a new patient, a nine years old child with a history of ROP came to the office. The left eye was phthisical with severe band keratopathy and the right eye had a normal anterior segment the posterior retina is seen above. The child had a degree of spasticity in her walk but was quite charming.

Her vision was around 20/100.

She was too light sensitive for an extended peripheral exam and certainly not for scleral depressed exam She had nystagmus and poor control of her eye. I did not see any fibrosis anteriorly or any detachment however my view was poor.

The macular heterotopia frequently is associated with peripheral traction retina detachment and many of the fibrous elements that cause the early detachment and macula heterotopia are risk factors for retina detachment throughout life. The rate of detachment is impossible to know because we do not have a cohort of ROP patients followed beyond 15 years. My personal estimate is about 20% of patients with stage 4A.

ROP is a life-long disease. Especially, if there are retinal residua like macula heterotopia, tractional elements or even inactive cicatrix.

I try to train the children to tolerate a full exam and in cases with only one eye and particular risks I do exams under anethesia. I have a few ROP "autistic" and developmental delay children that I follow with exams asleep every 3-4 months.

These cases are technically demanding and I am caring for three adults with ROP with late Retinal Detachment now. They are very difficult because the vitreoretinal interface is not clean and requires careful attention to strip and retinal breaks without stripping are likely to fail. I use a few special techniques that I hope to discuss in the future. As is often the case in rare diseases, the techniques are not published.

Retinoblastoma

I had a very interesting telephone consultation about a pregnancy. The father had a history of Retinoblastoma. On genetic testing the child had a deletion in the Retinoblastoma Gene.

The question was if there was any thing to do. They already decided not to abort.

Retinoblastoma can develop during pregnancy. I have seen the ultrasound of one of my patients showing the fetal eye full of tumor. On the other hand, many of the hereditary cases I have seen do not have much tumor at birth. We get generally better results treating smaller lower group tumors. So the first question is how to detect the tumor. The choices are high resolution ultrasound or fetal MRI

What to do?

Consider an early birth at 36 weeks, the chances of premature complications are very low and this will allow a better chance of normal visual development and retention of the eye.