A 49-year-old Haitian female presented for a routine eye exam and was found to have a striking bull’s eye maculopathy in each eye with perfect 20/20 visual acuity. She had never been on Plaquenil or other antimalarial medications. She was followed for over 10 years with excellent visual function until her visual function finally started to be affected. Why does she have a bull’s eye maculopathy?

No, I am not on Plaquenil.  

That’s what our patient said when we asked her after looking at her macula’s on her first visit with us in 2007. At the time, she was a 49-year-old Haitian female that was working as a nurse. She came in for a routine eye exam only having near vision complaints. Her uncorrected distance visual acuity was 20/20 in each eye. On her dilated fundus exam, we were surprised to see that she has an obvious bull’s eye maculopathy. There is a localized area of RPE mottling that completely and circumferentially surrounds both maculae. In addition, there are also numerous intraretinal crystals. The most important question – why?  

Number one on the differential diagnosis list for anybody that looks would be Plaquenil toxicity, except that the patient denied ever having been on Plaquenil; nor had she ever been on any antimalaria medications, which is a consideration as she was born and lived in Haiti for many years.  

How about a cone dystrophy? That was discounted after she was able to see 15/15 Ishihara color plates. Macular telangiectasia (MacTel) was also considered given the appearance and presence of intraretinal crystals, however a fluorescein angiogram ruled that out as there were no leaking telangiectatic retinal capillaries. What we do see on the FA is central hypofluoresence with surrounding hyperfluoresence in a characteristic bull’s eye pattern. Visual fields were done and showed generalized constriction.  

So, we didn’t have a good answer as to why she has a bull’s eye maculopathy. Given that she was asymptomatic with excellent visual function she was followed every six months.  

In 2009 full-field ERG’s were performed and were normal, however, multifocal ERG’s were “depressed.”  The electrodiagnostic studies were repeated again in 2016 and the full-field ERG’s continued to be normal. The multifocal ERG once again showed impaired responses centrally suggesting “localized macular dysfunction without diffuse retinal dysfunction.”

As time went on, her visual function remained stable until she developed cortical cataracts and started to have a slow decline in her visual acuity. Cataract surgery was done in 2016 when she was 58 years-old and her vision returned to 20/20 in each eye and still she did not have any symptoms until 2018 when her vision seemed to rapidly drop from 20/20 to 20/800 in the right eye. The left eye remained 20/20. She was seen by a retinal specialist but unfortunately, nothing could be done.  

She maintained excellent acuity in the left eye for the next three years until January 2021 when she noticed more difficulty reading in the left eye. By August 2021 the vision had dropped from 20/20 in September 2020 to 20/100 by August 2021. On her September 2021 exam her acuity measured RE 20/400 and LE 20/200, both with eccentric viewing. She was referred to the Miami Light House for a Low Vision evaluation and genetic testing was offered.   

Genetic testing via Sparks Therapeutics was done in 2022 and showed that she had two abnormal gene mutations. One on the EYS gene indicating that she was a carrier for autosomal recessive retinitis pigmentosa (RP) and the other on the TULP1 gene; also a carrier for AR Leber’s congenital amaurosis (LCA) and RP. Interestingly, her clinical findings did not fit either of the disease characteristics for RP or LCA.      

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations. Genetic mutations on EYS located on chromosome 6q12 is a major genetic cause of recessive RP worldwide, with prevalence of 5 to 30%1. All the reported cases on AR RP associated with the EYS gene have the typical features of RP including bony pigment spicules, attenuated retinal vessels and waxy appearing optic nerve. Our patient had none of those features. Nor did she have any of the typical symptoms for RP such poor night vision.  

Leber congenital amaurosis (LCA) is a family of congenital retinal dystrophies that results in severe vision loss usually at an early age.  Infants with LCA usually have nystagmus, sluggish or near-absent pupillary responses, severely decreased visual acuity, photophobia, and moderate to high hyperopia. There is a form of LCA that can occur slightly later in life, but those patients have mutations on the RPE65 gene. Our patient did not have this genetic mutation.  

It seems very clear based on genetic testing that our patient has some form of an inherited retinal degeneration (IRD) but unfortunately it doesn’t seem to fit any classical clinical presentation; certainly not for RP or LCA. From the time she was diagnosed with this peculiar bull’s eye maculopathy until she lost vision in the first eye was about 11 years and 14 years when the disease had finally affected visual function in both eyes to the point she was no longer able to drive or work as a nurse. By that time she was 62 years old.  

As a carrier, perhaps her children have signs of the disease or are at risk of developing it? She has two older sons, now in their mid-20’s, that have been examined numerous times over the years and both have had completely normal eye exams and excellent visual function. Of course, that doesn’t mean the disease won’t manifest later in life. After all, their mom wasn’t diagnosed until her late 40’s. There is also a risk they could pass this on to their children.  

Looking back over the course of her disease, even when she first presented in 2007, the hope was that the bull’s eye developed from some event that occurred sometime when she was much younger, and that the disease was stable and would not change. After all, she was 20/20 in each eye and was asymptomatic. For over 10 years that proved to be the case, until it wasn’t. Then she lost central vision in both eyes over a period of three years.  

Unfortunately, there is no cure for her condition. The hope is that it won’t get any worse or result in complete blindness. Meanwhile as we make progress in personalized medicine and gain a greater understanding of the role that genes play in the development of IRD, gene and cell therapies hold great promise for the future. With the approval of the first successful gene therapy for the treatment for LCA in 2017, the hope is the dominos will start to fall as more gene therapies become available and other IRD can be treated. Sadly, it will be too late for our patient, but maybe not for her future generations.   

 

This is the right and left eye of our patient that has a “classic” bull’s eye maculopathy. Her visual acuity was 20/20 in each eye.

 

The OCT images show loss of the ellipsoid zone and increased transmission into the choroid in the area of the bull’s eye surrounding the fovea.

 

By 2018 there is very minimal change in the appearance of bull’s eye maculopathy however, on this visit her acuity in the right eye dropped from 20/20 to less than 20/400.

 

In the b-scan OCT image of the right eye we are now seeing central loss of the ellipsoid zone which explains why her acuity is so poor. In the left eye there is a small area of the ellipsoid zone still intact. Also, note the increased transmission of light into the choroid of both eyes due to atrophy of the RPE.

 

Here are the fundus phots from 2023, 16 years after her initial presentation. By now she has lost central vision in both eye and her acuity is 20/400 with eccentric viewing in each eye.

 

The striking fundus autofluoresence (FAF) images in 2023 show the bulls eye pattern with central hypofluoresence and peripheral hyperfluoresence. FAF images from earlier years show a more significant hyperfluorescent pattern in the central macula. That has changed over the years as she has developed more central atrophy and photoreceptor loss.

 

Reference

  1.  Westin IM, Jonsson F, Osterman L, et al. EYS mutations and implementation of minigene assay for variant classification in EYS-associated retinitis pigmentosa in northern Sweden. Sci Rep 2021 Apr 8;11(1):7696. doi: 10.1038/s41598-021-87224-9. https://pubmed.ncbi.nlm.nih.gov/33833316/#:~:text=Retinitis%20pigmentosa%20(RP)%20is%20a,prevalence%20of%205%20to%2030%253