Case Study of Stargardt Disease Treatment in Four Siblings with Acetylcholinesterase Inhibitor (Incidence of Visual Acuity Progression)

Introduction

In 1909, the German ophthalmologist Karl Stargardt described seven patients from two families with a reduction of visual acuity and a normal retinal fundus appearance in young patients during the first or second decade of life.  Eventually, these patients developed the classic atrophic macular lesions surrounded by yellowish, deep retina-flecks.¹

Today, Stargardt disease is the most common inherited single-gene retinal disease.²  It usually has an autosomal recessive inheritance caused by mutations in the ABCA4 gene.  Stargardt disease inevitably leads to significant and previously irreversible loss of vision.  For example, Progstar Report Number 6, a study of 259 Stargardt disease patients, showed a measurable loss of visual acuity over a one-year period.³  Color vision loss has been reported in Stargardt disease patients.^4,5

Since August 2023, four Stargardt disease patients were observed and treated with Phospholine Iodide® / Echothiophate Iodide (PI/ECHO).  PI/ECHO is an Acetylcholinesterase Inhibitor (AChEI).  It was approved by the Food and Drug Administration (FDA) in 1959.  It has been used over the past 60 years for the treatment of glaucoma and accommodative esotropia.  FDA labeling shows safety and efficacy in both adults and children.  Currently PI/ECHO is manufactured by FERA Pharmaceuticals.  This is the only topical AChEI available worldwide.

Patients in this study are consecutive siblings, one female, the oldest, and three males.  The mean age is 57.1 with a range of 52 to 64.9.  They reside in the midwest U.S.  They all have diffuse retinal pigment epithelium (RPE) atrophy.  Patient demographics are shown in Table 1.

Analysis

Data for analysis comes from four patients (consecutive siblings).  

ETDRS recommends that patient baseline BCVA be 20 ETDRS letters or better for valid analysis.  None of the patients meet the requirement at 4 meters.  All patients meet the requirement at 1 meter.  Therefore, distance BCVA analysis is limited to 1-meter data.

Maximum visual improvement (MVI) is calculated by selecting the BCVA from the subsequent visits showing the greatest improvement over baseline.  To simplify the analysis, the eye for each patient showing the most improvement or change is utilized in the study (8 eyes).  BCVA calculations are performed using logMAR values.  Baseline BCVA is computed from Visits 1 and 2.1.  BCVA data from all visits is tabulated in logMAR.  BCVA changes with respect to baseline are tabulated in logMAR and, for convenience, ETDRS letters.  

Note that,

• 1 ETDRS letter is equivalent to 0.02 logMAR
• 1 line is equivalent to 5 letters or 0.10 logMAR

See Appendices A through D for detailed BCVA measurements of each patient.  BCVA data at 4 meters, although not analyzed, is included in the appendices.

Results

The mean age at first treatment is 57.1 with a range of 51 to 63.7 years.  The patients revealed myopia from -4.00 to -8.00 diopters.  All experienced early onset of vision loss at age 10.  Patient B032 is a heavy smoker who is unable to return after Visit 3 for health reasons.

Retinal findings on all patients reveal pallor of the optic nerve.  There are both central and diffuse retinal atrophy and pigment clumping on all patients.  These findings are present above and below the temporal arcades and on the nasal side of the retina.

At baseline, BCVA mean value of the group is 1.21 logMAR for distance vision and 0.94 for near vision.  Of note, baseline BCVA measured on consecutive days can vary by as much as 0.14 logMAR (7 letters).

Of the 156 BCVA data points analyzed 155 show stabilization of BCVA progression and/or improvement.  The one exception is Patient B026, Visit 6 where the left eye at near measured a loss of 0.04 logMAR (2 letters) from baseline.  This is attributed to a 14-hour automobile trip the day before the visit.  Visit 7, on the following day, revealed a BCVA improvement of 0.26 logMAR (13 letters) above baseline, a net change of 0.30 logMAR (15 letters) between the two days.  In review of all data, there are no other incidents of further progression of BCVA decline.

Distance Vision

Immediate improvement of distance BCVA occurs at 1 hour.  There is a maximum improvement of 0.28 logMAR (14 letters) with a mean of 0.250 logMAR (12.5 letters).  At 24 hours, there is a maximum improvement of 0.50 logMAR (25 letters) with a mean of 0.280 logMAR (14 letters).  The improvements are sustained at one month, six months and one year.  Table 3 shows distance BCVA improvement mean and range at each milestone.  Figure 1 shows distance BCVA improvement for each patient at each milestone.

Near Vision

Similar to distance vision, immediate improvement of near BCVA occurs at one hour.  There is a maximum improvement of 0.26 logMAR (13 letters) with a mean of 0.175 logMAR (8.75 letters).  At 24 hours, there is a maximum improvement of 0.28 logMAR (14 letters) with a mean of 0.205 logMAR (10.25 letters.)  The improvements are sustained at the one-month, six-month and one-year milestones.  Table 4 shows near BCVA improvement mean and range at each milestone.  Figure 2 shows near BCVA improvement for each patient at each milestone.

Patients exhibit visual acuity improvement after initial treatment at 1 hour, with maximum improvement occurring at the six-month milestone.  At distance the mean MVI is 0.460 logMAR (23.00 letters) with a range of 0.26 logMAR (13 letters) to 0.62 logMAR (31 letters).  At near the mean MVI is 0.330 logMAR (16.50 letters) with a range of 0.20 logMAR (10 letters) to 0.44 logMAR (22 letters).  Table 5 shows the distance and near vision MVI for each patient.

Table 6 shows the progression of mean MVI improvement at each milestone.  It indicates that visual acuity improvement progresses rapidly upon initiation of treatment.  For distance vision, 51% of the maximum improvement is attained one hour after the initial treatment.  At the one-month milestone, 77% of the maximum improvement is reached.

The MVI distance findings in this study correlate well with 44 patients with a baseline of 1.32 logMAR or less in a previous 309 patient, 20-year retrospective study.⁶  The patients in that study show a mean distance MVI of 0.39 logMAR (19.5 letters).

Color Vision

This study reveals a 100% incidence of extreme color vision deficiency at baseline.  The mean color vision improvement is 2.5 plates with a range of zero to 5 plates.  These findings correlate with a retrospective study of 309 Stargardt disease patients.⁶  That prior study reports an 86% incidence of color-vision loss.  The mean improvement is 2.75 plates with a range of zero to 10 plates.

Pupils

During treatment there is a reduction in pupil size (miosis).  The mean reduction is 1.1 millimeters.

Discussion

Stargardt disease, the most common inherited single gene retina disease, has an autosomal recessive inheritance.  The patients share the identical mutation of the ABCA4, 5461-10T>C variant gene and the ABCA4 5714+5G>A variant gene.  These gene variants were inherited from each parent who carried 1 recessive mutant gene but did not manifest the disease.

This midwestern, USA family consulted the Mayo Clinic in 1973.  They were informed that a cohort of four consecutive siblings with Stargardt disease and hybrid parents is very rare and that they were the only documented case in the world at that time.  Statistically, the chance of having four consecutive siblings with hybrid parents is 1/256 (0.39%).

This one-year prospective study shows the incidence of BCVA progression/degradation to be none.  There is an immediate improvement at one hour.  The improvement is sustained for 1 year.  The study presents evidence of an overall improvement for all four patients at all visits with the exception of a single visit (see explanation above).  These findings compare favorably with the natural history of Stargardt disease patients reported in Progstar Report Number 6.³  This report shows a loss of at least 1 line (0.10 logMAR, 5 letters) of vision in 12.9% of eyes and a loss of at least 3 lines (0.30 logMAR, 15 letters) in 2.8% of eyes over one year.  The degradation depends upon baseline BCVA.  

Due to reported natural degradation of BCVA for most Stargardt disease patients over time, stabilization of vision at baseline levels is considered an improvement over the natural progression of the disease.  BCVA is the most common outcome measure for efficacy studies of retinal diseases.⁷  In clinical trials a gain of 0.30 logMAR or 15 ETDRS letters is considered clinically significant.⁷  In this study 3 of the 4 patients meet this criterion.  Note that the fourth patient was unable to complete the program due to illness.

BCVA is an important visual function outcome directly related to participants' daily activities.⁸  Individuals with vision impairment are more likely to experience restrictions in their independence, mobility and educational achievement.  They also have an increased risk of falls, fractures, injuries, poor mental health, cognitive deficits and social isolation.  Likewise, restoration of partial to nearly complete color vision in some patients not only improves enjoyment of the color environment but adds to the safety for both the individuals and their communities.  The patients in this study reported improvement in maintaining independence and in performing the activities of daily living, e.g., cooking, shopping, watching television, reading, personal hygiene.  Please refer to patient comments about their functional improvements in Appendices A through C.

The retina is derived from the same embryologic germ cell layer, neural ectoderm, as is brain tissue and the nervous system.  And for many years pharmacological agents have successfully treated neurological diseases e.g., Parkinsonism, Alzheimer’s Disease, Clinical Depression.  Furthermore, there is corroborating evidence from a recent (January 2024) publication showing a reduced incidence of age-related macular degeneration in Alzheimer’s patients treated with AChEI.⁹

The exact mechanism of action of PI/ECHO in Stargardt disease patients is not yet known.  There may be several mechanisms, three of which are listed below.

1. The retina contains neural tissue.  Just as in Alzheimer's disease, the acetylcholinesterase, PI/ECHO may prevent the degradation of the neurotransmitter acetylcholine, increase its level and prolong the effect of the neurotransmitter in the retina.

   The specific neural biochemical mechanism of action in Stargardt disease is still under evaluation.  A number of retinal cells are known to be influenced by Acetylcholine (ACh).¹⁰  More specifically, a two-fold mechanism is postulated.  

1. Nicotinic ACh receptors are found on the outer segments of the photoreceptors and retinal pigment epithelial cells.  These cells are also known to produce ACh and activation of nicotinic ACh receptors mediates phosphoinositide turnover.  This supports the existence of cell to cell communication between photoreceptors and RPE cells via an ACh mediated mechanism.¹¹
2. The second mechanism is more speculative.  The ABCA4 gene, thought to be the causative variant in Stargardt's disease, encodes a protein in the outer cell membrane of retinal cells.  This protein plays a crucial role in the transport and removal of a toxic byproduct, N-retinylidene-PE (N-RPE), of the visual cell metabolism.  Accumulation of this substance can lead to toxic lipofuscin deposition with cell death and visual loss.  Phosphoinositides are lipids present in the cell membrane which assist in cell membrane dynamics.  ACh may stimulate the activity of these phosphoinositides and thus assist in delaying the deposition of toxic byproducts within the retinal cell.¹²

2. A positive side effect of PI/ECHO is narrowing of pupil size (miosis).  Pupil narrowing reduces the amount of UV light entering the eye and delays the incidence of BCVA progression.  This effect is similar to, but more effective than, the current recommendation for Stargardt disease patients to wear a baseball cap and/or sunglasses to limit UV light exposure.

3. PI/ECHO increases retinal blood flow (perfusion) and hypothetically, results in the amplification of the synaptic potential of the surviving photoreceptors and ganglion cells (dormant cells).  This results in enabling these reduced populations to achieve threshold and resume the propagation of visual information to the brain.

Stargardt disease is one of several degenerative retinal diseases, including dry age-related macular degeneration and retinitis pigmentosa, which may respond to PI/ECHO therapy.  If this turns out to be the case, the therapy may hold the potential to lessen the disability from several blinding retinal diseases.  Furthermore, PI/EHCO is currently available, non-invasive, safe and a relatively inexpensive treatment.

Although this paper shows data for four patients over one year, I can optimistically report that this treatment can be effective over many years.  A retrospective study⁶ presents data on a five-year, 31 patient group.  This study shows no degradation of visual acuity and sustained visual gains over baseline for five years.  

In summary, this one-year study presents positive evidence on the incidence of BCVA progression.  There is no evidence of BCVA degradation but rather immediate and sustained BCVA improvement in four siblings with Stargardt disease by the application of topical PI/ECHO.  

Patient Observations

• At age 50 the decrease in visual acuity affected my daily activities and work as an attorney.
• I have noticed a significant improvement in my vision.
• As an attorney with a busy litigation practice this is a life-changing event.
• I noticed contrast on computer screens and in images similar to switching a television to high definition.
• At a high school football game, I was able to see the endzone scoreboard from mid-field.
• I hope to be able to obtain a driver’s license which I have dreamed about since failing the vision test at age 16.

Patient Observations

• The drops seem to help me tolerate the sunlight better.
• Colors are brighter.
• Reading a measuring cup without a magnifier is easier.
• I can read some scores on TV from my chair.
• Putting on make-up is easier.
• If it was dark outside, I would have to have my husband help me put the sheets on the bed because I couldn’t tell which way the lines were facing even with the lights over the bed on. I can put the sheets on by myself now.
• I like to play games with my 4-year-old grandson. I was having trouble reading some of the game pieces. I can see them better now, so he can’t cheat!
• When I would go get a pedicure with my friends, I couldn’t read the receipt to tip, so my friends would add the tip and sign for me. I can read it now, so I can do it myself.
• Reading my phone is easier.
• Going up and down steps is easier.
• I love reading to my grandson. Even with my reader, it was hard to read to him. My reading was very choppy. My grandson had gotten to where he really didn’t want me reading to him. Now I can read fluently with the reading device. When I came to you, my most important goal was to be able to read to him. I’m so happy!
• My husband and I went to Acadia National Park. We love to hike. Usually, I have to get down and feel the rocks because of my depth perception. I was able to climb without having to get down often. I haven’t been able to do this in 15 - 20 years!

Patient Observations

• I have experienced significant visual improvement in both eyes.
• The world appears clearer.  
• Colors are more vivid.
• I can read smaller print more easily.
• The treatments have helped me most at work. 
• I can read my computer screen, phone and documents more easily.  
• These improvements have helped me continue to pursue my passion for teaching and my love for coaching football.