Stargardt Disease Treatment with Topical Cholinergic Medication, Patient 86

Gerard M Nolan, MD September 2021

Abstract

Purpose

To demonstrate visual acuity and color vision improvement realized by a Stargardt disease patient resulting from topical cholinergic medication (TCM).

Observations

Early and sustained improvement in both visual acuity and color vision in a patient with Stargardt disease.  The improvement was a result of topical application of low dose echothiophate iodide (0.015%).  The gains in visual acuity and color vision have been maintained through a period of observation of more than 15 years.

Conclusions and Importance

TCM, low dose echothiophate iodide therapy produced significant and sustained gains in BCVA and color vision for this patient.  This compares favorably to the natural degradation to legal blindness in untreated Stargardt disease patients.  Low dose echothiophate iodide therapy potentially provides a treatment for Stargardt disease where none was previously available.

Introduction

Today, Stargardt disease is the most common inherited single-gene retinal disease.  It usually has an autosomal recessive inheritance caused by mutations in the ABCA4 gene.1  Stargardt disease inevitably leads to significant and irreversible loss of vision.  Cholinergic stimulation (the parasympathetic nervous system) uses acetylcholine (ACh) at its receptors and synapses and is regulated by the enzyme acetyl cholinesterase.  Echothiophate iodide inhibits this enzyme acetyl cholinesterase and allows for the increase of endogenous acetylcholine.

This case history presents evidence of early and sustained improvement in visual acuity and color vision in a Stargardt Disease patient.  The improvement was a result of the application of TCM, low dose echothiophate iodide (0.015%).

Case Report / Findings

The present case involves a male patient diagnosed with Stargardt disease at age 11 in 2005.  This individual presented with no familial history of blindness or retinal disease.  The patient wore glasses since age 8.  He had a mild myopia of -2.00 diopter.  The past medical history was negative.

Visual acuity declined at a steady progressive rate until age 10, at which point the patient experienced an abrupt drop in central and night vision.  In 2005, the patient consulted multiple vitreal retinal specialists in Johnstown, Pittsburgh, State College and Philadelphia, Pennsylvania.  Each specialist confirmed a diagnosis of Stargardt disease.

The patient initially presented for baseline testing at age 12 on March 20, 2006.  The patient is included in a 20 year, 309 Stargardt disease patient study. The patient is also one of 22 patients in a one year, controlled proof-of-concept (POC) trial for Stargardt disease under the oversight of an Institutional Review Board (IRB).2  This ophthalmic clinical research was designed by PharmaLogic Development, Inc.3  This case report details the patient’s sustained improvement resulting from continued use of echothiophate iodide over 15 years.

Treatment Protocol

Prior diagnosis of Stargardt disease was verified via fluorescein angiography.  Best corrected visual acuity (BCVA) was established using the EDTRS system for distance and near vision and converted to logMAR for analysis.  Color vision was documented by the Ishihara 10 plate test.  The fluorescein angiogram revealed RPE dropout in both temporal and nasal retina.  The patient was classified as RPE Atrophy Stage IV in both eyes.  The World Health Organization (WHO) visual impairment category was moderate in both eyes distance and near vision.

Following the initial consultation (visit 1), the patient returned the next day (visit 2.1) for retesting of baseline BCVA.  The patient then received one drop of dilute (0.015%) echothiophate iodide in the lower cul-de-sac of both eyes and instructed to sit with eyes closed for one hour (visit 2.2).  The patient spontaneously reported an increase in overall vision brightness.   BCVA improved as follows:

Distance vision, right eye

5 letters (1.0 lines)

Distance vision, left eye

3 letters (0.6 lines)

Near vision, right eye

10 letters (2.0 lines)

Near vision, left eye

5 letters (1.0 lines)

Color vision improved as follows:

Color vision, right eye

3 plates

Color vision, left eye

2 plates

The dosage used for treatment of this patient was one drop of 0.015% echothiophate iodide, administered to each eye every two days, immediately prior to sleep.  The patient returned every month for the first three months and every three months for the next nine months.  The patient has continued treatment by visiting every 6 months thereafter.

Results

The pre-treatment examination (visit 1) determined the patient's right eye distance BCVA to be 20/125 (0.80 logMAR) and left eye distance BCVA to be 20/100-2 (0.74 logMAR).  Right eye near BCVA was 20/160 (0.90 logMAR) and the left eye was 20/125 (0.80 logMAR).  Color vision was 3 plates in the right eye and 5 in the left eye.

Examination 24 hours after initial treatment (visit 3) revealed no pupil narrowing.  The patient's right eye distance BCVA had improved to 20/100-2 (0.74 logMAR).  Left eye distance BCVA improved to 20/100+2 (0.66 logMAR).  Near BCVA in the right eye improved to 20/100 (0.70 logMAR) and to 20/80-1 (logMAR 0.62) in the left eye.  Color vision in the right eye improved to 6 plates and the left eye was unchanged at 5 plates.

The patient tolerated the medicine without any side effects.  None of the complaints of ocular burning, redness, irritation, dimming or blurring of vision, lacrimation or brow-ache associated with the traditional 0.25% and 0.125% concentrations of echothiophate iodide treatment of glaucoma have been reported by this patient.

Within the first month of therapy (visit 4), distance vision BCVA improved to 20/100-2 (0.74 logMAR) in the right eye and 20/100-2 (0.74 logMAR) in the left eye.  Near BCVA improved to 20/100 (0.70 logMAR) in the right eye and 20/80-1 (0.62 logMAR) in the left eye.  Color vision improved to 2 plates in the right eye and was unchanged in left eye.

At one year (visit 9) distance BCVA was 20/80-1 (0.62 logMAR) in the right eye and 20/80-1 (0.62 logMAR) in the left eye.  Near BCVA improved to 20/100-1 (0.72 logMAR) in the right eye and 20/100-1 (0.72 logMAR) in the left eye.  Color vision was 5 plates in the right eye and 7 plates in the left eye.

The patient exhibited significant BCVA and color vision improvement at one year:

BCVA improved as follows:

Distance vision, right eye

9 letters (1.8 lines)

Distance vision, left eye

6 letters (1.2 lines)

Near vision, right eye

9 letters (1.8 lines)

Near vision, left eye

4 letters (0.8 lines)

Color vision improved as follows:

Color vision, right eye

2 plates

Color vision, left eye

2 plates

Table 1 summarizes the patient’s distance and near visual acuity and color vision for the duration of the study.

Stargardt Disease Patient 2: BVCA Improvements

Discussion

TCM, dilute echothiophate iodide provided an effective, non-surgical therapy for this Stargardt disease patient.  After 9 months of treatment the patient reported a rapid improvement of vision. He reported that his color vision came back first.  He started to notice facial expressions and eye color for the first time in years.  He was able to identify animals, such as deer and rabbits, from a distance.  The patient was able to complete high school, graduate college and had relationships with several partners.

He was able to enjoy his favorite activities including fishing, hockey, ATVs, billiards, exercise, and has held a restricted Pennsylvania driver’s license for the past nine years.  The patient reported (email, May 14, 2021), that his life has been improved immeasurably and has had countless sighted memories with family and friends.  The patient summarized the results of treatment as “Without this opportunity many, if not all, of these [above activities] would have been impossible”.

For the last 15 years, the patient has been examined semi-annually and also followed locally by a Teacher of the Visually Impaired (TVI) in the Pennsylvania public school system (email, TVI to patient, May 14, 2021).  He has continued treatment and has maintained vision at or above baseline since initial presentation.  The TVI’s observations were consistent with the visual gains documented above.

In summary, this case study presents evidence of BCVA and color vision improvement for this Stargardt disease patient resulting from the application of low dose echothiophate.  The treatment resulted in a marked improvement of quality-of-life.

Conclusions

Stargardt disease is one of a number of degenerative retinal diseases, including dry age-related macular degeneration and retinitis  pigmentosa, which may respond to TCM therapy.  If this turns out to be the case, this therapy may hold the potential to lessen the disability from a number of blinding retinal diseases.

The exact mechanism of action of echothiophate iodide in Stargardt disease patients is not yet known.  Perhaps, dilute echothiophate iodide makes endogenous ACh more available to diseased neuroreceptor populations across the retina.  Increased ACh levels may amplify the synaptic potential of the surviving photoreceptors and ganglion cells, making it possible for these reduced populations to achieve threshold and resume the propagation of visual information to the brain. This effect would parallel previously described mechanisms of drug action in other neurological diseases, such as Parkinsonism, Alzheimer’s Disease and Clinical Depression.

Topical cholinergic medications, echothiophate iodide, pilocarpine, etc., have been a staple to treat glaucoma and strabismus.  Recently, the use of several different cholinergic therapeutics has been expanded to include treatment of presbyopia.  This case study illustrates a single Stargardt disease patient treated with a cholinergic medication, i.e., low dose (0.015%) echothiophate iodide.  The patient showed initial and long term improvement which has been maintained through a period of observation of more than 15 years.  The treatment resulted in a marked improvement of the patient’s quality-of-life.

This compares favorably to the natural degradation of visual acuity often leading to legal blindness caused by this untreatable disease.  Hopefully, the ophthalmology community will become aware of this Stargardt disease treatment regimen and add it to their tools for the treatment of this disease.

Patient consent

Written informed consent was obtained from the patient for publication of this case report. This report does not contain any personal identifying information.

Notes

  1. Michaelids M, Hunt DM, Moore AT.  The genetics of inherited macular dystrophies.  J Med Genet.  2003;40(9):641-650.
  2. IRB file number - 05175-01 (November 23, 2005) A Pilot, open-label study of low dose ocular echothiophate iodide for the treatment of Stargardt’s [sic] Disease.  Principal Investigator Number - 5575-001.  Sponsor - Independent Review Consulting, Inc. (IRC), Corte Medera, California
  3. PharmaLogic Development, Inc, San Rafael, California Ophthalmic Research and Development

Abbreviations and Acronyms:

ETDRS  =  Early Treatment Diabetic Retinopathy Study;   IRB  =  International Review Board;   RPE  =  retinal pigment epithelium;  TCM = topical cholinergic medication; WHO  =  World Health Organization