Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (S.M.A.R.T.)

Rationale

Stargardt disease (STGD) is the most common juvenile hereditary (genetic) disease of the macula and has an estimated incidence of at least 1 in 10,000 persons. The disease has been associated with mutations in at least three different genes (ABCA4, ELOVL4 and PROM1). Despite the genetic heterogeneity, a hallmark of STGD is premature accumulation of toxic yellowish material in the retinal pigment epithelium (RPE), death of the central photoreceptors (cones and rods) and the cells that support them, the RPE cells. It is the dysfunction and death of photoreceptors that accounts for the vision loss associated with STGD. Although most symptoms reported by patients with STGD are related to cone photoreceptor dysfunction (high definition vision and color vision), the mutant genes are also expressed in the rod photoreceptors, which are responsible for vision in dark conditions.

It has been found that in patients with macular degeneration, rod functional damage begins earlier and progresses more rapidly than cone sensitivity loss based on anatomic and functional measurements [1-5]. Rod dysfunction has been studied in STGD1 patients with conventional computerized threshold perimetry in a single pilot study that showed rod loss to progress more rapidly than cone loss [5].

In 2011, Dr. Crossland and collaborators described a new method to evaluate rod function using microprimetry (MP), the exam was called scotopic microperimetry [6]. The term scotopic refers to the ability of the human eye to see in the dark or very dim-light. Scotopic vision is driven by the rod photoreceptor visual pathway; therefore, scotopic tests have been largely used to identify problems in the rod system.

The fundus controlled MP technology emerged in 2003 to offer accurate identification of functionally impaired areas within the macula. The test consists of a systematic and quantitative evaluation of the macular sensitivity to different intensities of light. Due to an eye-tracking system, the technique also allows precise correlation between structural changes of the retina and the visual function, i.e., light sensitivity of the retina, at a specific point. MP-1 is the standard technique for microperimetric assessment and it tests the combined sensitivity of cones and rods.

Since scotopic vision demands very specific parameters of light wavelengths and luminance, a MP machine has to pass through a good number of adaptations and validation before being considered a scotopic exam [7]. In 2012, the MP-1 manufacturer (Nidek) released the MP-1S, a new version of the MP-1 machine, fully adapted to scotopic MP.

This novel technology is being used in the SMART study, an ancillary study of the ProgStar Prospective study envisioned to exclusively evaluate the involvement and progression of rod photoreceptor damage in STGD.

Study objectives

  • To investigate rod photoreceptor cell sensitivity during the natural course of the disease, through the multicenter prospective cohort study of the clinical course, prognosis, and risk factors for STGD (the ProgStar Study)
  • To assess the yearly rate of progression of STGD using macular sensitivity under scotopic testing conditions

Participating Sites

Johns Hopkins University School of Medicine
Wilmer Eye Institute
Hendrik P.N. Scholl, MD, MA

Greater Baltimore Medical Center
Hoover Low Vision Rehabilitation Services
Janet S. Sunness, MD

Retina Foundation of the Southwest
David G. Birch, PhD

Centre de Recherche Institut de la Vision Paris
José-Alain Sahel, MD

Universitaetsklinikum Tuebingen
Institute for Ophthalmic Research
Center for Ophthalmology
Eberhart Zrenner, MD

Moorfields Eye Hospital, NHS Foundation Trust
Michel Michaelides, MD, FRCOphth

References

  1. Scholl HPN, Bellmann C, Dandekar SS, Bird AC, Fitzke FW. Photopic and scotopic fine matrix mapping of retinal areas of increased fundus autofluorescence in patients with age-related maculopathy. Invest Ophthalmol Vis Sci 2004, 45(2):574-583
  2. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996, 37(7):1236-1249
  3. Curcio CA, Owsley C, Jackson GR. Spare the rods, save the cones in aging and age-related maculopathy. Invest Ophthalmol Vis Sci 2000, 41(8):2015-2018
  4. Owsley C, McGwin G, Jr., Jackson GR, Kallies K, Clark M. Cone- and rod-mediated dark adaptation impairment in age-related maculopathy. Ophthalmology 2007, 114(9):1728-1735
  5. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG et al. ABCA4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet 2009, 18(5):931-941
  6. Crossland MD, Luong VA, Rubin GS, Fitzke FW. Retinal specific measurement of dark-adapted visual function: validation of a modified microperimeter. BMC Ophthalmol 2011, 11:5
  7. Birch DG, Wen Y, Locke K, Hood DC. Rod sensitivity, cone sensitivity, and photoreceptor layer thickness in retinal degenerative diseases. Invest Ophthalmol Vis Sci 2011, 52(10):7141-7147