Spotlight Case: The Answer Is in the ERG

Paula Pecen, MD

Amy S. Babiuch, MD

Case history

 A 29-year-old Iraqi male who moved to the United States in 2013 presents for evaluation. He complains of a 10-year history of floaters with recent onset of flashes in both eyes. He also notes a long history of nyctalopia and states that he was diagnosed with an eye disease in Baghdad when he was 15 years old. A review of systems is notable for intermittent headaches. Family history of eye disease or major medical problems is negative.

Best-corrected visual acuity (BCVA) measured 20/40 in the right eye and 20/30 in the left eye. Pupils were minimally reactive to light in both eyes, with no afferent pupillary defect (APD). Confrontation visual fields revealed peripheral constriction in both eyes. Intraocular pressure (IOP) and extraocular motility were within normal limits. Anterior segment examination was significant for mild posterior subcapsular cataract in both eyes.

Fundus examination was notable for vitreous condensation, especially at the vitreous base in both eyes. Both optic nerves had small cup-to-disc ratios with mild pallor. Retinal pigment epithelial (RPE) changes were noted in both maculas. The periphery of both eyes revealed arteriolar narrowing, pigment clumping, and chorioretinal atrophy (Figure 1).

Figure 1: Wide-field fundus photos of the right and left eyes

Figure 2: Horizontal OCT scan of the right eye and vertical OCT scan of the left eye

OCT of the right and left macula demonstrated trace cystic retinal changes in both eyes (Figure 2). Fluorescein angiography (FA) exhibited normal arteriovenous transit times with no abnormal macular leakage. Electroretinogram (ERG) demonstrated significantly diminshed response to dim light in the dark-adapted state (Figure 3A). Responses to bright light under both dark- and light-adapted conditions reveal similarly delayed and reduced waveforms by about 30-50% (Figure 3B and 3C, respectively).

Figure 3A

Figure 3B

Figure 3C

Figure 3:  ERG showing significantly diminished response to dim light in the dark-adapted state (A) responses to bright light under dark-adapted (B) and light-adapted (C) conditions, both demonstrating similarly delayed and reduced waveforms by about 30-50%

What’s your diagnosis?

Clinical exam findings, including nummular pigmentary changes outside the arcades and trace cystoid changes on OCT, point to a vitreoretinal degenerative disease. An ERG revealing nearly extinguished rod responses, and similar responses to a standard single flash in both light-adapted and dark-adapted states, is suggestive of enhanced S-cone syndrome (ESCS). Further, genetic testing with a positive mutation in NR2E3 (retinal nuclear receptor subfamily 2, group E, member 3) clinches the ESCS diagnosis.

Discussion

ESCS was first described in 1990 as an autosomal recessive disorder related to mutations in NR2E3. Mutations in NR2E3 are also associated with Goldmann-Favre syndrome and clumped pigmentary retinal degeneration. These 3 retinal degenerative conditions display some phenotypic overlap and may be along a single disease spectrum.

NR2E3 is expressed in the outer nuclear layer of the retina and is thought to normally suppress cone differentiation during embryogenesis. A loss of NR2E3 function results in decreased expression of rod photoreceptors and an increase in cone photoreceptors, specifically expressing the S-cone opsin, at the expense of the M- and L-cones.[1]

Patients with ESCS will often complain of nyctalopia in the first decade of life. A dark-adapted scotopic rod ERG will usually be undetectable due to the absence of rods. Both the dark-adapted and light-adapted photopic ERGs will have similar delayed, reduced responses, as both responses are driven by the S-cone system.[2]

Typical fundus findings include nummular pigmentary changes at the level of the RPE located outside the vascular arcades, which may lead to peripheral field constriction. Cystoid or schisis changes in the macula without leakage on FA are also common. Patients may also exhibit circumferential fibrosis of the macula or peripapillary area, torpedo-like lesions along the arcades, or yellow dots in normal areas of the peripheral retina.[3]

Due to variability in presentation, patients with ESCS are often misdiagnosed as having atypical retinitis pigmentosa (RP), congenital stationary night blindness (CSNB), or X-linked retinoschisis. Patients with both RP and CSNB also complain of nyctalopia and exhibit diminished rod responses on ERG; however, neither syndrome will lead to similar responses to bright light in the dark-adapted and light-adapted ERG states as seen in ESCS. Patients with X-linked retinoschisis conversely deny nyctalopia and will have a history of X-linked inheritance.

There is no known effective treatment for this condition. If retinal tears or rhegmatogenous retinal detachment occur, standard vitreoretinal management is recommended.

Take-home points

  1. Typical fundus findings in ESCS are nummular pigmentary changes at the level of the RPE outside the vascular arcades and cystoid or schisis changes in the macula.
  2. A rod ERG will be nearly undetectable, and both light- and dark-adapted photopic ERGs will have similar, delayed, reduced responses in ESCS. This aids in differentiation from RP and CSNB.
  3. ESCS will exhibit a genetic mutation in NR2E3.
  4. There is no known treatment of ESCS.

References

  1. Tang S, Ding X, Luo Y. Hereditary vitreoretinal degenerations. In: Retina. 5th ed. New York, NY. Elsevier; 2013:847-848. doi:10.1016/B978-1-4557-0737-9.00041-2.
  2. Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs: A review and update. Retina. 2013;33(1):5-12. doi:10.1097/IAE.0b013e31827e2306.
  3. Yzer S, Barbazetto I, Allikmets R, et al. Expanded clinical spectrum of enhanced S-cone syndrome. JAMA Ophthalmol. 2013;131(10):1324-1330. doi:10.1001/jamaophthalmol.2013.4349.

 

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