will result in a reduction in the estimate of S. Factors that affect quantal catch include pigment content, receptor alignment, and preretinal screening of the ocular media and lens. However, changes in receptor alignment and preretinal screening are negligible over the first 4 months of life. A more likely cause of the increase in sensitivity would involve one or more of the principle proteins involved in phototransduction reaching more mature concentrations over this period.

Phototransduction in retinal rods is initiated by the absorption of a quanta of light by the rod pigment, rhodopsin. The photoisomerization of a single rod pigment molecule begins a series of biochemical events that leads to a decrease in the intracellular level of cyclic quanosine 3,5¢-monophosphate (cGMP) and to the closure of some of the cGMP-gated channels in the plasma membrane of the outer segment. The closure of the cGMP-gated channels decreases the circulating “dark-current” and produces an electrical response – the “generator” for the ERG a-wave. The literature on the human infants’ rod indicates postnatal changes in the quantity of rhodopsin that they contain [38]. Low rhodopsin concentration would predict a lower value of S because fewer photons can be captured by the available rhodopsin molecules. In addition, recent work suggests that there are also regional variations in concentration of rhodopsin, at least in the developing rat retina. Measures of rhodopsin absorbances in localized regions of the outer segment suggest that the accumulation of mature rhodopsin in the developing rod depends on increasing concentrations beginning at the base of the outer segment [39].

Fulton et al. [38] estimate the total amount of rhodopsin in infant eyes to be about 1/4 and 1/2 of adult values between 32 weeks gestational age and 6 months, or about 0.6 and 0.3 log unit, respectively, less than adults. The similarity to the change in a-wave sensitivity suggests that rhodopsin concentration is the major, if not the only, limiting variable accounting for the depressed log S values. This does not preclude the possibility that immaturities in other principle proteins in the transduction cascade contribute to the reduced sensitivity. However, there is evidence that other involved proteins reach adult values before rhodopsin, at least in mice and rats [40].

We conclude that the maturational changes in a-wave parameters of the rod photoresponse can be explained within the context of a model integrating localized changes in rhodopsin concentration and increasing

numbers of available cGMP channels in the outer segment membrane. Localized increases in the concentration of rhodopsin within the stacks of outer segment disk membranes result in an increase in quantal catch, which in turn causes an increase in the concentration of diffusible substance responsible for the closure of the channels in the outer segment membrane. The number of channels that are available for closure in the developing retina will depend on the length of the outer segment.

3.1.4  Clinical Uses of the Full-Field ERG

3.1.4.1  Retinitis Pigmentosa and Allied

Retinal Degenerations

Full-field ERGs are widely used as early diagnostic indicators of genetic eye diseases such as retinitis pigmentosa. Representative recordings from a normal subject, a patient with retinitis pigmentosa, a patient with cone-rod dystrophy, and a rod monochromat are shown in Fig. 3.7. While amplitude reductions can result from a wide variety of retinal diseases, delays in b-wave implicit time are highly suggestive of progressive retinal degeneration [41]. Rod b-wave implicit time is longer than normal in young patients with X-linked [42], recessive [43], and dominant [44] modes of inheritance. Cone flicker responses are delayed in all genetic types with the exception of an occasional young patient with autosomal dominant inheritance [45].

The full-field ERG is also useful for testing female relatives of males with retinitis pigmentosa. Carriers typically show mild amplitude reductions and/or delayed cone b-wave implicit times in at least one eye [46]. When combined with a careful fundus examination, the carrier state is detectable in virtually all obligate carriers [46, 47]. The ability to detect carrier females of X-linked retinitis pigmentosa is important for determining the mode of inheritance and visual prognosis. Young women showing the carrier state can be advised that they have a 50% chance of having an affected son or a 50% chance of having a carrier daughter with each birth.

Full-field ERGs are very useful for following patients with retinitis pigmentosa. Parents of young patients are particularly concerned about the rate of change in their particular form of disease. Yearly testing can help

establish broad guidelines for counseling. Repeated measurements from an infant with a rapidly progressive, early-onset form of retinitis pigmentosa are shown in Fig. 3.8. Fortunately, the rate of progression in most patients is much less severe. The average rate of change for large samples of patients with retinitis pigmentosa has been established in prospective natural history studies [48, 49]. Although the exact percentage varies slightly from response to response, the average yearly rate of decline in amplitude was 10–19% of the remaining ERG amplitude. These studies also established guidelines for significant change in a single patient with retinitis pigmentosa by measuring within-subject variability over short periods of time. For the dark-adapted cone flicker response, for example, a decrease in amplitude of 44% was statistically significant (p <0.01).

Cone-rod dystrophy, like retinitis pigmentosa, is a widespread, progressive retinal degeneration with symptoms often first evident in childhood. Patients with cone-rod dystrophy typically show reduced visual acuity as the presenting complaint and may initially be suspected of having a genetic form of macular

degeneration such as Stargardt disease. It is only with the full-field ERG that a more widespread cone-rod dystrophy is discovered. As shown in Fig. 3.7, patients with cone-rod dystrophy show delayed cone b-wave implicit times to 30 Hz flicker. Unlike retinitis pigmentosa, however, the rod b-wave is not only present, but typically more preserved than the cone b-wave.

Occasionally, patients have severe reductions in vision without obvious retinal disease. The presenting complaint may be nystagmus, with photophobia noted later in infancy. A classic example of this is the rod monochromat, who is born with virtually complete absence of functional cone photoreceptors due to recessively-inherited mutations in either the a-subunit [50, 51] or the b-subunit [52] of the cone photoreceptor cGMP-gated cation channel. As shown in the last column of Fig. 3.7, rod monochromats have a normal rod response. The standard combined response lacks the superimposed cone oscillatory potentials. Cone responses to 30 Hz flicker and cone responses in the presence of a background are completely absent. Functionally similar to rod monochromacy is blue

cone monochromacy, an X-linked genetic disorder that leads to the loss of functional middle (M) and long

(L)-wavelength sensitive cones.

3.1.4.2 Stationary Night Blindness

Autosomal recessive, X-linked recessive, and autosomal dominant forms of congenital stationary night blindness (CSNB) all occur. The dominant form is rare

and named after the first affected member (Jean Nougaret) in a genealogy dating back to the French revolution. The more common recessive and X-linked patients typically have poor night vision from birth. However, it is often the high myopia, and best-corrected visual acuity ranging from 20/40 to 20/200, that leads to the referral for a full-field ERG. As shown in Fig. 3.9, patients with CSNB typically show a negative ERG in the standard combined response. This results from a selective reduction of the rod b-wave. Miyake [53] first

noted that patients with CSNB fall into complete and incomplete subtypes, based on psychophysically-mea- sured thresholds and rod ERG amplitudes. In addition, complete and incomplete subtypes show characteristic differences in cone ERG waveforms [54]. More recently, the genetic basis of this classification has become apparent. The complete form results from mutations in the nyctalopin gene (NYX), which encodes a leucine-rich proteoglycan that may function as an adhesion molecule specifying the formation of synapses in the ON-pathway [55]. The incomplete form results from mutations in the a-1 subunit of the L-type calcium-channel gene (CACNA1F) [56].

3.1.4.3 Enhanced S-Cone Syndrome

Enhanced S-cone syndrome (ESCS) is an autosomal recessive retinal degenerative disease characterized

by night blindness and hypersensitivity of the S (blue) cone system. Although the phenotype is present from birth, the fundus typically appears normal in infancy and, therefore, the full-field ERG is instrumental in the diagnosis. It is known to be caused by mutations in the NR2E3 gene, which lead to an abnormality in cell-fate determination [57]. In patients with ESCS, the photoreceptor mosaic is dominated by cones expressing short-wavelength (S) opsin, while few cones express long/middle wavelength (L/M) opsin [58]. As shown in Fig. 3.9, the rod system is severely depressed in these patients so that very little signal is present in the standard rod ERG. The combined standard ERG has an a-wave that is as large as or larger than normal. The most unusual and distinctive feature is that this response remains essentially unchanged in the presence of a rod-saturating background [59]. The cone responses from L/M cones, which dominate the response to 30 Hz flicker ERGs,