The full-field ERG responses of our ESCS patient are the typical
slow waveforms of this syndrome (indeed, this subject was one of the
initial cases that defined this syndrome),
1 7 and the lack
of progression in 9 years is consistent with other reports that suggest
a stationary or extremely slow progressive disorder.
10
The normal multifocal ERG to white light shows little change in ERG
waveform across the posterior pole. Our results show that the
multifocal ERG in ESCS is characterized by a marked difference between
responses from the central macula (within 5–7° of the foveal center)
and those from more peripheral regions (7–20° eccentricity). In the
central area the ESCS responses had a relatively normal waveform that
was only modestly delayed in a-wave and b-wave time-to-peak. In the
more peripheral regions the waveforms showed a striking prolongation of
the a-wave, and the b-wave time-to-peak was much slower than normal.
The peripheral responses to white light match closely the appearance
and timing of the full-field ERG in ESCS.
The results to colored stimulation are more complicated. The full-field
ERG in ESCS shows much greater blue sensitivity than normal. However,
in the areas of posterior retina covered by the multifocal ERG, we
found blue responses to be only about twice normal in amplitude,
whereas red responses were of normal size. In the central 7° of
eccentricity, the ESCS responses to red and blue were relatively normal
in waveform (a bit delayed to blue stimuli). But in the more peripheral
areas (9–20° from center), the ESCS waveforms to both red and blue
were very prolonged and there was a marked difference in b-wave
time-to-peak between stimulation with red (50 msec) or blue (80 msec)
light.
How can these findings be explained? In a normal eye S cones are absent
in the central 100 μg of the foveola, but constitute 1% to 2% of
the cones in the fovea (with a density of
1–2000/mm
2), and approximately 8% of cones at
4° from the center.
4 If S cones increase to 75 times
normal density and replace rods in ESCS, as suggested by Hood et
al.,
3 there would be plenty of room for S cones outside
the macula where rods can reach a maximum density of approximately
140,000/mm
2, and S cones are normally only
600/mm
2. However, there would not be enough room
for a 75-fold increase in S cones added to the normal population of L
and M cones in the fovea (with a peak density of 140,000
mm
2).
11 Any large increase in S
cones in the foveal region would, to some degree, have to be at the
expense of L and M cones.
ESCS patients have trichromatic cone function centrally because they
have good acuity and color vision. However, the full-field cone ERG
signal to red light or 30-Hz flicker is weak. One possibility is that
ESCS patients have modestly reduced numbers of central L and M cones
(perhaps 50% of normal, as suggested by the borderline maculoscope
amplitudes), whereas the loss of peripheral L and M cones is more
severe (perhaps to 10%–20% of normal) to account for the low
full-field L and M cone ERG. An alternative possibility is that the
peripheral L and M cone pathways are abnormal so that the b-wave
responses are altered (as discussed further below). S-responding cones
in ESCS may have a density roughly 75 times normal over most of the
peripheral retina, but are perhaps only 20 to 30 times normal in the
central macula to allow space for the retained L and M cones. These
distributions would account in many respects for our ERG amplitude
results. The central ERG in ESCS is more blue- than red-sensitive,
because with blue stimuli there would be by this estimation 20 to 30
times more S cones than normally available to produce a response.
However, the response to red light should represent L and M cones only,
because the S cone spectral sensitivity curve does not reach
significantly into the band-pass of the red Wratten 29 filter. We thus
conclude that the peripheral response to red light owes its highly
abnormal waveform to an abnormal L and M cone pathway in the ESCS
patient. On the other hand, the spectral sensitivity of the M cones
does extend into the band-pass of the blue Wratten 47B filter. This is
confirmed by the relatively normal-looking L and M cone responses to
blue stimulation of the normal eye. In the ESCS patient, however, blue
stimulation produces additional waveforms that are not seen with the
red stimulus and that we presume represent responses from the large
numbers of S cones. The central b-wave has acquired a second peak at
around 42 msec (•), and there is a large and broad late peripheral
component peaking near 80 msec (♦), to which we found no homologous
feature in the normal eye.
The receptor potentials of L, M, and S cones have been shown to be
essentially identical.
12 Thus, the differences in b-wave
waveforms between normal S cones and normal L and M cones must reflect
differences in the pathway of these signals through the retinal
circuitry. Although L and M cones feed onto on- and off-bipolar cells,
both rods and S cones are believed to use predominantly an on-bipolar
pathway. This may underlie why the normal S cone ERG is slower and more
rod-like than the conventional L- and M-dominated cone ERG.
Alternatively, S cones may excite different systems of horizontal
cells, other integrative cells, or both, which modulate and slow the
development of the inner retinal potential changes that create the
b-wave. Greenstein et al. have shown that the S-sensitive cells in ESCS
are cones rather than rods.
13 The normal trichromatic
vision in ESCS suggests that L, M, and S cones centrally communicate
through relatively normal pathways. Indeed, the normal S cone ERG has a
time-to-peak of approximately 40 msec,
14 which is similar
to the 45-msec b-wave peak to blue light in the central rings of our
ESCS patient. Outside of the central macula, however, this 45-msec peak
diminishes rapidly and is overshadowed by a larger and slower response
that peaks closer to 80 msec (which is long even for a rod response).
It is conceivable that in the central macula of ESCS, the S cones use
predominantly normal S cone pathways through the retina, whereas in the
periphery where the massive numbers of S cones occupy space normally
occupied by rods, the S cones communicate abnormally through rod
pathways and generate an unusually slow b-wave response.
These explanations may also apply to the changes in a-wave
time-to-peak between the center and periphery. However, some of this
apparent shift in a-wave time-to-peak may reflect the fact that a
slower b-wave process in the periphery would be slower to reverse the
negative response of the a-wave.
One puzzling aspect of our data is the difference in the timing of ESCS
responses to red and blue light. In the central area, red light induces
a rapid b-wave that is delayed only slightly relative to normal. This
probably represents primarily a response of the L and M cones that are
present centrally in ESCS but may include a contribution from the
normal S cone ERG. However, it is harder to explain why the prominent
ESCS response to red light in the periphery peaks near 55 msec, and
thus is too slow for a normal S cone response but is more rapid than
the peripheral (possibly rod-pathway) S cone response in ESCS. This
difference in timing between red and blue peripheral responses in ESCS
is unlikely to be a result of differences in the effectiveness of our
red and blue stimuli on the S cone system alone, because the latter
should not respond at all to the red light. It seems more likely that
the peripheral L and M cones are in some way using or interacting with
the peripheral S cone pathways, rod on-pathways, or both. Neural
connections between different bipolar pathways are known at the
amacrine cell level,
15 although it is not known how they
affect ERG recordings. The timing differences between red and blue
peripheral responses may also reflect some aspect of the interactive
mechanism that leads to the differences in b-wave timing between normal
S and normal L and M cones, or reflect other differences in inner
retinal pathways that are unknown at present. The white light waveforms
in ESCS (↓ and ⇓ in
Fig. 4 ) have times-to-peak that are faster than
the blue-stimulus times-to-peak. These may in part represent summations
of the red and blue waveforms but may also reflect the tendency for
b-waves to show faster times-to-peak with brighter stimuli. The
responses from the normal eye were also faster to white stimuli, which
in these experiments were 100-fold brighter than red and blue.
Some further support for these general speculations on cone
distribution comes from our data on the on–off responses. Our data
from the normal subject are consistent with the finding of Kondo et
al.
16 that the amplitude of the off-response, relative to
the b-wave, increases with eccentricity. Our ESCS patient showed
off-responses in the central retina that were close in latency to those
from normal cones, but those in the peripheral retina seemed to be
absent. This can be explained if off-responses from the center are
dominated by the L and M cone circuitry, which appears to be functional
in this region of the ESCS eye. Off-responses have been observed in the
full-field ERG of some ESCS eyes, even though S cone pathways seem
primarily to use on-bipolar cells.
17 Our results suggest
that regional differences may be relevant to understanding these
observations.