Abstract
purpose. To compare visual and pupil afferent function in dominant optic atrophy
(DOA).
methods. Patients with DOA who belonged to families showing evidence of linkage
to the locus on chromosome 3q28-qter were recruited from the Moorfields
Genetic Register. Patients and healthy control subjects underwent
visual and pupil perimetry using a modified automated perimeter
(Octopus 1-2-3; Interzeag, Schlieren, Switzerland). Five stimulus
locations were tested: fixation, and at 17° eccentricity along the
45° and 135° meridians in all four quadrants. The visual deficit
(difference in decibels between the patient’s luminance threshold and
that in age-matched healthy control subjects) was compared directly
with the pupil deficit (difference in decibels between the stimulus
intensity giving the patient’s pupil response and that giving an
equivalent pupil response in healthy control subjects) at each test
location.
results. Visual deficits and pupil afferent deficits were found at all five
locations. The visual deficits were significantly greater than the
pupil deficits at the four peripheral locations (median difference = 6.3 dB, P < 0.001). At fixation, the difference
was not significant (median difference = 2.3 dB, P = 0.407).
conclusions. Pupil function appears less affected than visual function at four of
five locations tested. This result provides evidence that the
retinotectal fibers serving the pupil light reflex are less susceptible
to damage from the OPA1 genetic defect than the
retinogeniculate fibers serving vision.
The response of the pupil to light is invariably diminished
in optic neuropathies. When tested with a full-field light stimulus,
the size of the afferent pupil defect correlates well with the
proportion of field lost in kinetic perimetry
1 or the mean
defect in static automated perimetry.
2 3 When tested using
smaller light stimuli presented at discreet locations in visual space
(pupil perimetry), the pattern of afferent pupil deficit matches well
the pattern of visual loss.
4 These findings may be
interpreted either as evidence that the afferent pupil drive is
conveyed by collateral branches of the retinogeniculate fibers
mediating visual perception or that pupil afferent and visual afferent
fibers in the optic nerve have similar susceptibility to damage.
The universality of this correlation between afferent pupil and visual
function was recently brought into question by reports that patients
with Leber’s hereditary optic neuropathy (LHON) show better pupil
responses than would be expected from their poor visual
function.
5 6 7 The existence of pupillovisual dissociation
led us to hypothesize that the afferent pupil drive in humans may be
conveyed by a subpopulation of ganglion cells, which are largely
separate from the retinogeniculate system. In LHON, these pupil
afferent fibers appear to be less susceptible to the damaging effects
of the Leber’s mutation than the visual afferent fibers.
7
Compared with LHON, autosomal dominant optic atrophy (DOA) is a more
common inherited disease of the optic nerve with a prevalence of
approximately 1:10,000.
8 The majority of pedigrees show
linkage to a locus on chromosome 3q28-qter
(
OPA1)
9 although genetic heterogeneity has now
been demonstrated both in the United States
10 and in the
United Kingdom.
11 DOA shares some clinical features in
common with LHON, both conditions being characterized by bilateral,
symmetrical, central scotomata with relative preservation of the
peripheral field.
12 We are not aware of any published
studies of pupil function in DOA, although there is a single reported
case of paradoxical pupillary constriction to darkness.
13 In the present study we have investigated afferent pupil and visual
function in a genetically homogeneous cohort of patients with DOA to
determine whether pupillovisual dissociation is unique to LHON or can
be demonstrated in other inherited ganglion cell disorders. A
preliminary account of this study has been published
elsewhere.
14
In this study, we investigated visual and pupil function in
patients with DOA recruited from the Moorfields Genetic Register. In
all the pedigrees tested, the inheritance pattern was unequivocally
autosomal dominant with linkage to the same locus on 3q28-qter. On this
basis our cohort appears to be genetically homogeneous, although once
the
OPA1 gene is identified it may turn out that different
pedigrees have different mutations. The penetrance of
OPA1 is almost 100%,
15 but its expression is highly variable,
with visual loss ranging from subclinical deficit to
blindness.
12 For the purposes of this investigation we
have selected patients with severe visual loss (median VA = 3/60),
and it may not be possible to generalize our results to patients with
DOA at the milder or subclinical end of the spectrum.
The pupils in this cohort of patients with DOA were normal in size and
appearance with no signs of efferent deficit. We did not specifically
look for paradoxical constriction in response to darkness, but this
abnormal light-off response is of dubious localizing or clinical value
and has been reported in only one case of DOA in the
literature.
13 The only pupil abnormality found in our
cohort of patients with DOA was an afferent defect in the pupil light
reflex, supporting the clinical impression of DOA as an isolated optic
neuropathy with no associated dysfunction in the central or autonomic
nervous systems.
When visual and pupil perimetry results were compared at peripheral
test locations, the visual deficits significantly exceeded the pupil
deficits. Is this pupillovisual dissociation real or an artifact due
perhaps to eccentric fixation, patient strategy, or our method of
estimating the visual and pupil deficits? Fixation is always an issue
when attempting perimetry in patients with central scotomata. Without
directly visualizing the retinal locations stimulated during perimetry,
we cannot exclude the possibility that some or all our patients with
DOA adopted nonfoveal fixation. However, our experience in healthy
control subjects has been that unlike testing function at fixation,
measurements of pupil and visual sensitivity at 17° eccentricity
remain similar, even with quite marked degrees of eccentric fixation.
Moreover, when monitoring eye position using the video camera images
during testing, it was our impression that patients adopted similar
fixation strategies in both types of test. If this was the case then
visual and pupil function were compared at approximately the same
locations.
We have considered the possibility that our method of evaluating pupil
function systematically underestimates the size of the pupil deficit,
giving rise to spurious pupillovisual dissociation. The pupil response
amplitudes are routinely normalized with respect to the baseline pupil
area. We have reanalyzed our data using absolute measurements of pupil
response amplitude and found no difference in the overall results.
Furthermore, when testing a different cohort of patients recovering
from demyelinating optic neuritis (Bremner FD, unpublished data,
2000) we found that the pupil deficits exceeded the visual
deficits, demonstrating that pupil-sparing is not an inevitable
consequence of our methodology.
The data at fixation showed a smaller nonsignificant difference between
pupil and visual deficits in contrast to the striking pupillovisual
dissociation seen peripherally. At present, we are not certain how to
interpret this different result. It may be that after many years of
central visual loss the patients with DOA adopted eccentric fixation.
The effect of this would be a substantial overestimation of the pupil
deficit, but it might make less difference to measurements of luminance
threshold. The general point is that in patients with central visual
loss, pupillovisual dissociation may be more difficult to assess at
fixation, when the preferred retinal locus (PRL) has a substantial
influence but easier to detect in the periphery, where the PRL has less
effect on the measurements.
The results of this study are in broad agreement with those obtained in
patients with LHON, namely that estimates of visual deficit exceed
those of pupil deficit. Moreover, the degree of this pupillovisual
dissociation in DOA (6.6 dB) is similar to that found in LHON (7.5
dB).
7 These findings suggest that pupil afferent fibers
are not as susceptible to damage as retinogeniculate fibers from either
the
OPA1 defect or any of the primary LHON
mutations.
Supported by The Joseph Levy Foundation, which provided a grant used to
purchase the pupil perimetry equipment. EAT and JS-H were in part
supported by a grant from The Iris Fund.
Submitted for publication August 30, 2000; revised October 30, 2000;
accepted November 15, 2000.
Commercial relationships policy: N.
Corresponding author: Fion D. Bremner, Department of
Neuro-ophthalmology, National Hospital for Neurology and Neurosurgery,
Queen Square, London WC1N 3BG, UK.
fdbremner@doctors.org.uk
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