(Investigative Ophthalmology and Visual Science. 2001;42:675-678.)
© 2001
by The Association for Research in Vision and Ophthalmology, Inc.
The Pupil in Dominant Optic Atrophy
Fion D. Bremner1,
Elizabeth A. Tomlin1,
Josephine Shallo–Hoffmann2,
Marcela Votruba3 and
Stephen E. Smith1
1 From the National Hospital for Neurology and Neurosurgery and
2 Moorfields Eye Hospital, London, United Kingdom; and the
3 College of Optometry, Nova Southeastern University, Fort Lauderdale, Florida.
 |
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.
|
Introduction
|
|---|
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 perimetry1
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 States10
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
|
Methods
|
|---|
Subjects
Patients with clinically definite DOA were identified from the
Moorfields Genetic Clinic register. They were recruited into this study
if linkage analysis confirmed that they came from a family or pedigree
showing evidence of linkage to chromosome 3q28-qter,9
if
their visual function was poor (eligible for partial sight or blind
registration), and if they had no other medical condition and were not
taking any drugs likely to affect the visual system or the pupil light
reflex pathway (for example, patients with diabetes mellitus were
excluded). Eighteen patients from eight different pedigrees meeting
these criteria were examined (median age, 38 years; range, 16–66;
male-to-female ratio, 10:8). In all cases the onset of visual loss had
been in the first decade, with an interval of between 12 and 56 years
before evaluation in this study. For comparison, the tests were also
performed on 24 healthy control subjects (median age, 28 years; range,
21–51; male-to-female ratio, 12:11). The study followed the tenets of
the Declaration of Helsinki and was approved by the Ethical and
Scientific Committee of Moorfields Eye Hospital. All patients with DOA
and healthy control subjects gave informed written consent before
participating in this study.
Tests
Corrected distance acuity was determined using an illuminated
Snellen chart under standard room lighting conditions. Visual and pupil
perimetry were performed under mesopic conditions on the preferred eye
according to the methods described in Bremner et al.7
In
brief, an automated static perimeter was used to estimate the
perceptual thresholds at five locations in the visual field (fixation,
and at 17° eccentricity in the 45° and 135° meridians in each of
the four quadrants). To test pupil afferent function, a standard
intensity (4000 apostilb [asb]) suprathreshold light stimulus
(duration 500 msec) was then presented repeatedly at the same five
locations and the pupil responses recorded using infrared video
pupillographic techniques. The order of stimulus presentation and the
interstimulus interval (median, 5 sec; range, 4–6 sec, allowing full
recovery to baseline diameter between stimuli) were varied
pseudorandomly using customized software. In each patient and at each
test location the visual deficit (in decibels) was defined as the
difference between the patient’s perceptual threshold and that found
in normal age-matched control subjects. The pupil deficit (in decibels)
was defined as the difference between the stimulus intensity giving the
patient’s pupil response and that giving an equivalent pupil response
in normal age-matched control subjects.7
Analysis
Standard descriptive statistics have been used to summarize the
visual and pupil deficits at each of the five stimulus locations.
Medians are quoted rather than means, because with the patient
selection criteria, we could not assume the data were normally
distributed. At each location, the estimates of visual deficit were
compared with the estimates of pupil deficit by Wilcoxon’s
signed-ranks test. These results from patients with DOA were compared
with previously published results from patients with
LHON.7
|
Results
|
|---|
The visual acuities in this cohort of patients with DOA were all
poor, ranging from 6/18 to 1/120 (median 3/60). Only 2 of 18 patients
could read more than the test plate of the Ishihara pseudoisochromatic
color plates. Static perimetry within the central 30° field showed
three patterns of loss: a central scotoma (seven patients), diffuse
loss (six patients), or patchy loss (five patients). Threshold
estimations confirmed deficits at all five test locations, with the
deficits being on average greater at fixation (median = 17.5
dB) than at the eccentric locations (median deficit range, 6.5–11.5
dB; see Fig. 1 ).
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1. Results of threshold visual perimetry in patients with DOA. Median
visual deficit ±95% confidence intervals (defined as the difference
between the patient’s perceptual threshold and that measured in
healthy age-matched control subjects) at each of five stimulus
locations: fixation (F) and at 17° eccentricity along the 45° and
135° meridians in the quadrants of the visual field.
|
|
When examined by slit lamp, the patients with DOA all had pupils of
normal size and appearance and that constricted normally during an
accommodative effort. The pupillary responses to standard-intensity
(suprathreshold) light stimuli presented at each of the five test
locations were recorded. The latency and morphology of the reflex
responses in the patients with DOA appeared grossly normal (after
allowing for differences in response size), but the responses were
generally smaller than those recorded from healthy control subjects.
The results are summarized in Figure 2
. At fixation, the pupil responses were more than 40% smaller in the
patients with DOA than in the control subjects (P <
0.001, Student’s unpaired t-test). At the four eccentric
locations there was less difference in the size of the pupil responses
(superotemporal [ST]: 15% smaller, P = 0.03;
inferotemporal [IT]: 21% smaller, P = 0.006;
superonasal [SN]: 11% smaller, P = 0.11; inferonasal
[IN]: 17% smaller, P = 0.05).
View larger version (16K):
[in this window]
[in a new window]
|
Figure 2. Results of pupil perimetry. A standard intensity (4000 asb)
suprathreshold light stimulus was presented at each of the five
stimulus locations shown along the abscissa. The median size of the
pupil response (expressed as percentage of constriction of the pupil
area) ±95% confidence intervals is shown for patients with DOA
(filled symbols) and healthy control subjects
(open symbols).
|
|
The measurements of pupil response size in patients with DOA were
converted into estimates of afferent pupil deficit by interpolation
from previously published data relating stimulus intensity and pupil
response size in normal subjects.7
Figure 3
shows these pupil deficits plotted against the corresponding estimates
of visual deficit for light stimuli presented at fixation. In some
patients, the estimate of pupil deficit was greater than the estimate
of visual deficit. In other patients, the pupil deficit was smaller,
but overall, there was no significant difference between estimates of
pupil and visual deficit at fixation (P = 0.407,
Wilcoxon signed-ranks test). In contrast, a significant difference was
found at the four peripheral test locations (see pooled data in Fig. 4 ). When the stimulus was presented peripherally, the pupil deficits were
generally smaller than the visual deficits, with the median difference
being 6.3 dB (P < 0.001, Wilcoxon signed-ranks test).
View larger version (18K):
[in this window]
[in a new window]
|
Figure 3. Comparison of estimates of visual deficit and pupil deficit at fixation
in patients with DOA. Diagonal line: Equity where pupil
deficit is equal to visual deficit.
|
|
View larger version (22K):
[in this window]
[in a new window]
|
Figure 4. Scatterplot comparing estimates of visual deficit and pupil deficit at
the four peripheral test locations (ST, IT, SN, IN) in patients with
DOA. Diagonal line: equity where pupil deficit is equal
to visual deficit.
|
|
We summarize the averaged results for each of the five test locations
in Figure 5
. At fixation, the average pupil and visual deficits were not
significantly different. Peripherally, the average pupil deficit was
smaller than the average visual deficit at all four test locations. The
difference between estimates of pupil and visual deficit peripherally
showed some variation according to the tested quadrant (ST = 9.5
dB; IT = 5.3 dB; SN = 5.4 dB; IN = 6.3 dB),
but these differences did not achieve statistical significance
(P > 0.05, analysis of variance [ANOVA]). The size
of this pupillovisual dissociation appeared similar in all the
pedigrees examined and did not appear to correlate with age, gender,
pattern of visual field loss, extent of visual deficit or duration of
visual symptoms.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 5. Comparison of visual and pupil deficits in DOA. Data are median
estimates of pupil deficit (open symbols) and visual
deficit (filled symbols) ±95% confidence intervals at
each of the five stimulus locations tested.
|
|
There was some variation in the degree of pupillovisual dissociation
found in different patients with DOA. This is illustrated in Figure 6 : The ordinate shows the average difference between corresponding
estimates of visual and pupil deficit in each patient (from all test
locations), and the abscissa shows the rank order of these observed
differences. Measurements from patients with DOA are shown in filled
bars on the histogram. There were two patients who showed more pupil
deficit than visual deficit, but in the remaining 16 patients, the
visual deficits exceeded the pupil deficits. These estimates of
pupillovisual dissociation appear evenly distributed, and there is no
evidence of subgroups within this cohort showing different results. For
comparison, we show data from patients with LHON7
(open
bars; n = 19): The distributions of results from both
cohorts of patients are similar.
View larger version (24K):
[in this window]
[in a new window]
|
Figure 6. The distribution of results among patients with DOA (filled
bars) and LHON (open bars).
Ordinate: Average pupillovisual dissociation shown by
each patient, calculated by determining the mean of the difference
between corresponding estimates of visual deficit (VD) and pupil
deficit (PD) for all locations tested in the visual field. A positive
value indicates that, on average, visual deficits exceeded pupil
deficits in that particular patient (and vice versa).
Abscissa: Rank order of patients according to degree of
pupillovisual dissociation.
|
|
|
Discussion
|
|---|
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.
|
Footnotes
|
|---|
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{at}doctors.org.uk
|
References
|
|---|
-
Stanley, Thompson H, Montague, P, Cox, TA, Corbett, JJ (1982) The relationship between visual acuity, pupil defect and visual field loss Am J Ophthalmol 93,681-688[Medline][Order article via Infotrieve]
-
Kardon, RH, Haupert, CL, Stanley, Thompson H (1993) The relationship between static perimetry and the relative afferent pupil defect Am J Ophthalmol 115,351-356[Medline][Order article via Infotrieve]
-
Johnson, LN, Hill, RA, Bartholomew, MJ (1988) Correlation of afferent pupil defect with visual field loss on automated perimetry Ophthalmology 95,1649-1655[Medline][Order article via Infotrieve]
-
Kardon, RH, Kirkali, PA, Thompson, HS (1991) Automated pupil perimetry: pupil field mapping in patients and normal subjects Ophthalmology 98,485-496[Medline][Order article via Infotrieve]
-
Nakanishi, M, Mashima, Y, Hiida, Y, Suzuki, S, Oguchi, Y. (1994) Two cases of Leber’s hereditary optic neuropathy diagnosed as psychogenic visual loss [in Japanese] Ganka 36,811-814
-
Wakakura, M, Yokoe, J. (1995) Evidence for preserved direct pupil light response in Leber’s hereditary optic neuropathy Br JOphthalmol 79,442-446[Abstract/Free Full Text]
-
Bremner, FD, Shallo–Hoffmann, J, Riordan–Eva, P, Smith, SE (1999) Comparing pupil function with visual function in patients with Leber’s hereditary optic neuropathy Invest Ophthalmol Vis Sci 40,2528-2534[Abstract/Free Full Text]
-
Kjer, B, Eiberg, H, Kjer, P, Rosenberg, T. (1996) Dominant optic atrophy mapped to chromosome 3q region: clinical and epidemiological aspects Acta Ophthalmol Scand 74,3-7[Medline][Order article via Infotrieve]
-
Votruba, M, Moore, AT, Bhattacharya, SS (1997) Demonstration of a founder effect and fine mapping of dominant optic atrophy locus 3q28-qter by linkage disequilibrium method Hum Genet 102,79-86
-
Kerrison, JB, Arnould, VJ, Sallum, JMF, et al (1999) Genetic heterogeneity of dominant optic atrophy, Kjer type Arch Ophthalmol 117,805-810[Abstract/Free Full Text]
-
Seller, MJ, Behnam, JT, Lewis, CM, Johnston, RL, Burdon, MA, Spalton, DJ (1997) Linkage studies in dominant optic atrophy, Kjer type: possible evidence for heterogeneity J Med Genet 34,967-972[Abstract]
-
Votruba, M, Fitzke, FW, Holder, GE, Carter, A, Bhattacharya, SS, Moore, AT (1998) Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy Arch Ophthalmol 116,351-358[Abstract/Free Full Text]
-
Price, MJ, Thompson, HS, Judisch, GF, Corbett, JJ (1985) Pupillary constriction to darkness Br J Ophthalmol 69,205-211[Abstract/Free Full Text]
-
Bremner, FD, Tomlin, EA, Shallo–Hoffmann, S, Votruba, M, Smith, SE (2000) Comparing pupil and visual afferent fibre function in dominant optic atrophy Invest Ophthalmol Vis Sci 41(4),S310Abstract nr 1638.
-
Kivlin, JD, Lovrien, EW, Bishop, DT, Maumenee, IH (1983) Linkage analysis in dominant optic atrophy Am J Hum Genet 35,1190-1195[Medline][Order article via Infotrieve]
This article has been cited by other articles:
|
|
|
|
 
K. J. Kim and F. Rieke
Slow Na+ Inactivation and Variance Adaptation in Salamander Retinal Ganglion Cells
J. Neurosci.,
February 15, 2003;
23(4):
1506 - 1516.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
