(Investigative Ophthalmology and Visual Science. 1999;40:2528-2534.)
© 1999
by The Association for Research in Vision and Ophthalmology, Inc.
Comparing Pupil Function with Visual Function in Patients with Leber’s Hereditary Optic Neuropathy
Fion D. Bremner,
Josephine Shallo–Hoffmann,
Paul Riordan–Eva and
Stephen E. Smith
From the Department of Neuro-ophthalmology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
 |
Abstract
|
|---|
PURPOSE. To compare pupil function with visual function in patients with
Leber’s hereditary optic neuropathy (LHON) and age-matched normal
control subjects.
METHODS. Visual function was assessed by measuring the perceptual thresholds at
five central locations in the visual field using automated static
perimetry. Pupil function was assessed by recording the pupil responses
to a standard intensity light stimulus (size equivalent to a Goldmann V
target) presented at the same five locations in the visual field. The
extent of the pupil afferent defect in LHON patients was quantified by
establishing the relationship between stimulus intensity and the size
of the pupil response in normal subjects and then interpolating the
equivalent luminance deficit in LHON patients from the size of their
pupil responses.
RESULTS. At all five locations tested, the pupil responses were significantly
reduced in amplitude, and the perceptual thresholds were significantly
raised in LHON patients compared with normal control subjects. A
nonparametric analysis of perceptual and pupil responses to
perithreshold stimuli showed that a stimulus that was not perceived was
three times more likely to be followed by a pupil response in a LHON
patient than in a normal subject (P < 0.001). A
quantitative comparison showed that the visual deficits exceeded the
pupil deficits by on average 7.5 dB at all tested locations.
CONCLUSIONS. Although both visual and pupil function are abnormal in LHON, there
appears to be relative sparing of the pupil afferent
fibers.
|
Introduction
|
|---|
Leber’s hereditary optic neuropathy (LHON) is a rare disease
associated with mutations in mitochondrial rather than nuclear DNA.
Affected patients typically experience profound bilateral visual loss
(<6/60 in >95% of cases1
) with poor recovery. The
visual field most commonly shows a dense, large central scotoma.
Despite the poor visual function in this group of patients, it has
often been observed that the pupil shows a relatively normal response
to light.2
3
4
This clinical impression has been supported
by some studies in which infrared videopupillography was
used5
but not by other studies.6
If the pupil afferent pathway is not affected in LHON, then such
pupillovisual dissociation has intriguing implications regarding the
mechanism of damage in this disease. This would, however, be a
surprising result in that afferent pupil defects are invariably present
in other optic neuropathies. An alternative explanation is that the
pupil responds well in LHON patients because when tested with a
full-field light stimulus, the afferent drive from the intact
peripheral field is sufficient to generate apparently normal pupil
reflexes. Jacobson et al.7
recently reported a series of
10 cases of LHON in which vision had been lost in only one eye. Using
the swinging flashlight test and a full-field stimulus, they found a
relative afferent pupil defect (RAPD) in all cases and concluded that
the size of the RAPD matched the extent of the visual field defect with
no evidence of pupillovisual dissociation.
In the present study we have taken a different approach to this
question. Using a modified automated perimeter, we recorded the pupil
responses to much smaller light stimuli that were presented at discreet
locations within the visual field. By measuring the perceptual
thresholds at the same locations, we were then able to compare pupil
function with visual function directly in patients with LHON. Our
results confirm that both pupil and visual function are abnormal at
discrete locations within the central scotoma in this disease. However,
both a nonparametric and a quantitative comparison of the visual and
pupil deficits suggest that the pupil afferent fibers are
relatively spared. A preliminary account of these findings
has been published elsewhere.8
|
Methods
|
|---|
Subjects
Nineteen patients with LHON were included in this study.
Mitochondrial DNA analysis confirmed point mutations at positions
11,778 (12 cases), 3460 (2 cases), and 14,484(5 cases). All patients
were men, with a median age of 37 years (range, 21–71 years). In all
cases the visual loss was chronic, with on average 12.4 years (range,
2–32 years) between visual loss and evaluation in this study. For
comparison, we examined 24 control subjects with healthy eyes (M:F
ratio, 12:11; median age, 28 years [32 years in the male subjects]),
range, 21–51 years); all control subjects had normal visual function
with corrected Snellen acuities of 6/6 or better. Pupil and visual
function were assessed after a minimum of 10 minutes preadaptation to
mesopic conditions, and only the preferred eye was tested in each case.
All patient and control subjects gave their informed consent before
participating in this study, and the research followed the tenets of
the Declaration of Helsinki.
Assessment of Visual Function
Distance acuity was measured at 6 meters with appropriate
refractive correction using a Snellen chart. Visual thresholds were
estimated using static automated perimetry (Octopus 1-2-3; Interzeag
AG, Zurich, Switzerland). Five stimulus locations were tested:
fixation, and at 17° eccentricity along the 45°/135° meridians in
the superotemporal, inferotemporal, superonasal and inferonasal
quadrants. The stimulus size and duration were 0.4° (Goldmann III)
and 100 ms, respectively, with a background illumination of 31.4
apostilb (asb). Threshold determination was achieved using the 4-2-1 dB
staircasing strategy over a stimulus intensity range of 100 to 4000
asb. Subjects were asked to fixate on a nonaccommodative red target in
the center of the perimeter bowl: in cases where the patient was unable
to see the fixation target, the patient was asked to look into the
middle of the bowl using their intact peripheral vision to guide
centration. Fixation was monitored throughout using a magnified
infrared camera image: virtual cursors were manually adjusted before
each test to set a fixation "window," which, if transgressed by the
pupil margins, would stop the test until fixation was restored.
Assessment of Pupil Function
Pupil function was also evaluated with the Octopus 1-2-3 automated
perimeter using the same background illumination of 31.4 asb. The pupil
reflex response to a light stimulus presented at each of the above five
locations was recorded using an infrared video camera (temporal
resolution, 19.38 ms; spatial resolution, 0.05 mm). Throughout each
test, the light stimulus was presented repeatedly, and the sequence of
test locations and interstimulus intervals varied (mean interval, 5.0
seconds; range, 4.0–6.0 seconds) using computer software. The stimulus
parameters for intensity, size, and duration were changed for pupil
perimetry to 4000 asb, 1.7° (Goldmann V), and 500 ms, respectively,
to ensure reliable pupil reactions. The blink rate was minimized by
instilling a single drop of oxybuprocaine 0.4% in both eyes. Each
recording trial lasted 2 minutes; the subject was then rested between
trials to maintain optimum alertness. The pupil size was monitored in
real time throughout each recording trial using the magnified infrared
camera image incorporated into the Octopus 1-2-3 perimeter. Off-line
measurements of the baseline pupil diameter preceding each stimulus
presentation were obtained by computer analysis of the video images and
in all cases were found to lie within the normal age-matched range. In
a few cases fatigue waves were clearly visible in the recording: these
data were discarded, and the recording was repeated when the subject
was more alert.
Comparing Pupil and Visual Function
We used two different techniques for comparing pupil and visual
responses. First, during each pupil test the subject was instructed to
press a response button if the stimulus was seen. The pupil recordings
were examined independently and off-line by two of the authors (FB and
JS) and judged as showing either a reflex response to the stimulus or
no response. Nonparametric statistics were then used to compare the
pupil and perceptual responses to perithreshold light stimuli in both
LHON patients and normal control subjects.
A second, quantitative technique used the principle of a pharmacologic
assay. In normal control subjects we randomly varied the stimulus
intensity over a 40-dB range (fixation) or 20-dB range (eccentric
locations) to characterize (for each stimulus location) the
relationship between stimulus intensity and the amplitude of the pupil
response. We then used this relationship to interpolate the amount by
which you would have to reduce the stimulus intensity in a normal
control subject to produce a pupil response equivalent to that observed
in the patient: this value corresponds to the size of the pupil deficit
and may be compared directly with estimates of the visual deficit.
Data Analysis
The pupil recordings were analyzed on a computer using
commercially available curve-fitting software (Interzeag AG) to measure
the amplitude of the reflex response. For each subject standard
descriptive statistics were used to derive the best estimate of the
pupil response amplitude when stimulating each of the five locations.
Pupil response amplitudes were compared at different stimulus locations
and between patients and control subjects using Student’s
t-tests. The proportion of perithreshold stimuli that could
be seen by the subject and the proportion of these stimuli that
produced pupil responses were compared in the LHON and the normal
(control) study groups using the 
2 statistic.
A goodness-of-fit-test was used to determine whether the differences
between visual and pupil deficits were normally distributed. The mean
pupil deficit was compared with the mean visual deficit at each
stimulus location using the Wilcoxon signed-ranks test.
|
Results
|
|---|
Visual Function
All LHON patients in this study had poor vision. The median
corrected Snellen acuity was 1/60 (range, 6/9 to HM [hand movements])
with 74% of eyes tested seeing worse than 6/60. Threshold
determinations in the LHON patients are summarized in Figure 1
, which shows the mean difference (±95% confidence intervals) between
the patient threshold and the normal threshold at each of the five
locations tested. The greatest deficit was seen at fixation where the
visual sensitivity was reduced by on average 27 dB. However, even at
17° eccentricity we found an average difference of between 17 and 18
dB between the patient threshold and the normal threshold.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1. Visual sensitivity in LHON patients relative to normal subjects. Graph
shows the mean decibel difference (±95% confidence intervals) between
the normal perceptual threshold and that measured in LHON patients at
five stimulus locations. Locations tested were fixation (F) and at
17° eccentricity along the 45°/135° meridians in the
superotemporal (ST), inferotemporal (IT), superonasal (SN), and
inferonasal (IN) quadrants. Normal visual sensitivity appears as 0 dB
on this graph. In LHON patients the visual sensitivity was reduced
significantly at all five locations, with most deficit at fixation and
less at the four eccentric locations.
|
|
Pupil Function
The pupil responses to standard intensity (4000 asb) stimuli
presented at the same five locations were tested in both patients and
normal control subjects. The mean amplitude of these responses
(expressed as percentage constriction of the pupil area ± 95%
confidence intervals) is shown in Figure 2
. In control subjects, the largest pupil responses were obtained when
the stimulus was presented at fixation. When the same intensity of
stimulus was presented at 17° eccentricity, the pupil responses were
significantly smaller (mean difference, 46%, P <
0.001) with a tendency for stimuli presented in the inferonasal
quadrant to elicit the smallest responses. No difference was found
between male and female control subjects. In LHON patients, the pupil
responses were significantly smaller (P < 0.001) than
in normal control subjects at all five of the locations tested. The
magnitude of this difference was greatest for stimuli presented at
fixation (response amplitude on average was 65% smaller in LHON
patients than in normal control subjects) and less marked at 17°
eccentricity (42% smaller).
View larger version (15K):
[in this window]
[in a new window]
|
Figure 2. Pupil responses in LHON patients compared with normal control subjects.
Graph shows the mean amplitude (±95% confidence intervals) of the
pupil response to a standard intensity (4000 asb) light stimulus
presented at each of the five locations. Ordinate values
are scaled in percentage of constriction of the pupil area. Results are
shown for LHON patients (filled circles) and age-matched
normal control subjects (open circles). At all five
locations the pupil responses were significantly smaller in the LHON
patients, with the greatest difference being at fixation and less
difference at the four eccentric locations.
|
|
Nonparametric Comparison of Visual and Pupil Responses
Pupil responses were observed in LHON patients after subthreshold
stimuli. An example is shown in Figure 3
. A standard intensity light stimulus (4000asb) was presented 14 times
to the same location in the superotemporal quadrant; pupil responses
were present on every occasion with amplitudes ranging from 5% to 21%
(mean, 11%), and yet the patient could not perceive any of these
stimuli. In the course of this study we found seven similar cases in
which the standard intensity light stimulus was never perceived by the
patient: in all seven cases, pupil responses were observed with
frequencies ranging from 9% to 100% (median, 53%). In normal control
subjects the standard intensity stimulus always was perceived during
the pupil test, but when the stimulus intensity was reduced by 40 dB
(fixation) or 20 dB (eccentric locations), there were seven cases in
which the light stimulus was never perceived. In contrast to LHON
patients, in four of these seven cases no pupil responses were observed
after subthreshold stimuli; in the remaining three cases, pupil
responses were only rarely observed (frequencies in the range 6% to
15%).
View larger version (16K):
[in this window]
[in a new window]
|
Figure 3. Comparison of pupil and perceptual responses in a LHON patient.
Standard intensity (4000 asb) light stimuli were repeatedly presented
(n = 14) at 17° eccentricity in the
superotemporal quadrant. The chronological order of the stimulus
presentations is shown along the abscissa. Perceptual
responses to these stimuli are shown as squares
(open, perceived; filled, not perceived).
Pupil responses to these stimuli are shown as circles
(open, response present; filled, no
response), and the amplitudes of these pupil responses are shown on the
ordinate scale. None of the stimuli were perceived by
this patient, but all were followed by a pupil response. The mean
amplitude (±95% confidence intervals) of these pupil responses is
shown to the right of the axis breaks.
|
|
When all the perceptual responses to standard intensity light stimuli
in LHON patients are considered, there were 169/759 (22%) stimuli that
were not perceived, of which 89/169 (53%) were followed by a pupil
response. In normal control subjects using perithreshold light
intensities, a similar proportion of stimuli were not perceived
(133/645, 21%), but the proportion of these subthreshold stimuli that
were followed by a pupil response was three times lower (20/133, 15%).
A 2 test confirms that the difference in
results between the two study groups was highly significant
(2 = 32.17, P < 0.001).
A Quantitative Comparison of the Visual Deficit and the Pupil
Deficit
By varying the stimulus intensity, we characterized the
relationship between stimulus intensity and response size in normal
control subjects at each of the five tested locations. The results for
stimuli presented at fixation are illustrated in Figure 4
. The relationship is sigmoidal, with the lowest intensity stimuli
producing pupil responses more than 10 times smaller than those
following our "standard" intensity stimulus (4000 asb, which
corresponds to the 0-dB attenuation in Fig. 4
). Similar relationships
were found at the four eccentric locations. The pupil deficits in LHON
patients were interpolated from these graphs and have been plotted
against the corresponding estimates of visual deficit in Figure 5
.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 4. Relationship between stimulus intensity and the size of the pupil
response. Graph shows variation in the mean (±95% confidence
intervals) pupil response amplitude with stimulus intensity in normal
control subjects; all stimuli were presented at fixation.
|
|
View larger version (26K):
[in this window]
[in a new window]
|
Figure 5. Quantitative comparison of visual and pupil function in LHON. Graph
shows a scatterplot of the estimates of visual deficit
(abscissa) and pupil deficit (ordinate)
at all five tested locations in all 19 LHON patients
(n = 95). The diagonal line
represents values of visual deficit equal to pupil deficit; most of the
data lies below this line, implying that, in general, the visual
deficits exceeded the pupil deficits. The data from patient 15 is shown
in filled circles.
|
|
Most of the data points lie below the line of unit gradient (i.e., in
most cases the visual deficit exceeded the pupil deficit). We could
find no evidence to suggest that this general result applied only to
certain locations in the visual field, or to particular mitochondrial
mutations. The distribution of differences between the visual and the
pupil deficit was compared with a normal distribution using the
2 goodness-of-fit-test (see Fig. 6 ), but no departure from normality was found (2
= 0.179 with P > 0.05).
In general, all patients in this study showed similar results. However,
one patient (patient number 15) appeared to be different. The
greyscale of his visual field together with the estimates of visual
deficit and pupil deficit at each of our five standard locations are
shown in Figures 7
A and 7C, respectively. From the greyscale it is apparent that his
visual scotoma did not extend beyond the central 5° of the visual
field, and indeed his perceptual thresholds were normal at the four
standard eccentric locations (Fig. 7C
: filled symbols). In contrast,
his pupil responses were reduced substantially at these four eccentric
locations (Fig. 7C
: open symbols), suggesting that in this patient the
pupil scotoma extended beyond the visual scotoma. No other patient in
this study showed similar results. For comparison, the results from
another more typical patient (patient number 14) are shown in Figures 7B
and 7D
. In this patient, both the visual scotoma and the pupil
scotoma extend beyond 17° eccentricity, with the visual deficits
exceeding the pupil deficits at all four of the eccentric locations
tested.
View larger version (65K):
[in this window]
[in a new window]
|
Figure 7. Visual and pupil function in two patients with LHON.
(A, B) Greyscale representations of their visual
fields. (C, D) Mean estimates of the visual
deficits (filled circles) and the pupil deficits
(open circles) at the five stimulus locations tested.
(A, C) Results from an exceptional case (patient
number 15) in which the central scotoma does not extend beyond the
central 5°. Perceptual thresholds were normal at all four eccentric
locations tested, and yet the pupil responses were reduced
significantly, suggesting that in this case the pupil scotoma extended
beyond the visual scotoma. (B, D) Results from a
‘typical’ case (patient number 14), showing a large central scotoma
with the visual deficits exceeding the pupil deficits at all four
eccentric locations.
|
|
By way of summary, the mean estimates (±95% confidence intervals) of
visual deficit and pupil deficit in all 19 LHON patients at each of the
five tested locations are shown in Figure 8 . The mean visual deficit (filled circles) significantly exceeded the
mean pupil deficit (open circles) at all locations (P < 0.001; Wilcoxon signed-ranks test). The average difference between
the visual deficit and the pupil deficit was 7.5 dB (95% confidence
intervals, = 5.5–9.5 dB) and did not vary significantly between
locations (range, 5.2–9.6 dB).
View larger version (14K):
[in this window]
[in a new window]
|
Figure 8. Summary of visual and pupil function in LHON. Mean estimates (±95%
confidence intervals) of the visual deficit (filled
circles) and the pupil deficit (open circles) at
each stimulus location. At all five locations, the visual deficit
significantly exceeded the pupil deficit (P <
0.05; Wilcoxon signed-ranks test) with an average difference of 7.5
dB.
|
|
|
Discussion
|
|---|
Previous studies2
3
4
5
7
assessing pupil function in
LHON have relied on large or full-field light stimuli to elicit the
reflex, but the visual deficit in LHON patients is restricted to the
central 15° to 30°, with a relatively intact peripheral field. In
the present study the pupil light reflex was elicited using stimuli the
size of a Goldmann V target presented at five discreet locations within
the central scotoma. Light scatter will inevitably have caused some
spread of this stimulus, but all the patients in this study were young,
with negligible media opacities, and light scatter is likely to have
affected patients and control subjects to a similar extent. When tested
in this way, the pupil responses were significantly smaller than those
found in normal control subjects. Eccentric fixation in some of the
LHON patients may explain why stimuli presented in the center produced
poor pupil responses. However, eccentric fixation is unlikely to
account for a 65% reduction in response size, given that in normal
control subjects there is less than 46% difference in the pupil
response sizes to standard intensity stimuli presented at fixation and
at 17° eccentricity (see Fig. 2
). Moreover, fixation uncertainty does
not explain the poor pupil responses when stimulating peripheral
locations, where relatively large changes in stimulus location make
little difference to the amplitude of the pupil response. We therefore
conclude that there is a significant pupil afferent defect within the
visual scotoma in LHON patients.
A direct comparison of the visual and pupil defects is not possible
because different measures of function have been used; visual function
has been defined as the light intensity at which the stimulus is
perceived 50% of the time, whereas pupil function has been defined as
the response amplitude after a standard intensity suprathreshold
stimulus. One approach has been to compare the rates of pupil response
and perceptual response to perithreshold stimuli in both study groups.
This approach is unavoidably subjective. Nevertheless, the results
suggest that a stimulus that is below the perceptual threshold is more
than three times more likely to be followed by a pupil response in a
LHON patient than in a normal control subject, a difference that is
unlikely to have arisen by chance (P < 0.001).
A different approach has been to quantify the pupil defect in terms
that are more directly comparable to the measurement of visual defect.
Once again, eccentric fixation in some LHON patients will have affected
the estimates of both visual and pupil defect. However, we looked
carefully at the data but did not find evidence to suggest that
patients adopted different fixation strategies in the two tests; any
error due to eccentric fixation is therefore expected to have affected
both estimates similarly and may not adversely prejudice their
comparison. A more systematic difference between the pupil and visual
deficit estimates was generated by using different stimulus parameters
for the two tests. It is conceivable that "pupil-sparing" was
observed, because the larger target used in the pupil test (Goldmann V)
extended beyond the limits of the central scotoma, stimulating
functioning areas of the visual field not reached by the smaller target
used in the visual test (Goldmann III). We feel that this is unlikely
to account for our results for two reasons. Firstly, the reverse
situation (i.e., the visual test target lying just outside the edge of
the scotoma but the larger pupil test target overlapping the edge of
the scotoma) is just as likely to have occurred by chance and would
have led to just as many instances of the pupil deficit
exceeding the visual deficit. Second, the visual scotoma in
our LHON patients was uniformly deep and extended well beyond the
central 17° tested in this study, making it unlikely that a Goldmann
V target would have reached less affected areas of the visual field not
stimulated by a Goldmann III target.
The results of both nonparametric and quantitative analyses in
our study suggest that within the central scotoma in LHON the visual
deficit exceeded the pupil deficit. This general result was found in
all cases except one patient (patient number 15: see Fig. 7
). His
results appear different from the rest of the study group and are
contrasted with those of a more typical patient (patient number 14) in
Figure 7
. Both patients have the same mutation (11,778) and lost vision
about 12 years ago. Of interest, patient number 15 started smoking and
drinking heavily 2 years before the onset of his visual loss, whereas
MC has never smoked and drinks only in moderation. We cannot say
whether excessive alcohol or tobacco consumption influenced the results
in patient number 15 or whether these results represent phenotypic
variation in LHON. In all the other LHON patients included in this
study and at all locations tested, we found relative sparing of pupil
function compared with visual function. We did not examine any patients
with visual loss of less than 2 years standing and so cannot comment on
whether pupillovisual dissociation is present in the acute stages of
LHON.
Jacobson et al.7
were unable to find evidence of
pupillovisual dissociation in their recent study of 10 cases with
unilateral visual loss. They measured the size of the RAPD using
neutral density filters and then compared this with the RAPD expected
on the basis of the visual field results using published
templates.9
10
However, there is considerable scatter in
the data used to establish these published templates for both
kinetic9
and automated perimetry10
11
: we
would not expect any comparison of visual and pupil function using
these templates and the swinging flashlight-test to be sensitive enough
to detect the relatively small difference found between visual and
pupil deficits in this study (mean, 7.5 dB).
How are we to interpret "pupil-sparing" in LHON? Anatomic studies
in both cats12
and primates13
suggest that
the pupil light reflex is mediated by W-cells in the retina rather than
the X- and Y-cells mediating visual perception. W-cells comprise
approximately 10% of all fibers in the optic nerve. They differ from
X- and Y-cells in having smaller diameter axons, slower conduction
velocities, and lower discharge rates under constant luminance
conditions.12
The receptive fields of W-cells are similar
in size to that of Y-cells,12
and so it is unlikely that
the centrally placed stimuli used in this study generated pupil
responses mediated by peripherally situated ganglion cells. If similar
anatomic and neurophysiological differences exist between retinotectal
and retinogeniculate fibers in humans, then pupil sparing in LHON may
reflect a lower susceptibility of the pupil afferent fibers to this
disease than that of the visual afferent fibers.7
Two
recent reports lend support to this hypothesis. First, the photic blink
reflex, another retinotectal function thought to be mediated by
W-cells, also appears to be relatively preserved in
LHON.14
Second, a histopathologic study of the optic nerve
in a patient with LHON showed selective loss of larger diameter fibers
with relative preservation of small diameter axons.15
We are not aware of any other examples of pupillovisual dissociation in
the literature. However, there are few published studies that have
addressed this issue specifically in respect of other optic
neuropathies.16
It may be that the pupil sparing found in
our study is not a distinctive feature of LHON but also can be observed
in other diseases of the optic nerve when tested using similar
techniques. Of interest, in all three published studies correlating
visual field loss and the size of the RAPD,9
10
11
the
slopes of the regression lines are less than 1.0, implying that visual
loss usually exceeds pupil loss, with some evidence that the slope may
vary according to the type of optic nerve disease.10
If
the relationship between visual deficit and pupil deficit depends on
the type of disease, then a study of pupil function in different optic
neuropathies may have diagnostic potential. Moreover, the relative
susceptibility of pupil afferent fibers compared with visual afferent
fibers in different diseases has important implications regarding the
underlying mechanisms of damage.
|
Acknowledgements
|
|---|
The pupil perimetry equipment was purchased with a grant from the
Joseph Levy Foundation.
|
Footnotes
|
|---|
Supported by The Joseph Levy Foundation, The T.F.C. Frost Charitable Foundation (FDB), and The Iris Fund (JSH).
Submitted for publication November 25, 1998; revised March 24, 1999; accepted May 20, 1999.
Commercial relationships policy: N.
Corresponding author: F. D. Bremner, Department of
Neuro-ophthalmology, National Hospital for Neurology and Neurosurgery,
Queen Square, London WC1N 3BG, UK.
|
References
|
|---|
-
Riordan–Eva, P, Sanders, MD, Govan, GG, Sweeney, MG, Da Costa, J, Harding, AE (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation Brain 118,319-337[Abstract/Free Full Text]
-
Nakanishi, M, Mashima, Y, Hiida, Y, Suzuki, S, Oguchi, Y. (1994) Two cases of Leber’s hereditary optic neuropathy diagnosed as psychogenic visual loss Ganka (Ophthalmology) 36,811-814
-
Nikoskelainen, EK, Huopenen, K, Juvonen, V, Lamminen, T, Nummelin, K, Savontaus, M–L. (1996) Ophthalomologic findings in Leber’s hereditary optic neuropathy with special reference to mtDNA mutations Ophthalmology 103,504-514[Medline][Order article via Infotrieve]
-
Bynke, H, Bynke, G, Rosenberg, T. (1996) Is Leber’s hereditary optic neuropathy a retinal disorder? Report of a case Neuro-ophthalmology 16,115-123[Medline][Order article via Infotrieve]
-
Wakakura, M, Yokoe, J. (1995) Evidence for preserved direct pupil light response in Leber’s hereditary optic neuropathy Br J Ophthalmol 79,442-446[Abstract/Free Full Text]
-
Ludtke, H, Kriegbaum, C, Leo–Kottler, B, Wilhelm, H. (1999) Pupillary light reflexes in patients with Leber’s hereditary optic neuropathy Graefes Arch Clin Exp Ophthalmol 237,207-211[Medline][Order article via Infotrieve]
-
Jacobson, DM, Stone, EM, Miller, NR, et al (1998) Relative afferent pupil defects in patients with Leber’s hereditary optic neuropathy and unilateral visual loss Am J Ophthalmol 126,291-295[Medline][Order article via Infotrieve]
-
Bremner, FD, Shallo–Hoffmann, J, Smith, SE, Riordan–Eva, P. (1998) Relative sparing of pupillomotor fibres in Leber’s hereditary optic neuropathy Neuro-Ophthalmology 20,2
-
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]
-
Stone, J, Fukuda, Y. (1974) Properties of cat retinal ganglion cells: a comparison of W-cells with X- and Y-cells J Neurophysiol 37,722-748[Free Full Text]
-
Leventhal, AG, Rodieck, RW, Dreher, B. (1981) Retinal ganglion cell classes in the old world monkey: morphology and central projections Science 213,1139-1142[Abstract/Free Full Text]
-
Nakamura, M, Sekiya, Y, Yamamoto, M. (1996) Preservation of photic blink reflex in Leber’s hereditary optic neuropathy Invest Ophthalmol Vis Sci 37,2736-2743[Abstract/Free Full Text]
-
Saardati, HG, Hsu, HY, Heller, KB, Sadun, AA (1998) A histopathologic and morphometric differentiation of nerves in optic nerve hypoplasia and Leber’s hereditary optic neuropathy Arch Ophthalmol 116,911-916[Abstract/Free Full Text]
-
Poonyathalang, A, Wakakura, M, Yoshitomi, T, Ishikawa, S. (1998) Pupil perimetry and Humphrey field analysis in Leber’s hereditary optic neuropathy compared with optic neuritis Neuro-Ophthalmology 20,3
This article has been cited by other articles:
|
|
|
|
 
M S Rajan, F D Bremner, and P Riordan-Eva
Pupil perimetry in the diagnosis of functional visual field loss
J R Soc Med,
January 10, 2002;
95(10):
498 - 500.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. D. Bremner, E. A. Tomlin, J. Shallo–Hoffmann, M. Votruba, and S. E. Smith
The Pupil in Dominant Optic Atrophy
Invest. Ophthalmol. Vis. Sci.,
March 1, 2001;
42(3):
675 - 678.
[Abstract]
[Full Text]
|
|
|
Top
Abstract
Introduction
, where µ is the mean difference and