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The Lateral Geniculate Nucleus in Human Anisometropic Amblyopia
G. K. von Noorden, M. L. J. Crawford, and R. A. Levacy
amination, including ocular motility, applanation
tonometry, and examination of the ocular media,
anterior segments, and fundi, was normal. The diagnosis of anisometropic amblyopia in the right eye
was made, and the patient was given a prescription
for glasses based on the cycloplegic refraction.
The patient returned for routine follow-up in February 1981 at which time a complete ophthalmologic
examination was repeated and showed no significant
changes. It was suggested at that time to the patient
and his family that he may wish to donate his brain
after death for medical research, to which he agreed.
The patient expired suddenly in July 1982 of a
massive internal hemorrhage following erosion of a
major abdominal vessel by a gastric carcinoma. The
brain was removed six hours after death and preserved in 10% formalin. Six weeks later the LGNs
were dissected from the brain and embedded in celloidin. Coronal serial sections were cut at 10 microns
thickness and every 10th section stained with toluidine blue. Samples of 50 LGN cells from each of the
six layers within the posterior portion of the nucleus
were photographed, enlarged, and the cell bodies outlined and traced. The areas of the cell tracings were
measured using a HP85 graphics tablet and area measurement routine. Cell size differences between LGN
layers were assessed using the t-test, with an acceptance criterion at the 5% level of confidence. To avoid
any bias, the personnel involved with cell area measurements were kept unaware of the clinical history.
The code was not broken until all data were collected
and the statistical evaluation completed.
Results. The results of the histologic examination
of the LGN are shown in Table 1. Eight of ten comparisons of cell sizes in adjacent and in contralateral
parvocellular layers showed significantly smaller cells
in laminae connected with the amblyopic eye. Comparing contralateral laminae this difference varied
between 29% (layers 3) and 11% (layers 4). No significant difference existed between layers 6 and between the magnocellular layers 1 and 2. A significant
difference between the amblyopic layer 1 and layer
2 of the contralateral LGN (-15%) was offset by an
increase of cell sizes in the amblyopic layer 2 when
compared with layer 1 of the ipsilateral LGN (+15%).
Interlaminar comparison showed more pro-
Experimental amblyopia in animal models causes a reduction of cell sizes in lateral geniculate nucleus (LGN) laminae
connected with the amblyopic eye. However, direct evidence
that the human amblyopic visual system is affected in a
similar manner has been lacking. Histologic study of the
LGNs from a patient with ophthalmologically confirmed
anisometropic amblyopia shows a decrease of cell sizes in
the parvocellular layers innervated by the amblyopic eye.
This decrease was more pronounced in laminae receiving
crossed fibers. To our knowledge this is the first report
about structural alterations in the afferent visual pathway
of a human amblyope and the data reaffirm the validity of
the monkey model for further study of the basic mechanisms
in amblyopia. Invest Ophthalmol Vis Sci 24:788-790,1983
Anisometropia is a frequent cause of human amblyopia. Animal experiments have shown that anisohypermetropia produced in infant monkeys by removing the lens from one eye1 or in kittens by having
them wear a high minus lens before one eye2 causes
significant reduction in cell area sizes of lateral geniculate nucleus (LGN) laminae connected with the
amblyopic eye. Similar changes have been reported
in monkeys with behaviorally proven strabismic and
visual deprivation amblyopia.3 However, in view of
lack of appropriate human autopsy material, some
doubt has existed whether the visual system of a human amblyope reacts similarly in terms of structural
alterations of the afferent visual pathway as does that
of experimental animals. We report herein the histologic findings from the brain of a patient who had
an ophthalmologically confirmed anisometropic amblyopia.
Materials and Methods. A 69-year-old white man
was examined by one of us (RAL) in August 1979
when he presented for a routine eye examination. He
gave a history of having had poor vision in his right
eye all of his life. With his current glasses, his visual
acuity was 4/200 in the right eye and 20/20 — 1 in the
left eye. He was wearing a +5.50 sphere in both eyes
with a +2.50 bifocal addition. Cycloplegic refraction
showed a refractive error of + 11.75 sphere +.25 cylinder axis 180 in the right eye and +5.50 sphere
+.50 cylinder axis 45 in the left eye. With this correction his visual acuity was 20/400 in the right and
20/20 in the left eye. The remainder of the eye ex-
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No. 6
Reports
nounced cell size reduction in the contralateral left
LGN than in the ipsilateral right LGN.
Discussion. The human LGN is separated into six
distinct laminae of which the ventral two layers contain larger cells (magnocellular layers) than the dorsal
four parvocellular layers. Laminae 1, 4 and 6 are innervated from the contralateral eye via crossed fibers
and laminae 2, 3 and 5 contain the ipsilateral uncrossed retinal terminals.
The anatomy of the human and macaque monkey
LGN is comparable in most aspects. No appreciable
difference exists between average cell area sizes in the
corresponding contralateral and in the contiguous
ipsilateral parvo- and magno-cellular layers of normal
human4 and monkey5 LGNs. Thus, the differences
between parvocellular LGN layers receiving input
from the normal and amblyopic eye reported in this
study are highly significant. The cells innervated from
the amblyopic eye were uniformly smaller (on the
averge 18%) than those receiving input from the normal eye, whenever a difference existed between layers
innervated by the normal and amblyopic eye.
No such differences in cell sizes existed between
corresponding layers of the magnocellular laminae 1
and 2. However, cells in the amblyopic layer 1 of the
contralateral LGN were smaller (15%) than those in
the adjacent normal layer 2. Paradoxically, the reverse was true for a comparison between the ipsilateral layers 1 and 2 where cells from the amblyopic
layer 2 were actually larger (15%) than the adjacent
layer 1 from the normal eye. At present, we cannot
offer an explanation for the lack of consistent findings
in the magnocellular layers in the LGN of the human
amblyope. We have previously noted such differences
in terms of lesser sensitivity to abnormal visual input
between magno- vs parvo-cellular LGN layers in
monkeys with experimental amblyopia,6 and similar
observations were also made in human LGNs after
retrograde or anterograde degeneration.7"9 Nevertheless, the cell shrinkage occurring in the magnocellular
layer of monkeys with experimental anisohypermetropia was more consistent than that observed in this
study.1 Whether these results reflect differences in the
sensitivity to abnormal or decreased visual input of
human vs monkey LGN must await examination of
additional human autopsy material.
Changes in the LGN sizes described in this study
and in earlier animal experiments with artificial anisohypermetropia12 can be explained on the basis of
an afferent or retrograde effect of anisohypermetropia
on geniculate cell size. The retina of the more ametropic of the two hypermetropic eyes never receives
a clearly focused image as does its fellow eye. When
details are clearly focused on the retina of the less
hypermetropic eye there is no further accommodative
789
Table 1. Comparisons of cell area sizes of LGN
cells from a human patient with anisometropic
amblyopia in the right eye.
LGN Layer
Left LGN
KO
[336 ± 70]
X-15%*
396 ± 112
259 ± 46
t -19%*
[209 ± 44]
t -18%*
254 ± 78
X -19%*
[206 ± 41]
2(0
3(0
4(C)
5(0
6(c)
%
LE
«- + 4 %—
- -3% —
«
29%* —
<
11%* —
<
17%* - »
«- + 3 % —
Right LGN
324 ± 68
X +15%*
[383 ± 100]
[183 ± 4 0 ]
X -22%*
235 ± 52
X -10%*
[212 ± 4 0 ]
X +6%
199 ± 34
Square micrometers; N = 50 ea.; £, ±SD; * = P < 0.05; c = contralateral;
i = ipsilateral.
Data in brackets represent measurements from laminae connected with
amblyopic eye.
effort to produce a clear retinal image on the retina
of the more hypermetropic eye.10 Thus, the afferent
visual deprivation effect of a defocused image (amblyopia of disuse) may, at least in part, be responsible
for the cell shrinkage in the LGN. In support of this
concept are our findings in the anisohypermetropic
monkey that, in addition to the binocularly innervated LGN layers, cell shrinkage also occurs in the
monocularly innervated segments.1 Hickey et al. reported similar findings in unilaterally visually deprived kittens.11 Unfortunately, for technical reasons,
the monocular segments of the LGN under study
could not be subjected to histological analysis.
On the other hand, the cell shrinkage in the binocularly innervated LGN laminae could also be explained on the basis of a retrograde inhibitory effect
from competition between the focused and defocused
image from the two eyes. Guillery proposed that geniculate cells compete during development, probably
for available synaptic surfaces upon cortical cells,
perhaps in terms of interlaminar inhibitory mechanisms.12 Differences in binocular input in anisohypermetropia (focused vs blurred foveal images) may
upset this competitive balance in favor of the normal
eye. Thus, anisometropic amblyopia may well be
caused by a dual mechanism consisting of form vision
deprivation and active inhibition secondary to abnormal binocular interaction.
The data presented in this study have shown for
the first time that human amblyopia is accompanied
by structural changes in the afferent visual pathways
similar to those observed in animal experiments and,
thus, reaffirm the validity of the monkey model for
further study to clarify the basic mechanism of amblyopia.
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790
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / June 1983
Key words: amblyopia, anisohypermetropia, anisometropia, lateral geniculate nucleus, monkey, visual deprivation
Acknowledgments. The authors thank Dr. Peter Isaac for
obtaining the brain at autopsy and Mr. Dennis Skoog for
technical help.
From the Cullen Eye Institute, Baylor College of Medicine and
the University of Texas Graduate School of Biomedical Sciences,
Houston, Texas. Supported in part by grants EY 01120 and EY
02520 from the National Institutes of Health and the Charles De
Pauw Foundation for Pediatric Ophthalmology. Submitted for
publication December 6, 1982. Reprint requests: G. K. von Noorden, MD, Ophthalmology Service, Texas Children's Hospital, Box
20269, Houston, TX 77225.
References
1. von Noorden GK and Crawford MLJ: Form deprivation without light deprivation produces the visual deprivation syndrome
in Macaca mulatta. Brain Res 129:37, 1977.
2. Maguire GW, Smith EL III, Harwerth RS, and Crawford MLJ:
Optically induced anisometropia in kittens. Invest Ophthalmol
Vis Sci 23:253, 1982.
3. von Noorden GK: Histological studies of the visual system in
monkeys with experimental amblyopia. Invest Ophthalmol
12:727, 1973.
Vol. 24
4. Kupfer C: The laminar pattern and distribution of cell size in
the lateral geniculate nucleus of man. J Neuropath Exp Neurol
24:645, 1965.
5. von Noorden GK and Middleditch PR: Histological observations in the normal monkey lateral geniculate nucleus. Invest Ophthalmol 14:55, 1975.
6. von Noorden GK and Middleditch PR: Histology of the monkey lateral geniculate nucleus after unilateral lid closure and
experimental strabismus: Further observations. Invest
Ophthalmol 14:674, 1975.
7. Hechst B: Uber das Verhalten der ausseren Kniehbcker und
der Sehrinde bei einseitiger peripherer Blindheit. Arch Psychiat
Nervenkrankh 100:19, 1933.
8. Clark WE Le Gros: The laminar organization and cell content
of the lateral geniculate body in the monkey. J Anat 75:419,
1941.
9. Goldby F: A note on transneuronal atrophy in the human
lateral geniculate body. J Neurol Neurosurg Psychiat 20:202,
1957.
10. McMullen WH: Some points in anisometropia. Trans
Ophthalmol Soc UK 59:119, 1939.
11. Hickey TL, Spear PD, and Kratz KE: Quantitative studies of
cell size in the cat's dorsal lateral geniculate nucleus following
visual deprivation. J Comp Neurol 172:265, 1977.
12. Guillery RW: Binocular competition in the control of geniculate cell growth. J Comp Neurol 144:117, 1972.
Normal Fluorescein Iris Ang/ographlc Pattern in Subhuman Primates
Prem Singh Virdi ond Sohan Singh Hayreh
Normal fluorescein iris angiographic pattern in brown eyes
of cynomolgus and rhesus monkeys is described. Invest
Ophthalmol Vis Sci 24:790-793, 1983
In recent years, a number of detailed accounts have
been published of the normal pattern of iris circulation, as seen on fluorescein iris angiography in normal human eyes.1"3 However, no such description of
monkey irides is available. It is well established that
no satisfactory fluorescein iris angiograms are obtainable on brown pigmented irides in the human, and
only blue or green irides are suitable for angiography.'
Therefore, it was presumed that monkey eyes, being
almost always brown, would not be suitable for fluorescein iris angiography. In 1978, we discovered, to
our surprise, that good quality fluorescein angiograms
could be obtained in rhesus and cynomolgus monkeys in spite of their brown irides. Since then we have
conducted a number of in vivo experimental studies
of the iris circulation in rhesus and cynomolgus monkeys. During these studies we had first to establish
the normal pattern of fluorescein iris angiography in
these animals; we feel this information is important
for researchers who plan to use this technique in research.
Materials and Methods. The normal fluorescein
iris angiographic pattern was studied in 23 cynomolgus monkeys (46 eyes) and 12 rhesus monkeys
(24 eyes). All eyes were normal. The animals were
anesthetized with intravenous pentobarbital sodium
(10 mg/kg body weight). No topical medication was
used. Iris angiography was performed by using the
standard Zeiss photo slit lamp fitted with the anterior
segment fluorescein angiography equipment (capable
of taking serial pictures at the rate of one frame every
0.8 second) and Carl Zeiss Dataphot (with a time
recording device). Injected intravenously into a vein
of one of the four limbs was 0.15 ml of sodium fluorescein 25% solution. Serial angiograms were taken,
starting just before the appearance of the dye in the
anterior segment, and ending with late phase angiograms 3-5 min after the transit.
The anterior chamber was examined with the slit
lamp for fluorescence in the aqueous humor. Intraocular pressure was measured last of all using the
Goldmann applanation tonometer.
Results. Fluorescein iris angiographic pattern: The
filling of the iris vessels started from the root of the
iris and extended towards the pupillary margin (Fig.
1). The iris-vessel filling was considered to be com-
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