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Pupil abnormalities
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This article will summarise the relevant anatomy and physiology of pupillary control,
outline the pharmacological aspects of pupillary evaluation and discuss common
pupil abnormalities and their clinical significance.
There are a number of excellent reviews of this subject for the interested reader1-3.
The pupil is the diaphragm through which
light enters the eye. Its size is determined
by many factors including afferent drive from
the retina, central processing in the
brainstem, the balance of ‘tone’ in the
autonomic nervous system and local factors
within the muscles of the iris. Any
disturbance to these structures may result in
an abnormal size, shape or reactivity of the
pupil. In clinical practice, pupil abnormalities
rarely have a significant impact on visual
function and may not even be noticed by the
patient. However, examination of the pupil is
important because a pupil abnormality may
be the only sign of dysfunction in the eye or
brain.
Pupil anatomy
The size of the pupil is determined by the
balance of two antagonist muscles in the
iris: the sphincter muscle, which is under
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April 7, 2000 OT
Figure 1
Schematic diagrams of the
parasympathetic (A) and
sympathetic (B) nerve supply to the
pupil constrictor and dilator muscles
respectively. EWN=Edinger-Westphal
nucleus; AMN=antero-median
nucleus; CG=ciliary ganglion;
SPH=iris sphincter muscle;
HYP=postero-lateral hypothalamus;
CSC=ciliospinal centre of BudgeWaller; SCG=superior cervical
ganglion; DIL=iris dilator muscle
parasympathetic innervation (resulting in
miosis), and the dilator muscle, which is
under sympathetic innervation (resulting in
mydriasis). The parasympathetic supply is a
two-neurone chain (Figure 1A). The cell
bodies of the pre-ganglionic neurones lie in
the visceral mid-line nuclei4 (antero-median,
Edinger-Westphal and possibly Perlia’s
nucleus) of the upper mid-brain. Their axons
join with motor fibres from the ipsilateral
oculomotor nuclei to form the fascicle of
the third cranial nerve. The parasympathetic
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fibres accompany the oculomotor
nerve throughout its intracranial
course, lying superficially where
they are susceptible to
compressive injury5. Within the
orbit, the axons leave the
inferior division of the
oculomotor nerve and travel with
the nerve to the inferior oblique
muscle before terminating in the
ciliary ganglion. The cell bodies
of the post-ganglionic neurones
lie within the ciliary ganglion.
Their axons emerge with other
autonomic and somatosensory
fibres to form the short ciliary
nerves. These pass forwards in
the suprachoroidal space to
reach the iris sphincter muscle.
The sympathetic supply to the
iris dilator muscle probably
involves several neurones but is
classically described as a threeneurone chain (Figure 1B). The
first-order (central) neurones
start in the ipsilateral posterior
hypothalamus and descend
uncrossed through the lateral
part of the brainstem to
terminate in the ciliospinal
centre of Budge-Waller (level C8-
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T2). The second-order (preganglionic) neurones leave the
spinal cord with the ventral
spinal roots as the white rami
communicantes, and ascend in
the sympathetic chain without
synapse. On the left side, the
sympathetic chain splits around
the sub-clavian artery with the
posterior branch (ansa subclavia) lying close to the apex of
the lung. The
pre-ganglionic fibres on both
sides terminate in the superior
cervical ganglion at the level of
the angle of the mandible. From
here, the third-order (postganglionic) neurones travel on
the surface of the internal
carotid artery, passing with the
artery through the foramen
lacerum into the intracranial
space. Within the cavernous
sinus, they leave the artery to
join firstly the abducens nerve
and then the ophthalmic division
of the trigeminal nerve before
entering the orbit with the
nasociliary nerve and passing
forward to the iris dilator muscle
in the long ciliary nerves.
Pupil physiology
It is common knowledge that
the pupils are small in bright
light and larger in the dark. The
neural basis for this association
is a reflex arc (Figure 2)
composed of an afferent limb
(retinal ganglion cells which are
sensitive to the ambient
luminance level, decussate at
the optic chiasm and project to
the pretectal nuclei on both
sides of the mid-brain); central
processing (interneurones
emerging from these nuclei
which decussate in the posterior
commissure before projecting to
the Edinger-Westphal and
antero-median nuclei on both
sides of the mid-brain); and an
efferent limb (the
parasympathetic supply to the
iris sphincter muscle as detailed
above). Under normal
circumstances, this reflex arc
results in an inverse relationship
Figure 2
Schematic diagram of the reflex arc which generates the pupil response
to light. RGC=retinal ganglion cells; PTN=pretectal nuclei;
EWN=Edinger-Westphal nucleus; SPH=iris sphincter muscle. Other
supranuclear inputs to the parasympathetic neurones in the midbrain
include: the NEAR triad; RAS=reticular activating system;
HYP=hypothalamus; LS=limbic system; CX=cerebral cortex
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block this re-uptake mechanism leading to
an increased concentration of noradrenaline
at the neuro-effector junction and mydriasis
in normal eyes. The only pure agonist of
these receptors in clinical practice is
phenylephrine, which is used to dilate the
pupil, but other sympathomimetics, such as
adrenaline, dipivefrine, guanethidine,
brimonidine and aproclonidine (all glaucoma
treatments), may have mild effects on pupil
size. Chronic denervation of the iris dilator
muscle leads to up-regulation of adrenergic
receptors and supersensitivity to dilute
phenylephrine.
Abnormal pupil size
Figure 3
Schematic diagrams to illustrate key features of the parasympathetic (A) and sympathetic (B)
neuro-effector junctions. G=muscarinic receptor; IC=ion channel; Ach=acetylcholine;
NA=noradrenaline; HA=hydroxyamphetamine; COC=cocaine; a1=alpha-adrenergic sympathetic
receptor
between pupil size and the ambient light
level, tending to compensate for the
extremes of retinal illumination that would
otherwise exist at different times of day and
night.
There are a number of other influences
on pupil size. These include: alertness (the
reticular activating system sets pupil size
and the gain of the light reflex via a
supranuclear inhibitory tone on the
parasympathetic nuclei in the mid-brain);
emotions (psychic influences act via the
limbic system on the hypothalamus);
accommodation (through the near triad
synkinesis, the anatomy of which is still not
fully understood); and age (the pupils are
largest in adolescents and progressively
smaller thereafter). As a result, under
constant lighting conditions, there is
significant variation in pupil size from
moment to moment (hippus) and from
person to person. Moreover, 10-20% of the
population have pupils which are not the
same size as each other (anisocoria)6. This
anisocoria is physiological if it is caused by
‘normal’ differences in the balance of
parasympathetic and sympathetic drive to
the two pupils. The hallmarks of
physiological anisocoria are: that it lessens
when measured in bright light, it varies over
time (it may even reverse) and the reactions
of the pupil to a bright light or an
accommodative target are brisk and normal.
These features should be contrasted with
anisocoria due to parasympathetic or
sympathetic block (see later).
Pupil pharmacology
The iris sphincter muscle contains
muscarinic receptors to acetylcholine
(Figure 3A). These receptors, a member of
the ubiquitous family of G-proteins, are not
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April 7, 2000 OT
directly associated with transmembrane ion
channels (as are nicotinic receptors) but
instead their activation sets in motion a
cascade of phosphorylation reactions
leading to release of secondary intracellular
messengers which bring about muscle fibre
contraction. This process takes time and
adds considerably to the latency of the
pupil light reflex. Agonists of these
receptors constrict the pupil and include
pilocarpine and carbachol. Following
denervation of the muscle from any lesion
of the pre-ganglionic or post-ganglionic
parasympathetic fibres, receptor
up-regulation leads to supersensitivity of
the pupil to muscarinic agonists (for
example, the pupil will constrict to 0.1%
pilocarpine, a concentration at which there
would be no effect on a normal pupil7).
Conversely, receptor down-regulation occurs
following prolonged exposure to muscarinic
agonists, for example, in patients being
treated with pilocarpine for chronic
glaucoma. Antagonists of these receptors
(anti-muscarinics) are used clinically to
dilate the pupil, or to achieve cycloplegia
for refraction purposes, and include
tropicamide, cyclopentolate, homatropine
and atropine (in order of their duration of
action).
The iris dilator muscle contains alphaadrenergic receptors to noradrenaline
(Figure 3B). The noradrenaline is
synthesised and stored in the pre-junctional
sympathetic nerve endings. Topical 1%
hydroxyamphetamine drops cause release of
this stored noradrenaline and will therefore
dilate the pupil in subjects with intact
post-ganglionic sympathetic nerve fibres.
Once released, the action of noradrenaline
is principally terminated by an active reuptake process. Topical 4% cocaine drops
The most common pupil abnormality to be
noticed by a patient is anisocoria (unequal
pupil sizes). Because anisocoria does not
produce symptoms per se, the clinical
history from the patient is frequently
unrewarding; the patient usually finds it
difficult to date the onset of the anisocoria,
and in the absence of other signs has to
guess which side is abnormal. In these
circumstances, the clinician needs to adopt
a more direct line of questioning. The
patient should be asked about diplopia,
ptosis and difficulty with accommodation. A
detailed history of previous medical
conditions or surgical procedures in the eye
or in the brain should be requested, since
the patient will often not realise the
possible relevance to their anisocoria. A
general medical history may identify local or
systemic conditions likely to affect pupil
size (see later). Past photos will help to
establish whether the anisocoria is new or
longstanding.
Anisocoria may be physiological (see
earlier) or pathological due to denervation
of the iris sphincter or dilator muscles
(parasympathetic or sympathetic block
respectively). A flow diagram to illustrate
the logical approach to pathological
anisocoria is shown in Figure 4. When faced
with a patient who has pathological
anisocoria, the first and most challenging
question is which side is abnormal, the
larger pupil or the smaller one. The simplest
way to answer this question is to compare
the pupil sizes in the dark and in the light.
If the larger pupil is abnormal, then the
difference in pupil size will be exaggerated
in bright light; this implies parasympathetic
block. Conversely, if the smaller pupil is
abnormal, then the difference in pupil size
will be more apparent under dimmer
conditions; this implies sympathetic block.
Parasympathetic block
If the larger pupil is abnormal, then the
next step is to determine whether the
parasympathetic block is pre-ganglionic (the
unreactive pupil) or post-ganglionic (the
‘tonic’ pupil). Pre-ganglionic block is
characterised by a large, unreactive pupil,
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Module 2 Part 4
Figure 4
Flow diagram to illustrate the clinical steps necessary to evaluate anisocoria in a patient
absent accommodation and paresis of some
or all of the other muscles supplied by the
oculomotor nerve. When complete, the
external ophthalmoplegia produces
exotropia and hypotropia, but in milder
cases may be manifest only as diplopia on
upgaze or contralateral gaze.
The pupil signs of a third nerve palsy
may change over time. Immediately after
pre-ganglionic blockade, the pupil will not
constrict to dilute pilocarpine (0.1%), but
within a few weeks of disuse, atrophy of the
post-ganglionic fibres leads to receptor
up-regulation and ‘secondary’ denervation
supersensitivity7. Moreover, as the axons
regenerate following compression of the
third nerve (in particular by parasellar
lesions) some fibres terminate in the ‘wrong’
muscle leading to the development of
abnormal synkinesis; the most common
example is with medial rectus motor units
producing miosis during adduction
movements.
The association of pain and a pupilinvolving oculomotor nerve palsy is of great
clinical significance since in many of these
patients, the cause is a structural lesion
such as an intracranial aneurysm or tumour.
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As a general rule, any patient with a pupilinvolving third nerve palsy needs to be seen
urgently (i.e. the same day) by their GP or
the A&E department of the local hospital.
Post-ganglionic block may be difficult to
distinguish from pre-ganglionic block in the
acute phase since both are characterised by
a large, unreactive pupil and cycloplegia.
However, when the block is post-ganglionic,
the eye movements are normal (purely
‘internal’ ophthalmoplegia is almost never
seen with pre-ganglionic lesions3). Over
time, the clinical signs change because
there is aberrant regeneration of these postganglionic fibres, with fibres intended for
the ciliary muscle terminating instead in the
iris sphincter muscle (and vice versa). The
pupil starts to exhibit tonic behaviour with
light-near dissociation (the light reflex is
attenuated but the pupil constricts
maximally to an accommodative target) and
characteristically slow constriction and
redilatation after a light or near stimulus
(sometimes minutes). The shape of the
pupil often appears oval, and at the slit
lamp the iris stroma shows streaming (spiral
trabeculae) with vermiform (worm-like)
movements of the pupil margin due to
sectoral palsy and patchy reinnervation of
the sphincter muscle. These latter signs are
also seen in cases of herpes zoster or angle
closure glaucoma (where the damage is
ischaemic), but when they are due to postganglionic denervation there is no iris
transillumination. Accommodation recovers
quickly but the pupillary abnormalities
persist with gradual miosis over time. In
some cases, the pupil ends up smaller than
in the fellow eye8. Denervation
supersensitivity is readily demonstrated
within days of the initial damage using
0.1% pilocarpine.
The tonic pupil is most commonly found
in Adie’s syndrome, a benign idiopathic
condition which typically affects young
women in their third to fifth decades. An
example is shown in Figure 5. It is
unilateral in 80-90% of cases and may
present with sudden blurring of vision,
photophobia, anisocoria or without
symptoms as an incidental finding. Pain is
not a feature. The diagnosis is made by
demonstrating reduced deep tendon reflexes
(especially knee and ankle) and excluding
other ocular, orbital or systemic causes of a
tonic pupil. A small proportion of these
patients also have patchy hypohidrosis
(sweating) from involvement of sudomotor
fibres (Ross’ syndrome)9. Other causes of a
tonic pupil are much rarer but include
autonomic neuropathies10, amyloidosis,
orbital injuries, orbital surgery, orbital
tumours, herpes zoster, extensive panretinal
photocoagulation or cryotherapy.
In general, post-ganglionic blockade is
caused by less worrying pathology than
pre-ganglionic blockade and needs only a
routine referral to the local
ophthalmologist. The management of the
parasympathetic block should be directed at
the symptoms. For accommodative paresis,
reading glasses or bifocals may help. For
troublesome glare, dilute pilocarpine drops
(used sparingly) can be very effective but
the clinician needs to avoid triggering
accommodative spasm through ciliary
muscle supersensitivity. An alternative
approach is to use contact lenses with an
artificial pupil, particularly if cosmesis is
Figure 5
Patient with Adie’s syndrome
affecting the left eye
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Figure 6
Patient with left-sided Horner’s syndrome due
to carotid artery dissection. The pupil is
smaller, and there is ptosis of the upper lid
and elevation of the lower lid
the main concern of the patient. Many
patients with Adie’s syndrome require only
reassurance that the condition is benign
and limited to the pupil.
Mimics of parasympathetic blockade
abound. Non-neurological causes of a large,
unreactive pupil include aniridia (congenital
absence or hypoplasia of the iris which may
be asymmetric), trauma (blunt ocular
trauma may cause sphincter ruptures - best
demonstrated by retro-illuminating the pupil
margin), iris manipulation during intraocular
surgery (which may interfere with pupil size,
shape and reactivity), acute angle closure
glaucoma (the pupil signs are accompanied
by severe pain, visual loss and corneal
oedema), and anti-muscarinic drugs. The
use of atropine-like drugs may not be
offered in the history but is suggested by a
total internal ophthalmoplegia without
denervation supersensitivity, and with
normal ocular motility11. In doubtful cases
the passage of time will clarify the
situation.
Sympathetic block
Denervation of the sympathetic supply to
the eye produces a characteristic clinical
picture known as Horner’s syndrome (first
described by Ogle 11 years before Horner’s
publication12). Patients with unilateral
Horner’s syndrome may complain of
anisocoria or ptosis, but often it is an
incidental finding. Because it is frequently
not noticed by the patient, the clinician
should specifically look for an ipsilateral
Horner’s syndrome in all patients with
unexplained arm, neck or head pain. The
affected pupil is small (Figure 6), with
increased anisocoria in dim conditions, and
slowed redilatation following constriction to
a light or accommodative target. If the
sympathetic denervation is congenital or
perinatal, heterochromia iridis may be
present (sympathetic innervation is
important for the early development of iris
pigmentation); this can be a very helpful
sign in cases where it is not possible to
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April 7, 2000 OT
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date the onset of the Horner’s syndrome.
The pupil is not the only structure within
the eye to be affected by sympathetic
block. Other features of Horner’s syndrome
include ptosis, elevation of the lower lid
(the narrowed palpebral aperture gives rise
to apparent enophthalmos), conjunctival
injection and ocular hypotony. With
pre-ganglionic lesions, the ipsilateral skin
may feel warmer and drier due to
interruption of the sudomotor supply to the
face; post-ganglionic lesions distal to the
carotid bifurcation do not cause facial
anhydrosis apart from a small patch of skin
above the supraorbital notch which is
supplied by sudomotor fibres travelling with
the internal carotid artery. In practice, it is
rarely possible to distinguish between preand post-ganglionic Horner’s on the basis of
skin temperature. In all cases,
pharmacological evaluation should be
undertaken to make this distinction.
There are many causes of miosis and
ptosis other than sympathetic denervation,
so it is important in cases of suspected
Horner’s syndrome to confirm the diagnosis
with either drugs or infra-red
videopupillography. The drugs used in
evaluating Horner’s syndrome are
phenylephrine, cocaine and
hydroxyamphetamine. Receptor
up-regulation should lead to denervation
supersensitivity to dilute (1%)
phenylephrine in Horner’s syndrome, but
this is an unreliable test with a high false
negative rate. A better test for Horner’s is
topical 4% cocaine drops, which dilates
normal pupils by increasing the basal
sympathetic tone. In Horner’s, the
sympathetic nerve endings release so little
noradrenaline that preventing its re-uptake
makes little difference to the size of the
pupil. This test is made even more sensitive
if the degree of anisocoria before and after
cocaine drops is measured rather than the
absolute change in pupil diameter: a postcocaine anisocoria greater than 0.8mm is
highly diagnostic of Horner’s syndrome13.
When available, video-pupillography is
an alternative investigation for Horner’s
syndrome. An infra-red source illuminates
the iris and the pupil can then be observed
in darkness using an infra-red sensitive
video camera. The redilatation time
following a light reflex response can be
measured and is a sensitive indicator of
sympathetic function. Redilatation lag
confirms sympathetic block, and has the
advantage over the cocaine test of being
able to detect pathology in cases of
bilateral Horner’s syndrome.
Once Horner’s syndrome is confirmed,
it is important to distinguish between
pre- and post-ganglionic lesions. This is
best achieved using topical 1%
hydroxyamphetamine drops, which release
noradrenaline from intact post-ganglionic
nerve endings. Hydroxyamphetamine will
therefore dilate normal pupils and pupils
with pre-ganglionic Horner’s of recent
onset, but fails to dilate post-ganglionic
Horner’s14. In longstanding pre-ganglionic
Horner’s, the test is difficult to interpret
since there is often a degree of disuse
atrophy of the third-order neurone. If the
cocaine test is used to confirm the presence
of sympathetic block, it is necessary to
allow a wash out interval of 48 hours before
the hydroxyamphetamine test.
Like many pupil abnormalities, Horner’s
syndrome does not significantly affect
vision. Its importance lies in the nature of
the pathology which caused it. Horner’s
syndrome can be produced by lesions
anywhere along the lengthy course of the
sympathetic supply to the eye. The firstorder (central) neurone may be involved in
brainstem (pontine infarction, lateral
medullary syndrome, multiple sclerosis) or
cervical cord (trauma, tumours,
syringomyelia) lesions and is invariably
associated with other signs of axial
pathology. The second-order (preganglionic) neurone is susceptible to chest
(Pancoast’s tumour, cervical rib, surgery) or
neck (trauma, tumours, surgery) disease and
may be isolated or associated only with arm
pain. In children, any pre-ganglionic
Horner’s without a history of birth trauma,
regardless of iris pigmentation, requires
urgent imaging to exclude a neuroblastoma.
In adults, acquired pre-ganglionic Horner’s
needs further investigation since a
proportion of these patients harbour an
unsuspected malignancy. Isolated lesions of
the third-order (post-ganglionic) neurone
are usually benign, may be associated with
episodic pain in a trigeminal distribution
(Raeder’s paratrigeminal syndrome) and
require no further investigation. The
exception is acute-onset post-ganglionic
Horner’s associated with constant and
severe jaw or head pain in a patient with
systemic vascular disease or significant neck
trauma. These patients require urgent
magnetic resonance angiography
(arteriography is contra-indicated) to
exclude carotid dissection15. Bilateral
Horner’s is not uncommon but is often
missed clinically because the signs are
symmetrical in the two eyes. It is found in
a number of autonomic neuropathies
including diabetes mellitus, progressive
autonomic failure and amyloidosis.
Abnormal pupil shape
The normal pupil is round and central in the
iris. There are numerous conditions in
clinical ophthalmology which affect the
shape and position of the pupil. Among the
congenital conditions, Rieger’s anomaly
(one of a spectrum of rare anterior segment
anomalies due to mesodermal dysgenesis) is
characterised by unilateral pupillary
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Module 2 Part 4
distortion and displacement associated with
glaucoma. Trauma is a frequent cause of
pupillary distortion. Accidental trauma may
lead to iris sphincter ruptures, and it is
sometimes necessary during intraocular
surgery to cut the sphincter muscle
(shincterotomy) or iris (iridectomy).
Moreover, if the posterior capsule ruptures
during cataract extraction, vitreous may
prolapse forward distorting the pupil.
Inflammation in the anterior segment of the
eye (uveitis) may lead to irido-lenticular
adhesions (posterior synechiae); the pupil
has an irregular shape and will not dilate
concentrically with mydriatic agents. Other
medical conditions of the anterior segment,
which distort the pupil, include angle
closure glaucoma and iris rubeosis.
Ectropion uveae and pupillary distortion are
important signs suggesting malignancy in
tumours of the iris or ciliary body. Pupil
distortion, displacement and multiple pupils
are seen in the irido-corneal
endotheliopathy syndrome (ICE). In many
cases, the patient will already be aware of
their ophthalmic condition. If there is no
satisfactory explanation for the abnormal
shape of the pupil, then the patient
needs a slit lamp examination,
tonometry and a referral to the local
ophthalmologist.
Abnormal pupil reactions
The normal pupil constricts briskly to a
light stimulus or an accommodative target,
and redilates at a slightly slower rate
following cessation of the stimulus. Testing
these light and near responses of the pupil
is an essential part of the clinical
evaluation of the pupil. In cases of
parasympathetic or sympathetic block, the
pupil reactions are abnormal, but the
associated anisocoria (and other signs)
confirms that the lesion is in the efferent
pathways. In this section, pupils which
have a normal shape and position and
which are equal in size, but which do not
react normally to light and near stimuli will
be discussed. In these patients, the lesion
lies either in the afferent pathway of the
pupil light reflex or centrally within the
mid-brain.
Afferent defects
Examining the pupil response to light is
arguably the most useful test in a patient
with unexplained visual loss. Clinically, this
is assessed with the swinging light test16,
where a flashlight is rapidly alternated
between the two eyes and the pupil
reactions compared. This test is best
performed in dim light conditions using an
intense stimulus (such as the beam from
an ophthalmoscope) allowing enough time
for the pupils to equilibrate with the bright
light (1-2 seconds) but not so long that
the retinal pigment is bleached (>3
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Figure 7
Schematic diagram to illustrate pupil sizes during the swinging flashlight test
A: In a normal subject, the light stimulus produces maximal constriction of both pupils
regardless of which eye is stimulated
B: In a patient with a left-sided relative afferent pupil defect (RAPD), both pupils are more
constricted when the stimulus is presented to the right eye, and less constricted when the
stimulus is presented to the left eye. Note that afferent pupil defects do not cause anisocoria
seconds). The test is valid even when only
one pupil is functioning.
With unilateral or asymmetric afferent
defects the pupils constrict less to light
shone in the worse eye (Marcus-Gunn
pupil). In the mildest cases, this relative
afferent pupil defect (RAPD) is manifest as
asymmetry of the pupillary escape (escape
is pupillary redilatation before the stimulus
is withdrawn, a normal phenomenon which
is exaggerated if there is an afferent
defect). With more significant asymmetry
in the afferent drive, the pupils constrict
maximally when the flashlight is swung
from the worse eye to the better eye, but
dilate (i.e. are less constricted) when the
flashlight is swung from the better eye
back to the worse eye. If there is no
afferent function remaining then neither
pupil will react to light shone in the
affected eye (the amaurotic pupil). The
RAPD can be classified clinically as escapemild-moderate-marked and quantified for
research purposes using neutral density
filters or infra-red video pupillography.
The finding of an RAPD in a patient
needs careful interpretation. It indicates
asymmetry in the afferent signals from the
two eyes, and nothing more. It is rare for
pre-retinal disease to be so severe as to
produce a RAPD. Media opacities scatter
light but usually do not significantly
diminish the total afferent drive to the
pupil light reflex. In cases where there is a
poor view of the fundus due to advanced
cataract or vitreous haemorrhage, it is
unwise to ascribe the presence of a RAPD
to these media opacities17. Similarly,
although it is possible using infra-red
video pupillography to demonstrate subtle
abnormalities in the pupil light reflex
caused by retro-chiasmal lesions18, these
rarely produce a clinically detectable RAPD.
As a general rule, the presence of a RAPD
implies retinal or optic nerve disease.
The extent of the RAPD broadly
correlates with the degree of loss of visual
field rather than visual acuity19. An eye
may have a Snellen acuity of 6/6 and yet
the swinging light test shows a marked
RAPD because of extensive peripheral field
loss. It should be remembered that the
presence of an RAPD does not mean that
the ‘better’ eye is a normal eye, merely
that it is less affected. Occasionally,
bilateral afferent defects are found which
are truly symmetrical. In these cases, both
pupils show poor responses to light, no
RAPD and normal near reactions. The most
common causes of a RAPD include retinal
artery or vein occlusions, retinal
detachment, asymmetric field loss in
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glaucoma, anterior ischaemic optic
neuropathy and optic neuritis. Any patient
whose vision cannot be improved with
refraction should have their pupil reactions
tested and an urgent referral arranged for
cases with a RAPD.
Central defects
Unlike afferent defects where the abnormal
pupil reactions correlate with abnormal
vision, mid-brain lesions cause bilateral
symmetrical abnormalities of the pupil
reactions in the face of normal visual
function. These central pupil defects are
rare nowadays, and are usually associated
with other neurological signs of brainstem
disease. The two main patterns of
abnormality seen are Parinaud’s syndrome
and Argyll Robertson (AR) pupils.
Parinaud’s syndrome (also known as
dorsal mid-brain, pretectal, Sylvian
aqueduct or Koerber-Salus-Elschnig
syndrome) is characterised by large pupils,
which constrict briskly to an
accommodative target, but poorly if at all
to light (light-near dissociation).
Associated findings include vertical gaze
deficit, convergence-retraction nystagmus,
Collier’s sign (lid retraction on attempted
upgaze) and skew deviation. This pattern
of deficits implies a lesion affecting the
posterior commissure and pretectal nuclei,
with interruption to the more dorsal
afferent light pathway but preservation of
the more ventral near pathway. The most
common causes include pineal region
tumours, hydrocephalus (due to
enlargement of the third ventricle) or
intrinsic lesions of the dorsal mid-brain.
AR pupils are extremely rare nowadays,
but were much commoner in the
nineteenth century when untreated syphilis
was widespread20. They show similar lightnear dissociation but are small (often with
an irregular shape), dilating poorly in
darkness and showing an attenuated
response to topical mydriatic agents. These
features suggest interruption of both the
afferent light pathway and the central
inhibitory fibres ventral to the aqueduct
(although a corresponding focal lesion has
yet to be demonstrated). AR pupils are
usually considered pathognomonic of
tertiary syphilis but ‘pseudo-AR’ pupils
showing many or all of the above features
have been described in a number of other
conditions including diabetes mellitus,
multiple sclerosis, encephalitis and
myotonic dystrophy20.
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References
1. Loewenfeld, I.E. (1993) ‘The Pupil:
Anatomy, Physiology and Clinical
Applications’. Ames, Iowa, Iowa State
University Press; Detroit MI, Wayne State
University Press.
2. Kardon, R.H. (1998) “Anatomy and
physiology of the pupil”. In: Walsh and
Hoyt ‘Clinical Neuro-ophthalmology’.
Williams and Wilkins, Baltimore, MD; 5th
edition, Volume 1, Chapter 20.
3. Thompson, H.S. and Miller N.R. (1998):
“Disorders of pupillary function,
accommodation and lacrimation”. In: Walsh
and Hoyt ‘Clinical Neuro-ophthalmology’.
Williams and Wilkins, Baltimore, MD; 5th
edition, Volume 1, Chapter 24.
4. Kourouya, H.D. and Horton J.C. (1997)
“Transneuronal retinal input to the primate
Edinger-Westphal nucleus”. J. Comp. Neurol.
380: 1-13.
5. Kerr, F.W.L. and Hollowell, O.W. (1964)
“Location of pupillomotor and
accommodation fibres in the oculomotor
nerve”. J. Neurol. Neurosurg. Psychiatry 27:
473-481.
6. Loewenfeld, I.E. (1977) “Simple, central
anisocoria: a common condition, seldom
recognized”. Trans. Am. Acad. Ophthal.
Otolaryng. 83: 832-839.
7. Jacobson, D.M. (1990) “Pupillary responses
to dilute pilocarpine in pre-ganglionic third
nerve disorders”. Neurology 40: 804-808.
8. Thompson, H.S, Bell, R.A. and Bourgon, P.
(1979) “The natural history of Adie’s
syndrome”. In: ‘Topics in Neuroophthalmology’. Eds: Thompson, H.S.,
Daroff, R., Frisen, L. et al, pp 96-99;
Williams & Wilkins, Baltimore.
9. Ross, A.T. (1958) “Progressive selective
sudomotor denervation: a case with
coexisting Adie’s syndrome”. Neurology 8:
809-817.
10. Hope-Ross, M., Buchanan, T.A.S, Archer,
D.B. et al. (1990) “Autonomic function in
Holmes-Adie syndrome”. Eye 4: 607-612.
11. Thompson, H.S., Newsome, D.A. and
Loewenfeld, I.E. (1971) “The fixed dilated
pupil: sudden iridoplegia or mydriatic
drops? A simple diagnostic test”. Arch.
Ophthal. 86: 21-27.
12. Ogle, J.W. (1858) “On the influence of the
cervical portion of the sympathetic nerve
and spinal cord upon the eye and its
appendages, illustrated by clinical cases,
with observations”. Medicochirurg. Trans
41: 397-440.
13. Kardon, R.H., Denison, C.E, Brown C.K et al
(1990) “Critical evaluation of the cocaine
test in the diagnosis of Horner’s syndrome”.
Archives of Ophthalmology 108: 384-387.
14. Cremer, S.A., Thompson, H.S., Digre, K.B. et
al (1990) “Hydroxyamphetamine mydriasis
in Horner’s syndrome”. Am. J. Ophthal. 110:
71-76.
15. West, T.E.T., Davies, R.J. and Kelly, R.E.
(1976) “Horner’s syndrome and headache
due to carotid artery disease”. Brit. Med. J.
1: 818-820.
16. Stanley, S.A. and Baise, G.R. (1968) “The
swinging flashlight test to detect minimal
optic neuropathy”. Arch. Ophthal. 80: 769771.
17. Bullock, J.D. (1990) “Relative afferent pupil
defect in the ‘better’ eye”. J. Clin.
Neurooph. 10: 45-51.
18. Hamann, K-U., Hellner, K.A, Muller-Jensen,
A. and Zschocke, S. (1979)
“Videopupillographic and VER investigations
in patients with congenital and acquired
lesions of the optic radiation”.
Ophthalmologica 178: 348-356.
19. Kardon, R., Haupert, C. and Thompson, H.S.
(1993) “The relationship between static
perimetry and the relative afferent pupil
defect”. Am. J. Ophthal. 115: 351-356.
20. Lowenfeld, I.E. (1969) “The Argyll
Robertson pupil 1869-1969: a critical
survey of the literature”. Survey of
Ophthalmology 14: 199-299.
An answer return form is included in this issue.
It should be completed and returned to:
CPD Initiatives (NOE4),
OT, Victoria House, 178-180 Fleet Road, Fleet, Hampshire, GU13 8DA by May 3.
About the author
Dr Bremner is a specialist registrar in
ophthalmology at Moorfields Eye Hospital.
He has a particular interest in neuroophthalmology and works as a research
fellow in the pupil laboratory at the
National Hospital, Queen’s Square, London.
38
April 7, 2000 OT
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Module 2 Part 4
Multiple choice questions
Pupil abnormalities
Please note there
is only one correct answer.
1. Which one of the following
structures does not lie in
proximity to the sympathetic
nerve supply to
the iris dilator muscle?
a. Trigeminal nerve
b. External carotid artery
c. Abducens nerve
d. Nasociliary nerve
2. Which one of the following
statements regarding
physiological anisocoria is
incorrect?
a. It is variable
b. It may be of recent onset
c. The light reflex is sluggish
d. The anisocoria may be less
obvious in bright light
3. Which one of the following
statements regarding the
parasympathetic supply
to the iris sphincter muscle
is correct?
a. The fibres lie superficially in the
arachnoid portion of the oculomotor
nerve
b. Pre-ganglionic fibres terminate
in the superficial cervical ganglion
c. Post-ganglionic fibres travel in
the long posterior ciliary nerves
d. Acetycholine release causes muscle
contraction via nicotinic receptors
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4. Which one of the following does
not dilate the pupil?
a. 1% phenylephrine in Horner’s
syndrome
b. 4% cocaine in a normal eye
c. 1% tropicamide in a patient with a
pre-ganglionic sympathetic lesion
d. 1% hydroxyamphetamine in a
patient with a post-ganglionic
sympathetic lesion
8. Which one of the following may
cause a relative afferent pupil
defect (RAPD)?
a. Corneal ulcer in a soft contact lens
wearer (VA 6/60)
b. Mature cataract (VA counting fingers)
c. Macula-sparing retinal detachment in
a high myope (VA 6/5)
d. Age-related macular degeneration (VA
6/12)
9. A diagnosis of pre-ganglionic
parasympathetic block is
compatible with which one of the
following?
a. Miosis during adduction movements
b. Anisocoria that is worse in dim light
c. Normal accommodation
d. Normal eye movements
5. Which one of the
following causes miosis?
a. Carbachol
b. Parinaud’s syndrome
c. Oculomotor nerve palsy
d. Aproclonidine
10. Horner’s syndrome is suggested by
which one of the following?
a. Lower lid retraction
b. No response to 1%
hydroxyamphetamine
c. No response to 10% phenylephrine
d. A past history of cataract extraction
6. Which one of the following is
not a feature of Adie’s syndrome?
a. Slow pupillary constriction and
redilation following an
accommodative effort
b. Light-near dissociation
c. Vermiform movements
d. Iris transillumination
11. Which one of the following pupil
abnormalities requires urgent
(same day) referral to the
emergency medical services?
a. Large unreactive pupil
and diplopia (VA 6/9)
b. Adie’s pupil
c. Tonic pupil
d. Horner’s syndrome after thyroid
surgery
7. Which one of the following pupil
abnormalities is not associated
with direct trauma to the eye?
a. Unreactive pupil
b. Tonic pupil
c. Oval pupil
d. Horner’s syndrome
12. Which one of the following pupil
signs is always abnormal?
a. Hippus
b. Anisocoria
c. Oval shape
d. Heterochromia
39
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Multiple choice answers
Visual pathways Part 2
Here are the correct answers to Module 2 Part 3,
which appeared in our March 10 issue.
1. Which one of the following
statements regarding the divisions of
the cerebral hemispheres is
incorrect?
a. The occipital lobe is at the posterior
pole of each hemisphere
b. The central sulcus defines the border
between the frontal lobe and the
temporal lobe
c. The temporal lobe lies inferior to the
lateral fissure
d. The frontal lobe is anterior to the
central sulcus
b is the correct answer
The central sulcus defines the border between
the frontal lobe and the parietal lobe, not
between the frontal lobe and the temporal lobe.
The border between the frontal lobe and the
temporal lobe is the lateral fissure.
2. Which one of the following
statements regarding the geniculocortical pathway to the visual cortex
is correct?
a. The anterior cerebellar artery supplies
the region of the internal capsule
b. The geniculocortical axons course in
the anterior limb of the internal
capsule
c. The internal capsule is the route by
which axons from the lateral geniculate
nucleus enter the optic radiations
d. Only magnocellular cells of the lateral
geniculate nucleus send axons through
the posterior limb of the internal
capsule
c is the correct answer
The axons of all cells of the lateral geniculate
nucleus that project to the visual cortex pass
through the posterior limb of the internal
capsule to form the optic radiations en route to
the visual cortex.
3. Which one of the following
statements regarding the layers of
the primary visual cortex is correct?
a. Layer 4β receives the predominant
input from parvocellular cells of the
lateral geniculate nucleus
b. Layer 1 is the most inner layer and
contains many neurons
c. The stria of Gennari is another name for
layer 3
d. The lateral geniculate nucleus receives
an input from layer 6
d is the right answer
The major input to the lateral geniculate
nucleus is the descending input from the
visual cortex. The origin of this descending
input is in layer 6 of the visual cortex.
40
April 7, 2000 OT
4. Which one of the following
statements regarding layer 4Cα of
the primary visual cortex is
incorrect?
a. Layers 4Cα and 4Cβ receive their
inputs from the same layers in the
lateral geniculate nucleus
b. Cells in layer 4B send their axons to
more superficial layers of the
primary visual cortex
c. Layer 4 is otherwise known as the
internal granular layer
d. Layer 4Cα receives its input from
the magnocellular layers of the
lateral geniculate nucleus
a is the correct answer
Layers 4Cα and 4Cβ receive their thalamic
inputs from distinct cell types that are
segregated into different layers in the
lateral geniculate nucleus. The input to
layer 4Cα is from magnocellular cells of the
ventral two layers of the lateral geniculate
nucleus, whereas layer 4Cβ receives from
cells of the four dorsal, parvocellular, layers.
5. Which one of the following
statements with regard to the
receptive field properties of cells
in the primary visual cortex is
correct?
a. Only simple cells have elongated
receptive fields
b. Simple cell receptive fields are
localised in layer 2
c. The receptive fields of simple cells
are elongated with discrete
excitatory and inhibitory regions
d. Complex cells have receptive fields
with the same organisation as cells
of the lateral geniculate nucleus
c is the correct answer
Rather than the centre-surround
organisation of receptive fields found in the
lateral geniculate nucleus, cells of the visual
cortex possess receptive fields with a more
complex organisation. The receptive fields
of simple, complex and hypercomplex cells
in the visual cortex also tend to be
elongated, but only those of simple cells
possess distinct excitatory (ON) and
inhibitory (OFF) zones.
6. Which one of the following
statements regarding complex cells
is incorrect?
a. The receptive fields are larger than
simple cells
b. The receptive fields are elongated
c. Optimal response is elicited with a
sweeping stimulus
d. They are found close to layer 4
d is the correct answer
Simple cells appear to be most common close to
layer 4 in primary visual cortex (V1), whereas
complex cells tend to be more common at more
distant locations from the input layer. The
complex cell receptive fields are larger than
those of simple cells, but they are both
elongated. Unlike the simple cell, however, a
complex cell receptive field does not possess
such easily definable excitatory and inhibitory
regions and the optimal response is often
associated with sweeping the stimulus across
the receptive field rather than a specific
location within the field.
7. Which of the following statements
regarding the visual cortical areas is
incorrect?
a. Area V2 is adjacent to V1
b. V1 occupies the region in and around
the calcarine fissure
c. V2 does not possess
a retinotopic organisation
d. V4 contains many cells that are
selective for the colour of a stimulus
c is the correct answer
Retinotopic organisation is a feature of many
visual areas including the retinal representation
in V2.
8. Which one of the following
statements regarding the properties
of interblob cells is correct?
a. They have orientation specificity and
are responsive to chromatic stimuli
b. They are responsive to
chromatic stimuli only
c. They are wavelength sensitive
d. They possess orientation specificity
only
d is the correct answer
Cells in the blob regions possess receptive fields
that are not selective for orientation, but are
colour sensitive. In the interblob regions, the
cells are optimally responsive to the orientation
of the stimulus.
9. Which of the following statements
regarding the columnar organisation
of primary visual cortex is incorrect?
An electrode penetration through the
cortical layers perpendicular to the
surface would:
a. encounter cells with receptive fields all
in the same part of the visual world
b. encounter a random array of orientation
selectivities
c. encounter cells that were responsive
mainly to stimuli presented through one
eye
d. encounter cells in layer 4C that were
not selective for orientation of the
stimulus
b is the correct answer
An electrode penetration perpendicular to the
surface of the primary visual cortex would be
likely to encounter cells with very similar
orientation specificity, if the penetration
advanced through an interblob region. If the
electrode advanced through a blob region, cells
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Module 2 Part 4
above and below the blob would have similar
orientation tuning whereas those within the
blobs would have little or no orientation
preference.
c. Layer 4Cβ has connections with blob
and interblob regions
d. Layer 4β possesses a direct
connection to area V5
10. Which of the following statements
regarding the organisation of primary
visual cortex (V1) is correct?
a. Each part of the visual field is equally
represented in V1
b. This visual area is histologically
homogenous
c. Blobs are most clearly visible
in layers 2 and 3
d. Interblobs stain positively for the
enzyme cytochrome oxidase
b is the correct answer
Layer 4Cα receives its input from the
magnocellular division of the lateral
geniculate nucleus and conveys that on to
layer 4β. Layer 4Cβ receives from the
parvocellular layers of the lateral geniculate
nucleus.
c is the correct answer
In the primary visual cortex it is the blob
regions, primarily in layers 2/3, that stain
positively for the metabolic enzyme cytochrome
oxidase. The interblob regions are negative for
the stain for cytochrome oxidase.
12. Which of the following statements
regarding the connections of V2,
is correct?
a. Thin stripe regions in V2 receive
inputs from the interblobs
b. Pale stripes in V2 receive from
interblob cells
c. Most cells in the thick stripes possess
no direction selectivity
d. V5 receives only from cells in V2
11. Which of the following statements
with regard to the connections of V1,
is incorrect?
a. Layer 4Cα connects to layer 4β
b. Layer 4Cβ receives inputs from the
magnocellular layers
b is the correct answer
In V2, thick stripe regions receive input from
layer 4β of V1, thin stripes receive from cells
in the blob regions of V1, and pale stripes get
their input from cells in the interblob regions
of V1.
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41