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Module 2 Part 4 Optometrists
Pupil abnormalities
ABDO has awarded
this article
2 CET credits (GD).
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 Figure 1
light enters the eye. Its size is determined Schematic diagrams of the
by many factors including afferent drive from parasympathetic (A) and
the retina, central processing in the sympathetic (B) nerve supply to the
brainstem, the balance of tone in the pupil constrictor and dilator muscles
autonomic nervous system and local factors respectively. EWN=Edinger-Westphal
within the muscles of the iris. Any nucleus; AMN=antero-median
disturbance to these structures may result in nucleus; CG=ciliary ganglion;
an abnormal size, shape or reactivity of the SPH=iris sphincter muscle;
pupil. In clinical practice, pupil abnormalities HYP=postero-lateral hypothalamus;
rarely have a significant impact on visual CSC=ciliospinal centre of Budge-
function and may not even be noticed by the Waller; SCG=superior cervical
patient. However, examination of the pupil is ganglion; DIL=iris dilator muscle
important because a pupil abnormality may
be the only sign of dysfunction in the eye or
brain. parasympathetic innervation (resulting in the visceral mid-line nuclei4 (antero-median,
miosis), and the dilator muscle, which is Edinger-Westphal and possibly Perlias
Pupil anatomy under sympathetic innervation (resulting in nucleus) of the upper mid-brain. Their axons
The size of the pupil is determined by the mydriasis). The parasympathetic supply is a join with motor fibres from the ipsilateral
balance of two antagonist muscles in the two-neurone chain (Figure 1A). The cell oculomotor nuclei to form the fascicle of
iris: the sphincter muscle, which is under bodies of the pre-ganglionic neurones lie in the third cranial nerve. The parasympathetic
fibres accompany the oculomotor T2). The second-order (pre- Pupil physiology processing (interneurones
nerve throughout its intracranial ganglionic) neurones leave the It is common knowledge that emerging from these nuclei
course, lying superficially where spinal cord with the ventral the pupils are small in bright which decussate in the posterior
they are susceptible to spinal roots as the white rami light and larger in the dark. The commissure before projecting to
compressive injury5. Within the communicantes, and ascend in neural basis for this association the Edinger-Westphal and
orbit, the axons leave the the sympathetic chain without is a reflex arc (Figure 2) antero-median nuclei on both
inferior division of the synapse. On the left side, the composed of an afferent limb sides of the mid-brain); and an
oculomotor nerve and travel with sympathetic chain splits around (retinal ganglion cells which are efferent limb (the
the nerve to the inferior oblique the sub-clavian artery with the sensitive to the ambient parasympathetic supply to the
muscle before terminating in the posterior branch (ansa sub- luminance level, decussate at iris sphincter muscle as detailed
ciliary ganglion. The cell bodies clavia) lying close to the apex of the optic chiasm and project to above). Under normal
of the post-ganglionic neurones the lung. The the pretectal nuclei on both circumstances, this reflex arc
lie within the ciliary ganglion. pre-ganglionic fibres on both sides of the mid-brain); central results in an inverse relationship
Their axons emerge with other sides terminate in the superior
autonomic and somatosensory cervical ganglion at the level of
fibres to form the short ciliary the angle of the mandible. From
nerves. These pass forwards in here, the third-order (post-
the suprachoroidal space to ganglionic) neurones travel on
reach the iris sphincter muscle. the surface of the internal
The sympathetic supply to the carotid artery, passing with the
iris dilator muscle probably artery through the foramen
involves several neurones but is lacerum into the intracranial
classically described as a three- space. Within the cavernous
neurone chain (Figure 1B). The sinus, they leave the artery to
Figure 2
first-order (central) neurones join firstly the abducens nerve
Schematic diagram of the reflex arc which generates the pupil response
start in the ipsilateral posterior and then the ophthalmic division
to light. RGC=retinal ganglion cells; PTN=pretectal nuclei;
hypothalamus and descend of the trigeminal nerve before
EWN=Edinger-Westphal nucleus; SPH=iris sphincter muscle. Other
uncrossed through the lateral entering the orbit with the
supranuclear inputs to the parasympathetic neurones in the midbrain
part of the brainstem to nasociliary nerve and passing
include: the NEAR triad; RAS=reticular activating system;
terminate in the ciliospinal forward to the iris dilator muscle
HYP=hypothalamus; LS=limbic system; CX=cerebral cortex
centre of Budge-Waller (level C8- in the long ciliary nerves.
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Module 2 Part 4
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date the onset of the Horners syndrome. nerve endings. Hydroxyamphetamine will
The pupil is not the only structure within therefore dilate normal pupils and pupils
the eye to be affected by sympathetic with pre-ganglionic Horners of recent
block. Other features of Horners syndrome onset, but fails to dilate post-ganglionic
include ptosis, elevation of the lower lid Horners14. In longstanding pre-ganglionic
(the narrowed palpebral aperture gives rise Horners, the test is difficult to interpret
to apparent enophthalmos), conjunctival since there is often a degree of disuse
injection and ocular hypotony. With atrophy of the third-order neurone. If the
pre-ganglionic lesions, the ipsilateral skin cocaine test is used to confirm the presence
may feel warmer and drier due to of sympathetic block, it is necessary to
interruption of the sudomotor supply to the allow a wash out interval of 48 hours before
face; post-ganglionic lesions distal to the the hydroxyamphetamine test.
carotid bifurcation do not cause facial Like many pupil abnormalities, Horners
Figure 6
anhydrosis apart from a small patch of skin syndrome does not significantly affect
Patient with left-sided Horners syndrome due
above the supraorbital notch which is vision. Its importance lies in the nature of
to carotid artery dissection. The pupil is
supplied by sudomotor fibres travelling with the pathology which caused it. Horners
smaller, and there is ptosis of the upper lid
the internal carotid artery. In practice, it is syndrome can be produced by lesions
and elevation of the lower lid
rarely possible to distinguish between pre- anywhere along the lengthy course of the
and post-ganglionic Horners on the basis of sympathetic supply to the eye. The first-
the main concern of the patient. Many skin temperature. In all cases, order (central) neurone may be involved in
patients with Adies syndrome require only pharmacological evaluation should be brainstem (pontine infarction, lateral
reassurance that the condition is benign undertaken to make this distinction. medullary syndrome, multiple sclerosis) or
and limited to the pupil. There are many causes of miosis and cervical cord (trauma, tumours,
Mimics of parasympathetic blockade ptosis other than sympathetic denervation, syringomyelia) lesions and is invariably
abound. Non-neurological causes of a large, so it is important in cases of suspected associated with other signs of axial
unreactive pupil include aniridia (congenital Horners syndrome to confirm the diagnosis pathology. The second-order (pre-
absence or hypoplasia of the iris which may with either drugs or infra-red ganglionic) neurone is susceptible to chest
be asymmetric), trauma (blunt ocular videopupillography. The drugs used in (Pancoasts tumour, cervical rib, surgery) or
trauma may cause sphincter ruptures - best evaluating Horners syndrome are neck (trauma, tumours, surgery) disease and
demonstrated by retro-illuminating the pupil phenylephrine, cocaine and may be isolated or associated only with arm
margin), iris manipulation during intraocular hydroxyamphetamine. Receptor pain. In children, any pre-ganglionic
surgery (which may interfere with pupil size, up-regulation should lead to denervation Horners without a history of birth trauma,
shape and reactivity), acute angle closure supersensitivity to dilute (1%) regardless of iris pigmentation, requires
glaucoma (the pupil signs are accompanied phenylephrine in Horners syndrome, but urgent imaging to exclude a neuroblastoma.
by severe pain, visual loss and corneal this is an unreliable test with a high false In adults, acquired pre-ganglionic Horners
oedema), and anti-muscarinic drugs. The negative rate. A better test for Horners is needs further investigation since a
use of atropine-like drugs may not be topical 4% cocaine drops, which dilates proportion of these patients harbour an
offered in the history but is suggested by a normal pupils by increasing the basal unsuspected malignancy. Isolated lesions of
total internal ophthalmoplegia without sympathetic tone. In Horners, the the third-order (post-ganglionic) neurone
denervation supersensitivity, and with sympathetic nerve endings release so little are usually benign, may be associated with
normal ocular motility11. In doubtful cases noradrenaline that preventing its re-uptake episodic pain in a trigeminal distribution
the passage of time will clarify the makes little difference to the size of the (Raeders paratrigeminal syndrome) and
situation. pupil. This test is made even more sensitive require no further investigation. The
if the degree of anisocoria before and after exception is acute-onset post-ganglionic
Sympathetic block cocaine drops is measured rather than the Horners associated with constant and
Denervation of the sympathetic supply to absolute change in pupil diameter: a post- severe jaw or head pain in a patient with
the eye produces a characteristic clinical cocaine anisocoria greater than 0.8mm is systemic vascular disease or significant neck
picture known as Horners syndrome (first highly diagnostic of Horners syndrome13. trauma. These patients require urgent
described by Ogle 11 years before Horners When available, video-pupillography is magnetic resonance angiography
publication12). Patients with unilateral an alternative investigation for Horners (arteriography is contra-indicated) to
Horners syndrome may complain of syndrome. An infra-red source illuminates exclude carotid dissection15. Bilateral
anisocoria or ptosis, but often it is an the iris and the pupil can then be observed Horners is not uncommon but is often
incidental finding. Because it is frequently in darkness using an infra-red sensitive missed clinically because the signs are
not noticed by the patient, the clinician video camera. The redilatation time symmetrical in the two eyes. It is found in
should specifically look for an ipsilateral following a light reflex response can be a number of autonomic neuropathies
Horners syndrome in all patients with measured and is a sensitive indicator of including diabetes mellitus, progressive
unexplained arm, neck or head pain. The sympathetic function. Redilatation lag autonomic failure and amyloidosis.
affected pupil is small (Figure 6), with confirms sympathetic block, and has the
increased anisocoria in dim conditions, and advantage over the cocaine test of being Abnormal pupil shape
slowed redilatation following constriction to able to detect pathology in cases of The normal pupil is round and central in the
a light or accommodative target. If the bilateral Horners syndrome. iris. There are numerous conditions in
sympathetic denervation is congenital or Once Horners syndrome is confirmed, clinical ophthalmology which affect the
perinatal, heterochromia iridis may be it is important to distinguish between shape and position of the pupil. Among the
present (sympathetic innervation is pre- and post-ganglionic lesions. This is congenital conditions, Riegers anomaly
important for the early development of iris best achieved using topical 1% (one of a spectrum of rare anterior segment
pigmentation); this can be a very helpful hydroxyamphetamine drops, which release anomalies due to mesodermal dysgenesis) is
sign in cases where it is not possible to noradrenaline from intact post-ganglionic characterised by unilateral pupillary
Module 2 Part 4
Abnormal pupil reactions B: In a patient with a left-sided relative afferent pupil defect (RAPD), both pupils are more
The normal pupil constricts briskly to a constricted when the stimulus is presented to the right eye, and less constricted when the
light stimulus or an accommodative target, stimulus is presented to the left eye. Note that afferent pupil defects do not cause anisocoria
and redilates at a slightly slower rate
following cessation of the stimulus. Testing seconds). The test is valid even when only light but usually do not significantly
these light and near responses of the pupil one pupil is functioning. diminish the total afferent drive to the
is an essential part of the clinical With unilateral or asymmetric afferent pupil light reflex. In cases where there is a
evaluation of the pupil. In cases of defects the pupils constrict less to light poor view of the fundus due to advanced
parasympathetic or sympathetic block, the shone in the worse eye (Marcus-Gunn cataract or vitreous haemorrhage, it is
pupil reactions are abnormal, but the pupil). In the mildest cases, this relative unwise to ascribe the presence of a RAPD
associated anisocoria (and other signs) afferent pupil defect (RAPD) is manifest as to these media opacities17. Similarly,
confirms that the lesion is in the efferent asymmetry of the pupillary escape (escape although it is possible using infra-red
pathways. In this section, pupils which is pupillary redilatation before the stimulus video pupillography to demonstrate subtle
have a normal shape and position and is withdrawn, a normal phenomenon which abnormalities in the pupil light reflex
which are equal in size, but which do not is exaggerated if there is an afferent caused by retro-chiasmal lesions18, these
react normally to light and near stimuli will defect). With more significant asymmetry rarely produce a clinically detectable RAPD.
be discussed. In these patients, the lesion in the afferent drive, the pupils constrict As a general rule, the presence of a RAPD
lies either in the afferent pathway of the maximally when the flashlight is swung implies retinal or optic nerve disease.
pupil light reflex or centrally within the from the worse eye to the better eye, but The extent of the RAPD broadly
mid-brain. dilate (i.e. are less constricted) when the correlates with the degree of loss of visual
flashlight is swung from the better eye field rather than visual acuity19. An eye
Afferent defects back to the worse eye. If there is no may have a Snellen acuity of 6/6 and yet
Examining the pupil response to light is afferent function remaining then neither the swinging light test shows a marked
arguably the most useful test in a patient pupil will react to light shone in the RAPD because of extensive peripheral field
with unexplained visual loss. Clinically, this affected eye (the amaurotic pupil). The loss. It should be remembered that the
is assessed with the swinging light test16, RAPD can be classified clinically as escape- presence of an RAPD does not mean that
where a flashlight is rapidly alternated mild-moderate-marked and quantified for the better eye is a normal eye, merely
between the two eyes and the pupil research purposes using neutral density that it is less affected. Occasionally,
reactions compared. This test is best filters or infra-red video pupillography. bilateral afferent defects are found which
performed in dim light conditions using an The finding of an RAPD in a patient are truly symmetrical. In these cases, both
intense stimulus (such as the beam from needs careful interpretation. It indicates pupils show poor responses to light, no
an ophthalmoscope) allowing enough time asymmetry in the afferent signals from the RAPD and normal near reactions. The most
for the pupils to equilibrate with the bright two eyes, and nothing more. It is rare for common causes of a RAPD include retinal
light (1-2 seconds) but not so long that pre-retinal disease to be so severe as to artery or vein occlusions, retinal
the retinal pigment is bleached (>3 produce a RAPD. Media opacities scatter detachment, asymmetric field loss in
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glaucoma, anterior ischaemic optic References 11. Thompson, H.S., Newsome, D.A. and
neuropathy and optic neuritis. Any patient Loewenfeld, I.E. (1971) The fixed dilated
whose vision cannot be improved with 1. Loewenfeld, I.E. (1993) The Pupil: pupil: sudden iridoplegia or mydriatic
refraction should have their pupil reactions Anatomy, Physiology and Clinical drops? A simple diagnostic test. Arch.
tested and an urgent referral arranged for Applications. Ames, Iowa, Iowa State Ophthal. 86: 21-27.
cases with a RAPD. University Press; Detroit MI, Wayne State 12. Ogle, J.W. (1858) On the influence of the
University Press. cervical portion of the sympathetic nerve
2. Kardon, R.H. (1998) Anatomy and and spinal cord upon the eye and its
Central defects physiology of the pupil. In: Walsh and appendages, illustrated by clinical cases,
Unlike afferent defects where the abnormal Hoyt Clinical Neuro-ophthalmology. with observations. Medicochirurg. Trans
pupil reactions correlate with abnormal Williams and Wilkins, Baltimore, MD; 5th 41: 397-440.
vision, mid-brain lesions cause bilateral edition, Volume 1, Chapter 20.
3. Thompson, H.S. and Miller N.R. (1998): 13. Kardon, R.H., Denison, C.E, Brown C.K et al
symmetrical abnormalities of the pupil
Disorders of pupillary function, (1990) Critical evaluation of the cocaine
reactions in the face of normal visual test in the diagnosis of Horners syndrome.
function. These central pupil defects are accommodation and lacrimation. In: Walsh
and Hoyt Clinical Neuro-ophthalmology. Archives of Ophthalmology 108: 384-387.
rare nowadays, and are usually associated
Williams and Wilkins, Baltimore, MD; 5th 14. Cremer, S.A., Thompson, H.S., Digre, K.B. et
with other neurological signs of brainstem
edition, Volume 1, Chapter 24. al (1990) Hydroxyamphetamine mydriasis
disease. The two main patterns of 4. Kourouya, H.D. and Horton J.C. (1997) in Horners syndrome. Am. J. Ophthal. 110:
abnormality seen are Parinauds syndrome Transneuronal retinal input to the primate 71-76.
and Argyll Robertson (AR) pupils. Edinger-Westphal nucleus. J. Comp. Neurol. 15. West, T.E.T., Davies, R.J. and Kelly, R.E.
Parinauds syndrome (also known as 380: 1-13. (1976) Horners syndrome and headache
dorsal mid-brain, pretectal, Sylvian 5. Kerr, F.W.L. and Hollowell, O.W. (1964) due to carotid artery disease. Brit. Med. J.
aqueduct or Koerber-Salus-Elschnig Location of pupillomotor and 1: 818-820.
syndrome) is characterised by large pupils, accommodation fibres in the oculomotor
nerve. J. Neurol. Neurosurg. Psychiatry 27: 16. Stanley, S.A. and Baise, G.R. (1968) The
which constrict briskly to an swinging flashlight test to detect minimal
473-481.
accommodative target, but poorly if at all optic neuropathy. Arch. Ophthal. 80: 769-
6. Loewenfeld, I.E. (1977) Simple, central
to light (light-near dissociation). anisocoria: a common condition, seldom 771.
Associated findings include vertical gaze recognized. Trans. Am. Acad. Ophthal. 17. Bullock, J.D. (1990) Relative afferent pupil
deficit, convergence-retraction nystagmus, Otolaryng. 83: 832-839. defect in the better eye. J. Clin.
Colliers sign (lid retraction on attempted 7. Jacobson, D.M. (1990) Pupillary responses Neurooph. 10: 45-51.
upgaze) and skew deviation. This pattern to dilute pilocarpine in pre-ganglionic third
18. Hamann, K-U., Hellner, K.A, Muller-Jensen,
of deficits implies a lesion affecting the nerve disorders. Neurology 40: 804-808.
A. and Zschocke, S. (1979)
posterior commissure and pretectal nuclei, 8. Thompson, H.S, Bell, R.A. and Bourgon, P.
Videopupillographic and VER investigations
with interruption to the more dorsal (1979) The natural history of Adies
in patients with congenital and acquired
syndrome. In: Topics in Neuro-
afferent light pathway but preservation of lesions of the optic radiation.
ophthalmology. Eds: Thompson, H.S.,
the more ventral near pathway. The most Ophthalmologica 178: 348-356.
Daroff, R., Frisen, L. et al, pp 96-99;
common causes include pineal region Williams & Wilkins, Baltimore. 19. Kardon, R., Haupert, C. and Thompson, H.S.
tumours, hydrocephalus (due to 9. Ross, A.T. (1958) Progressive selective (1993) The relationship between static
enlargement of the third ventricle) or sudomotor denervation: a case with perimetry and the relative afferent pupil
intrinsic lesions of the dorsal mid-brain. coexisting Adies syndrome. Neurology 8: defect. Am. J. Ophthal. 115: 351-356.
AR pupils are extremely rare nowadays, 809-817. 20. Lowenfeld, I.E. (1969) The Argyll
but were much commoner in the 10. Hope-Ross, M., Buchanan, T.A.S, Archer, Robertson pupil 1869-1969: a critical
nineteenth century when untreated syphilis D.B. et al. (1990) Autonomic function in survey of the literature. Survey of
Holmes-Adie syndrome. Eye 4: 607-612. Ophthalmology 14: 199-299.
was widespread20. They show similar light-
near dissociation but are small (often with
An answer return form is included in this issue.
an irregular shape), dilating poorly in
It should be completed and returned to:
darkness and showing an attenuated
response to topical mydriatic agents. These CPD Initiatives (NOE4),
features suggest interruption of both the OT, Victoria House, 178-180 Fleet Road, Fleet, Hampshire, GU13 8DA by May 3.
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.
Module 2 Part 4
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Module 2 Part 4
above and below the blob would have similar c. Layer 4C has connections with blob
orientation tuning whereas those within the and interblob regions
blobs would have little or no orientation d. Layer 4 possesses a direct
preference. connection to area V5
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