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Module 2 Part 4 ✓ The College of Optometrists The College of Optometrists has awarded this article 2 CET credits. There are 12 MCQs with a pass mark of 60%. sponsored by F. D. Bremner MBBS, BSc, PhD, FRCOphth 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 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 32 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 www.optometry.co.uk sponsored by 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- www.optometry.co.uk 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 33 o t sponsored by 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 34 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, www.optometry.co.uk sponsored by 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. www.optometry.co.uk 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 35 o t 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 36 April 7, 2000 OT sponsored by 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 www.optometry.co.uk sponsored by 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 www.optometry.co.uk 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 37 o t 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. sponsored by 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 www.optometry.co.uk sponsored by 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 www.optometry.co.uk 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 o t sponsored by 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 www.optometry.co.uk sponsored by 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. www.optometry.co.uk 41