Pupil Anomalies: Reaction and Red Flags

Weon Jun, O.D., F.A.A.O.

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Table of Contents

Introduction
Clinical Anatomy and Physiology of the Pupillary Pathways
The Pupillary Light Reflex Pathway
Sympathetic Pupillary Pathway (Oculosympathetic)
Near Pupillary Reflex Pathway
Examination of the Pupils
Clinical Manifestations of the Pupillary Anomalies

 

Introduction

Examination of the pupils is one of the most important neuro-ophthalmologic testing that evaluates the integrity of the anterior visual pathways (afferent) and the autonomic nervous system: parasympathetic (efferent pupillary pathways) and sympathetic pathways (oculosympathetic).  Pupil testing becomes an essential part of the eye examination when evaluating a patient with ophthalmic manifestations of neurologic impairment such as sudden loss of vision, diplopia or ocular pain.  Pupil anomalies could be critical signs of vision or life threatening conditions.  The pupillary light reflex is also used to asses the function of the brain stem in a comatose patient.  It is one of the brain stem reflexes tested in the determination of the brain death.  A thorough understanding and knowledge of the pupil testing and its underlying principles are keys to accurate diagnosis and proper management of patients with pupillary anomalies.  It is important you take a systematic approach when evaluating patient's pupils.  This online CE will serve to provide clinical and practical guidelines including clinical pearls in assessing and managing pupillary anomalies in clinic. 

Clinical Anatomy and Physiology of the Pupillary Pathways

To fully understand the pupillary anomalies, an examiner must have a thorough understanding of the clinical anatomy and physiology of the pupillary pathways. Assessing the size and reactivity of the pupils provides information about the integrity and function of nervous system pathways from the optic nerve to the midbrain.

The iris consists of two types of smooth muscle fibers, the circumferential sphincter and the radial dilator, which serve to regulate the size and shape of the pupil. They are derived from the neural ectoderm. The pupillary sphincter is innervated by the parasympathetic nervous system which also supplies the ciliary muscle. The pupillary dilator is innervated by the sympathetic nervous system. Mechanically, the antagonistic actions of the sphincter and dilator muscles play a role in the diameter of the pupil.

In order to determine if a pupil is normal or abnormal, an examiner must be familiar with variations of normal pupils. The size of the normal pupil varies with age, sex and the intensity of ambient light. Obviously we all know that pupils react (constrict and dilate) to different levels of illumination. Pupillary reaction does not develop until 31 weeks of gestational age. (1) The amplitude of the light response gradually increase until it is almost 2 mm at term. (2) This slow arrival of pupillary light response is due to gradual development of parasympathetic nerves at the iris sphincter muscle. The dilator muscles develop sympathetic innervations at full term. This was evidenced by the fact that the pupils of premature infants do not dilate to hydroxyamphetamine but do dilate to phenylephrine. (3) Hence, mydriasis in a preterm infant should not be considered indicative of a central nervous system disorder, and a pupil unresponsive to light should not be considered suggestive of blindness until a preterm infant reaches at least 32 weeks' postconceptional age. (2) In neonates, neurologic or radiologic examination may be warranted if the pupil diameter in a dark environment is less than 1.8 mm or greater than 5.4 mm or if the pupils do not respond to light challenge after 31 weeks' postconceptual age. (4)

In general, pupils are often larger in adolescents and middle-age patients than in very young and old patients. Pupils tend to be larger in women than in men. Myopes usually have larger pupils than in hypermetropes. Pupils are larger in blue irides than brown irides. Pupil sizes also change with different emotional states such as surprise, fear and pain.

The Pupillary Light Reflex Pathway

The pupillary light reflex pathway consists of two parts:  afferent pupillary light reflex and efferent pupillary light reflex. 

Afferent Pupillary Light Pathway:
The afferent pupillary light pathway is used to assess the integrity of the anterior visual system since the afferent pupillary light pathway follows the visual pathway as far as the posterior optic tract, with the nasal pupillary fibers crossing at the chiasm.  The retina, optic nerve, chiasm, and optical tracts are composed of neural fibers that relay visual and pupillary afferent stimulus, so any damage along this pathway is likely to affect both the pupillary light reflex and visual function.  It is also important to note that the neural pupillary fibers from each eye decussate at the chiasm with 54% of the fibers crossing (nasal pupillary fibers) and 47% remaining ipsilateral (temporal pupillary fibers). (5)  This is the reason that you could have a relative afferent pupillary defect with hemianoptic visual field loss which will be discussed later in the article. 

The afferent pupillary light pathway originates in the retinal receptor cells and passes through the optic nerve, optic chiasm, and optic tract. (Figure 1)  Pupillary fibers follow the optic tract (posterior third of the optic tract) and separate from the optic tract just anterior to the lateral geniculate body.  They then enter the midbrain, where they synapse to pretectal nucleus.  The pupillary fibers leave the pretectal nucleus and distributes approximately equally to both Edinger-Westphal nuclei.  This tract is called the tectotegmental tract.  Thus, the optic tract carries pupillary fibers from both eyes, and the tectotegmental tract carries pupillary fibers from both pretectal nuclei. (6)  From these pupillary fiber arrangements, both pupils constrict in the consensual light reflex.     

Efferent Pupillary Light Pathway:  Parasympathetic Pupillary Pathway
The efferent pupillary light pathway begins at the Edinger-Westphal (E-W) nuclei.  This is located on the dorsal aspect of the third cranial nerve nucleus in the anterior dorsal mesencephalon at the level of the superior colliculus.  Efferent pupillary fibers from the E-W nuclei are carried in the superficial layer of the third cranial nerve to the cavernous sinus.  The efferent pupillary fibers eventually end in its inferior division, where they pass through the superior orbital fissure and synapse in the ciliary ganglion.  The anatomical location of the efferent pupillary fibers superficially on the third cranial nerve becomes critical, when evaluating patients with third cranial nerve palsy.  It is clinically important to note that the pupillary fibers are located superficially between the brain stem and the cavernous sinus.  Finally, postganglionic parasympathetic pupillary fibers synapse and pass through the short ciliary nerves to the iris sphincter and ciliary muscles.  Ninety-three to 97% of these parasympathetic fibers supply the ciliary muscles and 3 % to 7 % of the remaining supplies the iris sphincter muscles. (7)  The short ciliary nerves not only carry parasympathetic pupillary fibers, they also carry sensory and sympathetic pupillary fibers.         

Figure 1.  The Pupillary Light Reflex Pathway:  afferent and efferent pupillary pathways.  Image from http://www.neurology.arizona.edu/Training/newUNIT%2010_files/image026.jpg

 

Sympathetic Pupillary Pathway (Oculosympathetic):

The pupillodilator system is controlled by the sympathetic nervous system. The sympathetic nervous system is divided into central (first-order) neuron, preganglionic (second-order) neuron, and postganglionic (third-order) neuron. (Figure 2) The sympathetic fibers arise in the posterolateral area of the hypothalamus and descend, uncrossed, in the lateral portion of the midbrain, pons, medulla, and cervical spinal cord to the ciliospinal center of Budge at C8 to T2. This section of the sympathetic pathway is the central (first-order) neuron and is located in the brainstem and cervical cord. The preganglionic fibers travel upward in the sympathetic chain over the apex of the lungs and through the stellate ganglion, the inferior cervical ganglion, around the subclavian artery and through the middle cervical ganglion to the superior cervical ganglion at the carotid bifurcation. (1) The preganglionic (second-order) neuron is located in the chest and in the neck. The postganglionic fibers travel to the iris via the carotid plexus, the cavernous sinus and the long ciliary nerves. The postganglionic fibers run upward around the internal carotid artery into the cavernous sinus where they join with the ophthalmic division of the trigeminal nerve. They emerge from the cavernous sinus and pass into the orbit through the nasociliary branch of the ophthalmic division. Finally entering the eye through the long ciliary nerves and terminating at the iris dilator muscle. The postganglionic (third-order) neuron starts from the base of the skull and passes through the cavernous sinus to the orbit. The postganglionic fibers also distribute to orbital vasomotors, lacrimal gland and the smooth muscles of the upper and lower lids (Mueller) through the ophthalmic artery branches.

Figure 2.  Sympathetic Pupillary Pathway (Oculosympathetic).  Image from http://www.jeffmann.net/NeuroGuidemaps/anisocoria.htm

Near Pupillary Reflex Pathway:

The contraction of the pupil at near is not true reflex but believed to be an associated movement.  It is independent of any change in illumination.  When gaze is directed from a distance to a near object, a triad of responses occurs:  convergence, accommodation and pupillary constriction.  However, the contraction of the pupil at near does not depend on either the accommodation or the convergence and vise versa.  The pupillary near response depends on a supranuclear connection between the neurons serving the pupillary sphincters, the ciliary body muscles and the medial recti. (1)

The neural mechanisms of the triad responses are not as well understood as the pupillary pathways.  It is believed that the afferent pathway of the pupillary near response follows the visual pathway to the striate cortex (higher cortical centers).  From the striate cortex, information is relayed to the front eye fields, then to the oculomotor nucleus and the Edinger-Westphal nucleus, bypassing the pretectal nuclei in the dorsal midbrain.  It is believed that these arrangements of the light and near pupillary pathways cause light-near dissociation, when the dorsal midbrain and pretectal nuclei are damaged.  Finally, the medial rectus muscles are innervated via the oculomotor nerve.  The iris sphincter and ciliary body muscles are innervated by the parasympathetic pathway. (6)

Clinical Pearls:

1. Afferent pupillary light pathway follows the visual pathway as far as the posterior optic tract, with the nasal fibers crossing at the chiasm.
2. Pupillary fibers distribution at the chiasm is 54% of the fibers crossing (nasal pupillary fibers) and 47% remaining ipsilateral (temporal pupillary fibers).
3. Efferent pupillary fibers from the E-W nuclei are carried in the superficial layer of the third cranial nerve (pupil involvement) to the cavernous sinus. 
4. Near reflex fibers bypass the pretectal nuclei in the dorsal midbrain and synapse to the oculomotor nucleus and the Edinger-Westphal nucleus, causing a light-near dissociation. 

Examination of the Pupils

The normal pupils are round, regular, and centered within the iris.  In clinic, the acronym PERRLA (pupils equal, round, reactive to light and accommodation) is often noted and substituted for an accurate assessment of pupil function.  However, it is not necessary to test a near response when the pupillary light reflex is normal since there is no pathologic situation wherein the pupillary light is normal while the near response is defective.  Hence, the last step of PERRLA could be a wasted effort in clinic.  But, it is important to check near pupillary response if the pupillary light reflex is poor or absent to assess light-near dissociation. 

Pupillary light reflex is tested to determine if there is an afferent pupillary pathway defect and/or an efferent pupillary pathway defect.  It is important to proceed logically when examining the pupils.  The first step to examining the pupils is to measure pupil size in normal (constant stimulus) illumination, which is also known as static pupil evaluation.  If a pupillary anomaly is suspected, then pupil size must be measured in both dim and bright (changes in stimulus) illumination, which is called dynamic pupil evaluation.  Direct and indirect (consensual) pupillary light responses are tested with an afferent pupillary defect test (Marcus-Gunn or Swinging Flashlight).  A near response test should be also performed to assess accommodative pupillary reflex if the pupillary light reflex is poor to absent to rule out light-near dissociation.  In addition to the pupil testing, you may need to use various pharmacologic agents to confirm diagnosis. 

In clinic, pupil evaluations are usually performed using a transilluminator or penlight with a hemisphere scale or millimeter ruler.  Additional equipment could be helpful in enhancing pupil testing.  A Burton lamp or other ultraviolet light source allows the examiners to measure the size of the pupils with dark irides, especially under dark illumination.  A special infrared pupillometer is another device that could used to accurately measure the size of the pupils. 

Various techniques have been used to quantify or measure afferent pupillary defects.  A subject grading based on the amount of initial contraction and subsequent redilation of each pupil as the light is swung is usually used in clinic.  Neutral density filers and crossed polarized neutral density filters may be also used to identify and measure relative afferent pupillary defects. (8)  You also could purchase an expensive instrument such as pupillography which records specific features of the light response.

Testing errors in pupil evaluation may arise if an inadequate brightness light source or an inadequate accommodative target is used.  It is sometimes necessary to use a binocular indirect ophthalmoscope light under dark illumination (total darkness) to observe the pupillary light reflex if there is poor pupillary light reflex with a transilluminator.  It is also important to use proper techniques when assessing the pupillary light reflex because detecting a subtle relative apparent pupillary defect could be challenging.  When testing a pupillary light reflex, it is technically important that the light source is not shined directly into the patient’s eye.   The light source should be directed from slightly inferior and upward toward the patient's pupil.

In the evaluation of the pupils in clinic, there are several ways to record the pupillary findings and the following is one of the ways to document your pupillary observations and findings:

Additional testing:  Measurement of Pupil Sizes under Different Illuminations and Near Pupillary Reflex:

Abbreviations:

Clinical Manifestations of the Pupillary Anomalies (Types of Pupillary Anomalies)

Congenital defects of the ocular structures happen due to developmental anomalies and intrauterine insults such as infections and drugs during pregnancy.  During an exam, misplaced or ectopic pupils are frequently observed in clinic.  Polycoria is used to describe multiple pupils.  Ectopia describes displaced pupil.  Corectopia refers to displacement of the pupil.  Dyscoria refers to an abnormal shape of the pupil.  Aniridia implies total absence of the iris, but some iris tissue usually remains.  Both iris dilator and sphincter muscles are usually absent.  Abnormalities in iris color could result from albinism.  Heterochromia is used to describe a difference in color between two eyes.  Iris coloboma implies a defect in the structure of the lower part of the iris.  It is also described as keyhole pupil.  Congenital miosis and mydriasis could be present at birth.  

Anisocoria
Anisocoria is defined by a difference in the size of the two pupils of 0.4 mm or greater.   Roughly one fifth of the normal population has an anisocoria, but the difference in size is not more than 1mm. (9)  Anisocoria or a difference in pupil size may be normal but may be a sign of ocular or neurologic disease.  It should be considered a neurosurgical emergency if a patient has anisocoria with acute onset of third-nerve palsy and associated with headache or trauma.  It is also important to note that symmetrically rapid constriction in pupillary light response indicates that the anisocoria is not due to third-nerve palsy.        

To evaluate anisocoria, the examiner must determine which pupil is abnormal by noting pupil size under light and dark illumination.  If the difference in pupil size in both light and dark illumination is constant, then it is called physiologic or essential anisocoria.  Physiologic anisocoria could also vary in pupil size from day to day and it could switch sides.  When there is an imbalance of parasympathetic (efferent) and sympathetic innervations, an acquired anisocoria will be present.  The presence of anisocoria may help differentiate and localize a lesion to one of the parasympathetic (efferent) and sympathetic pupillary pathways, but does not localize the lesion’s location within those pathways.  Based on the anatomy and physiology of the pupillary pathways, lesions of the retina, optic nerve, chiasm, and optic tract do not cause anisocoria.  A lesion in the midbrain produces a subtle and transient anisocoria.  However, most neurologic causes of anisocoria involve lesions in the parasympathetic (efferent) and sympathetic pupillary pathways. 

If an anisocoria is noted, then one must measure pupil size under both dim and bright illumination in order help differentiate between the sympathetic pupillary pathway defects from the parasympathetic pupillary pathway defects. (Figure 3)  If the larger pupil is abnormal (poor constriction), the anisocoria is greatest in bright illumination, as the normal pupil becomes small.  This is caused from the disruption of the parasympathetic (efferent) pupillary pathway.  If the smaller pupil is abnormal (poor dilation), the anisocoria is greatest in dark illumination, as the normal pupil becomes large.  It is caused from the disruption of the sympathetic pupillary pathway.     

Disorders Characterized by Anisocoria (10)
Physiologic (essential) anisocoria
Alternating contraction anisocoria
Bernard’s syndrome
Horner’s syndrome
Episodic unilateral mydriasis
Adie’s tonic syndrome
Third-nerve palsy
Adrenergic mydriasis
Anticholinergic mydriasis
Argyll Robertson pupils
Local iris disease (e.g., sphincter atrophy, posterior synechiae, pseudoexofoliation syndrome)
Hutchinson’s pupil
Angle-closure glaucoma

Figure 3.  Flow chart of evaluation of anisocoria.  Image from http://www.opt.indiana.edu/riley/HomePage/Pupil_Abnormal/Graphics/2_anisocoria.GIF

Afferent Pupillary Defects
An afferent pupillary defect test is an important physical sign in an evaluation for neurologic disease.  A relative afferent pupillary defect (RAPD) is an objective sign of unilateral or asymmetric disease of the optic nerve head or retina.  The visual acuity does not necessarily correlate with an RAPD.  If there is an RAPD with good central vision, you are likely dealing with optic nerve diseases and not retinal diseases.  Usually retinal disease has to be quite severe for an RAPD to be clinically evident.  In addition, there are many conditions with a severe vision loss, but without an RAPD, such conditions are a complete vitreous hemorrhage and hyphema.        

When performing an afferent pupillary defect test, it is important to move the light away from one eye to the other eye quickly within 1 second and holding a 3-second pause in each eye.  This technique is reliable in detecting and quantifying the relative afferent pupillary defects, especially a subtle RAPD.  Also, using a 0.3 log unit neural density filter over the suspected subtle RAPD eye will help in enhancing the RAPD.  In a normal pupil, using a 0.3 log unit neural density filter does not enhance or change it.   It is also critical to have the same amount of light into each eye in approximately the same retinal area and same amount of time exposed to eliminate to any induced pseudo-afferent pupillary defect.  Sometimes, it is difficult to differentiate an RAPD from hippus, which is a normal fluctuation in pupillary size under steady illumination.  Importantly, the hippus should be equal in amplitude between two eyes to qualify as a normal variant.  If there is any difference in hippus amplitude between two eyes, then this may indicate a trace RAPD.         

Cox (11) concluded that the most sensitive criterion for detection of RAPD is difference in amplitude of initial consensual pupillary constriction versus the initial direct pupillary constriction.  An examiner should diagnose an RAPD when the consensual pupillary response is greater than the direct response.  This is opposite in a patient who has a non-reactive pupil with an RAPD.  A non-reactive pupil could be caused from dilation, constriction or trauma.  An examiner can test the non-reactive pupil for an RAPD by observing the direct response of the reactive pupil and the consensual response of the non-reactive pupil.  This method is known as reserve RAPD testing.  An RAPD is present if the direct pupillary response of the reactive pupil is greater than consensual pupillary response of the non-reactive pupil.       

There are many different methods to measure an RAPD in clinic.  A common method is using a qualitative 1-4+ grading scale.   

Grading Scale:  RAPD

Grade 1+:  A weak initial pupillary constriction followed by greater redilation
Grade 2+:  An initial pupillary stall followed by greater redilation
Grade 3+:  An immediate pupillary dilation
Grade 4+:  No reaction to light – Amaurotic pupil

However, this method lacks the quantitation that is necessary for comparison in follow ups.  The use of neutral density filters and crossed polarized filters provide a way to quantify the RAPD.  Using neutral density filters, an RAPD can be quantified by sequentially placing optical filters of increasing density from 0.3 to 1.6 log units in front of the normal eye until both pupils response equally to a light source as an examiner alternates the light source between the pupils.  The crossed polarized filters provide narrower scale ranges from 0.02 to 0.9 log units and the ranges could be increased by placing a standard neutral density filter over the polarized filter.  For example, using a 0.3 log unit density filter over the polarized filter, you could increase the range from 0.3 log unit (at 0 degrees) to 1.2 log units (at 90 degrees). (8) 

If there is a poor direct pupillary response, the lesions could be any location along the visual pathway from optic nerve to two-third of the optic tract.  They could also be located in the pretectal area, the ipsilateral parasympathetic pathway traveling in CN III, or the iris sphincter.  In addition, failure of the pupil to constrict to both direct and consensual stimuli indicates dysfunction of the efferent (parasympathetic) pupillary pathway.  Also, you should expect an afferent pupillary pathway interruption if a patient has a poor direct pupillary response, but the preservation of the consensual light reflex in the same eye.  An eye with no light perception should have no pupillary response to direct light stimulation as well.  This is called an amaurotic pupil.  The consensual response defect could arise from lesions of the contralateral optic nerve, the pretectal area, the ipsilateral parasympathetic traveling in CN III, or the iris sphincter. 

An RAPD could be presented in a hemianoptic visual field loss if the lesion is along the afferent pupillary pathway.  The RAPD will be found in the eye contralateral to the side of the lesion because 54% of the nasal fibers cross to the contralateral tract and 47% of the temporal fibers remain ipsilateral.  However, an RAPD would not be present when the hemianoptic lesions are beyond the lateral geniculate nucleus body, because the pupillary fibers are not involved.  There is also a greater pupillary escape with central visual field loss compared to peripheral visual field loss due to more concentrated afferent neurons in the central retina. (12) 

An RAPD does not cause anisocoria; however, anisocoria may cause an apparent RAPD in the smaller pupil due to more shading of the retina compared to the larger pupil.  This is more apparent when anisocoria is 2 mm or greater, or the pupil is very small.  Amblyopia may cause a mild RAPD, rarely exceeding 0.6 log units, mostly 0.3 or less. (13)  It has been also documented that RAPD is more likely to occur in anisometropic than strabismic amblyopia.  Usually the visual acuity would be 20/200, or worse.  However, in the presence of an RAPD, the diagnosis amblyopia should be made with caution, especially if an RAPD is greater than a mild grading.  Cataracts and other opacities in the ocular media generally do not produce an RAPD.  However, it has been reported that opaque white cataracts may produce a contralateral RAPD from excess retinal stimulation from light scatter. (14)

There are many different ocular or neurologic conditions which could cause an RAPD.  The following are a list of common ocular conditions causing an RAPD:

Unilateral optic nerve diseases:
Anterior ischemic optic neuropathy: 
Arteritic (Giant Cell Arteritis) and Non-arteritic
Optic neuritis
Central retinal arterial occlusion
Compressive optic neuropathy:
         Optic nerve tumor            
         Traumatic optic neuropathy
         Asymmetric glaucoma
         Homonymous hemianopsia (Lesions involving pupillary pathway)
Retinal conditions:
Branch retinal arterial occlusion
         Ischemic central retinal vein occlusion
         Retinal detachment, greater RAPD if involving macula
         Asymmetric macular disease with VA <20/200
         Unilateral panretinal photocoagulation 

Clinical Pearls:

• When performing an afferent pupillary defect test, it is important to move the light away from one eye to the other eye quickly within 1 second and holding a 3-second pause in each eye to detect an RAPD. 
• Using a 0.3 log unit neural density filter over the suspected subtle RAPD eye will help in enhancing the RAPD.  In a normal pupil, using a 0.3 log unit neural density filter does not enhance or change it.
• An RAPD could be presented in a hemianoptic visual field loss if the lesion is before LGN.  The RAPD will be found in the eye contralateral to the side of the lesion.
• Afferent pupillary defect does not cause anisocoria. 

Efferent Pupillary Defects (Parasympathetic)
Efferent pupillary defects will occur if there is any disruption along the parasympathetic pupillary fibers from E-W nuclei to iris sphincter via third cranial nerve.  An abnormal dilated pupil could be due to iris sphincter damage from trauma, pharmacologic agents or parasympathetic pupillary pathway defects.  In addition, traumatic iritis, uveitis, angle-closure glaucoma, and recent eye surgery can cause an abnormal dilated pupil.  The following is a list of etiologies for efferent pupillary defects:

Efferent Pupillary Defect Etiologies:

• Iris sphincter damage from trauma
• Tonic pupil (Adie’s pupil)
• Third-nerve palsy
• Pharmacologic agents:
• Unilateral use of dilating drops
• Atropine, cyclopentolate, homatropine, scopolamine, tropicamide, phenylephrine.
• Handling/administrating of sympathomimetic or anticholinergic agents (15):
• Sympathomimetic agents:
• OTC cold agents containing ephedrine
• Illegal street drugs:  cocaine, amphetamines, methamphetamine
• Dietary supplements:  ephedra alkaloids
• Very popular illicit designer drugs:  3, 4-methylenedioxy methamphetamine [MDMA, ”ecstasy”] 
• Anticholinergic agents including scopolamine patch.
• Other drugs causing mydriasis:
• LSD (lysergic acid diethylamide)
• Alcohol
• Marijuana
• Mescaline
• Jimson weed (Datura stramonium) containing belladonna alkaloids (active ingredients are atropine and scopolamine).  Some brands of eye make-up contain belladonna alkaloids. 
• Traumatic iritis, uveitis, angle-closure glaucoma, pseudoexofoliation syndrome and recent eye surgery
• Benign episodic unilateral mydriasis

 

An abnormal dilated pupil could be alarming to an examiner because you must rule out third-nerve palsy from pharmacologic pupil dilation and traumatic dilated pupil.  A traumatic dilated pupil could be ruled out clinically by careful history and biomicroscopic examination.  A patient with traumatic iris sphincter damage will present with torn pupillary margin or iris illumination defects seen on biomicroscopic examination.  With a careful examination for ptosis and abnormal extraocular muscle restrictions, an examiner should also be able to differentiate third-nerve palsy from pharmacologic pupil dilation.  Furthermore, pilocarpine may help differentiate the pharmacologic pupil dilation from other causes of an abnormally dilated pupil, such as third-nerve palsy, tonic pupil and iris sphincter damage.  With a lower concentration of 0.125% pilocarpine, a tonic pupil will constrict significantly more than the unaffected pupil because of the denervation supersensitivity.  With a higher concentration of 1% pilocarpine, even third-nerve palsy related pupil will constrict.  If the dilated pupil fails to constrict with 1% pilocarpine, an examiner could localize the problem at the iris sphincter muscles. (Figure 4)  The cause of problems could arise from pharmacologic dilation (Figure 5), synechiae, iritis, and traumatic iris sphincter damage.        

Figure 4.  1 % pilocarpine testing.  Image from http://www.jeffmann.net/NeuroGuidemaps/anisocoria.htm

Figure 5.  Left pharmacologic mydriasis:  no response to light and near reflex in the left eye, the left pupil remains dilated after instillation of 1 % pilocarpine in the left eye.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5820&locale=en

Tonic Pupil
The tonic pupil is sometimes called Adie’s tonic pupil or Adie’s pupil.  Adie’s tonic pupil refers to an idiopathetic tonic pupil and the term is mistakenly overused.  Adie’s pupil is used when there is only tonic pupil without association of the diminished deep tendon reflexes of the knee and ankle (hyporeflexia).  The term Adie’s syndrome is applied when both tonic pupil and associated hyporeflexia are present. (10)  Most cases of the tonic pupil are idiopathic or caused by trauma; however, the tonic pupil can be caused by local disorders such as tumor, inflammation, trauma, surgery or infection within the orbit affecting the ciliary ganglion.  In addition, systemic (autonomic or peripheral) neuropathies such as diabetes, Guillain-Barre syndrome, Ross’ syndrome and Riley-Day syndrome can also cause tonic pupil. (7)  An acute tonic pupil in patients over 60 years of age warrants an erythrocyte sedimentation rate to rule out giant cell arteritis.      

Adie’s pupil is usually unilateral in 80% to 90% of cases and may become bilateral at a rate of 4% per year. (16)  Adie’s pupil results from damage to the ciliary ganglion or postganglion fibers of the short posterior ciliary nerves.  This subsequently leads to dilated pupil and anisocoria (greater in light illumination than dark illumination). (Figure 6)  It has minimal or no reaction to light but slow reaction to accommodative response due to damage to the parasympathetic innervation to the eye.  An intact near pupillary reflex is believed to be due to the ratio of fibers that control the near pupillary reflex is much greater as compared to those that control the light pupillary reflex.  Furthermore, preservation of the pupil constriction in accommodation may be result of accommodative fiber aberrant regeneration.  Some accommodative fibers formerly destined for the ciliary body now travel to the pupil becoming misdirected and supply the iris sphincter.  This is why a lesion in the ciliary ganglion or short ciliary nerves shows a light-near dissociation (Figure 7), even though both light and near innervation of the iris sphincter follow an identical final common pathway. 

Figure 6.  Left tonic pupil: greater anisocoria in light illumination (above) than dark illumination (below).  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5832&locale=en

 

Figure 7.  Right tonic pupil (light-near dissociation from aberrant degeneration):  the dilated right pupil (above) constricts slowly and progressively until it becomes slightly smaller (below) than the simultaneously constricted left pupil.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5833&locale=en

 

Adie’s Pupil:

Symptoms: 

• Difference in the size of the pupils
• Unilateral blurred vision
• May be asymptomatic

Critical Signs:

• Anisocoria (greater in light illumination than dark illumination) (Figure 3) 
• Dilated pupil with minimal or no reaction to light
• Slow pupillary constriction to near response and slow redilation
• More common in young women between age 20 to 40 years
• Iris sphincter sector palsy
• Segmental pupil response – “vermiform” pupil response movement.

Other Characteristics:

• Decreased amplitude of  accommodation
• Associated with diminished deep tendon reflexes of the knee and ankle – Holmes-Adie syndrome.  
• Pupil becomes smaller over time

Pharmacologic testing:

• Supersensitivity to 0.125% pilocarpine

Syphilis needs to be worked up if a patient is male, and has bilateral tonic pupils.  An examiner should order a specific (FTA-ABS) and non-specific treponemal (RPR) test.  While syphilis may infrequently cause the tonic pupil, late syphilis is more commonly associated with the Argyll Robertson pupil.  Adie’s pupil initially is dilated but may become miotic over time.  Thus, the tonic pupil may look like Argyll Robertson pupil.  The difference is that the Argyll Robertson pupils are not tonic.  The Argyll Robertson pupils constrict quickly to near response and redilate quickly when removed from the near stimulus.  

Pharmacological testing helps in the diagnosis of Adie’s tonic pupil.  In 80-90% of patients with Adie’s tonic pupil, 0.125% pilocarpine (Figure 8) or 2.5% methacholine causes denervation supersensitivity. (7)  The concentration is too weak to cause constriction of the normal pupil. 

Pharmacologic testing steps:

• 0.125% pilocarpine (prepared by diluting one part 1% pilocarpine with 7 parts balanced salt solution)
• Patient is fixating at a distance to prevent near accommodative reflex.  Measure the pupil size of each eye.
• Instill a drop of 0.125 pilocarpine ophthalmic solution in each eye, and recheck the pupils in 10-15 minutes. 
• A positive test result – The tonic pupil constricts significantly more than the contralateral pupil

Figure 8.  Right tonic pupil:  dilated pupil with minimal reaction to light (above); the right pupil constriction (denervation supersensitivity) and no left pupil constriction with 0.125 % pilocarpine.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5831&locale=en

 

Figure 9.  Third-nerve palsy with pupil involvement in the right eye:  the right pupil is non-reactive; complete ptosis, hypoexotropia, impaired adduction, elevation and depression in the right eye.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5830&locale=en

 

As a rule of thumb, a patient with sudden onset of painful third-nerve palsy with pupil involvement and no history of trauma or vascular disease should assume an intracranial aneurysm until proven otherwise.  The most common site of an intracranial aneurysm causing third-nerve palsy is the posterior communicating artery; however, the internal carotid artery and basilar artery aneurysms are reported to produce third nerve palsies as well. (17)  This is a life-threatening emergency because there is a potential of rupturing and leading to subarachnoid hemorrhage (within hours or days), so the patient needs emergency neurological imaging and hospitalization. 

In most cases, third-nerve palsy improved with resolution of diplopia and ptosis over several weeks to months.  If there is no improvement of third-nerve palsy within 3 months, an examiner needs to order imaging study to rule out intracranial aneurysm or mass.  Also, it is important to monitor and follow up third-nerve palsy patients daily for 5-7 days from the onset of third-nerve palsy to check for delayed pupil involvement.  There may be slow growing mass or aneurysm.   
Evaluation of the pupil in third-nerve palsy patients involve checking for anisocoria (asymmetry greater in light than in dark) and pupil light reflex.  If a pupil is involved, the pupil will be fixed, dilated and minimally reactive to light.  If a pupil is spared, the pupil is not dilated and has normal reaction to light.  It is also possible to have relative pupil sparing where the pupil is partially dilated and sluggish in light reflex.  If there is unilateral compression on the pupillary fibers of the acute third-nerve palsy, the affected side of the pupil will not response to both direct and consensual pupillary reflex with no accommodative response; however, the non-affected side pupil will response to both direct and consensual stimulation due to the parasympathetic pathway arrangements (bilateral innervation of E-W nuclei).
Aberrant regeneration of the third-nerve palsy may occur and cause pupil anomalies in 3 months.  Aberrant regeneration could result from trauma, aneurysm, tumor, congenital, but not in microvascular. (18)  A pseudo-Argyll Robertson pupil (light-near dissociation) may develop from the aberrant regeneration, which displays a fixed and dilated pupil.  The pupil will not react to light, but it will constrict on convergence due to misdirection of fibers from the medial rectus to the pupil.

Clinical Pearls:

• As a rule of thumb, a patient with sudden onset of painful third-nerve palsy with pupil involvement and no history of trauma or vascular disease should assume an intracranial aneurysm until proven otherwise
• If there is no improvement of third-nerve palsy within 3 months, an examiner needs to order imaging study to rule out intracranial aneurysm or mass.
• It is important to monitor and follow up third-nerve palsy patients daily for 5-7 days from the onset of third-nerve palsy to check for delayed pupil involvement.
• Third-nerve palsy with aberrant regeneration (light-near dissociation) could result from trauma, aneurysm, tumor, congenital, but not in microvascular.  

Sympathetic Pupillary Defects
Sympathetic pupillary defects will occur if there is any disruption along the sympathetic pupillary fibers from hypothalamus to iris dilator.  The following are some of the causes of miotic pupils. 

Causes of Miotic Pupils:

• Horner's Syndrome (Oculosympathetic paralysis)
• Argyll Robertson Pupils
• Long-Standing Adie's Pupil
• Pharmacologic Agents:
• Unilateral use of miotic drops:
• Pilocarpine
• Drugs causing miosis     
• Narcotics (pinpoint)
• Barbiturates
• Chloral hydrate
• Morphine
• Propoxyphene
• Flomax (tamsulosin) *Must inform the cataract surgeon if a patient is taking Flomax to eliminate potential complications from intraoperative floppy iris syndrome.
• Uveitis, pseudoexofoliation syndrome and recent eye surgery

 

Horner’s Syndrome (Oculosympathetic Paresis)
The clinical signs of Horner’s syndrome are miosis, ptosis, anhidrosis and apparent enophthalmos.  The etiology of Horner’s syndrome could range from benign to serious neurological conditions.  In one large case study, 40 % of cases of Horner’s syndrome had an unknown diagnosis.  In the remaining 270 patients, 13 % were related to a first-order (central) lesion, 44 % to a second-order (preganglionic) lesion, and 43 % to a third-order (postganglionic) lesion. (19)  The common etiologies of acquired Horner’s syndrome include but are not limited to (Table 1):  cerebral vascular accident, demyelination, tumor including thyroid adenoma and Pancoast tumor, tuberculosis, aortic dissection, trauma (neck/head including surgery), internal carotid dissection, herpes zoster virus, and headache syndrome (Cluster/migraine headaches). (18)
Table 1.  Causes of Horner’s syndrome.  Table modified from http://www.emedicine.com/oph/topic336.htm

 

 

 

Patients with Horner’s syndrome are often asymptomatic, but sometimes they may complain of difference in the size of the pupils with droopy eyelid. (Figure 10)  The Horner’s pupil is miotic and the light and near pupillary reflex is intact.  In addition, the Horner’s pupil has a dilation lag in dark compared to the unaffected pupil.  This is due to a passive release of the sphincter muscles rather than active dilation from the pupillodilator muscles since it is damaged to the sympathetic nerve.  Other clinic features include a mild ptosis (less than 2mm) as a result of paralysis of the Muller’s muscle and anhidrosis if involves central and preganglionic neurons (first and second-order). 

Figure 10.  Right Horner’s syndrome:  miosis with approximately 2 mm of RUL ptosis.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5822&locale=en

It is important to take a good case history on Horner’s syndrome patients to help with the differential diagnosis of acquired Horner’s syndrome as mentioned above.  If a patient has Horner’s syndrome with other accompanying neurologic symptoms and signs, the patient should be referred for an emergent neurological work up including imaging studies.  It also helps to localize the lesion of the Horner’s syndrome from their associated neurologic symptoms and signs.  An isolated Horner’s syndrome accompanied by neck or head pain suggests an internal carotid dissection.  A Horner’s syndrome patient with arm pain and/or hand weakness suggests a lesion in the lung apex, Pancoast tumor.  If a patient has diplopia, vertigo, ataxia and lateralized weakness suggests brainstem localization.  A congenital Horner’s syndrome will present with heterochromia. (Figure 11)

Figure 11.  Right congenital Horner’s syndrome:  miosis, mild ptosis and hypochromic iris.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5821&locale=en

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Horner’s Syndrome (Oculosympathetic Paresis)