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Pupil Anomalies: Reaction and Red Flags

Weon Jun, OD, FAAO





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

Figure 1.  The Pupillary Light Reflex Pathway:  afferent and efferent pupillary pathways.  Image from


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

Figure 2.  Sympathetic Pupillary Pathway (Oculosympathetic).  Image from


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:

Pupil Size:  Normal Illumination

Pupil Shape/Color

Direct/Consensual Pupil Reflex

Afferent Pupillary Defect

OD:          OS:

OD:        /
OS:        /

OD:        /

OS:         /

(  ) APD OU

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

Light illumination:    OD:       OS: 

Near Pupillary Reflex:

Dark illumination:     OD:       OS: 

Brisk      /      Sluggish      /      None



Grey = Gy

Green = Gn

Brown = Bn

Blue = Bu


R =Round

O = Oval

S = Sector

IRR = Irregular