Pupillary responses can signal potentially serious problems

This is a quick way to gauge the integrity of the afferent and efferent systems and can help direct the differential diagnoses and management.

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The keen practitioner can gain helpful information simply by assessing pupillary responses. The pupils will offer substantial insight into one’s ocular health and the state of the visual pathways before even looking into a patient’s eyes. Having an understanding of the neural pathways that control the normal afferent and efferent pupillary responses is foundational, so we will review this before discussing abnormalities of the pupillary response.

Pupillary reflex pathways

The afferent (sensory) pupillary pathway begins with the retinal photoreceptors, passes through the optic nerve and optic chiasm and travels along the posterior third of the optic tract. The neural fibers separate from the tract just anterior to the lateral geniculate body. From there, they travel to the midbrain and synapse at the pretectal nucleus, at the level of the superior colliculus. They then leave the pretectal nucleus and distribute about equally to the two Edinger-Westphal nuclei via the tectotegmental tract. The consensual light reflex occurs because both the optic and tectotegmental tracts carry fibers from both eyes.

The efferent (motor) pupillary pathway has both parasympathetic and sympathetic nervous system actions.

The parasympathetic efferent pupillary pathway begins where the afferent pathway left off: the Edinger-Westphal nucleus. The fibers then travel in the superficial layer of the third cranial nerve to the cavernous sinus, follow the cranial nerve’s inferior division through the superior orbital fissure and synapse in the ciliary ganglion, which is posterior to the globe, within the muscle cone. Postganglionic parasympathetic pupillary fibers travel along the short ciliary nerves to the ciliary body muscle (93% to 97% of fibers) and to the circumferential iris sphincter (3% to 7% of fibers).

Sympathetic innervation to the eye involves a three-neuron chain. The sympathetic central (first-order) neuron begins in the dorsolateral hypothalamus and travels, uncrossed, through the brainstem to the ciliospinal center of Budge at the level of C8 to T2 in the cervical spinal cord. The preganglionic (second-order) neuron then travels up the sympathetic chain, over the lung apex and through several ganglia to synapse at the superior cervical ganglion, located where the carotid bifurcates. The postganglionic (third-order) neuron’s fibers then travels through the carotid plexus and cavernous sinus where they join the ophthalmic division of the trigeminal cranial nerve (CN 5); they follow the nasociliary branch then the long ciliary nerves to the radial iris dilator muscle. The eyelids’ smooth levator and Mueller muscles are also innervated by this route, but exit the carotid plexus and follow the oculomotor nerve (CN III) into the orbit.

When focus is changed from far to near, a triad of responses occurs: convergence, accommodation and pupillary constriction. The neural pathway for this triad of responses is not completely understood, but the pupillary response is dependent on a supranuclear (frontal and occipital lobe influence) connection between the pupillary sphincter, ciliary body muscles and medial recti neurons. The afferent aspect of the pupillary near response follows the afferent visual pathway to higher cortical centers in the striate cortex; that information is relayed to the frontal eye fields then to the oculomotor and Edinger-Westphal nuclei. This pathway bypasses the pretectal nuclei. Light-near dissociation with dorsal midbrain and pretectal nuclei damage is due to this pathway’s bypassing of the pretectal nucleus. Testing the near response is necessary only if the pupillary light reflex is abnormal; there is no pathologic situation where the near response will be abnormal with a normal pupillary light reflex. Having vision is not a requirement for an intact near response.

With the neurologic framework for the pupil’s responses now laid, we will discuss examination and abnormalities of the pupillary responses.

Pupil examination

A normal pupillary exam using a swinging flashlight will show equal constriction of both pupils, regardless of which eye the light is directed at, indicating an intact direct and consensual pupillary light reflex.

An afferent pupillary defect (APD) is observed when there is a reduced pupillary constriction of both eyes (direct and consensual responses) compared to the bilateral constriction response when the light is shone into the unaffected eye. Otherwise put, there is an APD when an eye’s response consensually is greater than its own direct response. An APD is always relative to the other eye (i.e., a bilateral APD is not possible). With a swinging flashlight, a pupil with an APD will constrict less (therefore appearing to partially dilate) when the light is swung from the unaffected to the affected eye.

Of note, a fixed pupil does not always exhibit an APD. If the light shone into the fixed eye causes a consensual response equal to the unaffected eye’s direct response, an APD is not present.

Neutral density filters of increasing density can be used over the unaffected eye until the pupillary responses are equal on the swinging flashlight test. This may be helpful to quantify the change in the relative depth of an APD; clinically, however, a subjective grading scale is usually used in lieu. The descriptions used in the grading scale indicate the reaction of the pupil with an APD when the light is swung from the unaffected to the affected pupil.

Also of note, anisocoria itself is not an indication of an APD; there most often is one without the other. Though they can coexist, generally an APD does not cause anisocoria.

Anisocoria indicates a difference in pupil sizes of 0.4 mm or greater. Physiologic anisocoria, which is less than 1 mm difference between pupils, is found in approximately 20% of the population. Nonphysiologic anisocoria implies a diseased efferent pathway and can be caused by a plethora of conditions, which will be further discussed.

Efferent parasympathetic pupillary defects will cause an abnormally dilated pupil and can occur due to disruption of the pupillary fibers anywhere along their path from the Edinger-Westphal nucleus to the iris sphincter. This will manifest with anisocoria greater in the light than dark, due to poor constriction of the larger (affected) pupil. An abnormally dilated pupil could also be due to trauma, recent ocular surgery, angle closure or contact with pharmacologic agents.

Sympathetic

Efferent sympathetic pupillary defects will cause an abnormally miotic pupil and can occur due to disruption of the pupillary fibers anywhere along their path from the hypothalamus to the iris dilator. This path is long and courses from the central head, down through the neck and back to the eye, so is susceptible to a variety of problems due to its long route. Pupillary fiber disruption along this path will manifest with anisocoria greater in the dark than light, due to poor dilation of the smaller (affected) pupil. An abnormally constricted pupil could also be due to uveitis or contact with pharmacologic agents. The accompanying table shows a list of some conditions that could cause efferent pupillary defects (and thus anisocoria).

We will briefly review some of these conditions. The review will primarily discuss pupillary responses and testing in these conditions and will only briefly cover management of the specific conditions.

Cranial nerve III (oculomotor) palsy

CN III innervates the levator; medial, superior and inferior recti; the inferior oblique; and the iris sphincter. Thus, CN III palsy usually presents with ipsilateral ptosis and hypoexotropia (“down and out”), limited ocular adduction, elevation and depression. The palsy may be complete or partial, depending on the cause and location of CN III disruption, and may be pupil involving or sparing. An involved pupil will be dilated and minimally reactive, but could be only partially involved and show a partially dilated and sluggishly responsive pupil. Because of the physical location of the efferent parasympathetic pupillary fibers that run superficially along CN III and CN III’s location within the cavernous sinus, whether or not the pupil is involved in an acute CN III palsy is extremely important to help differentiate the cause and emergent status of the palsy. CN III palsy due to compression (tumor, aneurysmal) is likely to be pupil involving because the pupillary fibers are superficial in the cranial nerve, whereas ischemic CN III palsies typically are pupil sparing.

It is important to reiterate that with compressive/aneurysmal lesions, the patient may have pupil involvement alone (i.e., a dilated/sluggish pupil without hypoexotropia and ptosis). Pupil involvement due to compression will result in lost direct, consensual and near responses in the affected eye. The unaffected eye’s consensual response will be normal. Aberrant regeneration may occur over several months and may lead to light-near dissociation, with the near response arising from misdirected innervation from the medial rectus.

In acute CN III palsies, whether or not the pupil is involved will help guide the management. Pupil-involving cases require emergent evaluation because it is likely to be associated with an aneurysm (see case report). Again, because of the nerve’s location within the cavernous sinus, an expanding mass such as an aneurysm, often involving the posterior communicating artery or any other compressive lesion could cause an acute CN III palsy and is likely to involve the pupillary fibers. Emergent imaging, preferably MRI and MRA, should be ordered to rule out aneurysm in acute pupil-involving presentations of CN III palsy and in patients with no vasculopathic risk factors, particularly young patients.

In pupil-sparing cases, where microvascular ischemia is the probable offender if the patient history includes vasculopathy (e.g., diabetes, hypertension, etc.) and more concerning etiologies are far less likely, the patient can be closely monitored. Daily observation is recommended for the first 5 days to monitor for delayed pupil involvement, then every 4 to 6 weeks thereafter. Improved function is expected within about 3 months. If it does not improve, if the pupil becomes involved, if aberrant regeneration appears or if any other neurologic symptoms develop, urgent MRI/MRA should be ordered. Aberrant regeneration takes time, so is most often congenital or associated with a history of trauma or a slowly expanding aneurysm or mass, but is not associated with microvascular CN III palsy. Pupil-sparing CN III palsies can also be related to giant cell arteritis, so in applicable patients, this must also be ruled out.

Adie’s tonic pupil

An Adie’s tonic pupil results from post-ganglionic denervation of the iris sphincter and ciliary body. The pupil is typically abnormally dilated, exhibits minimal or no response to light, but maintains a sluggish near response with slow redilation. The consensual pupillary response is also typically absent or sluggish. Accommodative tonicity may be similar, with a slow relaxation of the ciliary body after near focusing. The retained near response is likely due to more neural fibers controlling the near than light pupillary reflex. There may also be some aberrant regeneration of accommodative fibers redirecting to the iris sphincter, thus leading to this light-near dissociation. Adie’s pupil is often accompanied by a vermiform pupil response (best seen with slit lamp) due to segmental constriction with sectored iris sphincter palsy.

Adie’s pupil is most common in young women and is typically unilateral (80% to 90%); however, it may become bilateral (4% rate per year) and, interestingly, an affected pupil may slowly constrict over time and may even become smaller than the unaffected pupil. Most cases of Adie’s pupil are idiopathic, traumatic or following viral illness, but it could also be caused by any pathology (i.e., mass, inflammation, infection) or injury (i.e., trauma, surgery) affecting the ciliary ganglion or postganglionic fibers or systemic disease that causes neuropathy. Prolonged denervation in Adie’s pupil leads to hypersensitivity, so pharmacologic testing to confirm Adie’s pupil uses 0.125% pilocarpine; this will cause constriction of the affected pupil but is too weak to constrict a normal pupil.

Given that most cases of Adie’s pupil are idiopathic, traumatic or following viral illness, often no additional work up is warranted. However, if the patient has bilateral Adie’s pupils with no previous history of an Adie’s pupil, consider additional work-up, which should be guided by other patient symptoms and history.

Horner’s syndrome

Horner’s syndrome may be congenital or acquired and can be due to a number of etiologies anywhere along the sympathetic chain. Any disruption of this pathway will lead to ipsilateral Horner’s syndrome. The classic clinical triad of signs associated with Horner’s syndrome is ipsilateral ptosis (due to paralysis of Mueller’s muscle), miosis and anhydrosis. Anhydrosis will only occur if the central or preganglionic neuron is affected, because the skin’s nerve fiber supply follows the external carotid artery. There may also be heterochromia associated with Horner’s if congenital, or apparent enophthalmos. The affected, miotic pupil will have an intact light and near pupillary reflex, but due to an inactive pupillodilator muscle, the pupil will slowly dilate due to passive sphincter release in the dark.

Testing the pupils to confirm and localize the lesion in Horner’s syndrome has proven to be a bit of a clinical challenge due to the availability of the pharmacologic agents needed. The initial testing is to be done with either 4% or 10% cocaine. Cocaine blocks the neurotransmitter norepinephrine’s reuptake at the synaptic cleft, causing an accumulation of norepinephrine and dilation of a normal pupil; the affected, miotic pupil will not or will only minimally dilate due to a lack of norepinephrine at the nerve ending. Anisocoria of >0.8 mm 30 minutes after instillation of cocaine confirms the presence of a Horner’s pupil.

Because of the limited availability of ophthalmic cocaine as a schedule II controlled substance, 1% or 0.5% apraclonidine could possibly be used in lieu. Apraclonidine is an alpha-adrenergic agonist; denervation from Horner’s syndrome leads to upregulation and hypersensitivity of alpha-receptors, increasing apraclonidine’s usually weak effect on the iris dilator’s alpha-1 receptors in the affected eye. With apraclonidine, a confirmatory response for a Horner’s pupil would be reversal of the anisocoria (i.e., the Horner’s miotic pupil will become larger than the normal pupil). Note, however, that alpha-receptor upregulation takes several days to develop, so apraclonidine testing may not be useful in acute cases.

To localize the lesion in Horner’s syndrome, 1% hydroxyamphetamine is used, which causes endogenous norepinephrine release at the postganglionic synaptic cleft. The affected pupil will dilate (anisocoria increases by 1 mm or more) if the lesion is first or second order, but will not dilate (or minimal dilation) in a third-order neuron lesion due to a lack of norepinephrine in the pupillodilator’s synaptic cleft.

Phenylephrine 1% may also be helpful, used in lieu of hydroxyamphetamine, for differentiating postganglionic lesions in Horner’s syndrome. Again, denervation supersensitivity of the iris dilator allows this substitution; a postganglionic Horner’s pupil will dilate much more than a normal pupil.

There is no way to differentiate first- from second-order neuron lesions with topical ophthalmic pupillary testing.

While testing to localize the lesion causing Horner’s syndrome is possible, it is not necessarily practical clinically. Localizing the lesion to pre- or post-ganglionic with pharmacologic pupillary testing needs to be done on a separate day from the initial cocaine or apraclonidine testing; this can be done if the clinician prefers, but ancillary imaging studies should be ordered promptly once Horner’s syndrome has been confirmed (depending on history) and should not be delayed by waiting to follow up to localize the lesion to pre- or post-ganglionic with hydroxyamphetamine.

In cases of Horner’s syndrome, thorough patient history is vital. A longstanding Horner’s syndrome is more likely benign, whereas a recent onset is much more concerning. If the patient has any recent history of trauma or if there is any head, neck or chest pain associated, emergent MRA or CTA should be obtained to rule out an internal carotid artery or aortic dissection; concomitant MRI or CT of the rest of the sympathetic chain should also be acquired. Unless the patient history or testing has better isolated an area of concern, the imaging should include the entire sympathetic chain — the head and neck extending down to at least T2 (to rule out an apical lung mass). There are a plethora of possible etiologies, which include internal carotid or aortic dissection, stroke, tumor, tuberculosis or Pancoast’s tumor at the lung apex, trauma and cavernous sinus disease.

Argyll Robertson pupil

Light-near dissociation is a hallmark finding with an Argyll Robertson pupil, where the pupil reacts poorly to light but maintains a brisk near response. In addition to light-near dissociation, an Argyll Robertson pupil is typically miotic and irregularly shaped; this tends to be bilateral, but certainly can be asymmetric. Of importance, vision must be intact for this pupillary reaction to be described as an Argyll Robertson pupil.

An Argyll Robertson pupil is seen as a manifestation of neurosyphilis, but light-near dissociation itself can also be seen with other problems. Because of the anatomic arrangement of the fibers that cause the light and near reflexes, with those causing the near reflex being located more anteriorly, the near reflex may remain intact with lesions that affect the more posterior light reflex fibers.

If a patient is found to have an Argyll Robertson pupil, laboratory testing should be ordered to determine syphilitic activity: FTA-ABS (fluorescent treponemal antibody absorbed) or MHA-TP (microhemagglutination-Treponema pallidum) and RPR (rapid plasma reagin) or VDRL (Venereal Disease Research Laboratory).

Light-near dissociation

In addition to an Argyll Robertson pupil and aberrant regeneration after a CN III palsy, both previously described above, light-near dissociation can also be found in several other diseases involving midbrain pathology, including neoplasms (particularly pinealomas), brainstem strokes, midbrain hemorrhages, arteriovenous malformations, alcoholic midbrain degeneration, encephalitis, hydrocephalus and trauma. Dorsal midbrain (Parinaud) syndrome, which often results from direct or compressive injury to the dorsal midbrain, often from pinealomas, includes bilaterally mid-dilated pupils with light-near dissociation and is also associated with eyelid retraction, supranuclear upgaze paralysis and convergence retraction nystagmus.

Anisocoria evaluation

Newly noted anisocoria requires additional work-up to determine whether the anisocoria is physiologic or pathologic. A thorough case history is paramount. In addition to the discussion above, the table will help guide the practitioner through the anisocoria evaluation process.

Pupillary responses are a quick way to gauge the integrity of the afferent and efferent system, can clue the practitioner in to potentially serious problems and will help direct the differential diagnoses and management. Such a quick and useful tool should not be overlooked.