Pupillary and Eyelid Abnormalities

Pupil Anatomy and Neural Control

The size of the pupil is determined by the balance of action between two muscles embedded in the iris: the sphincter pupillae, under parasympathetic control, and the dilator pupillae, under sympathetic control. The sphincter is located circumferentially around the pupil and constricts the pupil. The dilator is situated radially and dilates the pupil. On exposure to light, the pupil constricts as a result of the pupillary light reflex ( Fig. 17.1 ). The afferent limb of the light reflex originates in the retinal ganglion cells and travels via the optic nerve, chiasm, and optic tract to the dorsal midbrain pretectum, just rostral to the superior colliculus, from which neuronal signals are relayed bilaterally to the paired parasympathetic Edinger-Westphal nuclei ( ). In primate studies, the pretectal olivary nucleus is identified as the primary relay between retinal ganglion cells and the Edinger-Westphal nuclei (see Fig. 17.1 ) ( ). The efferent limb of the light reflex consists of the preganglionic parasympathetic fibers traveling from the Edinger-Westphal nuclei in both oculomotor nerves to the ciliary ganglion and the postsynaptic, postganglionic short ciliary nerves carrying the parasympathetic innervation from the ciliary ganglion to the sphincter muscle (see Chapter 103 for a more extensive discussion of the oculomotor nucleus and nerve anatomy). The pupillary near reflex consists of pupillary constriction as a response to viewing of a near target. Thus miosis is a component of the near triad, along with lens accommodation and eye convergence. The anatomical substrate of the pupillary near reflex is less well defined than that of the light reflex, although a network of neurons including near-response cells has been identified in primates and may play a role in the near triad—especially the vergence and accommodation components ( ).

The sympathetic innervation destined for the dilator muscle passes along a chain of three neurons: first-, second-, and third-order neurons ( Fig. 17.2 ). First-order neurons originate in the posterolateral hypothalamus and descend in the dorsolateral brainstem and intermediolateral cell column of the spinal cord to the upper thoracic cord (T2). After the first-order neurons synapse in the spinal cord, second-order neurons exit to the paravertebral sympathetic chain via the ventral horns. They pass by the lung apex and then ascend with the common and internal carotid arteries to reach the superior cervical ganglion in the neck, at the angle of the jaw, where they synapse with the third-order neurons. At this point, sudomotor fibers related to facial sweating separate anatomically from those fibers serving pupillary dilation. From the superior cervical ganglion, third-order neurons continue their ascent with the internal carotid artery through the skull base and into the cavernous sinus, where they temporarily join the abducens nerve. They then join branches of the trigeminal nerve, with which they enter the orbit and reach the dilator muscle via the long ciliary nerves (see Fig. 17.2 ).

Normal Pupil Phenomena

Hippus, or pupillary unrest, is a nonrhythmical, small-amplitude (<1 mm) variation in pupil size that occurs in normal eyes after light stimulation and is not triggered by accommodation ( ). After a light stimulus, the pupil constricts, redilates, and then oscillates. The role (if any) of these oscillations in pupillary or visual function is unclear.

Physiological anisocoria (also termed central , simple , or benign anisocoria ; unequal pupils) occurs in up to 20% of the population; the difference in pupil size ranges from approximately 0.4 to 1 mm. The amount of anisocoria is usually the same in light compared with darkness, although it is sometimes slightly greater in darkness. It should not be accompanied by abnormalities of the pupillary light or near responses, nor should it be accompanied by ptosis or ophthalmoplegia.

With age, the pupils become smaller and less reactive to light. Such pupils generally do not require diagnostic evaluation. Although not a normal condition, diabetes similarly affects the pupils sufficiently often as to make small and poorly reactive pupils common in that clinical setting in the absence of any other pathological pupil state. Both parasympathetic and sympathetic pupillary dysfunction can occur in diabetes, and pupillary abnormalities are correlated with a number of other disease processes, including the presence of cardiovascular autonomic dysfunction, peripheral neuropathy, and retinopathy ( ).

Afferent Pathological Conditions of the Pupils

The relative afferent pupillary defect (RAPD), or Marcus Gunn pupil, is a hallmark of optic nerve disease. However, given that the initial synapse of the pupillary light reflex pathway occurs in the dorsal midbrain pretectal olivary nucleus, a unilateral lesion of the dorsal midbrain may also rarely produce an RAPD in the absence of vision loss ( ). It is a manifestation of unilateral or asymmetrical bilateral disruption of the afferent limb of the pupillary light reflex and occurs as a result of the consensual and bilateral nature of the light reflex. When a light stimulus is applied to one eye, both pupils constrict due to the bilateral connections between the pretectal olivary and Edinger-Westphal nuclei. When the swinging flashlight test is performed to evaluate for an RAPD, the light will be transmitted normally via an intact optic nerve and to a lesser extent by a diseased optic nerve. This results in the appearance of a brisk bilateral pupillary constriction when the light stimulus is applied to the normal eye and a lesser constriction with initial relative dilation when the light stimulus is transferred to the eye with the optic neuropathy, thus the RAPD. The greater the extent of retinal ganglion cell and optic nerve damage, the larger the relative dilation of the pupil will appear ( ). See Chapter 16 for a more detailed description and a table with step-by-step instructions on how to evaluate for an RAPD and for a more extensive discussion of optic nerve disease.

Efferent Pathological Conditions of the Pupils

Clinical Presentation and Examination

The medical history of a patient rarely begins with the statement “I noticed that I have unequal pupils.” Most patients have anisocoria brought to their attention by a doctor, friend, or relative. Those who notice anisocoria themselves may give a misleading account of the duration of the condition; magnification of old photographs of the patient may prove helpful in clarifying the duration of the anisocoria. Occasionally, a patient has visual symptoms caused solely by an abnormality in pupillary size. Photophobia can occur when a dilated pupil fails to protect the retina from increased illumination. Less often, a complaint of poor night vision (or dim daytime vision) may arise in patients with small, poorly reactive pupils; this occurs as a result of the pupils not dilating normally, thereby decreasing the light-gathering power of the eye under conditions of dim illumination.

The pupil examination of a patient being evaluated for a pupillary abnormality should begin with observation of the resting size of the pupils in ambient room light and of resting eyelid position. If anisocoria is present, the amount of anisocoria in light versus in darkness should be determined. Pupil size can be determined in the dark by having the patient look at a distant target in a dark room while the examiner shines just enough light indirectly from below to allow visualization of the pupils. Assessment in the light versus in darkness will help determine which pupil, if either, is the abnormal pupil. Anisocoria that is more pronounced in the light suggests that the large pupil is the abnormal pupil, because the small pupil will constrict normally to light, enhancing the difference in size between the small pupil and the large, nonconstricting pupil. The differential diagnosis for anisocoria greater in light includes parasympathetic outflow damage (tonic pupil, oculomotor palsy), iris sphincter injury or ischemia, pharmacological pupil dilation, and asymmetrical sympathetic activation. Anisocoria that is more pronounced in the dark suggests that the small pupil is the abnormal pupil, because the large pupil will dilate normally in the dark, enhancing the difference in size between the large pupil and the small, nondilating pupil. A caveat to the suggestion that the small pupil is abnormal in this situation is that physiological anisocoria will often be slightly greater in the dark ( ). The differential diagnosis for pathological anisocoria greater in the dark includes sympathetic outflow damage (Horner syndrome), iris pathology such as trauma or inflammation, and asymmetrical parasympathetic stimulation (e.g., pharmacological stimulation).

The next step in the examination is evaluation of the direct and consensual pupillary light reflexes, followed by evaluation of the pupillary near response ( ). The near response can be elicited by having the patient shift gaze from a distant target to their thumb, held several inches in front of their eyes. Under certain conditions, the pupils may have light-near dissociation with poor direct responses to light but relatively preserved constriction to near stimuli.

Once the abnormal pupil is identified, pharmacological testing with a number of topical eye drops can be used for confirmation of the diagnosis and assistance with localization ( Table 17.1 ). The general method is application of 1–2 drops of the pharmacological agent into each eye, followed by reexamination of the pupils 30–45 minutes later. Sensitivity of accurate response detection is increased with before-and-after photographic documentation. Diagnostic use of topical pharmacological agents and additional helpful examination findings for each of the specific disorders are described in detail in the sections of this chapter covering these disorders and outlined in a systematic guideline in Fig. 17.3 . The presence of mild ptosis on the side of the small pupil may indicate sympathetic dysfunction, whereas ptosis on the side of the large pupil may indicate oculomotor nerve dysfunction. Careful examination of vision, ocular motility, facial strength and sensation, and the ocular fundus should also be performed.

TABLE 17.1

Diagnostic Pupillary Eyedrop Testing

Testing	Mechanism of Action	Diagnostic Utility and Expected Response
Anisocoria Greater in the Light (Abnormal Larger Pupil)
Dilute pilocarpine (0.0625% or 0.1%)	Parasympathomimetic; direct sphincter stimulation	Tonic pupil will constrict and pupil affected by oculomotor palsy may constrict (denervation supersensitivity)
		Normal pupil and pupil affected by pharmacological blockade will not respond
Pilocarpine (1%)	Parasympathomimetic; direct sphincter stimulation	Normal pupil and pupil affected by oculomotor palsy will constrict fullyPupil affected by pharmacological blockade will not or only partially respond
Anisocoria Greater in the Dark (Abnormal Smaller Pupil)
Cocaine (2%–10%)	Inhibits norepinephrine reuptake at the sympathetic terminus	Horner pupil will not dilateNormal pupil will dilate
Hydroxyamphetamine (1%)	Induces third-order sympathetic neuron to release any stored norepinephrine	Preganglionic (first- or second-order neuron) Horner pupil will dilatePostganglionic (third-order neuron) Horner pupil will not dilate
Apraclonidine (0.5%)	Weak sympathetic agonist	Horner pupil will dilate (denervation supersensitivity)
		Normal pupil will not change or will constrict slightly