Pupillary 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, primarily under parasympathetic control, and the dilator pupillae, primarily under sympathetic control. The sphincter is located circumferentially around the pupil and constricts the pupil on exposure to light. The dilator is situated radially and dilates the pupil in darkness. The resting tone of the pupil is primarily determined by the degree of baseline parasympathetic innervation. On exposure to light, the pupil constricts as a result of the pupillary light reflex (Fig. 16.1). 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 of the oculomotor nerve (Akert et al., 1980; Nester et al., 2010; Papageorgiou, Wermund, and Wilhelm, 2009). In primate studies, the pretectal olivary nucleus is identified as the primary relay between retinal ganglion cells and the Edinger-Westphal nuclei (see Fig. 16.1) (Kourouyan and Horton, 1997; Pong and Fuchs, 2000; Warwick, 1954). 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 intraorbital ciliary ganglion and the postsynaptic, postganglionic short ciliary nerves carrying the parasympathetic innervation from the ciliary ganglion to the sphincter muscle (see Chapter 70 for a more extensive discussion of oculomotor nucleus and nerve anatomy). The pupillary near reflex consists of pupillary constriction as a response to viewing of a near target. Such miosis is a component of the near triad, along with lens accommodation and ocular convergence. The anatomic substrate of the pupillary near reflex is less well defined than that of the light reflex.

Fig. 16.1 Schematic diagram of the pupillary light reflex in the macaque monkey, showing the afferent limb via the retina, optic nerve, and chiasm; the midbrain connections between the pretectal olivary nuclei and the Edinger-Westphal nuclei; and the efferent limb via the oculomotor nerve and ciliary ganglion. For simplicity, a single neuron in the olivary nucleus is shown projecting to both Edinger-Westphal nuclei, and inputs from both olivary nuclei converge on a single neuron in the Edinger-Westphal nucleus.

(Courtesy J.C. Horton; republished with permission from Kourouyan, H.D., Horton, J.C., 1997. Transneuronal retinal input to the primate Edinger-Westphal nucleus. J Comp Neurol 381, 78.)

Sympathetic nerves destined for the dilator muscle consist of a chain of three neurons: first-, second-, and third-order neurons (Fig. 16.2). First-order neurons originate in the posterolateral hypothalamus and descend in the dorsolateral brainstem and in the intermediolateral cell column of the spinal cord to the thoracic level (T2). After the first-order neurons synapse in the spinal cord, second-order neurons exit to the paravertebral cervical sympathetic chain via the ventral horns. They ascend near the lung apex and then 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 carotid artery through the skull base and into the cavernous sinus, where they temporarily travel with the abducens nerve. They then join branches of the trigeminal nerve, with which they enter the orbital apex, bypass the ciliary ganglion, and reach the dilator muscle via long ciliary nerves (see Fig. 16.2).

Fig. 16.2 Parasympathetic and sympathetic pathways for innervation of the sphincter pupillae and the dilator pupillae. I. C., First cervical spinal cord segment; II Th., second thoracic segment; III, oculomotor nerve; V, trigeminal nerve.

(Adapted from Gray, H., 1918. Anatomy of the Human Body, plate 840.)

Normal Pupil Phenomena

Hippus, or pupillary unrest, is a nonrhythmical, small-amplitude (<1 mm) variation in pupil size that occurs in healthy eyes after light stimulation and is not triggered by accommodation (Hunter et al., 2000; Thompson et al., 1971). 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 is generally less than 0.5 mm, although it may occasionally be up to 1 mm. It should not be accompanied by abnormalities of pupillary light or near responses, nor should it be accompanied by ptosis.

With age, 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 “normal” in that clinical setting in the absence of any other pathological pupil state. Both parasympathetic and sympathetic pupillary dysfunction are reported 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 (Bremner and Smith, 2006; Bremner, 2009).

Afferent Pathological Conditions of the Pupils

The relative afferent pupillary defect (RAPD), or Marcus Gunn pupil, is a hallmark of optic nerve disease. It is a manifestation of a relative unilateral disruption of the afferent limb of the pupillary light reflex via the optic nerve 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 as a result of the bilateral connections between pretectal nuclei and the Edinger-Westphal nuclei. When the swinging flashlight test is performed to evaluate for RAPD, the light will be transmitted normally via one optic nerve and to a lesser extent by the 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 (Lagreze and Kardon, 1998). See Chapter 36 for a more detailed description and a table with step-by-step instructions on how to evaluate for an RAPD, and see Chapter 15 for an 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 confuse the diagnostician by giving a misleading account of the duration of the condition. Magnification of old photographs of the patient may prove helpful in this regard. Occasionally a patient has visual dysfunction caused solely by abnormal pupillary size. Photophobia and slow dark adaptation occur when a fixed, 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 symptom is caused by pupils not dilating normally, which decreases the light-gathering power of the eye in conditions of dim illumination.

The pupil examination (see Chapter 36 for additional discussion) of a patient being evaluated for a pupillary abnormality should begin with observation of the resting positions of the pupils in the ambient room light and of resting eyelid positions. If anisocoria is present, the degree of anisocoria in the light versus in the dark should be evaluated. Pupil evaluation in the dark is done by having the patient look straight ahead 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 the dark will help determine which pupil, if either, is the pathological 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 the light, enhancing the difference in size between the small pupil and the large, nonconstricting pupil. The differential diagnosis for this includes parasympathetic outflow damage (tonic pupil, oculomotor palsy), iris sphincter injury or ischemia, pharmacological pupil dilation, and excessive sympathetic activation. Anisocoria that is more pronounced in the dark suggests that the small pupil is the pathological 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 pathological in this situation is that the anisocoria will generally be slightly enhanced in the dark with physiological anisocoria, a normal situation in which neither pupil is pathological (Lam et al., 1987). The differential diagnosis for a pathologically small pupil includes sympathetic inhibition (Horner syndrome), local iris pathology such as inflammation, and 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 (Kasthurirangan and Glasser, 2006). The near response is best assessed by having the patient hold the thumb several inches in front of the eyes while looking across the room and then to have the patient shift and maintain gaze on the thumb. In certain abnormal conditions, the pupils may have light-near dissociation with poor direct light reflexes but relatively preserved constriction to near stimuli. Once the abnormal pupil is identified, pharmacological testing with a number of topical eye drops is often used for confirmation and assistance in localization (Table 16.1). The general method is application of a drop of the pharmacological agent into each eye, followed by reexamination of the pupils 30 to 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 respective sections of this chapter covering the disorders and outlined in a systematic guideline in Fig. 16.3. The presence of a slight degree of ptosis in the eye with the small pupil may indicate sympathetic dysfunction; ptosis in the eye with the larger pupil may indicate oculomotor nerve dysfunction. Careful examination of vision, ocular motility, facial strength and sensation, and ocular fundus should also be performed.

Table 16.1 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 (denervation supersensitivity)
		Normal pupil and pupil affected by oculomotor palsy or pharmacological blockade will not respond
Pilocarpine (1%)	Parasympathomimetic; direct sphincter stimulation	Normal pupil and pupil affected by oculomotor palsy will constrict
		Pupil affected by pharmacological blockade will not respond
ANISOCORIA GREATER IN THE DARK (ABNORMAL SMALLER PUPIL)
Cocaine (2% to 10%)	Inhibits norepinephrine reuptake at the sympathetic terminus	Horner pupil will not dilate
		Normal pupil will dilate
Hydroxyamphetamine (1%)	Induces third-order sympathetic neuron to release any stored norepinephrine	Preganglionic (first- or second-order neuron) Horner pupil will dilate
		Postganglionic (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

Fig. 16.3 Flowchart with systematic guidelines for evaluation of anisocoria.

Anisocoria Greater in the Light

Postganglionic Parasympathetic Dysfunction—Tonic Pupil

A tonic pupil is large and reacts poorly to light and slowly to near stimuli; after distance refixation, it exhibits a slow, tonic redilation (Fig. 16.4). After removal of the near stimulus, such tonic redilation transiently reverses the anisocoria, making the tonic pupil smaller than the normal pupil, because the normal pupil quickly redilates, and the tonic pupil does not (see Fig. 16.4, D). In the ophthalmology office, evaluation of a tonic pupil at the slit lamp reveals wormlike segmental constriction of some portions of the pupil and absent constriction of other portions. Because of parasympathetic denervation of the iris sphincter muscle, denervation supersensitivity may occur, and instillation of a dilute solution of the cholinergic agent, pilocarpine, may confirm the diagnosis (Fig. 16.5; see also Table 16.1). A 0.1% solution is often suggested, but false-positive results may be more frequent than with a 0.0625% solution (Ashker et al., 2008; Leavitt et al., 2002). Dilute pilocarpine will constrict the tonic pupil, but not a normal pupil or a dilated pupil from another cause such as oculomotor palsy or pharmacological toxicity. Solutions of pilocarpine less than 1% are not commercially available and must be prepared by dilution with preservative-free normal saline solution.

Fig. 16.4 Left tonic pupil. A, In darkness, anisocoria is minimal because the normal right pupil is dilated. B, In bright light, anisocoria is enhanced because the normal right pupil constricts, and the tonic pupil does not. C, A near stimulus results in constriction of the tonic pupil, demonstrating light-near dissociation. D, A few seconds after return of gaze to a distant target, the normal right pupil has redilated, and the tonic pupil remains small.

Fig. 16.5 Right tonic pupil. A, Anisocoria with larger right pupil prior to dilute pilocarpine administration. B, Thirty minutes after dilute pilocarpine, the right pupil is constricted and the left unchanged. Patient also has an unrelated congenital strabismus with an exotropia (outward deviation of the eyes) and full ocular motility without diplopia.

Tonic pupils result from damage to the intraorbital ciliary ganglion or short ciliary nerves from any etiology, including focal infectious (herpes zoster, syphilis) or noninfectious (giant cell arteritis) inflammation, malignant infiltration, paraneoplastic processes, and trauma. Tonic pupils may also be seen as a component of a systemic autonomic neuropathy (see Chapter 77) (Bremner and Smith, 2006; Yamashita et al., 2010), Guillain-Barré syndrome or its Miller Fisher variant, and botulism. Perhaps the most common and most easily recognizable tonic pupil is the benign Holmes-Adie pupil, which often presents with acute painless enlargement of the pupil and may be accompanied by complaints of photophobia and blurred near vision due to involvement of fibers serving the ciliary body for lens accommodation. In 80% of patients, the condition is unilateral. It is most common in healthy young women and is thought to be due to a viral ciliary ganglionitis. Additional examination findings may include decreased deep tendon reflexes and decreased corneal sensation. The affected pupil tends to become smaller over time and may even eventually become smaller than the unaffected pupil. Ross syndrome is the triad of tonic pupils, hyporeflexia, and segmental anhidrosis (Ross, 1958). It is unclear whether this syndrome is a variant of the Holmes-Adie syndrome or a mechanistically distinct disorder, but impaired thermoregulation is the distinguishing element (Nolano et al., 2006; Shin et al., 2000). Harlequin syndrome, failure of facial flushing to thermal or emotional stress, may also occur with tonic pupils and hyporeflexia, although Horner syndrome is more common (Bremner and Smith, 2008).