He sustained them in a desert land,

In an empty howling wasteland.

He encompassed them and raised them up,

Protecting them like the pupil* of His eye.

Deuteronomy 32:10

The pupil is a kinetic indicator of both ocular motor function and the the retina, the special sensory apparatus that it serves. The neural mechanisms that control pupil size and reactivity are highly complex, yet they may be sampled and evaluated by simple clinical procedures. Irene Loewenfeld's scholarly text, The Pupil: Anatomy, Physiology and Clinical Applications, is recommended reading for encyclopedic information about the pupil.¹

Pupillary function depends on the integrity of the structures along the course of the pupillomotor pathway (Fig. 1). These include: (1) retinal receptors; (2) ganglion cell axons in the optic nerve, optic chiasm, and optic tract (but not the lateral geniculate body); (3) brachium of the superior colliculus; (4) pretectal area of the mesencephalon and the interconnecting neurons to pupilloconstrictor motor cells in the oculomotor nuclear complex; (5) the efferent parasympathetic outflow to the pupillary sphincter and ciliary muscle; and (6) the efferent sympathetic pathway from the hypothalamus to the pupillary dilator muscle. The ocular sympathetics may influence pupillary size directly by dilator muscle innervation or indirectly by central inhibition of the oculomotor parasympathetics (Edinger-Westphal nucleus).² In addition, the size of the pupils is influenced by the intensity of retinal illumination, the near-effort reflex, the state of retinal light adaptation, and supranuclear influences from the frontal and occipital cortex above the pretectal area and from the reticular formation of the brain stem below. Iris color, on the other hand, may affect constriction amplitude and velocity but not pupillary size.³

At a given moment, any or all of the aforementioned factors may variably influence pupillary size and reactivity. It should be no wonder, then, that in the awake state, the pupil is rather constantly moving, a condition of physiologic unrest termed hippus. This incessant change in pupil size has no pathologic significance,⁴ although it is described in diverse conditions ranging from encephalitis to schizophrenia and from cataracts to hemorrhoids. Age affects both pupillary size and reactivity.^5,6 The pupil of the neonate is miotic but increases in size during the first decade of life; from the second decade on, the pupil steadily becomes smaller (Fig. 2). Pupillary reactivity, at least to “long” (3-second) light flashes, also seems related to age; the range of amplitude of the light reflex declines with increasing age (Fig. 3). Decreased central sympathetic inhibition to the Edinger-Westphal nucleus has been implicated as the mechanism for age-related diminished pupil size in dim illumination.²

The pupil may be considered to have three major optic functions:

• to regulate the amount of light reaching the retina;
  
• to diminish the chromatic and spherical aberrations produced by the peripheral imperfections of the optical system of the cornea and lens; and
  
• to increase depth of field (analogous to the f-stop setting of a camera).
  

As pupillary size increases, so does chromatic and spherical aberration. As pupillary size decreases, light diffraction at the pupil edge becomes a more significant factor in reducing image quality; this generally outweighs any benefit of miosis-induced increase in focal depth. In their experiments of optical line-spread function, Campbell and Gubisch⁷ found the optimal pupil diameter to be 2.4 mm; scatter and focusing defects have an increasing effect with larger pupils.

Mechanically, the diameter of the pupil is determined by the antagonistic actions of the iris sphincter and dilator muscles, with the radially arranged dilator fibers playing the minor role. The dilator muscle inserts at the iris root and extends from there to an area about 2 mm from the pupillary margin. The sphincter muscle has circumferential fibers, is more superficial in the iris stroma, and occupies an area about 2 to 4 mm from the pupillary margin. The sphincter can be seen in light or atrophic irides. Rather than retracting toward one quadrant when severed or ruptured, the sphincter continues to function except in the altered segment. Therefore, with prudence, the pupillary reactions may be evaluated even in the presence of iris atrophy, traumatic rupture of the sphincter, and congenital or surgical coloboma.

The pupillary light reflex pathway may be functionally considered a three-neuron arc (see Fig. 1): the afferent neurons from retinal ganglion cells to the pretectal area; an intercalated neuron from the pretectal complex to the parasympathetic motor pool (Edinger–Westphal nucleus) of the oculomotor nuclear complex and the efferent parasympathetic outflow with the oculomotor nerve to the ciliary ganglion; and from there to the pupillary sphincter.

Considerable evidence exists that the visual cells of the retina (i.e., the rods and cones) also serve as light receptors, controlling pupillomotor activity. For example, pupillomotor light thresholds follow the same shifts in spectral sensitivity as visual thresholds, depending on the state of light adaptation of the retina (Purkinje shift). Pupillomotor sensitivity of the retina also parallels visual form sensitivity, which is highest at the fovea and lowest in the periphery. In our present state of knowledge, it seems that the same afferent axons in the optic nerve transmit pupillomotor information to the pretectal area and visual information to the lateral geniculate nuclei. It is suspected, but unproved, that this dual function is accomplished by axonal bifurcation in the optic tract in humans.⁸ Therefore, we may consider two intimately related systems: retinogeniculate for visual perception and retinomesencephalic for pupillomotor control and foveation.

At the optic chiasm, slightly more than one half of the afferent axons in the optic nerve cross to the opposite optic tract, where they are mixed with noncrossing axons from the contralateral optic nerve. The ratio of crossed to uncrossed fibers is approximately 53:47.⁹ From the chiasmal level posteriorly, afferent visual and pupillomotor information from either eye is divided into crossed fibers (from nasal retinal receptors of the contralateral eye) and uncrossed fibers (from temporal retinal receptors of the ipsilateral eye). In the posterior aspect of the optic tract (pregeniculate), the pupillomotor branches of the afferent axons gain the pretectal nuclear area by transversing the brachium of the superior colliculus into the rostral midbrain. Intercalated neurons interconnect from the preolivary nucleus of the pos-terior commissure and lentiform nucleus¹⁰ to the Edinger–Westphal nuclei by crossing dorsal to the aqueduct in the posterior commissure and by coursing ventrally in the periaqueductal gray matter. This simplistic anatomic approach belies the true complexity of the neurophysiology and neuroanatomy of the pretectal nuclear complex. The reader is referred to articles by Smith et al.,¹⁰ Carpenter and Pierson,¹² Benevento et al.,¹³ Burde,¹⁴ and Irene Loewenfeld's¹ textbook.

The organization of the oculomotor nuclear complex in the mesencephalon (midbrain) depicted by Warwick¹⁵ in 1953 and Jampel and Mindel¹⁶ in 1967 was modified by Burde and Loewy¹⁷ and Burde,¹⁴ recognizing the anterior median nucleus rostrally and accessory cell columns caudally. The anteromedian nucleus is the source of special visceral efferent motor axons to the iris sphincter and ciliary musculature. This dorsal cell mass may be subdivided into a rostral portion associated with accommodation, a caudal portion—the stimulation of which produces pupil constriction, and a midportion associated with both accommodation and constriction. Direct input to the iris sphincter and ciliary body may also be provided by the nucleus of Perlia.^10,17 The pretectal olivary nuclei receive direct retinal input and, in turn, provide direct input to the Edinger–Westphal nucleus. The exact location of the Edinger–Westphal nucleus in humans is not known. Kourouyan and Horton¹⁸ injected tritiated H-proline into macaque monkey eyes and found the primary pretectal retinal projections terminating in the olivary nuclei, ipsilaterally and contralaterally. The label for the Edinger–Westphal nucleus was found bilaterally in the midbrain, ventral to the cerebral aqueduct, in the central gray matter, in well-defined columns, corresponding to an area termed the lateral visceral column in the classic literature (Fig. 4). Using multiple markers, including wheat germ agglutin, May and Fratkin¹⁹ have further isolated the Edinger-Westphal nucleus in the macaque monkey and deduced that it is comprised of a solitary column of cells. Whether this is the case in humans remains to be determined.

According to the degeneration studies by Warwick,²⁰ the ciliary ganglion contains more cells for innervation of the ciliary muscles than for innervation of the iris sphincter (about 30:1). Presumably, that same ratio occurs in the Edinger–Westphal nucleus, although the presence of diffuse projections may argue against it.

From the parasympathetic nucleus, the pupillomotor and ciliary fibers join the outflow of the oculomotor nuclei and exit from the substance of the midbrain with the oculomotor nerves as multiple rootlets in the interpeduncular space. According to Kerr and Hollowell,²¹ the pupillomotor fibers are located superficially in the nerve, lying just internal to the epineurium. It is believed that this superficial position makes the pupillomotor fibers especially vulnerable to compression. In a more rostral part of its projections and in more anterior segments (e.g., the cavernous sinus), however, pupillomotor fibers may be spared preferentially even in the presence of total oculomotor palsy. It is likely that involvement or “sparing” of the pupil sphincter reflects the nature and acuteness of the injury rather than merely the portion of the third nerve that is compromised.²²

At about the level of the superior orbital fissure, the oculomotor nerve divides into superior and inferior divisions, with parasympathetic fibers traveling in the latter to the ciliary ganglion via the branch to the inferior oblique muscle. Although the ciliary ganglion contains afferent sensory fibers (nasociliary nerve) and sympathetic fibers to the vessels of the globe and dilator of the iris, only the parasympathetic fibers synapse here. The parasympathetic postganglionic fibers then pass to the globe via the short ciliary nerves.

The weight of anatomic evidence supports the view that the parasympathetic pupillomotor fibers synapse in the ciliary ganglion.^20,23 Some experimental studies in monkeys using horseradish peroxidase techniques suggest the presence of a nonsynapsing pathway between the midbrain and the eye^24,25 but subsequent work by the same authors²⁶ ascribed their initial findings to transsynaptic passage of horseradish peroxidase. Parasympathetic denervation hypersensitivity does not occur solely with postsynaptic lesions. Preciliary ganglionic hypersensitivity to low-concentration methacholine and pilocarpine has been reported, with complete^27,28,29 and (inferior) divisional oculomotor palsies.³⁰ Warwick's²³ proposed synapsing pathways remain accepted generally.

The pretectal pupilloregulator mechanism is subject to a variety of supranuclear influences, which may be summarized as follows:

1. excitatory, retinomesencephalic (light stimulus) and occipitomesencephalic (near reflex) and
   
2. inhibitory, corticomesencephalic and hypothalamomesencephalic pathways and the ascending reticulomesencephalic system.
   

During sleep and obtunded states, these supranuclear inhibitory influences are diminished, with resultant miotic but reactive pupils. Arousal results in pupil dilatation because of the return of supranuclear inhibition. Sympathectomy does not eliminate this dilatation.

Sympathetic outflow to the iris dilator muscles begins in the posterolateral area of the hypothalamus and descends uncrossed through the tegmentum of the midbrain and pons (Fig. 5). At the level of the medulla, the sympathetics lie laterally, where they may be affected in lateral medullary plate infarction (i.e., Wallenberg's syndrome). The descending fibers, considered first-order preganglionic neurons, terminate in the intermediolateral cell column at the C8 to T2 cord level (the ciliospinal center of Budge). Second-order preganglionic fibers exit the cord primarily with the first ventral thoracic root (T1), but some pupillomotor sympathetics egress with C8 or T2. Via the white rami communicantes, the fibers enter the paravertebral sympathetic chain, which is closely related to the pleura of the lung apex. At this location, the sympathetics may be affected by neoplasms, (i.e., the Pancoast's syndrome; see discussion of Horner's syndrome).

The fibers detour with the ansa subclavia around the subclavian arteries, ascend without synapsing through the inferior and middle cervical ganglia, and terminate in the superior cervical ganglion at the base of the skull. Third-order postganglionic oculosympathetic fibers ascend the internal carotid to enter the skull, whereas fibers for sweat and piloerection of the face follow the external carotid and its branches.

The intracranial sympathetics to the eye follow a circuitous course that includes:

1. fibers to the tympanic plexus of the middle ear and petrous bone,
   
2. fibers temporarily joining the path of the intracavernous abducens nerve before anastomosing with the first division of the trigeminal nerve,
   
3. anastomoses with the ophthalmic-trigeminal nerve (the primary pupillomotor pathway via the nasociliary nerve), and
   
4. fibers surrounding the ophthalmic artery and ocular motor nerves at the level of the cavernous sinus.
   

Postganglionic sympathetics include fibers to:

1. orbital vasomotor,
   
2. pupillary dilators,
   
3. smooth muscles of the upper and lower lids (Müller's muscle),
   
4. the lacrimal gland, and
   
5. trophic fibers to uveal melanophores.
   

Vasomotor sympathetics to the globe pass without synapse through the ciliary ganglion and short posterior ciliary nerves.

The near reflex shares the same efferent pathway to the light reflex and is conveyed through the oculomotor nerve, synapsing in the ciliary ganglion. The afferent segment, however, is different. With accommodative effort, caused either by a blurred retinal image or conscious visual fixation on a near object of regard, a “near synkinesis” is evoked that includes: (1) increased accommodation of the lens, (2) convergence of the visual axes of the eyes, and (3) pupillary constriction. The neural mechanisms of this motor triad are not understood as well as the pathways for pupillary light reactions or the saccadic and pursuit ocular motor systems (see Chapter 2:9 Eye Movement Characteristics and recording techniques.). Awareness of decreased object distance probably evokes accommodative effort originating in frontal centers; blurred retinal images are sensed in the occipital cortex and corrected via occipitotectal tracts. Jampel³¹ obtained increased bilateral accommodation, convergence, and usually miosis by unilateral stimulation of the peristriate cortex (area 19) in primates. A group of midbrain cells subserving convergence has been identified in the monkey.³² The anteromedian nucleus in the midbrain rostrally and the Edinger–Westphal nucleus caudally have been mapped stereotactically,¹⁶ with the rostral portion concerned with accommodation, the caudal portion with pupillary constriction, and the middle segment with accommodation and constriction.

The final pathway for pupil constriction, whether evoked by light or accommodative effort, consists of the oculomotor nerve, ciliary ganglion, and short posterior ciliary nerves. The ratio of ciliary ganglion cells innervating ciliary muscle to cells innervating the iris sphincter is about 30:1.

Pupillary constriction evoked by the near reflex is not evaluated as easily as the light reaction. Accommodative vergence is under voluntary control, and the success of this maneuver is very much dependent on the patient's cooperation and capacity to converge. In the elderly, convergence is diminished and the near reflex is especially difficult to test. An accommodative target is helpful, including the use of the patient's own fingertips. Vision itself is not a requisite for the near response, which can be tested in the blind by proprioceptive “fixation” of the patient's fingertips. Indeed, accommodation and convergence may be held in abeyance by substituting plus lenses and base-out prisms, without eliminating pupillary constriction.

If pupillary reactions are brisk to light stimulus, the near reactions need not be examined. However, the student must learn this examination technique and become acquainted with the limits of normality. The light and near efforts are additive; that is, even with the eye brightly illuminated, further pupillary constriction is observed when gaze is shifted from distance to near. Therefore, when testing the light reflex, gaze (accommodation) should be controlled steadily by fixation on a distant target. If the pupil fails to react to light, the eye may be illuminated fully while the near reflex is examined.

In office practice, patients present with relatively few isolated “pupil” problems, including, pharmacologic accidents, sympathetic paresis (Horner's syndrome), pupillary light-near dissociation, and essential anisocoria (Table 1). It is extremely unlikely that a patient with oculomotor paresis resulting from a posterior communicating aneurysm or other basal tumor will present solely with an abnormal pupil and no ocular motor or sensory disturbances. The reader is referred to the section on oculomotor nerve palsies to locate a more detailed discussion of pupillary findings with posterior communicating artery aneurysms. Direct trauma to the anterior ocular segment or surgery, local disease of the iris (e.g., cyst, melanoma, rubeosis, sphincter rupture, iritis), and angle-closure glaucoma are slit-lamp diagnoses that need not be discussed here, other than to point out that such local iris lesions have been misinterpreted as neurologic deficits.

TABLE 1. Characteristics of Pupils Encountered in Neuro-ophthalmology

When there is a significant unilateral or asymmetric visual deficit caused by optic nerve or widespread retinal disease, the pupils show a subnormal response to light stimulation of the eye with the greater field or (generally) acuity loss. The pupils have a more extensive constriction response with light stimulation of the normal or less involved eye. It is this combination of subnormal direct pupillary light response and a normal indirect (consensual) response when the opposite eye is illuminated that constitutes the relative afferent pupillary defect (RAPD).

The RAPD can be demonstrated clinically by the alternate cover test, also known as the Marcus Gunn pupillary test, as described by Kestenbaum³³ or by the swinging flashlight test of Levatin³⁴ (Fig. 6). The swinging flashlight test compares pupillary responses to brief bursts of light stimulation and is more sensitive than the Marcus Gunn test, which detects pupillary dilatation after prolonged light exposure.^35,36

The swinging flashlight test is best performed in a dimly lit room, using a bright light, such as a muscle light or penlight. During the test, the patient must look at a distant fixation target to avoid accommodative miosis.

The test light is shone directly into the visual axis to first illuminate one pupil and then the other. The alternating or swinging light should pause 3 to 5 seconds in each eye, and this maneuver should be repeated several times. As a rule, the pupils are round and practically equal in diameter (see section on Essential Anisocoria) and briskly and symmetrically reactive to light stimuli. After an initial, prompt pupil constriction, a slight “release” dilation generally occurs. For example, in the presence of a right afferent defect (see Fig. 6), the following is observed with the swinging flashlight test: the pupillary diameters are equal and slightly larger bilaterally when the right eye is stimulated and bilaterally smaller when the normal left eye is illuminated. If only the illuminated pupil is observed—the other pupil being hidden in darkness—the following is seen: the normal left pupil constricts promptly on illumination; as the light is moved rapidly to the right, the right pupil is seen to dilate or “escape.” As the light moves again to the left, the left pupil again constricts briskly.

Afferent pupillary defects may be quantified conveniently by the use of neutral-density filters placed before the normal eye. While performing the swinging light test, the neutral density filter is increased until the pupil responses are “balanced.” The neutral density value at which a positive (asymmetric) swinging light test is neutralized is read in log units.³⁷ Previously used to assess the depth of amblyopia, the Sbisa bar (Bagolini filter bar) has also been found to be of comparable use in quantifying RAPD.³⁸ Whether a dim, bright, or brilliant light is best suited for pupil light-reaction testing is somewhat controversial,³⁹ but an indirect ophthalmoscope light set at 6 volts may be used as a handy “standardized” light source. Thompson and Jiang⁴⁰ stress the importance of avoiding asymmetric retinal bleach, by maintaining a rhythmic “equal time” alternation of the light from one eye to the other and by not swinging the light too many times between the eyes. Thompson et al.^37,41 provide detailed guidelines for proper performance of the pupillary examination and assessment of the RAPD.

Computerized infrared pupillography may allow the most reliable standardization of the swinging flashlight test.³⁵ Personal computer based infrared video pupillography has been developed for clinical use when detection and specific quantification is required. Proposed advantages to the swinging light test include the capacity to perform binocular tests, compensating for natural differences in midbrain decussation of the interneurons, asymmetric supranuclear influences on the Edinger-Westphal nucleus, and differences in efferent innervation of the pupils. Furthermore, the RAPD may be recorded at different light intensities independent of motion, pattern and color, and free of observer bias.⁴² Pupillography also measures response latency and cycling time, which can be delayed in diseases of the afferent and efferent visual pathway and amblyopia.⁴³

Quantification of RAPD may be used to gauge the degree to which the anterior visual pathway disruption has occurred or as a prognostic indicator for final visual recovery. In a small series, Alford et al.⁴⁴ found that patients with traumatic optic neuropathy and an initial RAPD of log 2.1 or greater showed minimal visual recovery even after megadose intravenous steroid therapy. Those with RAPD measurements less then log 2.1 recovered to visions of 20/30 or better.

An afferent pupillary defect may be assessed even if one of the pupils is unreactive because of mydriatics, miotics, oculomotor palsy, trauma (Fig. 7), or synechia formation. In such cases, when performing the swinging flashlight test, the direct and consensual responses of the single reactive pupil must be compared. The reactive pupil's direct light response reflects the afferent function of the ipsilateral eye; its consensual response reflects the afferent function of the contralateral eye.

Even severe unilateral visual loss due to retinal or optic nerve diseases associated with an afferent pupillary defect is not of itself a cause of anisocoria, despite past statements to the contrary (see later text: Behr's sign). If a patient with an RAPD also shows anisocoria, the pupillary inequality must be treated as a separate finding. The RAPD most typically provides objective evidence of optic nerve disease that is either unilateral or asymmetric, with more profound visual involvement on the side of the RAPD. In such cases, the RAPD is not specific and may reflect optic neuropathy due to demyelination, ischemia, compression, or asymmetric glaucoma.

Because slightly more fibers cross than remain uncrossed at the level of the chiasm, RAPDs may also be seen with optic tract lesions, where greater visual field loss occurs in one eye. An obvious example would be an optic tract lesion with a complete homonymous hemianopia. In such a case, a relative afferent pupillary defect would be expected in the eye with the temporal visual field loss (i.e., the eye contralateral to the side of the optic tract lesion).⁴⁵ Theoretically, the same kind of RAPD could be present without any associated visual field defect if there is a contralateral lesion affecting the pupillomotor fibers between the optic tract and pretectal region. The eye with the RAPD should have normal visual acuity, color vision, and visual field, and no other (occult) cause for the pupillary defect (i.e., no amblyopia, glaucoma, past optic neuritis). Ellis⁴⁶ has reported an afferent pupillary defect contralateral to a pineal region tumor, suggesting that this was due to involvement of afferent pupillary fibers between the optic tract and pretectal nucleus. Johnson and Bell⁴⁷ have also documented an RAPD in a pretectal lesion due to a pineal gland mixed-cell tumor.

Previous descriptions of an RAPD associated with anisocoria, with the larger pupil opposite the side of the optic tract lesion (Behr's sign of optic tract disease), has not been supported by subsequent reports. Loewenfeld¹ has argued that reports of this phenomenon resulted from observation errors or misinterpretation. Because all afferent optic fibers synapse in intercalated interneurons that project to either side of the Edinger-Westphal nucleus, pupillary innervation and, thus, responses are more or less symmetrical.¹ Therefore, unless another cause for anisocoria exists, anisocoria does not usually result from lesions causing RAPD.

RAPD most typically is an indicator of optic nerve disease. Retinopathy, maculopathy, or amblyopia can also lead to RAPD. However, even with very poor acuity and field depression, the latter diseases usually cause much less obvious RAPD than that found with optic neuropathy. An extensive retinal detachment, such as two detached quadrants, should cause an obvious RAPD, as do arterial occlusions. With unilateral or markedly asymmetric retinitis pigmentosa, one should see an RAPD; however, usually the disease process is quite symmetric, and thus an RAPD is typically not present.⁴⁸ RAPD in general is proportional to the extent of visual field loss, and the size of the visual field defect is more closely correlated with the extent of the RAPD than is visual acuity loss.^49,50 As a rule, strictly macular disease leads to a much less profound afferent pupillary defect than the bulk of diseases affecting the optic nerve.⁵¹ Patients with central choroidopathy, for example, show either a small or no RAPD.⁵² Furthermore, the RAPD is much more likely to persist with resolved optic neuritis than resolved central serous choroidopathy.⁵³ Patients have also been reported to have an RAPD⁵⁴ with central retinal vein occlusion, the RAPD being more obvious (generally greater than 1 log unit) in the ischemic than in the nonischemic variety, where most cases measure less than 0.3 log units. Thus, the RAPD may be helpful in distinguishing between ischemic and nonischemic central retinal vein occlusions.

RAPD may be observed in strabismic or refractive amblyopia,^55,56 but these are small, measuring 0.3 log units or less and do not correlate with visual acuity.⁵⁵ If a very obvious RAPD is seen in cases of amblyopia, advanced cataracts, retinopathy, or maculopathy, additional tests are recommended to rule out the possibility of a superimposed occult optic neuropathy that would better explain the pupillary findings. Occasionally, a small RAPD of neutral density filter of 0.3 log unit or less is detected in patients with other ocular pathology. These findings may be assumed to be benign if there are no etiologic clues from the history or clinical examination.^57,58 Follow-up with lack of progressive visual changes on subsequent examinations should provide further corroboration that the small isolated RAPD is indeed “benign.” Interesting but rarely encountered in the usual clinical setting are RAPDs induced by contralateral monocular occlusion or resulting from dense contralateral cataracts.^59,60,61

All pupils are not created equal. In fact, benign pupillary inequality exists in practically all individuals, but not necessarily all of the time. Using photographic techniques, Lam et al.⁶² determined pupil size in 128 healthy individuals, measuring greatest pupil diameter twice each day for 5 consecutive days. Forty-one percent showed anisocoria of 0.4 mm or greater at one time or another and 80% showed anisocoria of 0.2 mm or greater at some time. A majority of the subjects, therefore, had anisocoria of some degree at one time or another (Fig. 8). Anisocoria is as common in men as in women, in the morning as in the afternoon, in dark as in light irides, and in the young as in the aged (although Loewenfeld⁶³ suggested that anisocoria is more common in the elderly). In a study of healthy neonates, anisocoria of 0.5 mm or more was found in about 20% of infants, but none had anisocoria greater than 1 mm.⁶⁴ The physician can detect regularly a pupil difference of as little as 0.2 mm in diameter, given that clinical judgment of inequality is based more on impressions of pupil area than on measured diameter. Because the percentage difference in area is greater for smaller than for larger pupils, for any given diameter difference, anisocoria is detected more easily in smaller pupil pairs. The prevalence of anisocoria decreases in bright conditions when measured as a difference in pupil diameter but not when it is assessed as a ratio of pupil areas.⁶⁵

Essential or “central” anisocoria should be identified easily because the pupillary light and near reactions are normal, eyelid positions are normal, and eye movements are full. The relative difference between pupil diameters is constant under various levels of illumination. With sympathetic disruption or Horner's syndrome, the anisocoria is enhanced in dim lighting. Conversely, in parasympathetic disruption, the anisocoria is enhanced in bright illumination. Incidental ptosis due to traumatic or senile levator aponeurosis dehiscence and weakening, when ipsilateral to the smaller pupil of essential anisocoria, may be confused with a true Horner's syndrome.⁶⁶ When the distinction between true and pseudo-Horner's syndrome is difficult by simple inspection alone, pharmacologic testing usually resolves the dilemma. With essential anisocoria, pupillary responses to pharmacologic agents, including topical cocaine, are normal bilaterally.

The evaluation of anisocoria is facilitated by the presence of the following associated signs (see Table 1): mild upper ptosis as well as lower lid elevation on the side of a relatively miotic pupil (Horner's syndrome), a dilated pupil fixed to light but with very slow constriction on prolonged near fixation (tonic pupil), and small irregular pupils that react better to near than to light (A-R pupil).

Some individuals with long-standing anisocoria may suddenly discover the condition while shaving or applying makeup or may have it called to their attention over the breakfast table. In such situations, inspection of previous photographs is an invaluable aid in determining the nature and duration of pupil anomalies. A hand magnifying glass, a trial frame lens, an indirect ophthalmoscope lens, or even the high magnification of the slit-lamp beam⁶⁷ may prove useful for examining pupil details in snapshot or portrait-quality photographs (Fig. 9).

With exception of errors in testing techniques or poor patient cooperation, there is no pathologic situation in which pupillary light reflex is normal while the near response is defective. Therefore, if the pupils respond briskly to light, the near response need not be examined. Lack of direct and near responses, in the absence of ocular motility disturbances, should raise the question of bilateral pharmacologic pupillary dilation or local ocular disease, such as sphincter trauma or synechiae. Rarely such findings represent congenital mydriasis.⁶⁸ Paradoxical pupillary responses (pupillary constriction induced by darkness) have been reported in association with concomitant stationary night blindness and congenital achromatopsia and subsequently with other retinopathies and optic neuropathies.⁶⁹

Dissociation of the light-near response, when certain other criteria are met (Table 2), is diagnostic of neurosyphilis (see section on Argyll Robertson Syndrome). Other distinctive clinical syndromes demonstrating pupillary light-near dissociation include the Holmes-Adie tonic pupil syndrome and Parinaud's dorsal midbrain syndrome. The tonic pupil is characterized by light-near dissociation and supersensitivity to dilute parasympathomimetic agents. It is distinguished from the A-R pupil by certain characteristic features, including a larger pupil (see section on Tonic Pupil Syndrome). The dorsal midbrain syndrome produces light-near dissociation in association with moderate mydriasis and a constellation of signs, including vertical ocular motility deficits and accommodative defects (see section on Dorsal Midbrain Syndrome). Other causes of light-near dissociation include significant visual loss, diabetes mellitus, and aberrant oculomotor nerve regeneration.

TABLE 2. Characteristics of Tonic Pupil (Holmes–Adie) Syndrome

Any eye with a severe visual deficit due to retinal or optic nerve disease, with significant field loss, has a diminished ipsilateral pupillary response to light (RAPD) but an intact near reflex. For example, an eye blind from glaucoma demonstrates a light-near dissociation. Patients with profound bilateral visual loss caused by anterior visual pathway disease have bilaterally poor pupillary light responses but intact accommodative responses. Therefore, patients with bilateral end-stage glaucoma, total retinal detachments, or blindness resulting from optic nerve/chiasmal injuries should not be misconstrued as having dorsal midbrain disease on the basis of mid-dilated pupils and light-near dissociation alone because these findings may result solely from bilateral blindness. On occasion, patients with long-standing type I diabetes demonstrate moderate symmetric mydriasis with light-near dissociation that is clearly disproportionate to any concurrent retinopathy. Indeed some type I and type II diabetics may exhibit findings consistent with tonic pupils resulting from widespread autonomic dysfunction⁷⁰ or local nerve damage from diode laser photocoagulation.⁷¹ Diabetic patients may also have typical A-R pupils, including miosis.^72,73

When aberrant regeneration follows oculomotor nerve palsies, fibers originally associated especially with the medial rectus (although other oculomotor fibers are occasionally responsible) may anomalously innervate the pupillary sphincter as well. Frequently, aberrant regeneration results from chronic oculomotor nerve compression, typically from meningiomas and aneurysms,⁷⁴ as opposed to acute ischemic insults. In such cases, the light-paretic pupil can constrict when the medial rectus muscle acts, either in convergence or with conjugate lateral gaze. Therefore, a light-near dissociation (actually, a gaze-evoked) pupillary dissociation is observed. Unlike the A-R pupil, the aberrant-regeneration pupil is large rather than miotic and is accompanied by other signs of third-nerve palsy, some paretic and some with “misdirection” features.⁷⁵

Infrared videographic transillumination readily demonstrates denervated and aberrantly reinnervated sphincter segments.⁷⁶ Pupillary changes seen on a slit lamp examination may provide the early evidence of aberrant oculomotor regeneration; segmental pupillary sphincter contractions may be seen with attempted eye movements in the field of action of oculomotor innervated muscles.⁷⁷ In more obvious cases, the pupillary constriction may be grossly visualized with attempted efforts by any of the muscles normally innervated by the oculomotor nerve.⁷⁵ Ohno and Mukuno⁷⁸ report anomalous pupillary innervation by the oculomotor nerve in 6 of 10 patients with aberrant oculomotor regeneration; pupillary constriction was seen most commonly with downgaze or adduction and less frequently with upgaze. In two patients, pupillary dilation was noted on abduction. Spiegel and Kardon⁷⁹ evaluated 24 patients with aberrant oculomotor regeneration. Clinically, involvement of the eyelid and pupil was evident more commonly than that of ocular motility. Pupil signs of aberrant behavior, such as gaze-evoked anisocoria, were most noticeable in dim illumination.

One of the commonest causes of isolated internal ophthalmoplegia is the tonic pupil. First described in 1931, in two separate reports, it was recognized to occur with other neurologic anomalies and subsequently named Holmes-Adie syndrome (after GM Holmes and WJ Adie). Holmes-Adie syndrome has an annual incidence of 4.7 per 100,000.⁸⁰ Pupillotonia is usually unilateral, but bilateral cases do occur in which the eyes are involved either simultaneously or sequentially (Fig. 10). Unilateral cases become bilateral at a rate of 4% per year.⁸¹ Although all ages and both sexes are affected, there is an unexplained predilection for women in the third to fifth decades.

Typically, the involved pupil is larger than its fellow. Because both constriction and dilation are defective, however, the tonic pupil may appear smaller in dim illumination because the normal pupil is free to dilate widely. Thus the diameter of the normal pupil may be smaller (in bright illumination) or larger (in dim illumination) than the tonic pupil. With the passage of time, the anisocoria becomes less marked as the initially larger tonic pupil gradually becomes less dilated and eventually even miotic over the years^76,82 (Fig. 10).

As a rule, the tonic pupil is grossly defective in its reaction to light stimulus but may show some minimal degree of contraction. On slit-lamp examination, however, irregular spontaneous low-amplitude movements may be observed. Segmental sector contractions may be seen in the portions of the sphincter that are still either not denervated or reinnervated. Also, areas of sector palsy of the iris sphincter are seen. The combination of segmental contractions and areas of sphincter palsy exhibit the characteristic worm-like vermiform movements. With prolonged accommodative effort, the pupil slowly constricts, usually not extensively. When near effort is relaxed, the dilation movement is also gradual, requiring minutes or hours for redilation. Therefore, with accommodative effort and before redilations are complete, the tonic pupil can be relatively miotic with respect to its normal opposite. These pupillary kinetics constitute the “tonic pupil,”and pharmacologic testing (Fig. 10) is additive rather than diagnostic. Disruption of the final postganglionic nerve supply to the iris sphincter accounts for denervation supersensitivity, with pupillary constriction produced by dilute parasympathomimetic agents and is the basis for pharmacologic testing for the tonic pupil.

Supersensitivity to the parasympathomimetic drug methacholine 2.5%, with pupillary constriction, is a good but not foolproof test. Thompson⁸³ suggests the use of 0.125% pilocarpine as a substitute for methacholine. Actually, pilocarpine is, in some ways, the better drug because of its ready availability and stronger miotic action; supersensitivity is demonstrable in a greater proportion of patients with tonic pupils. Because it produces a more visible degree of anisocoria, a negative test is more valid with pilocarpine than with methacholine. Some authors have suggested the use of weaker solutions of pilocarpine, such as 0.0625% to 0.0313%.^84,85 These lower concentrations insignificantly constrict normal pupils and more reliably distinguish normal pupils from tonic pupils with parasympathetic supersensitivity. Weak concentration arecoline, a pilocarpine-like drug, has also been used; its advantage, if any, may be that it brings about maximal miosis more quickly.⁸⁶ Pupillary parasympathetic supersensitivity may occur with ganglionic lesions as well as with preciliary and postciliary ganglionic lesions.^27–30,78

Accommodation, like pupillary constriction-redilation, is also tonic and changes slowly from far to near gaze and from near to far gaze. Vision is blurred momentarily until the ciliary muscle “catches up” either while attempting to accommodate or after prolonged near effort. If accommodation is measured, it will be found to be deficient.

The tonic pupil's light-near dissociation (i.e., slow constriction on near effort and very poor reaction to light stimulation) is explained on the basis of misdirected regeneration and collateral sprouting of nerve fibers after injury to the ciliary ganglion and its postganglionic fibers.⁸⁷ Recall that some 97% of fibers from the ciliary ganglion innervate the ciliary muscle; the remaining 3% innervate the pupillary sphincter.²⁰ Because the great excess of neurons are destined to innervate the ciliary body, regenerated fibers and collateral sprouts are also much more likely to subserve accommodative function. This results in pupillary sphincter reinnervation almost entirely by fibers initially intended for accommodation. Kardon et al.,⁷⁶ using infrared transillumination, provide videographic demonstration of pupillary behavior in patients with Holmes-Adie's tonic pupil (Fig. 11). They also show that with time-extensive reinnervation and, therefore, a miotic (“little old Adie's”) pupil.

The tonic pupil is a clinical entity with multiple causes and associations (Table 3). In the absence of other signs and symptoms, it is a benign condition that neither heralds a neurologic nor systemic state, nor does it suggest an etiology or pathogenesis. The common pathway is disruption of parasympathetic transmission from the ciliary ganglion or its presynaptic and postsynaptic fibers. The association with diminished deep tendon reflex is the well-known Holmes-Adie syndrome. In the few pathologically studied cases, ganglion cells of the orbital ciliary ganglion are absent or grossly diminished.⁸⁸ Spinal cord dorsal column atrophy has also been documented.⁸⁹ In most instances the cause is unknown. Although nonspecific viral illnesses have been incriminated as causing Holmes-Adie syndrome, histopathologic data have failed to provide evidence of inflammation and scarring commonly seen with infections.⁸⁰

TABLE 3. Disorders Associated with Tonic Pupil

Temporal relations with Herpes virus infections^90,91 have led some to suspect a causal relation between the infection and tonic pupil. Indeed, local ciliary ganglion inflammation has been implicated in tonic pupils associated with sarcoidosis.⁹² Orbital trauma, including surgery, is the most direct cause of pupillotonia. Optic nerve fenestration, especially when done by the temporal approach, can lead to ciliary ganglion injury and secondary tonic pupil. Orbital ciliary ganglion ischemia is the proposed mechanism for reported cases of tonic pupils associated with vasculitides, such as giant cell arteritis,⁹³ polyarteritis nodosa,⁹⁴ and status migrainosus.⁹⁵ Orbital neural-glial hamartoma⁹⁶ and congenital neuroblastoma⁹⁷ have been associated with congenital tonic pupils, possibly resulting from direct compression or developmentally abnormal ciliary ganglia.

Bilateral pupillotonia may occur in association with primary or idiopathic dysautonomia, including orthostatic hypotension, progressive segmental hypohydrosis (Ross syndrome),^{98,99,100,101} chronic cough,¹⁰² forme fruste familial dysautonomia,¹⁰³ and the typical Riley-Day syndrome.¹⁰⁴ Hereditary demyelinating polyneuropathies, such as Charcot-Marie-Tooth and Dejerine-Sottas disease may also result in widespread dysautonomia and tonic pupils.¹⁰⁵

Associations with secondary polyneuropathies, which are often variable combinations of autonomic and somatic neuropathies, have been described. Autonomic neuropathy and chronic relapsing polyneuropathy due to paraneoplastic disease have been reported to cause tonic pupils,^{106,107,108,109} as have acute ophthalmoplegic polyneuritis or Guillain-Barre syndrome⁹¹ and its variant, Miller-Fisher syndrome.^110,111 The presumed mechanism of neuronal damage in these cases is autoimmune inflammation¹⁰⁹ and demyelination.⁹¹ Likewise in the polyneuropathy of Sjogren's syndrome, tonic pupils are suspected to result from autoimmune ciliary ganglionitis.¹¹² Bilateral pupillotonia, including denervation hypersensitivity to low concentration pilocarpine may be also caused by syphilis; if so, other manifestations of neurosyphilis, such as tabes dorsalis, typically should be present as well.^113,114

Both pupillary sphincter and ciliary muscle dysfunction may cause symptoms in patients with tonic pupils. Although symptoms of unilateral defective accommodation may prompt an office visit, anisocoria is usually the more dramatic signal. Symptoms that are related to pupillary mydriasis rarely need treatment, although some patients prefer the cosmetic effect of symmetrical pupils brought about by low-concentration pilocarpine. The ciliary symptoms may at times be more troublesome and may manifest as unilateral accommodative paresis, induced astigmatism, and ciliary spasms. Pharmacologic treatment of ciliary symptoms is often ineffective, but on occasion, low-concentration anticholinesterase (physostigmine), low concentration cholinergic (pilocarpine), or anticholinergic (tropicamide, atropine) drops may help.^115,116 In children with whom the tonic pupil may cause asymmetric accommodative efforts and amblyopia, correction of the refractive error and occlusion therapy have been recommended.⁹⁰

Dorsal midbrain lesions to the pretectal nuclear complex with disruption of retinotectal fibers and preservation of more ventral supranuclear accommodative pathways produces light-near dissociation. Damage to the interstitial nucleus of Cajal and/or rostral MLF subserving vertical gaze results in supranuclear upgaze and occasionally downgaze palsies. The associated moderate mydriasis results from damage to the pretectal pupilloconstrictor nuclei (Fig. 12). These “midbrain” pupils and the associated gaze palsies comprise the dorsal midbrain syndrome (also known as periaqueductal syndrome, pretectal syndrome, and sylvian aqueduct syndrome). The eponym Parinaud's syndrome honors Henri Parinaud, the 19th century French ophthalmologist who originally described abnormal conjugate gaze and convergence insufficiency. Subsequent descriptions have recognized the full constellation of signs: supranuclear paralysis of upgaze, lid retraction (Collier's sign), defective convergence with convergence-nystagmus on attempted upgaze, retraction-nystagmus (also elicited on attempted rapid upgaze or as optokinetic targets are moved downward), and both accommodative paresis and accommodative “spasm” (failure of relaxation of accommodation following near effort). Skew deviations and horizontal gaze anomalies may also occur (Table 4).

TABLE 4. Features of Parinaud's Syndrome

Parinaud's syndrome usually results from local midbrain insults, although various systemic etiologies have been implicated. Obstructive hydrocephalus with dilation and damage of the periaqueductal gray matter is a common cause in children. Symptoms and signs will often resolve following successful decompression.¹¹⁷ Pinealomas are the commonest tumors causing this syndrome and typically occur in younger male patients. Although rare, local midbrain abscesses, including neurocysticercosis, tuberculoma, and toxoplasma, may produce Parinaud's syndrome and usually suggest widespread neurologic disease and in some cases immunosuppression.¹¹⁸ Other causes of the dorsal midbrain syndrome include cerebrovascular accidents, arteriovenous malformations, aneurysms, glioma, trauma, demyelination (multiple sclerosis and Miller-Fisher syndrome), and Wernicke's encephalopathy.¹¹⁹

Although signs of Parinaud's syndrome may be incidental findings, some patients present with symptoms of diplopia and blurred vision at near and difficulty with upgaze. Treatment results in partial or complete resolution of symptoms and signs. Residual convergence/accommodative deficiencies are usually minor and may be managed with plus lenses and prisms with reasonable effect.

In 1869, Douglas Argyll Robertson described abnormal pupils characterized by miosis, unresponsive to light stimulus, and contraction on near effort in eyes with intact visual function. Since that time, the Argyll Robertson (A-R) pupil has been recognized as the hallmark of late central nervous system syphilis.

Although an absolute defect of light reaction was described initially, it is clear that the critical point in the light-near dissociation is simply a more extensive reaction to near than to light; some degree of light reaction may be observed (Fig. 13). In fact, A-R pupils with impaired, rather than absent, light reaction are by far more common. It is tempting to consider that the incomplete A-R pupil with impaired light reaction represents an incipient form of the light-fixed pupil, however, currently there is no documentation of such progression.

The Argyll Robertson syndrome must include miosis to exclude nonsyphilitic causes of light-near dissociation (e.g., blindness, tonic pupil, amaurotic pupils, and midbrain pupils). When viewed in darkness, the pupils neither constrict well to light stimulus nor, as a rule, do they dilate in darkness. The characteristics of this syndrome are listed in Table 5.

TABLE 5. Characteristics of Argyll-Robertson Syndrome

In most cases, the A-R syndrome is bilateral, although not invariably so, and the pupils also tend to be irregular in shape. If the criteria listed in Table 5 are met, the diagnosis of neurosyphilis may be made. Serologic screening tests—Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) tests in conjunction with specific confirmatory tests: fluorescent treponemal antibody absorption (FTA-abs) or microhemagglutination treponema pallidum (MHA-TP)—should be obtained. Patients with late or tertiary syphilis often will have negative screening tests and positive confirmatory tests.

Numerous causes of A-R-like pupils have been proposed with similarly miotic pupils and some degree of light-near dissociation, including Charcot-Marie-Tooth syndrome,¹²⁰ diabetes mellitus,¹²¹ and neurosarcoidosis.¹²² Syphilis is also capable of producing large pupils that are fixed and unresponsive to both light stimulus and near effort (Fig. 14). These abnormalities occur typically in taboparesis. In addition, bilaterally tonic pupils may occur in patients with neurosyphilis. Fletcher and Sharpe¹¹⁴ have recommended that serologic test for syphilis be performed on all patients with bilaterally tonic pupils, to rule out this potentially treatable disease. Of their five luetic patients with bilaterally tonic pupils, two had tabes dorsalis and another two had manifestations of neurosyphilis.

The complicated course of the oculosympathetic pathways has been outlined previously. In essence, the ocular sympathetic chain may be interrupted partially or totally in any location, from the hypothalamus down through the brain stem to the cervical cord, in the apex of the chest, in relation to the carotid sheaths, or in the cavernous sinus or orbit. The resulting collection of signs was first recognized in humans by a Swiss ophthalmologist, Johann Friedrich Horner (1831–1886), from whom the syndrome derives the eponym, Horner's syndrome.¹²³ The clinical manifestations of this syndrome are summarized in Table 6.

TABLE 6. Characteristics of Horner's Syndrome

Horner's syndrome consists of mild to moderate ptosis of the upper lid due to paresis of Muller's muscle, pupillary miosis, apparent enophthalmos, and ipsilateral anhydrosis. The lid fold is lost (Fig. 15) and is a subtle confirmatory sign. The lower lid may be somewhat elevated because of paresis of smooth muscle attached to the inferior tarsal plate. This can be evaluated by noting the relationship of the lower lid margin to the corneoscleral junction (inferior limbus). Ptosis of the upper lid and elevation of the lower lid narrow the interpalpebral fissure. Thus, the eye may be described as looking “smaller” or seeming to be enophthalmic. This enophthalmos is more apparent than real.^124,125

The pupil is variably miotic, depending on the location, completeness, and chronicity of the defect. The pupillary diameter is usually reduced by 0.5 to 1 mm. Although it reacts normally to light and near stimulation, the Horner's pupil demonstrates delayed redilatation in the pupillary light reflex.¹²⁶ Anisocoria due to Horner's syndrome is more marked in dim illumination (evoking dilation) than in bright light. Furthermore, other stimuli that usually increase sympathetic tone, such as pain and sudden loud noises also increase the anisocoria.

Heterochromia with Horner's syndrome (the lighter iris in the same eye) is usually considered a sign that the sympathoparesis is congenital or acquired in infancy. However, progressive heterochromia has been reported following acquired Horner's syndrome in adults.^127,128 It must be stressed that heterochromia occurs in a multitude of ophthalmic conditions, some of which are outlined in Table 7.

TABLE 7. Differential Diagnosis of Heterochromia

With the complete syndrome, the ipsilateral face is anhidrotic, warm, and hyperemic because of denervation of sweat and vasoconstrictor fibers that are distributed to the face through branches of the external carotid artery. These defects are for the most part transient, being rapidly overcome by denervation supersensitivity to circulating adrenergic substances. Ocular hypotony and defective accommodation have been described with sympathetic denervation, but these are, at best, transient and inconstant signs and are of little help in diagnosis. The pupillary reaction to light or near stimulus is normal, but slowed redilation can be documented photographically or pupillographically.

Although the pattern of facial sweating may be helpful in localizing Horner's lesions, it is by pharmacologic means that the site of involvement is most often ascertained. Numerous pharmacologic tests have been used for the diagnosis or confirmation of oculosympathetic paresis. Cocaine 4% is the most widely used agent, although dilute solutions of epinephrine (0.001%) and hydroxyamphetamine 1% (Paredrine) are also useful.¹²⁹ Thompson believes that the use of dilute epinephrine is a poor test with inconclusive results, but that the use of phenylepherine 1% dramatically demonstrates supersensitivity in postganglionic Horner's syndrome. Ramsay⁸⁴ reported catecholaminergic hypersensitivity to 1% phenylepherine in 71% of tested patients with Horner's syndrome.

Cocaine blocks the reuptake of norepinephrine released at the myoneural junction and therefore induces mydriasis when instilled in patients with intact oculosympathetic pathways. In Horner's syndrome, cocaine instillation results in poor or no dilation, regardless of the site of the lesion. The cocaine test therefore corroborates the diagnosis of Horner's syndrome but does not allow distinction between a central (brain stem or cervical cord), preganglionic (chest or neck), or postganglionic (above superior cervical ganglion) cause of sympathetic denervation. A cocaine test that induces 1 mm or more of anisocoria is strongly supportive (>95% probability) of the diagnosis of Horner's syndrome.^130,131 Patients should be informed that their urine may be positive for the cocaine metabolite, benzoylecgonine, up to 48 hours after topical instillation of cocaine.¹³²

Hydroxyamphetamine (Paredrine) causes release of norepinephrine stored in the presynaptic terminals of pupils with intact third-order (postganglionic) neurons and causes pupillary dilation normally in first-order (central) and second-order (preganglionic)—but not third-order (postganglionic)—oculosympathetic lesions.^133,134 Therefore, the Paredrine test is useful in identifying patients whose Horner's syndrome is postganglionic.¹³⁵ A Paredrine test that induces 1 mm or more of anisocoria identifies postganglionic Horner's syndrome with high probability (90% or more).¹³⁴ Although a false-negative response to Paredrine can occur in congenital^136,137 and acute Horner's syndrome (of less than 2 weeks' duration)^138,139 the test is generally very useful and reliable clinically. Paredrine is no longer available commercially but hydroxyamphetamine hydrobromide 1% can be “special-ordered” from a number of pharmacies. Pholedrine, an n-methyl derivative of hydroxyamphetamine (methamphetamine), has been used by some as a substitute for pharmacologic test for distinction between central (first-order) and preganglionic (second-order)^140,141 oculosympathetic lesions.

In all pharmacologic tests for sympathetic denervation, drops should be instilled in both eyes so that the reaction of the normal pupil serves as a control. Tonometry, testing of corneal sensitivity, or any procedures that may mechanically or chemically disturb corneal epithelium, should not be performed before these drops are instilled. If cocaine is used, the hydroxyamphetamine reaction should not be tested before 48 hours have elapsed. Differences in observed pharmacologic reaction between the two pupils are more common than absolute dilation failure: the eye with the partial sympathetic denervation may dilate less extensively than the normal pupil, rather than demonstrating no dilation at all. Bilateral cases of Horner's syndrome, such as may occur with diabetic autonomic neuropathy,^126,142 amyloidosis and familial dysautonomia may be difficult to diagnose without the benefit of a normal eye for comparison. Smith and Smith¹²⁶ have recommended utilizing delayed pupillary redilatation. They reported an abnormally prolonged redilatation (time taken to reach three-quarter recovery) in the light reflex. They reported a 70% sensitivity and a 95% specificity for detecting Horner's syndrome.

The topical diagnosis of Horner's syndrome is very much dependent on accompanying signs and symptoms. Causative lesions may be the result of cerebrovascular disease, cervical trauma (Fig. 15), chest tumors, intracavernous lesions, or even a form of vascular headaches. Horner's syndrome arising from a brain stem lesion is unlikely to be isolated. The sympathoparesis may accompany the lateral medullary or Wallenberg's syndrome that results from posterior inferior cerebellar artery occlusion or insufficiency. The signs include dysphagia (laryngeal and pharyngeal paralysis), analgesia in ipsilateral face and contralateral trunk and extremities (spinal tract and nucleus of trigeminal nerve and ascending lateral spinothalamic tracts) and ipsilateral cerebellar ataxia, and rotatory nystagmus. Skew deviation may occur, with vertical diplopia. A central Horner's syndrome has been reported in association with cerebral and hypothalamic infarction caused by internal carotid artery occlusion.¹⁴³ The interruption of the hypothalamospinal tract leads to ipsilateral hemianhidrosis, ptosis, and miosis associated with contralateral hemiplegia and variably homonymous hemianopsia and aphasia. This constellation of findings has been termed telodiencephalic ischemic syndrome by Schiffter.^144,145 Other causes of central Horner's syndrome include cervical cord lesions, including trauma (Fig. 15), syringomyelia, tumors, and, rarely, demyelinating disease.

In the chest apex and superior mediastinum, destructive lesions may interfere with sympathetic fiber as they pass in close proximity to the apical pleura and great vessels. Pancoast superior sulcus syndrome is usually caused by bronchogenic carcinoma and, rarely, breast cancer, lymphoma, sarcoma, or metastases. Oculosympathetic paresis may be the first sign of disease. Such lesions typically cause pain in the shoulder and arm from brachial plexus infiltration. Thus, patients with an acquired, nontraumatic, preganglionic oculosympathetic paresis and arm or shoulder pain require appropriate radiologic studies of the pulmonary apex, chest, and cervical spine.

In the neck, as the sympathetic fibers ascend in relationship with the carotid sheath, oculosympathetic paresis may ba caused by enlarged lymph nodes, tumors, abscess, trauma^146,147,148 and acute carotid thrombosis.¹⁴⁹ Horner's syndrome with associated ipsilateral neck, facial, or orbital pain¹⁵⁰ and, less frequently, amaurosis fugax, disagreeable taste (dysgeusia),¹⁵¹ or facial numbness and dysesthesia,¹⁵² strongly suggests spontaneous internal carotid artery dissection. Bougousslavsky et al.¹⁵³ reported the presence of Horner's syndrome in 20% of their patients with spontaneous carotid dissection. Biousse et al.¹⁵⁴ studied 146 consecutive patients with extracranial internal carotid dissection and found 52% had ophthalmic findings that were initial manifestations of dissection. Fourty-five percent of patients had painful Horner's syndrome, and this remained an isolated finding in 50% of these cases. Hydroxyamphetamine 1% provides rapid corroboration of a postganglionic (third-order neuron) level lesion, and cerebral angiography or—less invasively and perhaps preferably—cervical magnetic resonance imaging is diagnostic^156,157 (Fig. 16).

At the level of the brachial plexus, the sympathetic fibers may be damaged by birth trauma, and Horner's syndrome may accompany Klumpke's paralysis of the ipsilateral arm. Perinatal neck trauma is the proposed mechanism of a congenital postganglionic oculosympathetic lesion with associated carotid artery fibromuscular dysplasia.¹⁵⁷ It is possible that most congenital Horner's syndromes originate from trauma sustained during labor or delivery (Fig. 15). Rarer causes, such as congenital varicella syndrome, and neuroblastoma¹⁵⁸ and internal carotid agenesis,¹⁵⁹ have also been described. Neoplastic infiltration or disruption of the cervical sympathetics also may result in Horner's syndrome. These tumors include schwannoma,^160,161 neuroblastoma,^162,163 paraganglionoma^164,165 and chordoma,¹⁶⁶ benign and malignant thyroid tumors, and lymphomas.

Iatrogenic causes of Horner's syndrome occur typically within the neck and account for 10% to 18.5% of all cases. Eighty-four percent of these cases involve the second-order neuron.¹⁶⁷ Iatrogenic injuries include internal carotid stenting,¹⁶⁸ internal jugular catheterization,¹⁶⁹ carotid endarterectomy,¹⁷⁰ radical neck dissection, cervical sympathectomy, and thyroidectomy.¹⁷¹

When Horner's syndrome is caused by lesions of the base of the skull or cavernous sinus, the accompanying cranial neuropathies frequently make localization possible. The coexistence of a postganglionic Horner's syndrome and ipsilateral abducens palsy should suggest a cavernous sinus lesion (Fig. 17). Parkinson¹⁷² has provided an illustration of the theoretic location for such a lesion, where the intracavernous oculosympathetic temporarily run with the abducens nerve before joining the first division of the trigeminal division. Parkinson's syndrome—a Horner's and abducens nerve palsy in the absence of other cranial neuropathies—is clinically uncommon but has been documented with trauma, intracavernous carotid aneurysm, and metastasis.^173,174

In an adult outpatient ophthalmology setting, isolated postganglionic oculosympathetic defects are most frequently the result of third-order neuron lesions, including status postendarterectomy, other neck surgery or trauma, or in the context of vascular headaches of the “cluster” type. Although the cause is inconclusive, undetected carotid disease is presumed. In cadaver studies, superior cervical ganglion compression has been demonstrated, caused by tortuous atherosclerotic internal carotid artery that, at times, produced actual indentation of the ganglion (Fig. 18); perhaps this mechanism accounts for a benign postganglionic Horner's syndrome in elderly patients. Another autopsy study¹⁷⁵ disclosed that some internal carotid arteries give off small-caliber branches in their extracranial segments within 3 cm from base of the skull. Typically, these branches were associated intimately with the sympathetic carotid plexus, and the authors suggested that isolated Horner's syndrome may result from interruption of small caliber arterial branches arising from the carotid, supplying the sympathetic plexus. Postganglionic oculosympathetic lesions do not include anhidrosis but only ptosis and miosis. Unilateral recurrent cranial or facial pain in the trigeminal distribution, in combination with a third-order Horner's syndrome, constitutes a common enough variant of vascular-mediated headaches, the Raeder's syndrome. When not accompanied by para-sellar cranial nerve deficits, this headache syndrome is likely to follow a benign course, with resolution within a few months.¹⁷⁶

Whether first, second, or third-order sympathetic lesions are encountered most frequently is a function of whether outpatient ophthalmologic or inpatient neurologic data are assayed. Several authors have reported on their series.^{177,178,179,180,181} Giles and Henderson's¹⁷⁸ retrospective review of 216 patients from the University of Michigan Hospital suggests that most frequently Horner's syndrome is due to tumors. In this study tumors occurred in about one-third of all patients and in more than half of patients with a known cause for Horner's syndrome. Of all tumors, about three-fourths were malignant and most were due to lesions in the neck, involving either the preganglionic or extracranial postganglionic sympathetic chain; about 10% of the cases were localized to the first-order neuron. In contradistinction, Keane's¹⁸⁰ neurologic series of 100 hospitalized patients, most (approximately two-thirds) Horner's syndromes were first-order neuron lesions, mostly stroke related. About one-fourth of the cases were preganglionic and an eighth were postganglionic; of all cases with a known cause, approximately one-fourth were due to tumors, about two-thirds of which were preganglionic and one-third postganglionic. Grimson and Thompson's¹⁷⁹ 120 cases were rarely due to a central lesion; of all cases with a known etiology, close to one half were preganglionic. More than one-third were postganglionic, and only a minority were of central origin. In this series, about half of all preganglionic lesions were due to neoplasia, whereas postganglionic lesions were mostly caused by vascular headache or head trauma.

The subject population of Maloney et al.¹⁸¹ consists of both inpatients and outpatients. Forty percent of the 450 patients studied had no known cause for the oculosympathetic defect. Of 270 patients with known cause of Horner's syndrome, Maloney found a minority to be central (13%) and about an equal number to be preganglionic (43%) and postganglionic (44%). Whereas 13% of the 450 patients had tumors, 3% had occult malignancies. This suggests that it is rare for Horner's syndrome to be the presenting sign of an occult malignancy.

In the pediatric population, the implications of Horner's syndrome may be more ominous because Horner's syndrome can be an important ocular sign of neuroblastoma¹⁸² and is often associated with a severe underlying disease, such as tumor metastasis, leukemia, lymphoma, or aneurysm.¹⁸³ Some authors have suggested that routine diagnostic imaging is unneccesary in isolated Horner's syndrome.¹⁶³ However, localization using facial flushing (Harlequin sign) and pharmacologic testing may yield conflicting results in congenital cases.¹³⁶ Therefore, unless an obvious and plausible precipitant precedes the occurrence of Horner's syndrome, such as chest surgery, we recommend vigorous investigation. These should include neuro-imaging and 24-hour urinary catecholamine measurement to look for possible neuroblastoma.¹⁸⁴

Thus, in the evaluation of patients with Horner's syndrome, the most important clues to diagnosis are the clinical history and the accompanying neurologic signs and symptoms. When combined with cranial nerve palsies or other localized signs and symptoms, sympathoparesis is often caused by tumor, trauma, or vascular disease. If any doubt exists about whether a patient has a false or true Horner's syndrome,⁶⁰ the cocaine test should be performed. If the clinical assessment shows a Horner's syndrome to be an isolated finding, 1% hydroxyamphetamine is instilled in both eyes to pharmacologically distinguish a postganglionic lesion from a preganglionic or central one. In neonates and in the pediatric population, an isolated Horner's syndrome not considered congenital requires further assessment to search for neuroblastoma or other underlying malignancy. In adults, truly isolated postganglionic lesions often remain unexplained: these are presumed to be of vascular origin and are compatible with a benign course. Isolated preganglionic Horner's lesions in adults require further investigation, with special attention to the pulmonary apex and chest. Appropriate consultations and radiologic studies (lordotic X-ray views of the chest, mediastinal computed tomography cervical spine images) should be obtained. Several authors have provided guidelines for selective imaging of patients with oculosympathetic lesions.^185,186

A mydriatic pupil, unresponsive to light or near reflex, occurring as an isolated sign unaccompanied by ptosis or any oculomotor dysfunction, is almost always caused by inadvertent or factitious application of a pharmacologic agent. Table 8 gives a list of common mydriatic agents and their duration of action. Intravenous lidocaine and accidental instillation of lidocaine with epinephrine have been observed to cause pupillary dilatation.^187,188 Ipratropium bromide used as a metered aerosol, likewise, may cause mydriasis.¹⁸⁹ Medical personnel, including nurses, physicians, and pharmacists, are especially liable to accidental instillation of mydriatic agents (Fig. 19), which more often than not also lead to cycloplegia, photophobia, and even a headache. These signs and symptoms should not be construed as an ominous warning of intracerebral disease.

TABLE 8. Common Mydriatic and Cycloplegic Agents: Times for Maximum Effect and Duration of Action

Accidental instillation of the fluid of many plants that contain belladonna and atropine-like alkaloids, such as jimson weed and angel's trumpet,¹⁹⁰ have parasympatholytic action and may cause mydriasis. Exposure to certain insecticides, especially in children, may result in mydriasis.^{191,192,193,194} Frequently, associated intercurrent signs, such as altered consciousness, seizures, shock, arrhythmias, and respiratory depression, may also occur.^191,193,194 Mydriasis may be used as a sign of adequate response to atropine therapy following anticholinesterase insecticide intoxication.¹⁹⁵ Since the introduction of retroauricular scopolamine patches for motion sickness, reports have appeared about associated unilateral mydriasis (196, 197, 198).^196,197,198 This probably occurs as a result of finger contamination with scopolamine, followed by inadvertent eye contact. Perfumes and cosmetics may also contain agents capable of dilating the pupil.

On occasion, both young and elderly patients intentionally apply a mydriatic agent to the eye and subsequently deny such a maneuver. Thompson¹⁹⁹ reviewed the problem of the fixed dilated pupil and pointed out the practicality of identifying pharmacologic mydriasis by the use of weak solutions of miotics. If pilocarpine (1%) is instilled in an eye with a dilated pupil because of parasympathetic denervation (e.g., oculomotor palsy, tonic pupil), prompt miosis occurs. However, pilocarpine miosis is diminished or absent in patients with pharmacologic mydriasis (see Fig. 19). Both eyes should be subjected to pilocarpine instillation, with the normal eye serving as a control.

Intraocular iron foreign bodies can lead to fixed dilated pupils, even before the development of heterochromia or visual loss. In a report of two such cases, the patients, both young boys, failed to report their past ocular injuries.²⁰² A dilated, atonic pupil can rarely develop after uncomplicated penetrating keratoplasty or cataract extraction.²⁰³ Whether keratoplasty or cataract surgery, the history of onset after intraocular surgery and failure to constrict with pilocarpine (1%) should distinguish these pupils from typical tonic pupil syndrome.²⁰³ A rare clinical syndrome consisting of a fixed dilated pupil, iris atrophy, and glaucoma, known as Uretts-Zavalia syndrome, has been observed following penetrating keratoplasty and deep lamellar keratoplasty for keratoconus.²⁰⁴ In one small series excimer laser keratoplasty has also been associated with postoperative mydriasis.²⁰⁵ The degree of anisocoria did not correlate with laser energy, ablation depth, or refractive correction.

Episodic unilateral mydriasis, lasting minutes to weeks and usually accompanied by blurred vision and headache, has been reported and reviewed by Hallett and Cogan.²⁰⁶ This periodic phenomenon remains controversial and, most of the time, is not entirely free of suspicion of pharmacologic misadventure. However, there remain “pure” cases that lend credence to this dramatic if unexplained pupillary phenomenon (i.e., the “springing pupil”). A clinical pattern may be defined as follows:

1. brief, episodic, unilateral mydriasis occurring in young, otherwise healthy, females;
   
2. peculiar sensations in and about the affected eye, often progressing to headache (but not typical migraine); and
   
3. defective accommodation, but without any other signs of lid or extraocular muscle dysfunction.
   

Transient pupillary distortion with segmental iris dilator spasm has been reported by Thompson²⁰⁷ and termed tadpole pupil. The condition probably represents a subset of the larger group of patients who carry the less precise diagnosis of springing pupil. The clinical pattern and prognosis of patients with tadpole pupil appear to be similar to those described previously.

Periodic unilateral pupil dilation has been reported in association with migraine.^{207,208,209,210,211} Suggested causes for the periodic mydriasis include transient sympathetic hyperactivity²⁰⁷ or transient parasympatholytic activity^209,210 or both,²¹² perhaps as a variant of ophthalmologic migraine. Oculosympathetic spasm has been observed several months after spinal cord injury,²¹³ and, according to the authors, the pupillary dilation, brought on by elevation and stretch of the ipsilateral arm or leg, possibly represents a localized form of autonomic hyperreflexia.

Because a fixed dilated pupil in an unconscious patient is usually interpreted as a sign of temporal lobe herniation or aneurysmal compression, it should be noted that transient unilateral mydriasis on occasion may accompany convulsive disorders in children^214,215 or in adults.²¹⁶

As discussed previously, the neural pathways controlling the near reflex and accommodation are not defined precisely. As a rule, in those disorders that interrupt the parasympathetic supply to the pupil sphincter, accommodation is also defective because of denervation of the ciliary musculature. In certain situations, however, where the convergence–accommodation mechanism is faulty, pupillary reflexes are spared or minimally involved.

The accommodative power of the eye is difficult to assess because of the subjective nature of the end point and the great dependency on cooperation of the patient. A unilateral accommodative deficiency is easier to define because the uninvolved eye serves as a normal “control.” Accommodation is usually measured in terms of near point: the shortest distance from the naked eye at which an accommodative target can no longer be focused and appears blurred. Alternatively, the maximum power of minus lenses that the eye can overcome to see clearly with best-corrected distance acuity may be used.

The most common defect of accommodation is presbyopia and is related to aging. Currently, it is thought to result from progressive thickening and stiffness of the lens, which changes its refractive power with age. However, the degree to which the aging lens and other factors, such as changes in the ciliary muscle and declining accommodative convergence, contribute to presbyopia has yet to be determined. In the presbyopic eye, accommodation is difficult to assess and unilateral defects are rare. Unilateral or asymmetric lens opacities or brunescence, however, may present with “accommodative” symptoms, but slit-lamp examination quickly resolves this diagnostic dilemma.

Occasionally, rapid changes in the refractive power of the eyes take place during poorly controlled diabetes mellitus, with resulting increase in the refractive index of the lenses. In this case, the patient becomes more myopic and reports blurring of distant vision; however, presbyopic patients may suddenly be able to read without the aid of bifocals. This situation should immediately suggest a state of hyperglycemia.

Defective accommodation almost always accompanies pupillotonic syndromes and also peripheral oculomotor nerve palsies, in which instance blurred vision is the least dramatic aspect and may go unnoticed by both the patient and the physician. Local ocular disease, traumatic, inflammatory, or otherwise, need not be discussed.

Many individuals complain of rather vague problems of “focusing” the eyes, and, as a rule, nothing is found. Fortunately, these patients are usually well equipped with other aches, pains, and ill-defined asthenopic symptoms. In some instances, however, symptoms of accommodative and convergence insufficiency appear to be valid residue of cerebral concussion or cervicocranial hyperextension injury (“whiplash”). These symptoms may extend from weeks to years in duration and are, at times, miraculously relieved by litigation settlements. Here the physician is at the mercy of variations in patient cooperation and strictly subjective end points. It may be impossible to separate the patient with true posttraumatic accommodative–convergence insufficiency from the dissembler, unless objective signs are present or a positive response to therapy excludes the latter possibility.

Paralysis of accommodation classically occurs in children with diphtheria, a disorder encountered rarely in the United States. Postdiphtheritic paralysis is attributed to a demyelinating toxin with a special predilection for cranial nerves. Contamination of food with Clostridium botulinum is responsible for a serious form of food poisoning (i.e., botulism). Typically, botulism is caused by ingestion of toxin that has been produced in contaminated foods. In infants and rarely in adults, botulism can also be caused by in vivo toxin production after colonization of the gastrointestinal tract by C. botulinum organisms.²¹⁷ The elaborated exotoxin interferes with cholinergic transmission, resulting in the clinical picture, similar to insecticide poisoning, of an alert patient with dilated nonreactive pupils, accommodative paralysis, dry mouth, and respiratory distress. Tyler²¹⁸ has pointed out that only one-third of patients experience an acute gastrointestinal episode (nausea, vomiting, and diarrhea). Dizziness, headache, blurred vision, diplopia, and swallowing difficulties should alert the physician to the possibility of botulism.²¹⁹

The pupillary and ciliary musculature may be paretic in the ophthalmoplegic form of acute idiopathic polyneuritis. Clinical involvement of the internal ocular muscles in myasthenia probably does not occur, although this is a controversial subject. The presence of internal ophthalmoplegia, as a rule, makes a diagnosis of ocular myasthenia untenable (unless the patient has another cause of the internal ophthalmoplegia).

Rostral–dorsal midbrain lesions may result in a state of spastic–paretic accommodation, usually accompanied by moderately dilated, light-near dissociated pupils, upgaze palsy, and retraction nystagmus (the periaqueductal syndrome). When shifting gaze from distance to near, accommodation is paretic; on attempted upward gaze, accommodative spasms occur such that distant vision is blurred because of momentary myopia (see previous discussion of periaqueductal syndrome).

Spasm of the near reflex may be associated with organic disease.^220,221,222 However, even then there may be an element of functional disturbance superimposed on the organic process. In most instances, spasms of accommodation are of functional origin. Some degree of convergence excess is common, such that an esotropic deviation may mimic a unilateral or bilateral abduction deficiency (Fig. 20). Pupils that become constricted on lateral gaze attempts should be the clue to such hysterical “spasm of the near reflex.” Atropinization, nonspecific “eye exercises,” time, and litigation settlements may all have salutary effects.

Systemic agents may enhance or retard accommodation. Transient myopia (and thus enhanced accommodation) may occur as a toxic reaction to sulfa-derived drugs (including sulfonamides and acetazolamide), tetracycline, prochlorperazine (Compazine), promethazine (Phenergan), autonomic blocking agents used to treat hypertension,²²³ diuretics, isoretinon,²⁰¹ and isosorbide dinitrate (Isordil), an organic nitrate used to treat angina.²²⁴ Accommodative insufficiency may result from administration of systemic drugs, such as anticholinergics (atropine and scopolamine) antihistamines, chloroquine, tricyclic antidepressants, and phenothiazines (especially when used with benztropine). Because the lacrimal gland receives parasympathetic innervation, drugs with intrinsic anticholinergic activity may further induce blurred vision by way of corneal desiccation.²⁰¹

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