748 CLINICAL NEURO-OPHTHALMOLOGY gia, paralysis of vertical gaze, loss of convergence, exotro- EFFERENT ABNORMALITIES: ANISOCORIA pia, ptosis, and other defects of ocular movement. The presence of anisocoria usually indicates a structural defect of one or both irides or a neural defect of the efferent Paradoxical Reaction of the Pupils to Light and pupillomotor pathways innervating the iris muscles in one Darkness or both eyes. A careful slit-lamp examination to assess the health and integrity of the iris stroma and muscles is an Barricks et al. described three unrelated boys, 2, 6, and important step in the evaluation of anisocoria. If the irides 10 years of age, with congenital stationary night blindness, are intact, then an innervation problem is suspected. As most myopia, and abnormal electroretinograms, who showed a efferent disturbances causing anisocoria are unilateral, two ‘‘paradoxical’’ pupillary constriction in darkness (108). In simple maneuvers are helpful in determining whether it is a lighted room, all three patients had moderately dilated pu- the sympathetic or parasympathetic innervation to the eye pils; however, when the room lights were extinguished, the that is dysfunctional: (1) checking the pupillary light reflex patients’ pupils briskly constricted and then slowly redilated. and (2) measuring the anisocoria in darkness and in bright Subsequent investigators confirmed this observation and re- light. ported similar paradoxical pupillary responses in children When the larger pupil has an obviously impaired reaction and adults with congenital achromatopsia, blue-cone mono- to light stimulation, it is likely the cause of the anisocoria. chromatism, and Leber congenital amaurosis (109,110). In One can presume the problem lies somewhere along the addition, such responses occasionally occur in patients with parasympathetic pathway to the sphincter muscle. Common optic disc hypoplasia, dominant optic atrophy, and bilateral etiologies include an acute tonic pupil, oculomotor nerve optic neuritis. Flynn et al. suggested that the pupillary re- palsy, or pharmacologic blockade. If both pupils have a good sponses seen in these patients occur not from abnormalities light reflex and the degree of anisocoria decreases in bright in the central nervous system (CNS) but from selective de- light (i.e., anisocoria is greater in darkness), then there is lays in afferent signals from the retinal photoreceptors to the either a deficit of sympathetic innervation to the dilator mus- pupillomotor center (111). cle in the eye with the smaller pupil (as in Horner syndrome) Figure 16.5. Steps that assist the evaluation of anisocoria. DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 749 or a physiologic anisocoria. The evaluation of anisocoria is album, can be a valuable diagnostic tool (Fig. 16.7). In the described in the following sections and outlined in Figure latter case, the anisocoria usually can be traced back to in- 16.5 fancy or early childhood. Anisocoria Greater in Darkness Horner Syndrome Physiologic (Benign) Anisocoria When the sympathetic innervation to the eye is inter- rupted, the retractor muscles in the eyelids are weakened, Inequality of pupil size becomes clinically observable allowing the upper lid to droop and the lower lid to rise. when the difference between pupils is about 3 mm. In dim The dilator muscle of the iris also is weakened, allowing light or darkness, almost 20% of the normal population has the pupil to become smaller, and vasomotor and sudomotor an anisocoria of 0.4 mm or more at the moment of examina- control of parts of the face may be lost. This combination tion. In room light, this number drops to about 10% of ptosis, miosis, and anhidrosis is called Horner syndrome (112–114). This form of anisocoria is known by several (Fig 16.8) names, including physiologic anisocoria, simple central ani- socoria, essential anisocoria, and benign anisocoria. It is HISTORICAL BACKGROUND typically 0.6 mm or less; a difference in size of 1.0 or more is rare (114–116) (Fig. 16.6). The degree of pupillary ine- In 1869, Johann Friedrich Horner, a Swiss ophthalmolo- quality in physiologic anisocoria may change from day to gist, published a short case report in which he emphasized day or even from hour to hour, however. The anisocoria that eyelid ptosis could be caused by a lesion as far away usually diminishes slightly in bright light, perhaps because from the eye as the neck by denervating the sympathetically the smaller pupil reaches the zone of mechanical resistance innervated muscle in the upper lid that had recently been first, giving the larger pupil a chance to make up the size described by H. Mu¨ller. Although he was not the first to difference (117). report the clinical condition, his meticulous and scientifically Physiologic anisocoria is not caused by damage to the substantiated account of the clinical effects of cervical sym- peripheral nerves that innervate the sphincter and dilator pathetic paralysis has firmly attached his name to this syn- muscles of the iris. The pupillary reactions to light and dark- drome (118). In the French literature, this condition is called ness are normal. Instead, it is presumed to occur because the Claude Bernard-Horner syndrome to honor the work of the supranuclear inhibition of the parasympathetic pupillo- Claude Bernard in 1852 on the physiology of the sympa- constrictor nuclei in the midbrain is not balanced with any thetic nerves. more precision than is necessary for clear, binocular vision. Although Horner and Bernard generally are credited with It is unrelated to refractive error. Occasionally, a reversal of identifying the clinical signs of oculosympathetic paresis, physiologic anisocoria is seen, a phenomenon termed ‘‘see- these signs were first produced experimentally in the dog saw anisocoria’’ (112,116). by Franc¸ois Pourfour du Petit in 1727. Pourfour du Petit was When physiologic anisocoria is suspected, reviewing old never recognized for these contributions; however, Pourfour photographs, such as a driver’s license or especially a family du Petit syndrome is the term used for the combination of Figure 16.6. Physiologic (benign) anisocoria. The patient was a 5-year-old boy whose parents noted that the right pupil was larger than the other. The anisocoria was more obvious in dark than in light, and both pupils reacted normally to light stimulation. A, Appearance of the patient. Note anisocoria with right pupil larger than left. B, 45 minutes after instillation of a 10% solution of cocaine into both inferior conjunctival sacs, both pupils are dilated, indicating that anisocoria is not caused by sympathetic denervation. 750 CLINICAL NEURO-OPHTHALMOLOGY Figure 16.7. Value of old photographs in the assessment of anisocoria. A, This 3-year-old boy was noted by his parents to have intermittent anisocoria, with the right pupil larger than the left. The anisocoria was greater in darkness than in light, and both pupils reacted normally to light stimulation. B, Photograph of patient at age 7 months shows obvious anisocoria. signs caused by sympathetic stimulation (i.e., lid retraction, usually is slightly elevated, producing an ‘‘upside-down pto- mydriasis, and conjunctival blanching). This eponym is re- sis,’’ further narrowing of the palpebral fissure, and an ap- markable because Pourfour du Petit never actually stimu- parent enophthalmos. That the enophthalmos is apparent lated the sympathetic nerve in his experimental animals rather than real has been confirmed by several studies (119). (119,121,122). Pupillary Signs. Miosis. The palsy of the iris dilator CLINICAL CHARACTERISTICS muscle in Horner syndrome allows unantagonized action of the iris sphincter, producing a smaller pupil. However, in Ptosis. The affected eye often looks small or sunken in some patients in the setting of intense emotional excitement, patients with Horner syndrome. The upper eyelid is slightly the pupil on the side of the sympathetic lesion becomes drooped because of paralysis of the sympathetically inner- larger than the normal pupil. Likewise, if the dilator muscle vated smooth muscle (Mu¨ller muscle) that contributes to the is stimulated directly (e.g., after an adrenergic eye drop is position of the opened upper eyelid. This ptosis sometimes used), the pupil will dilate widely. This ‘‘paradoxical pupil- is so slight and variable that it escapes attention. In one lary dilation’’ is caused by denervation supersensitivity of study, ptosis was frankly absent in 12% of patients (120). the dilator muscle to circulating and topical adrenergic sub- Similar smooth muscle fibers in the lower eyelid also lose stances. their nerve supply in Horner syndrome; thus, the lower lid Topical apraclonidine is an alpha-adrenergic receptor ago- Figure 16.8. Horner syndrome in two patients. A, Congenital right Horner syndrome. Note associated heterochromia iridis and minimal ptosis. B, Left Horner syndrome after neck trauma. DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 751 nist that has little or no effect on a normal pupil but can eyes tangentially from below with a hand-held flashlight, dilate a Horner pupil due to denervation supersensitivity of and then abruptly turning the room lights out. The normal the alpha-1 receptors on the iris dilator muscle. Thus, rever- pupil will immediately dilate, but several seconds will elapse sal of anisocoria following topical instillation of apracloni- before the Horner pupil begins to dilate. The dilation dynam- dine has been seen in patients with unilateral Horner syn- ics of a normal pupil compared with a Horner pupil have drome (123,124). been well documented using continuous recording pupillog- Anisocoria. Any anisocoria, when caused by weakness raphy (119). Immediately following a bright light flash, both of a single iris muscle, increases in the direction of action pupils are strongly constricted. In the first second of dark- of that muscle. With a unilateral oculosympathetic defect, ness, both pupils synchronously enlarge a small degree, pre- the weakness of the dilator muscle in the affected eye (and sumably from acute inhibition of parasympathetic impulses.