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CHAPTER 16
Disorders of Pupillary Function,
Accommodation, and Lacrimation
Aki Kawasaki
DISORDERS OF THE PUPIL DISORDERS OF LACRIMATION Structural Defects of the Iris Hypolacrimation Afferent Abnormalities Hyperlacrimation Efferent Abnormalities: Anisocoria Inappropriate Lacrimation Disturbances in Disorders of the Neuromuscular Junction Drug Effects on Lacrimation Drug Effects GENERALIZED DISTURBANCES OF AUTONOMIC FUNCTION Light–Near Dissociation Ross Syndrome Disturbances During Seizures Familial Dysautonomia Disturbances During Coma Shy-Drager Syndrome DISORDERS OF ACCOMMODATION Autoimmune Autonomic Neuropathy Accommodation Insufficiency and Paralysis Miller Fisher Syndrome Accommodation Spasm and Spasm of the Near Reflex Drug Effects on Accommodation
In this chapter I describe various disorders that produce dysfunction of the autonomic nervous system as it pertains to the eye and orbit, including congenital and acquired disorders of pupillary function, accommodation, and lacri-
DISORDERS OF THE PUPIL
The value of observation of pupillary size and motility in the evaluation of patients with neurologic disease cannot be overemphasized. In many patients with visual loss, an abnormal pupillary response is the only objective sign of organic visual dysfunction. In patients with diplopia, an im- paired pupil can signal the presence of an acute or enlarging intracranial mass. An adequate clinical examination of the pupils requires little time and can be meaningful when ap- proached with a sound understanding of the principles of pupillary innervation and function. In most cases, one needs only a hand light with a bright, even beam, a device for measuring pupillary size (preferably in half-millimeter steps), a few pharmacologic agents, and an examination room that permits easy control of the background illumina- tion. This section commences with an overview of congenital and acquired diseases of the iris that affect pupil size, shape,
739
mation. Although many of these disorders are isolated phenomena that affect only a single structure, others are systemic disorders that involve various other organs in the body.
and reactivity because these structural defects may be the cause of ‘‘abnormal pupils’’ and often are easy to diagnose at the slit lamp. Furthermore, if a preexisting structural iris defect is present, it may confound interpretation of the neuro- logic evaluation of pupillary function; at the very least, it should be kept in consideration during such evaluation.
STRUCTURAL DEFECTS OF THE IRIS
Congenital Defects
Aniridia
Aniridia is a rare congenital abnormality in which the iris is partially hypoplastic or completely absent (1,2) (Fig. 16.1 A ). Patients with aniridia initially may be thought to have fixed, dilated pupils until a more careful examination is performed. In almost all cases, histologic or gonioscopic
740 CLINICAL NEURO-OPHTHALMOLOGY
Figure 16.1. Iris anomalies that may simulate neurologic pupillary abnormalities. A , Aniridia. Note associated upward lens dislocation. B , Typical iris coloboma. C , Acquired corectopia in iridocorneal–endothelial adhesion syndrome. D , Persistent pupillary membrane. E , Pseudopolycoria from iridocorneal–endothelial adhesion syndrome. F , Heterochromia iridis in a patient with congenital Horner syndrome. The lighter iris is in the eye with Horner syndrome. ( A and B , Courtesy of Dr. Irene H. Maumenee. C , Courtesy of Dr. Harry A. Quigley. D, From Gutman ED, Goldberg MF. Persistent pupillary membrane and other ocular abnormalities. Arch Ophthalmol 1976;94156–157. E, Courtesy of Dr. Harry A. Quigley.)
742 CLINICAL NEURO-OPHTHALMOLOGY
Peninsula Pupils
Bosanquet and Johnson reported 40 patients from New- foundland and Labrador with an unusual form of partial iris sphincter atrophy that resulted in an oval pupil (17). The condition, called peninsula pupils, was bilateral in most cases. The anomaly was confined to the iris, and there were no associated systemic disorders. Most of the affected indi- viduals were male, and all had blue irides. Three of the pa- tients believed that their pupils had been large and oval since birth. This pupillary anomaly may be an inherited trait pecul- iar to the Newfoundland-Labrador region.
Ectopic (Misplaced) Pupils
Misplaced or ectopic pupils (corectopia, ectopia pupillae) are observed frequently. Isolated ectopic pupils may be in- herited as either a dominant or a recessive trait. The condi- tion usually is usually bilateral and symmetric (18). Al- though the pupils may be displaced in any direction, they often are up and out from the center of the cornea. Such displacement of the pupils is frequently associated with ec- topia lentis, congenital glaucoma, microcornea, ocular colo- boma, and high myopia (19). Ectopic pupils also occur in some patients with albinism and some patients with Axen- feld-Rieger anomaly. In addition, three families were re- ported in which affected members had ectopic pupils, ptosis, and ophthalmoplegia (20–22). Although acquired corectopia may occur in patients with severe midbrain damage, the clinical setting and the variabil- ity of the acquired defect usually allow the physician to dis- tinguish easily between the congenital and acquired forms (23–25). Similarly, the corectopia that occurs during the course of purely ocular disorders such as the iridocor- neal–endothelial (ICE) adhesion syndromes and posterior polymorphous corneal dystrophy should be differentiated easily from congenital and neurologic corectopia by the clin- ical setting and the associated ocular signs (Fig. 16.1 C ).
Persistent Pupillary Membrane Remnants
Persistent pupillary membrane remnants are vestiges of the embryonic pupillary membrane that can appear as thread- like bands running across the pupillary space and attaching to the lesser circle of the iris (26,27) (Fig. 16.1 D ). Occasion- ally, such remnants are attached to the lens and may be associated with an anterior capsular cataract. Persistence of the entire membrane can block visual input, but most cases are visually insignificant. Excision of the membrane has been performed in young patients who are at risk for ambly- opia and in others with visual impairment during pupillary constriction (e.g., in bright sunlight) (28).
Polycoria and Pseudopolycoria
In true polycoria, the extra pupil or pupils are equipped with a sphincter muscle that contracts on exposure to light (29). This is an extremely rare condition. Most additional pupils are actually just holes in the iris without a separate sphincter muscle. This pseudopolycoria may be a congenital disorder, such as an iris coloboma or persistent pupillary
membrane, or it may be part of one of several syndromes characterized by mesodermal dysgenesis (30). A distinctive feature of pseudopolycoria is passive constriction, distortion, or even occlusion of the accessory pupil when the true pupil is dilated (31). More commonly, pseudopolycoria occurs as an acquired disorder from direct iris trauma including sur- gery, photocoagulation, ischemia, or glaucoma or as part of a degenerative process such as the ICE syndrome (Fig. 16.1 E ).
Congenital Miosis
Congenital miosis usually is bilateral and characterized by extremely small pupils that react slightly to light stimuli and dilate poorly after instillation of sympathomimetic agents (32,33). The anomaly appears to result from congeni- tal absence of the iris dilator muscle. Additionally, the iris sphincter muscle may be contracted excessively because of the lack of counterpull normally supplied by the dilator mus- cle. Congenital miosis may occur sporadically or may be inherited. Most of the inherited cases are transmitted as an autosomal-dominant trait, although pedigrees with autoso- mal-recessive inheritance have been reported (34,35). Congenital miosis may be an isolated phenomenon, or it may be associated with other ocular abnormalities, including microcornea, iris atrophy, myopia, and anterior chamber angle deformities (32). In addition, congenital miosis can occur in patients with systemic disorders. Patients with con- genital miosis also may have albinism, the congenital rubella syndrome, the oculocerebrorenal syndrome of Lowe, Marfan syndrome, or multiple skeletal anomalies (33,36–39). Con- genital miosis was noted in four members of a family with hereditary spastic ataxia, and it is one of the main features in Stormorken syndrome, a dominantly inherited metabolic disorder also characterized by bleeding tendency, thrombo- cytopathia, muscular weakness, postexertional muscle spasms, ichthyosis, asplenia, dyslexia, and headache (40).
Congenital Mydriasis
Congenital mydriasis may be similar to or identical with the condition described above as square pupils. This condi- tion may be difficult to distinguish from aniridia unless a careful ocular examination is performed. Caccamise and Townes described a 73-year-old woman with bilaterally large, round pupils that were present from birth (41). The condition appeared to have been inherited as an autosomal- dominant trait, although all other affected family members were female. Both pupils constricted to topical 4% pilocar- pine solution, suggesting an intact iris sphincter muscle, and both pupils dilated rapidly to topical 10% phenylephrine so- lution, indicating an intact iris dilator muscle. However, nei- ther pupil reacted to a potent topical cholinesterase inhibitor, suggesting an abnormality of acetylcholine production at the parasympathetic neuromuscular junction. Magnetic resonance (MR) imaging has shown an enlarged fourth ventricle and atrophy of the cerebellar vermis in one case report of congential mydriasis (42). In another patient with bilateral congenital mydriasis and absent accommoda- tion, the pupils did not react to light, lid closure, or adminis-
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 743
tration of topical 1% pilocarpine solution; however, both pupils dilated further after topical administration of 2.5% phenylephrine (43). A patient with the Waardenburg syn- drome who had a unilateral, congenitally fixed, dilated pupil has been reported (44). Pharmacologic studies in this patient suggested the possibility of congenital agenesis of the iris sphincter muscle.
Congenital Abnormalities of Iris Color
The color of the iris depends on the pigment in the iris stroma. In albinism, there is failure of mesodermal and ecto- dermal pigmentation. Consequently, the iris has a transpar- ent, grayish-red color and transilluminates readily. In a number of congenital and acquired conditions, the iris of one eye differs in color from the iris of the other eye. In other instances, one iris is entirely normal, and a part of the iris in the opposite eye has a different color than the rest of the iris surrounding it (iris bicolor). These abnormalities, collectively called heterochromia iridis, may occur ( a ) as an isolated congenital anomaly; ( b ) in association with other ocular abnormalities, such as iris or optic disc coloboma; ( c ) in association with systemic congenital abnormalities, as in patients with the Waardenburg syndrome, congenital Horner syndrome, or incontinentia pigmenti; or ( d ) from an acquired ocular condition (45) (Fig. 16.1 F ). When iris heterochromia is part of a pathologic condition, it is neces- sary to determine which iris is abnormal. For example, the darker iris is abnormal in patients with a diffuse iris and ciliary body melanoma and in siderosis from an intraocular foreign body or vitreous hemorrhage. The lighter iris is pathologic in congenital Horner syndrome, in Fuchs heter- ochromic iridocyclitis, and after iris atrophy following a uni- lateral iritis or acute glaucoma.
Acquired Defects
Inflammation
Iritis or iridocyclitis in its acute stages produces swelling of the iris, miosis, and slight reddening of the circumcorneal tissues. The miosis of iritis results from the release of a neurohumor, substance P, that produces miosis through in- teraction with a specific receptor in the iris sphincter muscle (46). In patients with intraocular inflammation, dilation of the pupil with mydriatics may be difficult because of adhesions between the iris and the lens (posterior synechiae). These adhesions in chronic iritis may distort the shape of the pupil. They also may fix the pupil in a dilated position. Occasion- ally, the adhesions are not evident until the pupil is further dilated by a mydriatic. Such adhesions and black pigment on the lens suggest iritis, active or inactive. True neurogenic, paralytic mydriasis may occur as part of certain inflamma- tory disorders that affect the eye and orbit, such as herpes zoster.
Ischemia
Ischemia of the anterior segment of the globe may be acute or chronic. Both types can produce iridoplegia. Transient
dilation of the pupil may occur during an episode of monocu- lar amaurosis associated with carotid occlusive disease, mi- graine, or Raynaud disease. This unilateral pupillary change is not caused by the blindness but by the hypoxic process that affects the entire eye, including the iris sphincter. Em- boli that enter the central retinal artery frequently involve other branches of the ophthalmic artery, particularly the pos- terior ciliary arteries. If venous outflow from the globe is briefly impaired, the retina may shut down temporarily with- out producing an ipsilateral mydriasis. If the whole globe is ischemic (as in angle-closure glaucoma), iris ischemia will relax the iris sphincter and dilate the pupil (47). Chronic ischemia of the anterior segment of the globe results in neovascularization of the chamber angle and the surface of the iris (rubeosis iridis), producing iris atrophy, ectropion of the pigment layer at the pupillary margin (ec- tropion uveae), glaucoma, and immobility of the iris. This type of chronic ischemia of the anterior segment may result from severe occlusive disease in the carotid system or the aortic arch. It also may be produced by microvascular dis- ease or drug toxicity (e.g., quinine). Severe, generalized atherosclerosis may result in vascular insufficiency of both irides, producing oval pupils from bi- temporal palsy of the pupillary sphincters (48). Such patients have no evidence of iris atrophy or synechiae. Conversely, local iris ischemia was postulated to cause focal temporal atrophy of the iris and a nonreactive pupil in a patient with advanced keratoconus (49).
Tumor
Very few tumors affect the iris, but those that do can cause irregularity of the iris border, anisocoria, and an abnormally reactive pupil. Leiomyoma, malignant melanoma, and lym- phoma can all present in this fashion.
Trauma
Spastic miosis is a constant and immediate result of trauma to the globe and occurs immediately after blunt trauma to the cornea. A similar spastic miosis follows perfo- rating injury to the eye. The constriction of the pupil is pro- found but usually transient and often followed by iri- doplegia. Transient spasm of accommodation often occurs in this setting and lasts 1–2 hours. Dilation of the pupil frequently occurs after concussion of the globe and often is followed by paralysis of accommo- dation after the initial intense miosis has resolved. Because both the iris sphincter and dilator muscles are involved, the term ‘‘traumatic mydriasis’’ is misleading, as it suggests injury to the sphincter alone. The functions of the iris and ciliary muscle usually are affected together, but occasionally one is impaired without the other. The clinical picture is that of a moderately dilated pupil with both the direct and consensual reactions to light and near stimuli being dimin- ished or absent. The deformity may resolve in a few weeks, but it usually is permanent. This abnormality may have sev- eral causes. The frequent absence of detectable pathologic change suggests that the effect may occur from injury of the fine nerves of the ciliary plexus. These may be damaged or
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 745
Figure 16.4. Iris atrophy following several attacks of herpes zoster oph- thalmicus. (Courtesy of Dr. David L. Knox.)
ment dispersion syndrome and anisocoria had greater transil- lumination defects of the iris on the side of the larger pupil (51). Histologic studies of affected irides in patients with this syndrome show both atrophic and hypertrophic focal changes in the dilator muscle. The etiology of the anisocoria in these patients remains unclear; in some cases, it stems from an unrelated, coexisting condition such as a tonic pupil, Horner syndrome, or physiologic anisocoria. In others, the anisocoria may be a result of structural change or irritative stimulation of the iris due to pigment dispersion (51–53). With age, the iris may become gray and of a more uniform color. Its stroma becomes thin, and the sphincter appears as a gray-brown ring. Stromal fibers may be partly torn and may float in the anterior chamber (iridoschisis). Typical of the aged iris are changes on the edge of the pupil, which becomes thin and loses its pigment so that it resembles a fine lacework. Another characteristic finding easily seen by slit-lamp biomicroscopy in elderly persons is the deposition of hyaline about the pupillary margin (54). Histologic exami- nation of excised iris tissue in such cases shows deposition of hyaline in the iris stroma and in the muscles of the iris that also are atrophic.
Postoperative Mydriasis
In 1963, Urrets-Zavalia described several patients who suffered an irreversible mydriasis and pupillary immobility after an otherwise uncomplicated keratoplasty for keratoco- nus (55). In the typical case, a patient with keratoconus and a normally reacting pupil undergoes an uncomplicated pene- trating keratoplasty, following which the pupil dilates and will not react to miotics of any type or strength. The cause of this dilation is unknown, but certain patients may be pre- disposed to develop this disorder because of preexisting hy- poplasia of the iris stroma (56). In patients who develop microperforations in Descemet’s membrane during deep la- mellar keratoplasty, a fixed and dilated pupil can occur after the air/gas injection into the anterior chamber (57). The mechanism here is speculated to be induced pupil block
causing an acute rise of intraocular pressure and secondary iris ischemia. Postoperative mydriasis occasionally occurs after an otherwise uneventful cataract extraction with placement of an intraocular lens (58,59). It sometimes is called an ‘‘atonic pupil.’’ This condition presumably occurs from direct dam- age to the iris sphincter muscle during surgery. Surgical or laser-induced damage to the short ciliary nerves or ciliary ganglion can produce a postoperative tonic pupil. Affected patients show a mild mydriasis with anisoco- ria that is less than 1.0 mm. The most common setting is after excimer laser photorefractive keratectomy. The mechanism may be a medication effect of topical steroids on a suscepti- ble cornea. The mydriasis seems to improve with time in these cases (60).
AFFERENT ABNORMALITIES
Relative Afferent Pupillary Defect
The relative afferent pupillary defect (RAPD) is one of the most important objective signs of dysfunction in the afferent visual pathway. The methods of RAPD detection and quanti- fication were reviewed in Chapter 15. In this section, we discuss the various conditions that should be considered when one finds an RAPD.
Optic Nerve Disorders
Most patients with a unilateral or asymmetric bilateral optic neuropathy, regardless of the cause, have an RAPD (61). In general, the magnitude of an RAPD correlates with the extent of central visual field loss (62–64). The correla- tion is higher with compressive and ischemic optic neuropa- thies than with demyelinating optic neuritis (62,65). Patients with acute optic neuritis have a substantial RAPD (1.0–3. log units) (66). After recovery, even when there are no re- maining visual complaints, there often is a small RAPD (0.3–0.6 log units) still present in the affected eye. In optic nerve compression, the RAPD can be used as an additional test to monitor progression or recovery of optic nerve dam- age. Patients with glaucoma have an RAPD when the cup- ping and field loss is unilateral or asymmetric (67,68). Like- wise, patients with optic disc drusen have an RAPD when there is functional asymmetry of vision between the two eyes (68). Initial studies of patients with visual loss from Leber he- reditary optic neuropathy (LHON) found that their pupil re- sponses were not significantly different from those of normal persons and suggested that this visual–pupil dissociation was a characteristic finding of this optic neuropathy (69). Subsequent studies of patients with LHON, including those with clinical or electrophysiologic evidence of uniocular in- volvement, have demonstrated a pupil response deficit con- sistent with the visual deficit (70,71). Bremner et al. quanti- fied the focal pupil and visual sensitivity at various points within the visual scotoma of patients with LHON (72). A pupil deficit was detected at all test locations, but it was smaller than the corresponding visual deficit (about 7.5 dB difference; i.e., a relative pupil sparing). The authors hypoth-
746 CLINICAL NEURO-OPHTHALMOLOGY
esized that there may be a lower susceptibility of pupil fibers to damage in LHON. The RAPD appears to have some prognostic value in trau- matic optic neuropathy. In 19 patients with indirect traumatic optic neuropathy treated acutely with similar megadoses of methylprednisolone, patients who had an initial RAPD less than 2.1 log units improved to visual acuity of 20/30 or better. Patients with an initial RAPD larger than 2.1 log units showed little improvement of vision (73).
Retinal Disease
Diseases of the retina are uncommon causes of an RAPD. Most of the pupillomotor input derives from the central ret- ina, so in a suspected retinopathy, the presence of a RAPD usually indicates macular involvement (see Table 15.1). In macular visual loss with visual acuity of 20/200 or better, the RAPD usually is 0.5 log units or less. A RAPD greater than 1.0 log units with a lesion confined to the macula is unusual (74,75). Kerrison et al. demonstrated that in mon- keys with controlled laser destruction of the macula, approxi- mately 25–50% loss of ganglion cells was needed to produce a 0.6 log-unit RAPD (76). Central serous maculopathy pro- duces very little RAPD, usually 0.3 log units or less. When the subretinal fluid disappears, so does the RAPD (77). An RAPD can occur in a patient with a retinal detachment (78). In this setting, each quadrant of a fresh, bullous detachment produces about 0.3 log of RAPD, and when the macula de- taches, the RAPD increases by about another 0.7 log units (79). An RAPD can be used to help separate nonischemic from ischemic central retinal vein occlusion (CRVO). Servais et al. studied 120 patients with a unilateral CRVOand found that 90% of nonischemic CRVOs had an RAPD of 0.3 log units or less, and none had an RAPD larger than 0.9 log units (80). In contrast, in 33 patients with ischemic CRVO, 91% had an RAPD of 1.2 log units or more, and none had an RAPD smaller than 0.6 log units. In eyes that initially were nonischemic, a significant increase in the RAPD was an early indicator of ischemic conversion, even when the fundus appeared relatively unchanged.
Induced RAPD from Asymmetric Retinal Adaptation
An eye that is occluded by a ptotic lid or eye patch be- comes increasingly dark-adapted during the first 30 minutes of occlusion. This can produce up to 1.5 log units of a false RAPD in the unpatched eye (81,82). Therefore, assessment of an RAPD in a patient wearing an eye patch should not be performed immediately after patch removal because of underlying asymmetry of retinal light sensitivity between the two eyes. This is particularly important to remember in patients with traumatic optic neuropathy (a real RAPD in the patched eye may be overlooked) and in patients with nonorganic visual loss (an RAPD may mistakenly be attrib- uted to the opposite eye). After 10–15 minutes in room light with both eyes open, retinal sensitivity equalizes, and any RAPD detected should be considered valid. An anisocoria of 2 mm or more, especially if one pupil is very small, can produce a clinically significant difference
in the amount of light entering the retina. A general rule put forth is 0.1 log unit RAPD on the side of the smaller pupil for every 1 mm of anisocoria (83).
Amblyopia
A small RAPD, generally less than 0.5 log units, often can be seen in an amblyopic eye. The magnitude of the RAPD does not correlate well with the visual acuity (84,85), nor does it predict the effect of occlusion therapy (86). That such pupillomotor asymmetry is not always observed sug- gests that it may be seen only in patients who do not take up fixation in the amblyopic eye, even though a bright light is effectively blocking the good eye.
Local Anesthesia and RAPD
A transient RAPD typically is seen following local anes- thesia in the orbit. In one study, the method of anesthetic delivery (peribulbar versus retrobulbar versus sub-Tenon) did not affect the degree of induced RAPD or its recovery time (87).
Media Opacities
Dense intraocular hemorrhage that mechanically blocks light from reaching the retina can produce an RAPD that resolves as the hemorrhage clears (88). In contrast, a dense unilateral cataract does not produce an RAPD in the affected eye. Instead, a very small RAPD occasionally is found in the opposite eye. This may be partly because of the dark- adapted retina behind the cataract and partly because the incoming light is scattered by the opaque lens, allowing more light to hit the macular area directly (89–92). DuBois and Sadun also suggested that retinal sensitivity may be upregu- lated slowly behind a cataract by a neurogenic mechanism that is unrelated to routine receptor photochemistry (81).
Optic Tract Disorders
A complete or nearly complete lesion of the optic tract produces a contralateral homonymous hemianopia and a small to moderate RAPD (0.3–1.6 log units) in the contralat- eral eye (i.e., the eye with the temporal field loss) (93–95). Assuming an asymmetric distribution of crossed and un- crossed pupillomotor fibers in each optic tract similar to that of visual fibers, the contralateral side of the RAPD found in optic tract (and midbrain tectal) lesions can be understood. However, the large range and magnitude of tract RAPDs is not explained by the percentage of decussating pupillomotor input and may be related instead to individual differences in the pupillomotor sensitivity of the temporal and nasal retina. Additionally, an asymmetric distribution of efferent impulses from each pretectal nucleus to the Edinger-West- phal nuclei would produce an efferent deficit in the eye con- tralateral to the lesion (i.e., the eye with the afferent deficit). This relative efferent deficit, which is most evident when comparing only the direct pupil response between the two eyes in a patient with an optic tract (or tectal) lesion, can lead to overestimation of the RAPD. Cox and Drewes sug- gested that this efferent part of the asymmetry can be avoided
748 CLINICAL NEURO-OPHTHALMOLOGY
gia, paralysis of vertical gaze, loss of convergence, exotro- pia, ptosis, and other defects of ocular movement.
Paradoxical Reaction of the Pupils to Light and Darkness
Barricks et al. described three unrelated boys, 2, 6, and 10 years of age, with congenital stationary night blindness, myopia, and abnormal electroretinograms, who showed a ‘‘paradoxical’’ pupillary constriction in darkness (108). In a lighted room, all three patients had moderately dilated pu- pils; however, when the room lights were extinguished, the patients’ pupils briskly constricted and then slowly redilated. Subsequent investigators confirmed this observation and re- ported similar paradoxical pupillary responses in children and adults with congenital achromatopsia, blue-cone mono- chromatism, and Leber congenital amaurosis (109,110). In addition, such responses occasionally occur in patients with optic disc hypoplasia, dominant optic atrophy, and bilateral optic neuritis. Flynn et al. suggested that the pupillary re- sponses seen in these patients occur not from abnormalities in the central nervous system (CNS) but from selective de- lays in afferent signals from the retinal photoreceptors to the pupillomotor center (111).
Figure 16.5. Steps that assist the evaluation of anisocoria.
EFFERENT ABNORMALITIES: ANISOCORIA
The presence of anisocoria usually indicates a structural defect of one or both irides or a neural defect of the efferent pupillomotor pathways innervating the iris muscles in one or both eyes. A careful slit-lamp examination to assess the health and integrity of the iris stroma and muscles is an important step in the evaluation of anisocoria. If the irides are intact, then an innervation problem is suspected. As most efferent disturbances causing anisocoria are unilateral, two simple maneuvers are helpful in determining whether it is the sympathetic or parasympathetic innervation to the eye that is dysfunctional: (1) checking the pupillary light reflex and (2) measuring the anisocoria in darkness and in bright light. When the larger pupil has an obviously impaired reaction to light stimulation, it is likely the cause of the anisocoria. One can presume the problem lies somewhere along the parasympathetic pathway to the sphincter muscle. Common etiologies include an acute tonic pupil, oculomotor nerve palsy, or pharmacologic blockade. If both pupils have a good light reflex and the degree of anisocoria decreases in bright light (i.e., anisocoria is greater in darkness), then there is either a deficit of sympathetic innervation to the dilator mus- cle in the eye with the smaller pupil (as in Horner syndrome)
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 749
or a physiologic anisocoria. The evaluation of anisocoria is described in the following sections and outlined in Figure
Anisocoria Greater in Darkness
Physiologic (Benign) Anisocoria
Inequality of pupil size becomes clinically observable when the difference between pupils is about 3 mm. In dim light or darkness, almost 20% of the normal population has an anisocoria of 0.4 mm or more at the moment of examina- tion. In room light, this number drops to about 10% (112–114). This form of anisocoria is known by several names, including physiologic anisocoria, simple central ani- socoria, essential anisocoria, and benign anisocoria. It is 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- quality in physiologic anisocoria may change from day to day or even from hour to hour, however. The anisocoria usually diminishes slightly in bright light, perhaps because the smaller pupil reaches the zone of mechanical resistance first, giving the larger pupil a chance to make up the size difference (117). Physiologic anisocoria is not caused by damage to the peripheral nerves that innervate the sphincter and dilator muscles of the iris. The pupillary reactions to light and dark- ness are normal. Instead, it is presumed to occur because the supranuclear inhibition of the parasympathetic pupillo- constrictor nuclei in the midbrain is not balanced with any more precision than is necessary for clear, binocular vision. It is unrelated to refractive error. Occasionally, a reversal of physiologic anisocoria is seen, a phenomenon termed ‘‘see- saw anisocoria’’ (112,116). When physiologic anisocoria is suspected, reviewing old photographs, such as a driver’s license or especially a family
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.
album, can be a valuable diagnostic tool (Fig. 16.7). In the latter case, the anisocoria usually can be traced back to in- fancy or early childhood.
Horner Syndrome
When the sympathetic innervation to the eye is inter- rupted, the retractor muscles in the eyelids are weakened, allowing the upper lid to droop and the lower lid to rise. The dilator muscle of the iris also is weakened, allowing the pupil to become smaller, and vasomotor and sudomotor control of parts of the face may be lost. This combination of ptosis, miosis, and anhidrosis is called Horner syndrome (Fig 16.8)
HISTORICAL BACKGROUND
In 1869, Johann Friedrich Horner, a Swiss ophthalmolo- gist, published a short case report in which he emphasized that eyelid ptosis could be caused by a lesion as far away from the eye as the neck by denervating the sympathetically innervated muscle in the upper lid that had recently been described by H. Mu¨ller. Although he was not the first to report the clinical condition, his meticulous and scientifically substantiated account of the clinical effects of cervical sym- pathetic paralysis has firmly attached his name to this syn- drome (118). In the French literature, this condition is called the Claude Bernard-Horner syndrome to honor the work of Claude Bernard in 1852 on the physiology of the sympa- thetic nerves. Although Horner and Bernard generally are credited with identifying the clinical signs of oculosympathetic paresis, these signs were first produced experimentally in the dog by Franc¸ois Pourfour du Petit in 1727. Pourfour du Petit was never recognized for these contributions; however, Pourfour du Petit syndrome is the term used for the combination of
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 751
nist that has little or no effect on a normal pupil but can dilate a Horner pupil due to denervation supersensitivity of the alpha-1 receptors on the iris dilator muscle. Thus, rever- sal of anisocoria following topical instillation of apracloni- dine has been seen in patients with unilateral Horner syn- drome (123,124). Anisocoria. Any anisocoria, when caused by weakness of a single iris muscle, increases in the direction of action of that muscle. With a unilateral oculosympathetic defect, the weakness of the dilator muscle in the affected eye (and resultant anisocoria) is most apparent in darkness. Con- versely, the anisocoria almost disappears in light because the normal action of both sphincters (oculoparasympathetic activity) constricts the pupils to almost equal sizes. In regular room light, the degree of anisocoria in Horner syndrome is rather small, on the order of 1.0 mm or less, and can be overlooked or mistakenly attributed to simple anisocoria (125). Furthermore, when a patient is fatigued or drowsy, the size of the pupils and the degree of anisocoria diminish as the hypothalamic sympathetic outflow to both eyes sub- sides and uninhibited parasympathetic outflow augments. Some patients with Horner syndrome have anisocoria mea- suring up to 2.5 mm; such a large anisocoria is not seen with benign anisocoria. The actual amount of anisocoria in Horner syndrome thus varies with ( a ) the resting size of the pupils; ( b ) the completeness of the injury; ( c ) the alertness of the patient; ( d ) the extent of reinnervation of the dilator muscle; ( e ) the brightness of the examiner’s light or the am- bient light in the room; ( f ) the degree of denervation super- sensitivity; ( g ) the fixation of the patient at distance or near; and ( h ) the concentration of circulating adrenergic sub- stances in the blood. Dilation Lag. Paresis of the iris dilator muscle results in a smaller resting pupil size (miosis) and also in impaired pupillary movement during dilation, called dilation lag. Dila- tion lag can be seen clinically by illuminating the patient’s
Figure 16.9. Pupillogram of a patient with a left Horner syndrome ( solid line is a normal pupil; broken line is a Horner pupil). Point a is the resting size of both pupils (and anisocoria) in darkness. Following a 1-second pulse of light, the pupils are maximally constricted at b. As the pupils redilate in the darkness, increasing anisocoria seen in c is due to the relative inactivity of the Horner pupil. Addition of a sensory stimulus after the pulse of light further enhances the asymmetric dilation dynamics (d) between the normal pupil and the Horner pupil. In e, the dilation of both pupils is observed over a longer period of time. After the initial increase in anisocoria, there is a gradual decreasing of the anisocoria as the slowly dilating Horner pupil eventually recovers its baseline size in darkness.
eyes tangentially from below with a hand-held flashlight, and then abruptly turning the room lights out. The normal pupil will immediately dilate, but several seconds will elapse before the Horner pupil begins to dilate. The dilation dynam- ics of a normal pupil compared with a Horner pupil have been well documented using continuous recording pupillog- raphy (119). Immediately following a bright light flash, both pupils are strongly constricted. In the first second of dark- ness, both pupils synchronously enlarge a small degree, pre- sumably from acute inhibition of parasympathetic impulses. In the next few seconds, the normal pupil, stimulated by an active burst of sympathetic discharges, rapidly dilates, whereas the Horner pupil, denervated of sympathetic im- pulses, hardly moves. This results in an increasing anisocoria during in the first 5 seconds or so of darkness. Thereafter, the Horner pupil slowly dilates from decreasing parasympa- thetic tone and catches up in size to the normal pupil. Thus, if both pupils are observed simultaneously for 15–20 sec- onds after turning off the room light, one sees an initial increase in the degree of anisocoria, followed by decreasing anisocoria (Fig. 16.9). A psychosensory stimulus such as a sudden noise will cause a normal pupil to dilate. When looking for dilation lag in darkness, interjection of a sudden loud noise just as the lights go out tends to augment the initial increase in anisocoria when a unilateral oculosympathetic defect is pres- ent. One can also pinch the patient’s neck (the ciliospinal reflex), press over McBurney’s point (Meyer’s iliac sign), or flex the patient’s neck (Flatau’s neck mydriasis) to bring this out (126). There remains controversy about which aspect of pupil- lary reflex dilation in darkness best identifies the impaired dilation dynamics of a Horner syndrome. Several methods of detecting dilation lag have been proposed. Taking Polaroid photographs 5 seconds after the lights go out and again after 15 seconds of darkness is a simple and readily available
752 CLINICAL NEURO-OPHTHALMOLOGY
Figure 16.10. Dilation lag in a patient with a left Horner syndrome, observed using reg- ular flash color photos. Top, Photo taken 5 seconds after the room lights were turned off. Bottom, Photo taken after 15 seconds of darkness. The right pupil is already maxi- mally dilated within 5 seconds of turning the room lights off, but the left pupil still has not dilated maximally after 15 seconds of darkness.
means to assess for dilation lag. Patients with Horner syn- drome show more anisocoria in the 5-second photograph than in the 15-second photograph, emphasizing that the ab- sence of continued dilation after 5 seconds in darkness (i.e., demonstration of decreasing anisocoria in the later phase of dilation) is a defining characteristic of an oculosympathetic defect (127,128) (Fig. 16.10). Videography with infrared il- lumination is one of the best ways to show this phenomenon (129). Others have reported that a single measurement of anisocoria taken within the first 5 seconds of darkness (i.e., assessment of the increase in anisocoria in the early phase of dilation) is adequate for identifying dilation lag. One study reported that 0.6 mm or more at 4 seconds was 82% sensitive for diagnosing a unilateral Horner syndrome (130) Using a binocular infrared video pupillometer with continuous re- cording of pupil diameters, Smith and Smith found that after a light flash, a delay in the time needed to recover three quarters of the baseline pupil size had a 70% sensitivity and 95% specificity of detecting unilateral Horner syndrome (131). This definition of dilation lag based on a measure of time, instead of the degree of anisocoria, is particularly use- ful for detecting bilateral Horner syndrome. Hypochromia Iridis. Depigmentation of the ipsilateral iris is a typical feature of congenital Horner syndrome and occasionally is seen in patients with a long-standing, ac- quired Horner syndrome (132). It is never seen in patients with an acute or recently acquired Horner syndrome. Anhidrosis. Characteristic vasomotor and sudomotor changes of the facial skin can occur on the affected side in some patients with Horner syndrome. Immediately follow- ing sympathetic denervation, the temperature of the skin rises on the side of the lesion because of loss of vasomotor control and consequent dilation of blood vessels. Addition- ally, there may be facial flushing, conjunctival hyperemia, epiphora, and nasal stuffiness in the acute stage. Some time after the injury, the skin of the ipsilateral face
and neck may have a lower temperature and may be paler than that of the normal side. This occurs from supersensitiv- ity of the denervated blood vessels to circulating adrenergic substances, with resultant vasoconstriction. The distribution of the loss of sweating (anhidrosis) and flushing depends on the location of sympathetic lesion. For example, in lesions of the preganglionic neuron, the entire side of the head, the face, and the neck down to the clavicle usually are involved, whereas in postganglionic lesions, an- hidrosis is limited to a patch on the forehead and the medial side of the nose. In a warm environment, the skin on the affected side will feel dry, whereas the skin on the nor- mal side will be so damp that a smooth object, such as a plastic bar, will not slide easily on the skin but will stick. Because most persons live and work in temperature- controlled spaces, patients with Horner syndrome rarely complain of disturbances of sweating or asymmetric facial flushing. Paradoxic unilateral sweating with flushing of the face, neck, and sometimes the shoulder and arm can be a late development in patients with a surgically induced Horner syndrome following cervical sympathectomy (133) or a cer- vical injury. Apparently, some axons in the vagus nerve nor- mally pass into the superior cervical ganglion. These para- sympathetic axons can establish, by collateral sprouting, anomalous vagal connections with postganglionic sympa- thetic neurons to the head and neck. Affected patients may experience bizarre sudomotor and pilomotor (gooseflesh) ac- tivity and vasomotor flushing geared reflexively to certain functions of the vagus nerve. The patterns of anomalous sweating vary but often involve the central portions of the face and forehead (119). Accommodation. Most reports describe an increase in accommodative amplitude on the side of a Horner syndrome (119). It would appear that an intact sympathetic innervation of the ciliary muscle helps that muscle loosen and tighten the
754 CLINICAL NEURO-OPHTHALMOLOGY
aptic (139). A patient with Horner syndrome after a transient ischemic episode showed only a lesion in the ipsilateral insu- lar cortex (140). From the posterolateral hypothalamus, sym- pathetic fibers pass through the lateral brain stem and extend to the ciliospinal center of Budge in the intermediolateral gray column of the spinal cord at C8–T1. A central Horner syndrome caused by damage to any of these structures is ipsilateral to the lesion and almost always unilateral. A lesion in this neuron often produces a hemihypohidrosis of the en- tire body. Lesions of the hypothalamus such as tumor or hemorrhage can cause an ipsilateral Horner syndrome (141,142) with contralateral hemiparesis, contralateral hyp- esthesia, or both. Patients with a central Horner syndrome caused by a lesion of the thalamus also show a contralateral hemiparesis that often is ataxic (143). Contralateral hypes- thesia, vertical gaze paresis, and dysphasia are other associ- ated findings. The occurrence of a unilateral Horner syndrome and a contralateral trochlear nerve paresis indicates a lesion of the dorsal mesencephalon. The lesion injures either the trochlear nucleus on the side of the Horner syndrome or the ipsilateral fascicle (140,144–146). Although a Horner syndrome associated with an ipsi- lateral abducens nerve paresis is most often caused by a lesion in the cavernous sinus (see below), this combination of signs also may occur in patients with pontine lesions (147). In such cases, the Horner syndrome is central rather than postganglionic. The classical brain stem syndrome characterized in part by a central Horner syndrome is Wallenberg syndrome, also called the lateral medullary syndrome. The typical findings of Wallenberg syndrome are ipsilateral impairment of pain and temperature sensation over the face, Horner syndrome, limb ataxia, and a bulbar disturbance causing dysarthria and dysphagia. Contralaterally, pain and temperature sensation is impaired over the trunk and limbs. The symptoms of Wal- lenberg syndrome include vertigo and a variety of unusual sensations of body and environmental tilt, often so bizarre as to suggest a psychogenic origin (148,149). Patients may report the whole room tilted on its side or even upside down; with their eyes closed, they may feel themselves to be tilted. Lateropulsion, a compelling sensation of being pulled to- ward the side of the lesion, is often a prominent complaint and also is evident in the ocular motor findings (150,151). If the patient is asked to fixate straight ahead and then gently close the lids, the eyes deviate conjugately toward the side of the lesion. This is reflected by the corrective saccades that the patient must make on eye opening to reacquire the target. Lateropulsion may even appear with a blink. Wal- lenberg syndrome is most commonly caused by thrombotic occlusion of the ipsilateral vertebral artery, although isolated posterior inferior cerebellar artery disease is occasionally seen (152). In a series of 130 patients with lateral medullary infarction, the pathogenesis was large vessel infarction in 50%, arterial dissection in 15%, small vessel infarction in 13%, and cardiac embolism in 5% (153). Demyelinating dis- ease of the medulla has also been reported in a case of Wal- lenberg syndrome (154). Although most patients with a central neuron Horner syn-
drome have other neurologic deficits, occasional patients with cervical spondylosis present only with a Horner syn- drome and perhaps some neck pain. An isolated central Hor- ner syndrome also can occur from a brain stem syrinx (155). Lesions of the spinal cord (lower cervical or upper tho- racic area) can cause a central Horner syndrome. In most cases there are other neurologic deficits, although in some patients the Horner syndrome is the only neurologic abnor- mality. Spinal cord lesions that may cause a central Horner syndrome include trauma (most common), inflammatory or infectious myelitis, vascular malformation, demyelination, syrinx, syringomyelia, neoplasms, and infarction. What ap- pears to be an alternating Horner syndrome (i.e., alternating oculosympathetic deficit) can be seen in patients with cervi- cal cord lesions and in some patients with systemic dysauto- nomias (156–159). Other patients have attacks of autonomic hyperreflexia that excite the ciliospinal center of Budge on the affected side (the C8–T1 intermediolateral gray column may, in fact, be supersensitive as a result of its disconnec- tion). This excess firing of sympathetic impulses (oculosym- pathetic spasm) dilates the pupils, lifts the eyelid, blanches the conjunctiva, and increases sweating of the face (160). When the oculosympathetic spasm occurs unilaterally and intermittently on the side of an underlying Horner syndrome, the anisocoria appears to reverse; this mechanism may ac- count for some cases of alternating Horner syndrome (161). Preganglionic (Second-Order Neuron) Horner Syn- drome. The preganglionic (second-order) neuron exits from the ciliospinal center of Budge and passes across the pulmonary apex. It then turns upward, passes through the stellate ganglion, and goes up the carotid sheath to the supe- rior cervical ganglion, near the bifurcation of the common carotid artery. In one large series, malignancy was the cause of about 25% of cases of preganglionic Horner syndrome (162). The most common tumors, not surprisingly, were lung and breast cancer, but Horner syndrome was not an early sign of either of these tumors. Indeed, by the time the Horner syndrome had appeared, the tumor already was known to be present. Apical lung lesions that spread locally at the superior tho- racic outlet cause symptoms of ipsilateral shoulder pain (the most common initial symptom) and pain and paresthesia along the medial arm, forearm, and fourth and fifth digits (the distribution of the C8 and T1 nerve roots) as well as a preganglionic Horner syndrome and weakness/atrophy of the hand muscles. This combination of signs is called the Pancoast syndrome. The majority of lesions causing Pan- coast syndrome are carcinomas of the lung (163). Other tu- mors and infectious processes, including tuberculosis, bacte- rial pneumonias, and fungal infection, have been reported. A patient with a preganglionic Horner syndrome and ipsilateral shoulder pain should be investigated thoroughly for neoplas- tic involvement of the pulmonary apex, the pleural lining, and the brachial plexus. Tumors that spread behind the carotid sheath at the C level may produce a preganglionic Horner syndrome associ- ated with paralysis of the phrenic, vagus, and recurrent laryn- geal nerves: the Rowland Payne syndrome (164). Just 3 inches lower, at the thoracic outlet, these nerves are more
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 755
widely separated and less likely to be involved together. Thus, if a patient is newly hoarse and has a preganglionic Horner syndrome, a chest radiograph may be warranted to see whether the hemidiaphragm ipsilateral to the Horner syn- drome is elevated. Nonpulmonary tumors that produce a preganglionic Hor- ner syndrome include sympathetic chain or intercostal nerve schwannoma, paravertebral primitive neuroectodermal tu- mor, vagal paraganglioma, mediastinal tumors or cysts, and thyroid carcinoma. Injury to the brachial plexus or spinal roots, pneumothorax, fracture of the first rib, or neck hema- toma should be considered in patients whose preganglionic Horner syndrome follows neck or shoulder trauma. The preganglionic neuron is the most common site of in- jury for an iatrogenic Horner syndrome. The varied anes- thetic, radiologic, and surgical procedures that can produce the condition include coronary artery bypass surgery, lung or mediastinal surgery, carotid endarterectomy, insertion of a pacemaker, epidural anesthesia, interpleural placement of chest tubes, internal jugular catheterization, and stenting of the internal carotid artery (165–170). Despite advances in neuroimaging and other diagnostic tests, many cases of preganglionic Horner syndrome have no explanation. In one series, about 28% of cases of pregan- glionic Horner syndrome were of unknown etiology (125). Postganglionic (Third-Order Neuron) Horner Syn- drome. The postganglionic (third-order) sympathetic neu- ron to the iris dilator muscle begins in the superior cervical ganglion and travels in the wall of the internal carotid artery, where it is called the carotid sympathetic plexus or some- times the carotid sympathetic nerve. The latter may be a more appropriate term, as the majority of sympathetic fibers ascend as a single bundle. Within the cavernous sinus, the sympathetic fibers leave the internal carotid artery, join briefly with the abducens nerve, and then leave it to join the ophthalmic division of the trigeminal nerve, entering the orbit with its nasociliary branch (171,172). The sympathetic fibers in the nasociliary nerve divide into the two long ciliary nerves that travel with the lateral and medial suprachoroidal vascular bundles to reach the anterior segment of the eye and innervate the iris dilator muscle. Most lesions that damage the postganglionic sympathetic neuron are vascular lesions that produce headache or ipsi- lateral facial pain as well and often are lumped under the clinical description of a ‘‘painful postganglionic Horner syn- drome.’’ Responsible lesions may be extracranial, affecting postganglionic sympathetics in the neck, or intracranial, af- fecting the sympathetics at the base of the skull, in the carotid canal and middle ear, or in the region of the cavernous sinus. It is unusual for an orbital lesion to produce an isolated Horner syndrome. Lesions of or along the internal carotid artery are a com- mon cause of a painful postganglionic Horner syndrome, the most common being a traumatic or spontaneous dissection of the cervical internal carotid artery. In 146 such patients, a Horner syndrome was the most common ocular finding (44%) (173). In half of these cases, the Horner syndrome was the initial and sole manifestation of the carotid artery dissection. In the other half, an associated ocular or cerebral
ischemic event occurred within a mean of 7 days of the Horner syndrome, emphasizing the need for early recogni- tion and diagnosis of this cause of Horner syndrome. Carotid dissections are discussed in Chapter 40. Pathologic conditions of the internal carotid artery other than dissection that are associated with a Horner syndrome include aneurysms, severe atherosclerosis, acute thrombosis, fibromuscular dysplasia, and arteritis (174). Mass lesions in the neck that can compress the carotid sympathetic neuron include tumors, inflammatory masses, enlarged lymph nodes, and even an ectatic jugular vein (175,176). In the deep retroparotid space and around the jugular fora- men, oculosympathetic fibers are in close proximity with several lower cranial nerves. Lesions in this area of the neck, usually trauma, tumors, and masses, can result in a Horner syndrome associated with ipsilateral paralysis of the tongue, soft palate, pharynx, and larynx. Such lesions may cause dysphagia, dysphonia, and hoarseness. The ipsilateral poste- rior pharynx may be hypesthetic. This combination of paral- ysis of the cervical sympathetics and the last four cranial nerves (the glossopharyngeal, vagus, accessory, and hypo- glossal nerves) is called Villaret syndrome (177). The superior cervical ganglion lies about 1.5 cm behind the palatine tonsil and thus can be damaged by iatrogenic or traumatic penetrating intraoral injury. Tonsillectomy, in- traoral surgery, peritonsillar injections, and accidental punc- tures through the soft palate are some of the etiologies that have been reported to cause a postganglionic Horner syn- drome from damage to the superior cervical ganglion (178,179). Lesions at the skull base can cause a postganglionic Hor- ner syndrome. A middle fossa mass encroaching on Meck- el’s cave and on the internal carotid artery at the foramen lacerum can produce a postganglionic Horner syndrome as- sociated with trigeminal pain or sensory loss. A basal skull fracture involving the petrous bone can damage the postgan- glionic sympathetic fibers within the carotid canal, produc- ing a postganglionic Horner syndrome associated with an ipsilateral abduction deficit, facial palsy, and/or sensorineu- ral hearing loss (abducens, facial, and vestibulocochlear cra- nial nerves) (180). Any lesion in the cavernous sinus may produce a postgan- glionic Horner syndrome. In many cases, there is associated ipsilateral ophthalmoparesis caused by involvement of one or more ocular motor nerves as well as pain or dysesthesia of the ipsilateral face caused by trigeminal nerve dysfunc- tion. The occurrence of an abducens palsy and a postgangli- onic Horner syndrome (Parkinson sign) without other neuro- logic signs should raise suspicion of a cavernous sinus lesion (181–183). When a Horner syndrome and oculomotor nerve palsy occur together, there is combined sympathetic and parasympathetic dysfunction of the iris muscles. In such cases, the anisocoria is minimal or absent despite the im- paired light reaction of the affected pupil, and pharmacologic testing may be the only means to detect an underlying sym- pathetic paresis (184). Cluster headaches are severe lancinating unilateral head- aches that usually occur in middle-aged men. The headaches often are nocturnal, last 30–120 minutes, and are accompa-
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 757
ganglionic sympathetic neuron. Such a pupil should dilate to a weak, direct-acting topical adrenergic drug, such as a 1% solution of phenylephrine hydrochloride or a 2% solution of epinephrine due to adrenergic denervation supersensitiv- ity of the iris dilator muscle. Indeed, such a pupil not only will dilate but also will become larger than the opposite normal pupil. Denervation supersensitivity of the iris to ad- renergic drugs apparently does not occur immediately after damage to the postganglionic sympathetic nerve but may take as long as 17 days to develop (195). Occasionally, this test is used to differentiate a mechanically restricted pupil (e.g., iris damage) from a postganglionic Horner pupil be- cause the restricted pupil fails to dilate to direct-acting adren- ergic agents.
ACQUIRED HORNER SYNDROME IN CHILDREN
Horner syndrome in childhood (under age 18 years) may be congenital (42%), postoperative (42%), or truly acquired (15%) (196). It is this last group that often results from an underlying neoplasm or serious neurologic disease. For ex- ample, neuroblastoma is responsible for up to 20% of such cases (197). Other reported etiologies include spinal cord tumors, brachial plexus trauma, intrathoracic aneurysm, em- bryonal cell carcinoma, rhabdomyosarcoma, thrombosis of the internal carotid artery, and brain stem vascular malforma- tions (196,198). Thus, an acquired Horner syndrome in a child with no prior surgical history, even if the finding is isolated, warrants immediate further investigation. This is particularly important for neuroblastoma because younger age (less than 1 year) is strongly correlated with better out- come.
CONGENITAL HORNER SYNDROME
Patients with a congenital Horner syndrome have ptosis, miosis, facial anhidrosis, and hypochromia of the affected iris (119,199). Even a child with very blue eyes usually has a paler iris on the affected side from impaired development of iris melanophores, causing hypochromia of the iris stroma. This occurs whether the lesion is preganglionic or postganglionic because of anterograde transsynaptic dys- genesis (200). Children with naturally curly hair and a congenital Horner syndrome have straight hair on the side of the Horner syndrome (201). The reason for this abnormality is unclear, but it probably relates to lack of sympathetic innervation to the hair shafts on the affected side of the head. Parents of an infant with congenital Horner syndrome sometimes report that the baby develops a hemifacial flush when nursing or crying. The flushed side probably is the normally innervated side that appears dramatically reddish when seen against the opposite side with pallor from im- paired facial vasodilation and perhaps overactive vasocon- striction as well. In other words, hemifacial flushing in in- fants is likely to be opposite the side of a congenital Horner syndrome (202,203). Sometimes, a cycloplegic refraction unexpectedly answers the question by producing an atropinic
Figure 16.13. Lack of atropinic flushing in a child with a congenital left Horner syndrome. The atropinic flush is present only on the side of the face opposite the Horner syndrome.
flush. This reaction occurs only when there is an intact sym- pathetic innervation to the skin (Fig. 16.13). Some patients with congenital Horner syndrome have clinical evidence that indicates a preganglionic lesion (e.g., facial anhydrosis, evidence of a brachial plexus injury, his- tory of thoracic surgery), but pharmacologic localization with hydroxyamphetamine indicates a postganglionic lesion. Possible explanations include an embryopathy directly in- volving the superior cervical ganglion, damage to the vascu- lar supply of the superior cervical ganglion, and transsynap- tic dysgenesis of the superior cervical ganglion following a defect located more proximally in the sympathetic pathway (200,204). Birth trauma probably is the most common etiology of congenital Horner syndrome (196). Use of forceps, history of shoulder dystocia, and fetal rotation can lead to injury of the sympathetic plexus along its course in the neck or near the thoracic outlet. Associated upper extremity weakness is indicative of concomitant damage to the ipsilateral brachial plexus (200) (Fig. 16.14). Neuroblastoma was found in one of 31 congenital cases (‘‘congenital’’ being defined as a Horner syndrome detected before 4 weeks of age) (196). Even if the definition of ‘‘congenital’’ is extended to include
758 CLINICAL NEURO-OPHTHALMOLOGY
Figure 16.14. Horner syndrome ( top ) associated with injury of the right brachial plexus at birth. Note the underdeveloped right arm and forearm ( bottom ).
cases of Horner syndrome detected within the first year of life, the incidence of neuroblastoma is low, less than 10% (200,205). Other etiologies include congenital tumors, post- viral complication, iatrogenic Horner syndrome, and abnor- malities of the internal carotid artery such as fibromuscular dysplasia and congenital agenesis (206–209). Many cases of congenital Horner syndrome are idiopathic, even after initial work-up and long-term follow-up. George et al. reported that no etiology was found in 16 of 23 (70%) infants who were found to have a Horner syndrome in the first year of life. In young infants with an isolated Horner syndrome and no history of birth trauma, a congenital basis may be suspected. Careful general examination and a urine test for catecholamines, with regular follow-up thereafter, constitutes the minimum evaluation (205). For infants in whom the onset of Horner syndrome is firmly established after the first 4 weeks of life (i.e., an acquired process), immediate and thorough imaging is recommended.
Pharmacologic Stimulation of the Iris Sphincter
Almost all cases of acute pharmacologically induced ani- socoria are caused by parasympathetic blockade of the iris sphincter muscle, resulting in a fixed and dilated pupil. In such cases, the anisocoria is greater in light than darkness. However, in rare instances, a pharmacologic agent produces anisocoria by stimulating the parasympathetic system, thus producing a fixed miotic pupil in which the anisocoria is greater in darkness. In such cases, a 1% solution of tropica- mide typically fails to dilate the pharmacologically con- stricted pupil. Anisocoria caused by parasympathetic stimu- lation can occur after handling of a pet’s flea collar (210,211) that contains an anticholinesterase pesticide or a garden in- secticide that contains parathion, a synthetic organophos- phate ester.
Pharmacologic Inhibition of the Iris Dilator
Brimonidine tartrate is an alpha-2-adrenergic agonist that presumably decreases iris dilator action by its effect at the presynaptic alpha-2 inhibitory receptors of postganglionic sympathetic neurons. The resultant pupillary miosis is more apparent in darkness than in light (212).
Anisocoria Greater in Light
Damage to the Preganglionic Parasympathetic Outflow to the Iris Sphincter
The efferent pupillomotor pathway for pupillary constric- tion to light and near stimulation begins in the mesencepha- lon with the visceral oculomotor (Edinger-Westphal) nuclei and continues via the oculomotor nerve to the ciliary gan- glion. The postganglionic impulses are carried through the short ciliary nerves to reach the iris sphincter (see Chapter 14). Because accommodative impulses begin in the same midbrain nuclei as pupilloconstrictor impulses and follow the same peripheral course to the eye, accommodative paral- ysis frequently accompanies pupillary paralysis in lesions of the efferent parasympathetic pathway to the iris sphincter. This combination of iridoplegia and cycloplegia was called internal ophthalmoplegia by Hutchinson to distinguish it from the external ophthalmoplegia that occurs when the ex- traocular muscles are paralyzed in the setting of normal pu- pillary responses. Lesions anywhere along the two-neuron parasympathetic pathway to the intraocular muscles cause mydriasis at rest and impaired reflex constriction that ranges from mildly sluggish light reactions to complete pupillary unreactivity. Damage to the preganglionic portion of this pathway to the iris sphincter is caused by lesions involving the parasympa- thetic midbrain nuclei and the oculomotor nerve.
The Edinger-Westphal Nuclei
When there is isolated damage to the Edinger-Westphal nuclei, bilateral pupillary abnormalities are the rule. Most lesions in this region that produce pupillary abnormalities also affect other parts of the oculomotor nucleus, causing ptosis, ophthalmoparesis, or both.
