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 mation. Although many of these disorders are isolated dysfunction of the autonomic nervous system as it pertains phenomena that affect only a single structure, others are to the eye and orbit, including congenital and acquired systemic disorders that involve various other organs in the disorders of pupillary function, accommodation, and lacri- body. DISORDERS OF THE PUPIL The value of observation of pupillary size and motility in and reactivity because these structural defects may be the the evaluation of patients with neurologic disease cannot cause of ‘‘abnormal pupils’’ and often are easy to diagnose be overemphasized. In many patients with visual loss, an at the slit lamp. Furthermore, if a preexisting structural iris abnormal pupillary response is the only objective sign of defect is present, it may confound interpretation of the neuro- organic visual dysfunction. In patients with diplopia, an im- logic evaluation of pupillary function; at the very least, it paired pupil can signal the presence of an acute or enlarging should be kept in consideration during such evaluation. intracranial mass. An adequate clinical examination of the pupils requires little time and can be meaningful when ap- STRUCTURAL DEFECTS OF THE IRIS proached with a sound understanding of the principles of pupillary innervation and function. In most cases, one needs Congenital Defects only a hand light with a bright, even beam, a device for Aniridia measuring pupillary size (preferably in half-millimeter steps), a few pharmacologic agents, and an examination Aniridia is a rare congenital abnormality in which the room that permits easy control of the background illumina- iris is partially hypoplastic or completely absent (1,2) (Fig. tion. 16.1A). Patients with aniridia initially may be thought to This section commences with an overview of congenital have fixed, dilated pupils until a more careful examination and acquired diseases of the iris that affect pupil size, shape, is performed. In almost all cases, histologic or gonioscopic 739 740 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;94Ϻ156–157. E, Courtesy of Dr. Harry A. Quigley.) DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 741 examination reveals small remnants of iris tissue. The iris A ‘‘complete’’ iris coloboma extends the full thickness is only minimally developed, and the iris musculature usu- of the iris and typically produces an oval-shaped or keyhole- ally is hypoplastic. Patients with aniridia often have photo- shaped pupil, whereas an ‘‘incomplete’’ iris coloboma is a phobia, poor visual acuity, and other ocular defects, includ- partial-thickness defect best seen as a wedge-shaped transil- ing glaucoma, cataracts, ectopia lentis, corneal opacification, lumination defect of the iris (7). An isolated coloboma in a ciliary body hypoplasia, optic nerve hypoplasia, foveal hy- microphthalmic eye has an established autosomal-dominant poplasia, strabismus, and nystagmus (3). The condition usu- inheritance pattern, but penetrance is incomplete. A few ped- ally is bilateral, and two thirds of cases are inherited in auto- igrees supporting an autosomal-recessive or X-linked–reces- somal-dominant fashion (4). sive inheritance pattern have been reported. Nevertheless, The gene defect resulting in aniridia is a nonsense or regardless of the type, location, and completeness of a colo- frameshift mutation in the large PAX6 gene on chromosome bomatous defect, patients with a coloboma should undergo 11p13 (3). The PAX6 gene is a master regulator gene, critical an evaluation to determine whether it truly is an isolated in the development of the eye and central nervous tissues. finding or part of a multisystem disorder. Mutations of this gene are associated with other ocular ab- One well-known congenital multisystem syndrome with normalities, such as anterior segment defects and foveal hy- heterogeneous etiologies is the CHARGE association (colo- poplasia, in addition to aniridia. Mutations can be sporadic boma, heart defects, atresia of the choanae, retardation of or inherited; in most cases, loss of one allele (heterozygous growth and development, genital hypoplasia, and ear anoma- PAX6 mutation) is sufficient to result in ocular structural lies or hearing loss) (6). Patients with the phenotypic defects. Detection of a PAX6 mutation necessitates genetic CHARGE association can be given a more specific diagnosis counseling. if an etiologic basis is found, such as a teratogenic agent Systemic abnormalities found in patients with aniridia are (retinoic acid) or a gene defect (partial tetrasomy of chromo- many and varied. They include polydactyly, oligophrenia, some 22, the cat-eye syndrome) (8). cranial dysostosis, malformations of the extremities and ex- Cat-eye syndrome is one clinical phenotype resulting from ternal ears, hydrocephalus, and mental retardation (2). The a genomic disorder of 22q11. Specifically, there is a partial most important association, however, is with the childhood tetrasomy (four copies) of this region of chromosome 22. cancer, Wilms’ tumor. Aniridia occurs in 1 in 73 patients Patients commonly have ocular colobomata, anal atresia, and with Wilms’ tumor, compared with a frequency of 1 in preauricular skin tags. Other anomalies include heart defects 50,000–100,000 in the general population (1). The reason (particularly total anomalous pulmonary venous return), for this high association is the close proximity of the aniridia renal malformations, craniofacial anomalies, genital anoma- gene to the gene for Wilms’ tumor (WT1) (5). The associa- lies, and mental retardation (9). tion of Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation is known as WAGR syndrome and is due to a contiguous defect on chromosome 11p13 that encom- Square Pupils passes both the PAX6 and the WT1 genes. Although sponta- Square pupils are thought to represent incomplete aniridia. neous deletions can occur simultaneously in both genes, the White and Fulton observed, in homozygous twins whose detection of an intragenic PAX6 mutation in a patient with mother showed the same defect, large, irregular, roughly sporadic aniridia can eliminate the need for routine kidney quadrilateral pupils that responded to constricting stimuli ultrasounds (3). only in certain quadrants (10). Similar pupils were observed in a mother and daughter with incomplete aniridia and cata- Coloboma of the Iris racts (11). A coloboma is a notch, hole, or fissure in any of the ocular structures (cornea, iris, ciliary body, zonules, choroids, ret- Elliptic Pupils ina, and optic disc) due to defective embryogenesis. Affected eyes are frequently microphthalmic. The term ‘‘typical’’ col- Elliptic pupils occasionally occur. In strong illumination, oboma specifically refers to one caused by defective closure such pupils take on the form of elliptical slits (12,13). of the fetal fissure. Typical colobomata occur in the inferona- sal quadrant and are the most common type (Fig. 16.1B). Scalloped Pupils According to Pagon, only iris colobomata that are ‘‘typical’’ are associated with chorioretinal or optic disc colobomas Irregular, cup-shaped indentations in the pupillary mar- (6). ‘‘Atypical’’ colobomata may result from (a) interference gins have been described as a congenital anomaly in large with embryonic growth of the neuroepithelial layers; (b) me- pupils that otherwise react normally to light and near stimuli chanical blockage of the advancing neuroectoderm by meso- (14). Scalloped pupils probably are more commonly an ac- dermal elements present at the edge of the optic cup; and quired disorder, particularly in familial amyloidosis (15,16). (c) occlusion of vessels within the embryonic iris tissue, The pupil also may develop a scalloped appearance after with subsequent iris atrophy. When an atypical iris coloboma trauma to the sphincter muscle, causing multiple tears, seg- does not extend to the pupillary margin, it produces pseudo- mental sphincter atrophy, or both. A scalloped pupil can polycoria, a defect in the iris that has the clinical appearance occur after uveitis