25 - 34 Disorders of the Eye

34 Disorders of the Eye

■ ■FURTHER READING Aquino G et al: Towards the neurobiology of insomnia: A systematic

review of neuroimaging studies. Sleep Med Rev 73:101878, 2024. Cash RE et al: Association between sleep duration and ideal cardio­ vascular health among US adults, National Health and Nutrition Examination Survey. Prev Chronic Dis 17:E43, 2020. Chinoy ED et al: Unrestricted evening use of light-emitting tablet computers delays self-selected bedtime and disrupts circadian timing and alertness. Physiol Rep 6:e13692, 2018. Cribb L et al: Sleep regularity and mortality: A prospective analysis in the UK Biobank. Elife 12:RP88359, 2023. Holth JK et al: The sleep-wake cycle regulates brain interstitial fluid PART 2 Cardinal Manifestations and Presentation of Diseases tau in mice and CSF tau in humans. Science 363:880, 2019. Landrigan CP et al: Effect on patient safety of a resident physician schedule without 24-hour shifts. N Engl J Med 382:2514, 2020. Lee ML et al: High risk of near-crash driving events following nightshift work. Proc Natl Acad Sci USA 113:176, 2016. Liblau RS et al: The immunopathogenesis of narcolepsy type 1. Nat Rev Immunol 24:33, 2024. Scammell TE: Narcolepsy. N Engl J Med 373:2654, 2015. Scammell TE et al: Neural circuitry of wakefulness and sleep. Neuron 93:747, 2017. Sletten TL et al: The importance of sleep regularity: A consensus statement of the National Sleep Foundation sleep timing and vari­ ability panel. Sleep Health 9:801, 2023. VIDEO 33-1  A typical episode of severe cataplexy. The patient is joking and then falls to the ground with an abrupt loss of muscle tone. The electromyogram recordings (four lower traces on the right) show reductions in muscle activity during the period of paralysis. The electroencephalogram (top two traces) shows wakefulness throughout the episode. (Video courtesy of Giuseppe Plazzi, University of Bologna.) VIDEO 33-2  Typical aggressive movements in rapid eye movement (REM) sleep behavior disorder. (Video courtesy of Dr. Carlos Schenck, University of Minnesota Medical School.) Section 4 Disorders of Eyes, Ears, Nose, and Throat Jonathan C. Horton

Disorders of the Eye THE HUMAN VISUAL SYSTEM The visual system provides a supremely efficient means for the rapid assimilation of information from the environment to aid in the guid­ ance of behavior. The act of seeing begins with the capture of images focused by the cornea and lens on a light-sensitive membrane in the back of the eye called the retina. The retina is actually part of the brain, banished to the periphery to serve as a transducer for the conversion of patterns of light energy into neuronal signals. Light is absorbed by pigment in two types of photoreceptors: rods and cones. In the human retina, there are 100 million rods and 5 million cones. The rods operate in dim (scotopic) illumination. The cones function under daylight (photopic) conditions. The cone system is special­ ized for color perception and high spatial resolution. The majority of cones are within the macula, the portion of the retina that serves the central 10° of vision. In the middle of the macula, a small pit

termed the fovea, packed exclusively with cones, provides the best visual acuity. Photoreceptors hyperpolarize in response to light, activating bipolar, amacrine, and horizontal cells in the inner nuclear layer. After process­ ing of photoreceptor responses by this complex retinal circuit, the flow of sensory information ultimately converges on a final common path­ way: the ganglion cells. These cells translate the visual image impinging on the retina into a continuously varying barrage of action potentials that propagates along the primary optic pathway to visual centers within the brain. There are a million ganglion cells in each retina and hence a million fibers in each optic nerve. Ganglion cell axons sweep along the inner surface of the retina in the nerve fiber layer, exit the eye at the optic disc, and travel through the optic nerve, optic chiasm, and optic tract to reach targets in the brain. The majority of fibers synapse on cells in the lateral geniculate nucleus, a thalamic relay station. Cells in the lateral geniculate nucleus project in turn to the primary visual cortex. This afferent retinoge­ niculocortical sensory pathway provides the neural substrate for visual perception. Separate classes of ganglion cells project to subcortical visual nuclei involved in other functions. Pupillary constriction and circadian rhythms are governed by ganglion cells that are intrinsically light sensitive, owing to a pigment named melanopsin. Pupil reflexes are mediated by a projection to the pretectal olivary nuclei. Their output is supplied to the Edinger-Westphal nuclei, which provide para­ sympathetic innervation to the iris sphincter via an interneuron in the ciliary ganglion. Circadian rhythms are timed by melanopsin ganglion cells that project to the suprachiasmatic nucleus. Visual orientation and eye movements are served by retinal input to the superior colliculus. Gaze stabilization and optokinetic reflexes are governed by a cluster of small retinal targets known collectively as the brainstem accessory optic system. The eyes must be rotated constantly within their orbits to place and maintain targets of visual interest on the fovea. This activity, called foveation, or looking, is governed by an elaborate efferent motor system. Each eye is moved by six extraocular muscles that are supplied by cranial nerves from the oculomotor (III), trochlear (IV), and abducens (VI) nuclei. Activity in these ocular motor nuclei is coordinated by pontine and midbrain mechanisms for smooth pursuit, saccades, and gaze stabilization during head and body move­ ments. Large regions of the frontal and parietooccipital cortex con­ trol these brainstem eye movement centers by providing descending supranuclear input. CLINICAL ASSESSMENT OF VISUAL FUNCTION ■ ■REFRACTIVE STATE In approaching a patient with reduced vision, the first step is to decide whether refractive error is responsible. In emmetropia, parallel rays from infinity are focused perfectly on the retina. Sadly, this condition is enjoyed by only a minority of the population. In myopia, the globe is too long, and light rays come to a focal point in front of the retina. Near objects can be seen clearly, but distant objects require a diverging lens in front of the eye. In hyperopia, the globe is too short, and hence, a converging lens is used to supplement the refractive power of the eye. In astigmatism, the corneal surface is not spherical, necessitating a cylindrical corrective lens. Most patients elect to wear eyeglasses or contact lenses to neutralize refractive error. An alternative is to perma­ nently alter the refractive properties of the cornea by performing laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). With the onset of middle age, presbyopia develops as the lens within the eye becomes unable to increase its refractive power to accommo­ date on near objects. To compensate for presbyopia, an emmetropic patient must use reading glasses. A patient already wearing glasses for distance correction usually switches to bifocals. The only exception is a myopic patient, who may achieve clear vision at near simply by remov­ ing glasses containing the distance prescription. Refractive errors usually develop slowly and remain stable after ado­ lescence, except in unusual circumstances. For example, the acute onset

of diabetes mellitus can produce sudden myopia because of lens edema induced by hyperglycemia. Testing vision through a pinhole aperture is a useful way to screen quickly for refractive error. If acuity is improved by viewing through a pinhole, the patient needs a refraction to obtain best corrected visual acuity. ■ ■VISUAL ACUITY The Snellen chart is used to test acuity at a distance of 6 m (20 ft). A portable scale version of the Snellen chart called the Rosenbaum card is held at 36 cm (14 in.) from the patient (eFig. 34-1: available at accessmedicine.com/harrisons). All subjects should be able to read the 6/6 m (20/20 ft) line with each eye using their refractive correction, if any. Patients who need reading glasses because of presbyopia must wear them for accurate testing with the Rosenbaum card. If 6/6 (20/20) acuity is not present in each eye, the deficiency in vision must be explained. If it is worse than 6/240 (20/800), acuity should be recorded in terms of counting fingers, hand motions, light perception, or no light perception. Legal blindness is defined by the Internal Revenue Service as a best corrected acuity of 6/60 (20/200) or less in the better eye or a binocular visual field subtending 20° or less. Loss of vision in one eye only does not constitute legal blindness. For driving, the laws vary by state, but most require a corrected acuity of 6/12 (20/40) in at least one eye for unrestricted privileges. Patients who develop a hom­ onymous hemianopia should not drive. ■ ■PUPILS The pupils should be tested individually in dim light with the patient fixating on a distant target. There is no need to check the near response if the pupils respond briskly to light, because isolated loss of constric­ tion (miosis) to accommodation does not occur. For this reason, the ubiquitous abbreviation PERRLA (pupils equal, round, and reactive to light and accommodation) implies a wasted effort with the last step. However, it is important to test the near response if the light response is poor or absent. Light-near dissociation occurs with neurosyphilis (Argyll Robertson pupil), with lesions of the dorsal midbrain (Parinaud’s syndrome), and after aberrant regeneration (oculomotor nerve palsy, Adie’s tonic pupil). An eye with no light perception has no pupillary response to direct light stimulation. If the retina or optic nerve is only partially injured, the direct pupillary response will be weaker than the consensual pupil­ lary response evoked by shining a light into the healthy fellow eye. A relative afferent pupillary defect (Marcus Gunn pupil) is elicited with the swinging flashlight test. It is an extremely useful sign in retrobulbar optic neuritis and other optic nerve diseases, in which it may be the sole objective evidence for disease. In bilateral optic neuropathy, no afferent pupil defect is present if the optic nerves are affected equally. Subtle inequality in pupil size, up to 0.5 mm, is a fairly common finding in normal persons. The diagnosis of essential or physiologic anisocoria is secure as long as the relative pupil asymmetry remains constant as ambient lighting varies. Anisocoria that increases in dim light indicates a sympathetic paresis of the iris dilator muscle. The triad of miosis with ipsilateral ptosis and anhidrosis constitutes Horner’s syndrome, although anhidrosis is an inconstant feature. A drop of 1% apraclonidine produces no effect on the normal pupil, but the miotic pupil dilates because of denervation hypersensitivity. Brainstem stroke, carotid dissection, and neoplasm impinging on the sympathetic chain occasionally are identified as the cause of Horner’s syndrome, but most cases are idiopathic. Anisocoria that increases in bright light suggests a parasympathetic palsy. The first concern is an oculomotor nerve paresis. This possibility is excluded if the eye movements are full and the patient has no ptosis or diplopia. Acute pupillary dilation (mydriasis) can result from dam­ age to the ciliary ganglion in the orbit. Common mechanisms are infec­ tion (herpes zoster, influenza), trauma (blunt, penetrating, surgical), and ischemia (diabetes, temporal arteritis). After denervation of the iris sphincter, the pupil does not respond well to light, but the response to near is often relatively intact. When the near stimulus is removed, the pupil redilates very slowly compared with the normal pupil, hence the term tonic pupil. In Adie’s syndrome, a tonic pupil is present, sometimes

in conjunction with weak or absent tendon reflexes in the lower extremities. This benign disorder, which occurs predominantly in healthy young women, is assumed to represent a mild dysautonomia. Tonic pupils are also associated with multiple system atrophy, segmen­ tal hypohidrosis, diabetes, and amyloidosis. Occasionally, a tonic pupil is discovered incidentally in an otherwise completely normal, asymp­ tomatic individual. The diagnosis is confirmed by placing a drop of dilute (0.125%) pilocarpine into each eye. Denervation hypersensitivity produces pupillary constriction in a tonic pupil, whereas the normal pupil shows no response. Pharmacologic dilatation from accidental or deliberate instillation of anticholinergic (atropine, scopolamine) drops can produce pupillary mydriasis. Gardener’s pupil refers to mydriasis induced by exposure to tropane alkaloids, contained in plants such as deadly nightshade, jimsonweed, or angel’s trumpet. When an anticho­ linergic agent is responsible for pupil dilation, 1% pilocarpine causes no constriction.

Disorders of the Eye CHAPTER 34 Both pupils are affected equally by systemic medications. They are small with opiate use and large with anticholinergics (scopolamine). Parasympathetic agents (pilocarpine) used to treat glaucoma produce miosis. In any patient with an unexplained pupillary abnormality, a slit-lamp examination is helpful to exclude an occult foreign body, perforating injury, intraocular inflammation, adhesions (synechia), angle-closure glaucoma, and iris sphincter rupture from blunt trauma. ■ ■EYE MOVEMENTS AND ALIGNMENT Eye movements are tested by asking the patient, with both eyes open, to pursue a small target such as a pen tip into the cardinal fields of gaze. Normal ocular versions are smooth, symmetric, full, and main­ tained in all directions. Saccades, or quick refixation eye movements, are assessed by having the patient look back and forth between two stationary targets. The eyes should move rapidly and accurately in a single jump to their target. Ocular alignment can be judged by hold­ ing a penlight directly in front of the patient at about 1 m. If the eyes are straight, the corneal light reflex will be centered in the middle of each pupil. To test eye alignment more precisely, the cover test is use­ ful. The patient is instructed to look at a small fixation target in the distance. One eye is occluded with a paddle or hand, while the other eye is observed. If the viewing eye shifts position to take up fixation on the target, it was misaligned. If it remains motionless, the first eye is uncovered and the test is repeated on the second eye. If neither eye moves, the eyes are aligned orthotropically. If the eyes are orthotropic in primary gaze but the patient complains of diplopia, the cover test should be performed with the head tilted or turned in whatever direc­ tion elicits diplopia. With practice, the examiner can detect an ocular deviation (heterotropia) as small as 1° with the cover test. In a patient with vertical diplopia, a small deviation can be difficult to detect and easy to dismiss. The magnitude of the deviation can be measured by placing a prism in front of the misaligned eye to determine the power required to neutralize the fixation shift evoked by covering the other eye. Temporary press-on plastic Fresnel prisms, prism eyeglasses, or eye muscle surgery can be used to restore binocular alignment. ■ ■STEREOPSIS Stereoacuity is determined by presenting targets with retinal disparity separately to each eye by using polarized images. The most popular office tests measure a range of thresholds from 2000 to 40 s of arc. Normal stereoacuity is 40 s of arc. If a patient achieves this level of stereoacuity, one is assured that the eyes are aligned orthotropically and that vision is intact in each eye. Random dot stereograms have no mon­ ocular depth cues and provide an excellent screening test for strabismus. ■ ■COLOR VISION The retina contains three classes of cones, with visual pigments of differing peak spectral sensitivity: red (560 nm), green (530 nm), and blue (430 nm). The red and green cone pigments are encoded on the X chromosome, and the blue cone pigment on chromosome 7. Mutations of the blue cone pigment are exceedingly rare. Mutations of the red and green pigments cause congenital X-linked color blindness in 8% of males. Affected individuals are not truly color blind; rather, they differ

from normal subjects in the way they perceive color and how they combine primary monochromatic lights to match a particular color. Anomalous trichromats have three cone types, but a mutation in one cone pigment (usually red or green) causes a shift in peak spectral sen­ sitivity, altering the proportion of primary colors required to achieve a color match. Dichromats have only two cone types and therefore will accept a color match based on only two primary colors. Anomalous tri­ chromats and dichromats have 6/6 (20/20) visual acuity, but their hue discrimination is impaired. Ishihara color plates can be used to detect red-green color blindness. The test plates contain a hidden number that is visible only to subjects with color confusion from red-green color blindness. Because color blindness is almost exclusively X-linked, it is worthwhile screening only male children.

PART 2 Cardinal Manifestations and Presentation of Diseases The Ishihara plates often are used to detect acquired defects in color vision, although they are intended as a screening test for congenital color blindness. Acquired defects in color vision frequently result from disease of the macula or optic nerve. For example, patients with a history of optic neuritis often complain of color desaturation long after their visual acuity has returned to normal. Color blindness also can result from bilateral strokes involving the ventral portion of the occipital lobe (cerebral achromatopsia). Such patients can perceive only shades of gray and also may have difficulty recognizing faces (prosopagnosia) (Chap. 32). Infarcts of the dominant occipital lobe sometimes give rise to color anomia. Affected patients can discriminate colors but cannot name them. ■ ■VISUAL FIELDS Vision can be impaired by damage to the visual system anywhere from the eyes to the occipital lobes. One can localize the site of the lesion with considerable accuracy by mapping the visual field deficit by finger confrontation and then correlating it with the topographic anatomy of the visual pathway (Fig. 34-1). Quantitative visual field mapping is per­ formed by computer-driven perimeters that present a target of variable intensity at fixed positions in the visual field (Fig. 34-1A). By generat­ ing an automated printout of light thresholds, these static perimeters provide a sensitive means of detecting scotomas in the visual field. They are exceedingly useful for serial assessment of visual function in chronic diseases such as glaucoma and pseudotumor cerebri. The crux of visual field analysis is to decide whether a lesion is before, at, or behind the optic chiasm. If a scotoma is confined to one eye, it must be due to a lesion anterior to the chiasm, involving either the optic nerve or the retina. Retinal lesions produce scotomas that correspond optically to their location in the fundus. For example, a superior-nasal retinal detachment results in an inferior-temporal field cut. Damage to the macula causes a central scotoma (Fig. 34-1B). Optic nerve disease produces characteristic patterns of visual field loss. Glaucoma selectively destroys axons that enter the superotempo­ ral or inferotemporal poles of the optic disc, resulting in arcuate scoto­ mas shaped like a Turkish scimitar, which emanate from the blind spot and curve around fixation to end flat against the horizontal meridian (Fig. 34-1C). This type of field defect mirrors the arrangement of the nerve fiber layer in the temporal retina. Arcuate or nerve fiber layer scotomas also result from optic neuritis, ischemic optic neuropathy, optic disc drusen, and branch retinal artery or vein occlusion. Damage to the entire upper or lower pole of the optic disc causes an altitudinal field cut that follows the horizontal meridian (Fig. 34-1D). This pattern of visual field loss is typical of ischemic optic neuropathy but also results from retinal vascular occlusion, advanced glaucoma, and optic neuritis. About half the fibers in the optic nerve originate from ganglion cells serving the macula. Damage to papillomacular fibers causes a cecocen­ tral scotoma that encompasses the blind spot and macula (Fig. 34-1E). If the damage is irreversible, pallor eventually appears in the temporal portion of the optic disc. Temporal pallor from a cecocentral scotoma may develop in optic neuritis, nutritional optic neuropathy, toxic optic neuropathy, Leber’s hereditary optic neuropathy, Kjer’s dominant optic atrophy, and compressive optic neuropathy. It is worth mentioning that the temporal side of the optic disc is slightly paler than the nasal side in most normal individuals. Therefore, it sometimes can be difficult to

decide whether temporal pallor visible on fundus examination repre­ sents a pathologic change. Pallor of the nasal rim of the optic disc is a less equivocal sign of optic atrophy. At the optic chiasm, fibers from nasal ganglion cells decussate into the contralateral optic tract. Crossed fibers are damaged more by compression than are uncrossed fibers. As a result, mass lesions of the sellar region cause a temporal hemianopia in each eye. Tumors ante­ rior to the optic chiasm, such as meningiomas of the tuberculum sella, produce a junctional scotoma characterized by an optic neuropathy in one eye and a superior-temporal field cut in the other eye (Fig. 34-1G). More symmetric compression of the optic chiasm by a pituitary ade­ noma (see Fig. 392-1), meningioma, craniopharyngioma, glioma, or aneurysm results in a bitemporal hemianopia (Fig. 34-1H). The insidi­ ous development of a bitemporal hemianopia often goes unnoticed by the patient and will escape detection by the physician unless each eye is tested separately. It is difficult to localize a postchiasmal lesion accurately, because injury anywhere in the optic tract, lateral geniculate nucleus, optic radiations, or visual cortex can produce a homonymous hemianopia (i.e., a temporal hemifield defect in the contralateral eye and a match­ ing nasal hemifield defect in the ipsilateral eye) (Fig. 34-1I). A unilat­ eral postchiasmal lesion leaves the visual acuity in each eye unaffected, although the patient may read the letters on only the left or right half of the eye chart. Lesions of the optic radiations tend to cause poorly matched or incongruous field defects in each eye. Damage to the optic radiations in the temporal lobe (Meyer’s loop) produces a superior quadrantic homonymous hemianopia (Fig. 34-1J), whereas injury to the optic radiations in the parietal lobe results in an inferior quadrantic homonymous hemianopia (Fig. 34-1K). Lesions of the primary visual cortex give rise to dense, congruous hemianopic field defects. Occlu­ sion of the posterior cerebral artery supplying the occipital lobe is a common cause of total homonymous hemianopia. Some patients have macular sparing, because the central field representation at the tip of the occipital lobe is supplied by collaterals from the middle cerebral artery (Fig. 34-1L). Destruction of both occipital lobes produces cortical blindness. This condition can be distinguished from bilateral prechiasmal visual loss by noting that the pupil responses and optic fundi remain normal. Partial recovery of homonymous hemianopia has been reported through computer-based rehabilitation therapy. During daily train­ ing sessions, patients fixate a central target while visual stimuli are presented within the blind region. The premise of vision restoration programs is that extra stimulation can promote recovery of partially damaged tissue located at the fringe of a cortical lesion. When fixation is controlled rigorously, however, no improvement of the visual fields can be demonstrated. No effective treatment exists for homonymous hemianopia caused by permanent brain damage. DISORDERS ■ ■RED OR PAINFUL EYE Corneal Abrasions  Corneal abrasions are seen best by placing a drop of fluorescein in the eye and looking with the slit lamp, using a cobalt-blue light. A penlight with a blue filter will suffice if a slit lamp is not available. Damage to the corneal epithelium is revealed by yellow fluorescence of the basement membrane exposed by loss of the overly­ ing epithelium. It is important to check for foreign bodies. To search the conjunctival fornices, the lower lid should be pulled down and the upper lid everted. A foreign body can be removed with a moistened cotton-tipped applicator after a drop of a topical anesthetic such as proparacaine has been placed in the eye. Alternatively, it may be pos­ sible to flush the foreign body from the eye by irrigating copiously with saline or artificial tears. If the corneal epithelium has been abraded, antibiotic ointment and a patch may be applied to the eye. A drop of an intermediate-acting cycloplegic such as cyclopentolate hydrochloride 1% helps reduce pain by relaxing the ciliary body. The eye should be reexamined the next day. Minor abrasions may not require patching, antibiotics, or cycloplegia.

Monocular prechiasmal field defects: C D E F A B 30° 30° Blind spot Central scotoma Normal field right eye Nerve-fiber bundle (arcuate) scotoma Altitudinal scotoma Cecocentral scotoma Enlarged blind-spot with peripheral constriction Binocular chiasmal or postchiasmal field defects: (Left eye) (Right eye) G 30° 100° 60° Junctional scotoma H 30° Bitemporal hemianopia I 30° Optic nerve Homonymous hemianopia J Optic chiasm 30° Optic tract Superior quadrantanopia K Lateral geniculate body 30° Optic radiations Inferior quadrantanopia L 30° Primary visual cortex Homonymous hemianopia with macular sparing FIGURE 34-1  Ventral view of the brain, correlating patterns of visual field loss with the sites of lesions in the visual pathway. The visual fields overlap partially, creating 120° of central binocular field flanked by a 40° monocular crescent on either side. The visual field maps in this figure were done with a computer-driven perimeter (Humphrey Instruments, Carl Zeiss, Inc.). It plots the retinal sensitivity to light in the central 30° by using a gray scale format. Areas of visual field loss are shown in black. The examples of common monocular, prechiasmal field defects are all shown for the right eye. By convention, the visual fields are always recorded with the left eye’s field on the left and the right eye’s field on the right, just as the patient sees the world. Subconjunctival Hemorrhage  This results from rupture of small vessels bridging the potential space between the episclera and the con­ junctiva. Blood dissecting into this space can produce an impressive red eye, but vision is not affected and the hemorrhage resolves without treatment. Subconjunctival hemorrhage is usually spontaneous but can result from blunt trauma, eye rubbing, or vigorous coughing. Occa­ sionally, it is a clue to an underlying bleeding disorder. Pinguecula  Pinguecula is a small, raised conjunctival nodule, usually at the nasal limbus. In adults such lesions are extremely common and have little significance unless they become inflamed

30° 30° 30° 30° Disorders of the Eye CHAPTER 34 Right Left G H J K I L (pingueculitis). They are more apt to occur in workers with outdoor exposure. A pterygium resembles a pinguecula but has crossed the limbus to encroach on the corneal surface. Removal is justified when symptoms of irritation or blurring develop, but recurrence is common. Blepharitis  This refers to inflammation of the eyelids. The most common form occurs in association with acne rosacea or seborrheic dermatitis. The eyelid margins usually are colonized heavily by staphy­ lococci. Upon close inspection, they appear greasy, ulcerated, and crusted with scaling debris that clings to the lashes. Treatment consists of strict eyelid hygiene, applying warm compresses, and eyelash scrubs

with a cleansing agent. An external hordeolum (stye) is caused by staphylococcal infection of the superficial accessory glands of Zeis or Moll located in the eyelid margins. An internal hordeolum occurs after suppurative infection of the oil-secreting meibomian glands within the tarsal plate of the eyelid. Topical antibiotics such as bacitracin/ polymyxin B ophthalmic ointment can be applied. Systemic antibiot­ ics, usually tetracyclines or azithromycin, sometimes are necessary for treatment of meibomian gland inflammation (meibomitis) or chronic, severe blepharitis. A chalazion is a painless, chronic granulomatous inflammation of a meibomian gland that produces a pealike nodule within the eyelid. It can be incised and drained, but injection with glucocorticoids is equally effective. Basal cell, squamous cell, or mei­ bomian gland carcinoma should be suspected with any nonhealing ulcerative lesion of the eyelids.

PART 2 Cardinal Manifestations and Presentation of Diseases Dacryocystitis  An inflammation of the lacrimal drainage sys­ tem, dacryocystitis can produce epiphora (tearing) and ocular injec­ tion. Gentle pressure over the lacrimal sac evokes pain and reflux of mucus or pus from the tear puncta. Dacryocystitis usually occurs after obstruction of the lacrimal system. It is treated with topical and systemic antibiotics, followed by probing, silicone stent intubation, or surgery to reestablish patency. Entropion (inversion of the eyelid) or ectropion (sagging or eversion of the eyelid) can also lead to epiphora and ocular irritation. Conjunctivitis  Conjunctivitis is the most common cause of a red, irritated eye. Pain is minimal, and visual acuity is reduced only slightly. The most common viral etiology is adenovirus infection. It causes a watery discharge, a mild foreign-body sensation, and photophobia. Bacterial infection tends to produce a more mucopurulent exudate. Mild cases of infectious conjunctivitis usually are treated empirically with broad-spectrum topical ocular antibiotics such as sulfacetamide 10%, polymyxin-bacitracin, or a trimethoprim-polymyxin combina­ tion. Smears and cultures usually are reserved for severe, resistant, or recurrent cases of conjunctivitis. To prevent contagion, patients should be admonished to wash their hands frequently, not to touch their eyes, and to avoid direct contact with others. Allergic Conjunctivitis  This condition is extremely common and often is mistaken for infectious conjunctivitis. Itching, redness, and epiphora are typical. The palpebral conjunctiva may become hypertropic with giant excrescences called cobblestone papillae. Irrita­ tion from contact lenses or any chronic foreign body also can induce formation of cobblestone papillae. Atopic conjunctivitis occurs in sub­ jects with atopic dermatitis or asthma. Symptoms caused by allergic conjunctivitis can be alleviated with cold compresses, topical vaso­ constrictors (naphazoline), antihistamines (olopatadine), and mast cell stabilizers (cromolyn). Topical glucocorticoid solutions provide dramatic relief of immune-mediated forms of conjunctivitis, but their long-term use is ill advised because of the complications of glaucoma, cataract, and secondary infection. Topical nonsteroidal anti-inflammatory drugs (NSAIDs; ketorolac) are better alternatives. Keratoconjunctivitis Sicca  Also known as dry eye, this produces a burning foreign-body sensation, injection, and photophobia. In mild cases, the eye appears surprisingly normal, but tear production mea­ sured by wetting of a filter paper (Schirmer strip) is deficient. A variety of systemic drugs, including antihistaminic, anticholinergic, and psy­ chotropic medications, result in dry eye by reducing lacrimal secretion. Disorders that involve the lacrimal gland directly, such as sarcoidosis and Sjögren’s syndrome, also cause dry eye. Patients may develop dry eye after radiation therapy if the treatment field includes the orbits. Ocular drying is also common after lesions affecting cranial nerve V or VII. Corneal anesthesia is particularly dangerous, because the absence of a normal blink reflex exposes the cornea to injury without pain to warn the patient. Dry eye is managed by frequent and liberal applica­ tion of artificial tears and ocular lubricants. In severe cases, the tear puncta can be plugged or cauterized to reduce lacrimal outflow. Keratitis  Keratitis is a threat to vision because of the risk of corneal clouding, scarring, and perforation. Worldwide, the two leading causes

of blindness from keratitis are trachoma from chlamydial infection and vitamin A deficiency related to malnutrition. In the United States, con­ tact lenses play a major role in corneal infection and ulceration. They should not be worn by anyone with an active eye infection. In evaluat­ ing the cornea, it is important to differentiate between a superficial infection (keratoconjunctivitis) and a deeper, more serious ulcerative process. The latter is accompanied by greater visual loss, pain, photo­ phobia, redness, and discharge. Slit-lamp examination shows disrup­ tion of the corneal epithelium, a cloudy infiltrate or abscess in the stroma, and an inflammatory cellular reaction in the anterior chamber. In severe cases, pus settles at the bottom of the anterior chamber, giving rise to a hypopyon. Immediate empirical antibiotic therapy should be initiated after corneal scrapings are obtained for Gram’s stain, Giemsa stain, potassium hydroxide (KOH) prep, and cultures. Fortified topi­ cal antibiotics are most effective, supplemented with subconjunctival antibiotics as required. A fungal etiology should always be considered in a patient with keratitis. Fungal infection is common in warm humid climates, especially after penetration of the cornea by plant or vegetable material. Acanthamoeba keratitis is associated with improper disinfec­ tion of contact lenses. Herpes Simplex  The herpesviruses are a major cause of blindness from keratitis. Most adults in the United States have serum antibod­ ies to herpes simplex, indicating prior viral infection (Chap. 197). Primary ocular infection generally is caused by herpes simplex type 1 rather than type 2. It manifests as a unilateral follicular blepharocon­ junctivitis that is easily confused with adenoviral conjunctivitis, unless telltale vesicles are present on the eyelids or conjunctiva. Recurrent ocular infection arises from reactivation of latent herpesvirus. A den­ dritic pattern of corneal epithelial ulceration revealed by fluorescein staining is pathognomonic for herpes infection but often not present. Involvement of both eyes is extremely rare. Corneal stromal inflamma­ tion produces edema, vascularization, and iridocyclitis. Herpes kerati­ tis is treated with cycloplegia and either a topical antiviral (trifluridine, ganciclovir) or an oral antiviral (acyclovir, valacyclovir) agent. Topical glucocorticoids are effective in mitigating corneal scarring but gener­ ally are reserved for cases involving stromal damage. Risks include corneal melting, perforation, prolonged infection, and glaucoma. Herpes Zoster  Herpes zoster from reactivation of latent varicella (chickenpox) virus causes a dermatomal pattern of painful vesicular dermatitis (Chap. 198). Ocular symptoms can occur after zoster eruption in any branch of the trigeminal nerve but are particularly common when vesicles form on the nose, reflecting nasociliary (V1) nerve involvement (Hutchinson’s sign). Herpes zoster ophthalmicus produces corneal dendrites, which can be difficult to distinguish from those seen in herpes simplex. Stromal keratitis, anterior uveitis, raised intraocular pressure, ocular motor nerve palsies, acute retinal necrosis, and postherpetic scarring and neuralgia are other common sequelae. Herpes zoster ophthalmicus is treated with antiviral agents and cyclo­ plegics. In severe cases, topical steroids may be added to reduce corneal scarring. Shingles should be prevented by vaccination of all healthy adults aged 50 years and older. Episcleritis  This is an inflammation of the episclera, a thin layer of connective tissue between the conjunctiva and the sclera. Episcleritis resembles conjunctivitis, but it is a more localized process and discharge is absent. Most cases of episcleritis are idiopathic, but some occur in the setting of an autoimmune disease. Scleritis refers to a deeper, more severe inflammatory process that frequently is associated with a connec­ tive tissue disease such as rheumatoid arthritis, lupus erythematosus, polyarteritis nodosa, granulomatosis with polyangiitis, or relapsing polychondritis. The inflammation and thickening of the sclera can be diffuse or nodular. In anterior forms of scleritis, the globe assumes a violet hue and the patient complains of severe ocular tenderness and pain. With posterior scleritis, the pain and redness may be less marked, but there is often proptosis, choroidal effusion, reduced motility, and visual loss. Episcleritis and scleritis should be treated with NSAIDs. If these agents fail, topical or even systemic glucocorticoid therapy may be necessary, especially if an underlying autoimmune process is active.

Anterior Uveitis  Involving the anterior structures of the eye, uve­ itis was previously called iritis or iridocyclitis. The diagnosis requires slit-lamp examination to identify inflammatory cells floating in the aqueous humor or deposited on the corneal endothelium (keratic precipitates). Anterior uveitis develops in sarcoidosis, ankylosing spon­ dylitis, juvenile idiopathic arthritis, inflammatory bowel disease, pso­ riasis, reactive arthritis, and Behçet’s disease. It also is associated with herpes infections, syphilis, Lyme disease, onchocerciasis, tuberculosis, and leprosy. Although anterior uveitis can occur in conjunction with many diseases, no cause is found to explain the majority of cases. For this reason, laboratory evaluation usually is reserved for patients with recurrent or severe anterior uveitis. Treatment is aimed at reducing inflammation and scarring by judicious use of topical glucocorticoids. Dilatation of the pupil reduces pain and prevents the formation of synechiae. Posterior Uveitis  This diagnosis is made by observing inflam­ mation of the vitreous, retina, or choroid on fundus examination. It is more likely than anterior uveitis to be associated with an identifiable systemic disease. Some patients have panuveitis, or inflammation of both the anterior and posterior segments of the eye. Posterior uve­ itis is a manifestation of autoimmune diseases such as sarcoidosis, Behçet’s disease, Vogt-Koyanagi-Harada syndrome, and inflammatory bowel disease. It also accompanies diseases such as toxoplasmosis, onchocerciasis, cysticercosis, coccidioidomycosis, toxocariasis, and histoplasmosis; infections caused by organisms such as Candida, Pneu­ mocystis carinii, Cryptococcus, Aspergillus, herpes, and cytomegalovirus (see Fig. 200-1); and other diseases, such as syphilis, Lyme disease, tuberculosis, cat-scratch disease, Whipple’s disease, and brucellosis. In multiple sclerosis, chronic inflammatory changes can develop in the extreme periphery of the retina (pars planitis or intermediate uveitis). Glucocorticoids have been the mainstay of treatment for noninfectious uveitis. Biologic agents that target proinflammatory cytokines, such as the tumor necrosis factor alpha (TNF-α) inhibitor adalimumab, are effective at preventing vision loss in chronic uveitis. Acute Angle-Closure Glaucoma  This is an unusual but fre­ quently misdiagnosed cause of a red, painful eye. Asian populations have a particularly high risk of angle-closure glaucoma. Susceptible eyes have a shallow anterior chamber because the eye has either a short axial length (hyperopia) or a lens enlarged by the gradual development of cataract. When the pupil becomes mid-dilated, the peripheral iris blocks aqueous outflow via the anterior chamber angle and the intraocular pressure rises abruptly, producing pain, injection, corneal edema, obscurations, and blurred vision. In some patients, ocular symptoms are overshadowed by nausea, vomiting, or headache, prompting a fruitless workup for abdominal or neurologic disease. The diagnosis is made by measuring the intraocular pressure during an acute attack or by performing gonioscopy, a procedure that allows one to observe a narrow chamber angle with a mirrored contact lens. Acute angle closure is treated with acetazolamide (PO or IV), topical beta blockers, prostaglandin analogues, α2-adrenergic agonists, and pilocarpine to induce miosis. If these measures fail, a laser can be used to create a hole in the peripheral iris to relieve pupillary block. Many physicians are reluctant to dilate patients routinely for fundus examination because they fear precipitating an angle-closure glaucoma. The risk is actually remote and more than outweighed by the potential benefit to patients of discovering a hid­ den fundus lesion visible only through a fully dilated pupil. Moreover, a single attack of angle closure after pharmacologic dilatation rarely causes any permanent damage to the eye and serves as an inadvertent provocative test to identify patients with narrow angles who would benefit from prophylactic laser iridectomy. Endophthalmitis  This results from bacterial, viral, fungal, or parasitic infection of the internal structures of the eye. It usually is acquired by hematogenous seeding from a remote site. Chronically ill, diabetic, or immunosuppressed patients, especially those with a history of indwelling IV catheters or positive blood cultures, are at greatest risk for endogenous endophthalmitis. Although most patients have ocular

Disorders of the Eye CHAPTER 34 FIGURE 34-2  Roth’s spot, cotton-wool spot, and retinal hemorrhages in a 48-yearold liver transplant patient with candidemia from immunosuppression. pain and injection, visual loss is sometimes the only symptom. Septic emboli from a diseased heart valve or a dental abscess that lodge in the retinal circulation can give rise to endophthalmitis. White-centered retinal hemorrhages known as Roth’s spots (Fig. 34-2) are considered pathognomonic for subacute bacterial endocarditis, but they also appear in leukemia, diabetes, and many other conditions. Endophthal­ mitis occurs as a complication of ocular surgery, especially glaucoma filtering, occasionally months or even years after the operation. An occult penetrating foreign body or unrecognized trauma to the globe should be considered in any patient with unexplained intraocular infection or inflammation. ■ ■TRANSIENT OR SUDDEN VISUAL LOSS Amaurosis Fugax  This term refers to a transient ischemic attack of the retina (Chap. 438). Because neural tissue has a high rate of metabolism, interruption of blood flow to the retina for more than a few seconds results in transient monocular blindness, a term used interchangeably with amaurosis fugax. Patients describe a rapid fading of vision like a curtain descending, sometimes affecting only a portion of the visual field. Amaurosis fugax usually results from an embolus that becomes stuck within a retinal arteriole (Fig. 34-3). If the embolus breaks up or passes, flow is restored and vision returns quickly to nor­ mal without permanent damage. With prolonged interruption of blood flow, the inner retina suffers infarction. Ophthalmoscopy reveals zones of whitened, edematous retina following the distribution of branch retinal arterioles. Complete occlusion of the central retinal artery pro­ duces arrest of blood flow and a milky retina with a cherry-red fovea (Fig. 34-4). Emboli are composed of cholesterol (Hollenhorst plaque), calcium, or platelet-fibrin debris. The most common source is an ath­ erosclerotic plaque in the carotid artery or aorta, although emboli can also arise from the heart, especially in patients with diseased valves, atrial fibrillation, or wall motion abnormalities. Urgent evaluation is appropriate, because of the risk of stroke. In rare instances, amaurosis fugax results from low central retinal artery perfusion pressure in a patient with a critical stenosis of the ipsi­ lateral carotid artery and poor collateral flow via the circle of Willis. In this situation, amaurosis fugax develops when there is a dip in systemic blood pressure or a slight worsening of the carotid stenosis. Sometimes there is contralateral motor or sensory loss, indicating concomitant hemispheric cerebral ischemia. Retinal arterial occlusion also occurs rarely in association with retinal migraine, lupus erythematosus, anticardiolipin antibodies, anticoagulant deficiency states (protein S, protein C, and antithrombin

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-3  Hollenhorst plaque lodged at the bifurcation of a retinal arteriole proves that a patient is shedding emboli from the carotid artery, great vessels, or heart. deficiency), Susac’s syndrome, pregnancy, IV drug abuse, blood dys­ crasias, dysproteinemias, and temporal arteritis. Marked systemic hypertension causes sclerosis of retinal arteri­ oles, splinter hemorrhages, focal infarcts of the nerve fiber layer (cotton-wool spots), and leakage of lipid and fluid (hard exudate) into the macula (Fig. 34-5). In hypertensive crisis, sudden visual loss can result from ischemia induced by vasospasm of retinal arterioles. In addition, visual loss can occur from ischemic optic disc swelling. Patients with acute hypertensive retinopathy should be treated by low­ ering the blood pressure. However, the blood pressure should not be reduced precipitously, because there is a danger of optic disc infarction from sudden hypoperfusion. Impending branch or central retinal vein occlusion can produce pro­ longed visual obscurations that resemble those described by patients with amaurosis fugax. The veins appear engorged and phlebitic, with numerous retinal hemorrhages (Fig. 34-6). In some patients, venous FIGURE 34-4  Central retinal artery occlusion in a 78-year-old man reducing acuity to counting fingers in the right eye. Note the splinter hemorrhage on the optic disc and the slightly milky appearance to the macula with a cherry-red fovea.

FIGURE 34-5  Hypertensive retinopathy with blurred optic disc, scattered hemorrhages, cotton-wool spots (nerve fiber layer infarcts), and foveal exudate in a 62-year-old man with chronic renal failure and a systolic blood pressure of 220. blood flow recovers spontaneously, whereas others evolve a frank obstruction with extensive retinal bleeding (“blood and thunder” appearance), infarction, and visual loss. Venous occlusion of the retina is often idiopathic, but hypertension, diabetes, and glaucoma are prominent risk factors. Polycythemia, thrombocythemia, or other factors leading to an underlying hypercoagulable state should be cor­ rected; aspirin treatment may be beneficial. Anterior Ischemic Optic Neuropathy (AION)  This is caused by insufficient blood flow through the posterior ciliary arteries that supply the optic disc. It produces painless monocular visual loss that is sudden in onset, followed sometimes by stuttering progression. The optic disc is edematous and usually bordered by nerve fiber layer splin­ ter hemorrhages (Fig. 34-7). AION is divided into two forms: arteritic and nonarteritic. The nonarteritic form is most common. No specific cause is known, although diabetes, renal failure, and hypertension are FIGURE 34-6  Central retinal vein occlusion can produce massive retinal hemorrhage (“blood and thunder”), ischemia, and vision loss.

FIGURE 34-7  Anterior ischemic optic neuropathy from temporal arteritis in a 64-year-old woman with acute disc swelling, splinter hemorrhages, visual loss, and an erythrocyte sedimentation rate of 60 mm/h. common risk factors. Case reports have linked erectile dysfunction drugs to AION, but a causal association is doubtful. Evidence is strong that a crowded disc architecture and small optic cup predispose to the development of nonarteritic AION. In patients with such a “disc-at-risk,” the advent of AION in one eye increases the likelihood of the same event occurring in the other eye. No treatment is available for nonar­ teritic AION; glucocorticoids should not be prescribed. About 5% of patients, especially Caucasian females aged >60, have the arteritic form of AION in conjunction with giant cell (temporal) arteritis (Chap. 375). It is urgent to recognize arteritic AION so that high doses of glucocorticoids can be instituted immediately to prevent blindness in the second eye. Tocilizumab, a monoclonal antibody against interleukin 6 receptor, is an effective alternative to glucocor­ ticoids for sustained suppression of giant cell arteritis. Symptoms of polymyalgia rheumatica may be present; the sedimentation rate and C-reactive protein level are usually elevated. In a patient with visual loss from suspected arteritic AION, temporal artery biopsy is manda­ tory to confirm the diagnosis. Administer glucocorticoids immediately, without waiting for the biopsy to be completed. The biopsy should be obtained as soon as practical, because prolonged glucocorticoid treat­ ment can hide inflammatory changes. It is important to harvest a long arterial segment and to examine a sufficient number of tissue sections. The histologic features of granulomatous inflammation are often quite subtle in temporal artery specimens. If an adequate biopsy is declared negative by an experienced pathologist, the diagnosis of arteritic AION is highly unlikely and glucocorticoids should usually be discontinued. Posterior Ischemic Optic Neuropathy  This is an uncommon cause of acute visual loss, induced by the combination of severe anemia and hypotension. Cases have been reported after major blood loss dur­ ing surgery (especially in patients undergoing cardiac or lumbar spine operation), shock, gastrointestinal bleeding, and renal dialysis. The fundus usually appears normal, although optic disc swelling develops if the process extends anteriorly far enough to reach the globe. Vision can be salvaged in some patients by immediate blood transfusion and reversal of hypotension. Optic Neuritis  This is a common inflammatory disease of the optic nerve. In the Optic Neuritis Treatment Trial (ONTT), the mean age of patients was 32 years, 77% were female, 92% had ocular pain (especially with eye movements), and 35% had optic disc swelling. In most patients, the demyelinating event was retrobulbar and the ocular fundus appeared normal on initial examination (Fig. 34-8), although optic disc pallor slowly developed over subsequent months.

Disorders of the Eye CHAPTER 34 FIGURE 34-8  Retrobulbar optic neuritis is characterized by a normal fundus examination initially, hence the rubric “the doctor sees nothing, and the patient sees nothing.” Optic atrophy develops after severe or repeated attacks. Virtually all patients experience a gradual recovery of vision after a single episode of optic neuritis, even without treatment. This rule is so reliable that failure of vision to improve after a first attack of optic neuritis casts doubt on the original diagnosis. Treatment with highdose IV methylprednisolone (250 mg every 6 h for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) makes no difference in ultimate acuity 6 months after the attack, but the recovery of visual function occurs more rapidly. Therefore, when visual loss is severe (worse than 20/100), IV followed by PO glucocorticoids are often recommended. For some patients, optic neuritis remains an isolated event. How­ ever, the ONTT showed that the 15-year cumulative probability of developing clinically definite multiple sclerosis after optic neuritis is 50%. A brain magnetic resonance (MR) scan is advisable in every patient with a first attack of optic neuritis. If two or more plaques are present on initial imaging, treatment should be considered to prevent the development of additional demyelinating lesions (Chap. 455). A particularly severe optic neuritis, often involving a long segment of nerve, occurs in neuromyelitis optica (NMO); it may be bilateral and associated with myelitis. NMO can occur as a primary disorder, in the setting of systemic autoimmune disease, or rarely, as a paraneoplastic condition. Detection of circulating antibodies directed against aqua­ porin-4 or myelin oligodendrocyte glycoprotein (MOG) is diagnostic. Treatment for acute episodes consists of glucocorticoids followed by satralizumab, eculizumab, or inebilizumab to prevent relapse. Neuro­ myelitis optica is discussed in detail in Chap. 456. ■ ■LEBER’S HEREDITARY OPTIC NEUROPATHY This disease usually affects young men, causing progressive, painless, severe central visual loss in one eye, followed weeks to years later by the same process in the other eye. Acutely, the optic disc appears mildly plethoric with surface capillary telangiectasias but no vascular leakage on fluorescein angiography. Eventually, optic atrophy ensues. Leber’s optic neuropathy is caused by a point mutation at codon 11778 in the mitochondrial gene encoding nicotinamide adenine dinucleotide dehy­ drogenase (NADH) subunit 4. Additional mutations responsible for the disease have been identified, most in mitochondrial genes that encode proteins involved in electron transport. Mitochondrial mutations that cause Leber’s neuropathy are maternally inherited by all children, but for unknown reasons, only 10% of cases occur in females. Clinical trials of gene therapy for this condition have been unsuccessful. Toxic Optic Neuropathy  This can result in acute visual loss with bilateral optic disc swelling and cecocentral scotomas. Cases have been

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-9  Optic atrophy is not a specific diagnosis but refers to the combination of optic disc pallor, arteriolar narrowing, and nerve fiber layer destruction produced by a host of eye diseases, especially optic neuropathies. FIGURE 34-10  Papilledema in a young, obese woman with idiopathic intracranial hypertension (top), showing resolution after placement of a lumboperitoneal shunt (bottom). reported from exposure to methyl alcohol (moonshine) and ethylene glycol (antifreeze). More commonly, visual loss develops gradually and produces optic atrophy (Fig. 34-9) without a phase of acute optic disc edema. Ethambutol causes a dose-dependent toxic optic neuropathy in 2% of patients. Other agents have been implicated in toxic optic neuropathy, but supporting evidence is often weak. The following is a partial list of potential offending drugs or toxins: disulfiram, carbon monoxide, ethchlorvynol, chloramphenicol, amiodarone, monoclonal anti-CD3 antibody, ciprofloxacin, digitalis, streptomycin, lead, arse­ nic, thallium, d-penicillamine, isoniazid, emetine, and sulfonamides. Metallosis (chromium, cobalt, nickel) from hip implant failure is a rare cause of toxic optic neuropathy. Deficiency states induced by starva­ tion, malabsorption, alcoholism, or gastric bypass can lead to insidious visual loss. Thiamine, vitamin B12, and folate levels should be checked in any patient with unexplained bilateral central scotomas and optic pallor. Papilledema  This connotes bilateral optic disc swelling from raised intracranial pressure (Fig. 34-10). Headache is a common but not invariable accompaniment. All other forms of optic disc swelling (e.g., from optic neuritis or ischemic optic neuropathy) should be called “optic disc edema.” This convention is arbitrary but serves to avoid confusion. Often it is difficult to differentiate papilledema from other forms of optic disc edema by fundus examination alone. Transient

visual obscurations are a classic symptom of papilledema. They occur in only one eye or simultaneously in both eyes. They usually last seconds but can persist longer. Obscurations follow abrupt shifts in posture or happen spontaneously. When obscurations are prolonged or spontaneous, the papilledema is more threatening. Visual acuity is not affected by papilledema unless the papilledema is severe, longstanding, or accompanied by macular edema and hemorrhage. Visual field testing shows enlarged blind spots and peripheral constriction (Fig. 34-1F). With unremitting papilledema, peripheral visual field loss progresses in an insidious fashion while the optic nerve develops atrophy. In this setting, reduction of optic disc swelling is an ominous sign of a dying nerve rather than an encouraging indication of resolv­ ing papilledema. Evaluation of papilledema requires neuroimaging to exclude an intracranial lesion. Noninvasive MR vascular imaging may be useful in selected cases to search for a dural venous sinus thrombosis or an arteriovenous shunt. If neuroradiologic studies are negative, the sub­ arachnoid opening pressure should be measured in the lateral decu­ bitus position by lumbar puncture. Inaccurate pressure readings are a common pitfall. An elevated pressure, with normal cerebrospinal fluid, points by exclusion to the diagnosis of pseudotumor cerebri (idiopathic intracranial hypertension). Almost all patients are female, and most are obese. Treatment with a carbonic anhydrase inhibitor such as acet­ azolamide lowers intracranial pressure by reducing the production of cerebrospinal fluid and improves the visual fields. Weight reduction is vital: treatment with a glucagon-like peptide-1 receptor agonist is rec­ ommended in patients who cannot lose weight by diet control. If vision loss is severe or progressive, a shunt (preferably lumboperitoneal) should be performed without delay to prevent blindness. Endovascular placement of a stent across the junction of the transverse and sigmoid dural sinuses, where stenosis is usually present, has emerged as a new treatment option. Optic nerve sheath fenestration is a less effective approach and does not address other neurologic symptoms, such as headache. Occasionally, fulminant papilledema produces rapid onset of blindness. In such patients, emergency surgery should be performed to install a shunt. Optic Disc Drusen  These are refractile, glittering particles within the substance of the optic nerve head (Fig. 34-11). They are unrelated to drusen of the retina, which occur in age-related macular degen­ eration. Optic disc drusen are most common in people of northern European descent. Their diagnosis is obvious when they are visible on the surface of the optic disc. However, in many patients, they are hid­ den beneath the surface, producing pseudopapilledema. It is important FIGURE 34-11  Optic disc drusen are calcified, mulberry-like deposits of unknown etiology within the optic disc, giving rise to “pseudopapilledema.”

to recognize optic disc drusen to avoid an unnecessary evaluation for papilledema. When optic disc drusen are buried, B-ultrasound is the most sensitive way to detect them. They appear hyperechoic because they contain calcium. They are also visible on computed tomography (CT) or optical coherence tomography (OCT), a technique for acquir­ ing cross-section images of the retina. In most patients, optic disc dru­ sen are an incidental, innocuous finding, but they can produce visual obscurations. On perimetry, they give rise to enlarged blind spots and arcuate scotomas from damage to the optic disc. With increasing age, drusen tend to become more exposed on the disc surface as optic atrophy develops. Hemorrhage, choroidal neovascular membrane, and AION are more likely to occur in patients with optic disc drusen. No treatment is available.

Disorders of the Eye CHAPTER 34 Vitreous Degeneration  This occurs in all individuals with advancing age, leading to visual symptoms. Opacities develop in the vitreous, casting annoying shadows on the retina. As the eye moves, these distracting “floaters” move synchronously, with a slight lag caused by inertia of the vitreous gel. Vitreous traction on the retina causes mechanical stimulation, resulting in perception of flashing lights. Photopsia is brief and is confined to one eye, in contrast to the bilateral, prolonged scintillations of cortical migraine. Contraction of the vitreous can result in sudden separation from the retina, heralded by an alarming shower of floaters and photopsia. This process, known as vitreous detachment, is a common involutional event in the elderly. It is not harmful unless it damages the retina. A careful examination of the dilated fundus is important in any patient complaining of floaters or photopsia to search for peripheral tears or holes. If such a lesion is found, laser application can forestall a retinal detachment. Occasion­ ally a tear ruptures a retinal blood vessel, causing vitreous hemorrhage and sudden loss of vision. On attempted ophthalmoscopy the fundus is hidden by a dark haze of blood. Ultrasound is required to examine the interior of the eye for a retinal tear or detachment. If the hemorrhage does not resolve spontaneously, the vitreous can be removed surgically. Vitreous hemorrhage also results from the fragile neovascular vessels that proliferate on the surface of the retina in diabetes, sickle cell ane­ mia, and other ischemic ocular diseases. Retinal Detachment  This produces symptoms of floaters, flashing lights, and a scotoma in the peripheral visual field corresponding to the detachment (Fig. 34-12). If the detachment includes the fovea, there is an afferent pupil defect and the visual acuity is reduced. In most eyes, retinal detachment starts with a hole, flap, or tear in the peripheral retina (rhegmatogenous retinal detachment). Patients with peripheral FIGURE 34-12  Retinal detachment appears as an elevated sheet of retinal tissue with folds. In this patient, the fovea was spared, so acuity was normal, but an inferior detachment produced a superior scotoma.

retinal thinning (lattice degeneration) are particularly vulnerable to this process. Once a break has developed in the retina, liquefied vit­ reous is free to enter the subretinal space, separating the retina from the pigment epithelium. The combination of vitreous traction on the retinal surface and passage of fluid behind the retina leads inexorably to detachment. Patients with a history of myopia, trauma, or prior cata­ ract extraction are at greatest risk for retinal detachment. The diagnosis is confirmed by ophthalmoscopic examination of the dilated eye.

Classic Migraine  (See also Chap. 441) This usually occurs with a visual aura lasting about 20 min. In a typical attack, a small central disturbance in the field of vision marches toward the periphery, leav­ ing a transient scotoma in its wake. The expanding border of migraine scotoma has a scintillating, dancing, or zigzag edge, resembling the bastions of a fortified city, hence the term fortification spectra. Descrip­ tions of fortification spectra vary widely and can be confused with amaurosis fugax. Migraine patterns usually last longer and are per­ ceived in both eyes, whereas amaurosis fugax is briefer and occurs in only one eye. Migraine phenomena also remain visible in the dark or with the eyes closed. Generally, they are confined to either the right or the left visual hemifield, but sometimes, both fields are involved simultaneously. Patients often have a long history of stereotypic attacks. After the visual symptoms recede, headache develops in most patients. PART 2 Cardinal Manifestations and Presentation of Diseases Transient Ischemic Attacks  Vertebrobasilar insufficiency may result in acute homonymous visual symptoms. Many patients mis­ takenly describe symptoms in the left or right eye when, in fact, symptoms are occurring in the left or right hemifield of both eyes. Interruption of blood supply to the visual cortex causes a sudden fogging or graying of vision, occasionally with flashing lights or other positive phenomena that mimic migraine. Cortical ischemic attacks are briefer in duration than migraine, occur in older patients, and are not followed by headache. There may be associated signs of brainstem ischemia, such as diplopia, vertigo, numbness, weakness, and dysarthria. Stroke  Permanent vision loss occurs when interruption of blood supply from the posterior cerebral artery to the visual cortex is pro­ longed. The only finding on examination is a homonymous visual field defect that stops abruptly at the vertical meridian. Occipital lobe stroke usually is due to thrombotic occlusion of the vertebrobasilar system, embolus, or dissection. Lobar hemorrhage, tumor, abscess, and arterio­ venous malformation are other common causes of hemianopic cortical visual loss. Factitious (Functional, Nonorganic) Visual Loss  This is claimed by hysterics or malingerers. The latter account for the vast majority, seeking sympathy, special treatment, or financial gain by feigning loss of sight. The diagnosis is suspected when the history is atypical, physical findings are lacking or contradictory, inconsisten­ cies emerge on testing, and a secondary motive can be identified. In our litigious society, the fraudulent pursuit of recompense often drives factitious visual symptoms. ■ ■CHRONIC VISUAL LOSS Cataract  Cataract is a clouding of the lens sufficient to affect vision. Most cataracts develop slowly as a result of aging, leading to gradual impairment. The formation of cataract occurs more rapidly in patients with a history of uveitis, diabetes mellitus, ocular trauma, or vitrectomy. Cataracts are acquired in a variety of genetic diseases, such as myotonic dystrophy, neurofibromatosis type 2, and galactosemia. Radiation therapy and glucocorticoid treatment can induce cataract as a side effect. Such cataracts typically have a posterior subcapsular loca­ tion. Cataract can be detected by noting an impaired red reflex when viewing light reflected from the fundus with an ophthalmoscope or by examining the dilated eye with the slit lamp. The only treatment for cataract is surgical extraction of the opaci­ fied lens. Thirty million cataract operations are performed each year around the globe. The operation generally is done under local anesthe­ sia on an outpatient basis. A plastic or silicone intraocular lens is placed

within the empty lens capsule in the posterior chamber, substituting for the natural lens and leading to rapid recovery of sight. More than 95% of patients who undergo cataract extraction can expect an improve­ ment in vision. In some patients, the lens capsule remaining in the eye after cataract extraction eventually turns cloudy, causing secondary loss of vision. A small opening, called a posterior capsulotomy, is made in the lens capsule with a laser to restore clarity. Glaucoma  Glaucoma is a slowly progressive, insidious optic neu­ ropathy that usually is associated with chronic elevation of intraocu­ lar pressure. After cataract, it is the most common cause of blindness in the world. It is especially prevalent in people of African descent. The mechanism by which raised intraocular pressure injures the optic nerve is not understood. Axons entering the inferotemporal and superotemporal aspects of the optic disc are damaged first, producing typical nerve fiber bundle defects called arcuate scotomas. As fibers are destroyed, the neural rim of the optic disc shrinks and the physi­ ologic cup within the optic disc enlarges (Fig. 34-13). This process is referred to as pathologic “cupping.” The cup-to-disc diameter is expressed as a fraction (e.g., 0.2). The cup-to-disc ratio ranges widely in normal individuals, making it difficult to diagnose glaucoma reliably simply by observing an unusually large or deep optic cup. Careful documentation of serial examinations is helpful. In a patient with physiologic cupping, the large cup remains stable, whereas in a patient with glaucoma, it expands relentlessly over the years. Obser­ vation of progressive cupping and detection of an arcuate scotoma or a nasal step on computerized visual field testing is sufficient to establish the diagnosis of glaucoma. OCT reveals corresponding loss of fibers along the arcuate pathways in the nerve fiber layer and thin­ ning of the ganglion cell complex. Most patients with glaucoma have open anterior chamber angles. The cause of elevated intraocular pressure is usually unknown. Although a positive family history is a risk factor, genetic mutations impairing aqueous filtration from the eye have been identified in only a minority of cases. Surprisingly, a third of patients with open-angle glaucoma have an intraocular pressure within the normal range of 10–20 mmHg. Among patients with this normal-tension form of glau­ coma, high myopia is more common. Chronic angle-closure glaucoma and chronic open-angle glaucoma are usually asymptomatic. Only acute angle-closure glaucoma causes a red or painful eye, from abrupt elevation of intraocular pressure. In all forms of glaucoma, foveal acuity is spared until end-stage disease is reached. For these reasons, severe and irreversible damage can occur FIGURE 34-13  Glaucoma results in “cupping” as the neural rim is destroyed and the central cup becomes enlarged and excavated. The cup-to-disc ratio is about 0.8 in this patient.

before either the patient or the physician recognizes the diagnosis. Screening of patients for glaucoma by noting the cup-to-disc ratio on ophthalmoscopy and by measuring the intraocular pressure is vital. Glaucoma is treated with topical adrenergic agonists, cholinergic ago­ nists, beta blockers, prostaglandin analogues, and carbonic anhydrase inhibitors. Occasionally, systemic absorption of beta blocker from eyedrops can be sufficient to cause side effects of bradycardia, hypoten­ sion, heart block, bronchospasm, or depression. Laser treatment of the trabecular meshwork in the anterior chamber angle improves aqueous outflow from the eye. If medical or laser treatments fail to halt optic nerve damage from glaucoma, a filter must be constructed surgically (trabeculectomy) or a drainage device placed to release aqueous from the eye in a controlled fashion. Macular Degeneration  This is a major cause of gradual, painless, bilateral central visual loss in the elderly. It occurs in a nonexudative (dry) form and an exudative (wet) form. Inflammation may be impor­ tant in both forms of macular degeneration; susceptibility is associated with variants in the gene for complement factor H, an inhibitor of the alternative complement pathway. The nonexudative process begins with the accumulation of extracellular deposits called drusen under­ neath the retinal pigment epithelium. On ophthalmoscopy, they are pleomorphic but generally appear as small discrete yellow lesions clus­ tered in the macula (Fig. 34-14). With time, they become larger, more numerous, and confluent. The retinal pigment epithelium becomes focally detached and atrophic, causing visual loss by interfering with photoreceptor function. Treatment with vitamins C and E, beta-carotene, and zinc may slightly retard dry macular degeneration. Exudative macular degeneration, which develops in only a minority of patients, occurs when neovascular vessels from the choroid grow through defects in Bruch’s membrane and proliferate underneath the retinal pigment epithelium or the retina. Leakage from these vessels produces elevation of the retina, with distortion (metamorphopsia) and blurring of vision. Although the onset of these symptoms is usually gradual, bleeding from a subretinal choroidal neovascular membrane sometimes causes acute visual loss. Neovascular membranes can be difficult to see on fundus examination because they are located beneath the retina. Fluorescein angiography and OCT are extremely useful for their detection. Major or repeated hemorrhage under the retina from neovascular membranes results in fibrosis, development of a round (disciform) macular scar, and permanent loss of central vision. Exudative macular degeneration can be treated with intraocu­ lar injection of antagonists to vascular endothelial growth factor. FIGURE 34-14  Age-related macular degeneration consisting of scattered yellow drusen in the macula (dry form) and a crescent of fresh hemorrhage temporal to the fovea from a subretinal neovascular membrane (wet form).

Bevacizumab, ranibizumab, aflibercept, or brolucizumab is admin­ istered by direct injection into the vitreous cavity, beginning on a monthly basis. These antibodies cause the regression of neovascular membranes by blocking the action of vascular endothelial growth fac­ tor, thereby improving visual acuity.

Central Serous Chorioretinopathy  This primarily affects males between the ages of 20 and 50 years. Leakage of serous fluid from the choroid causes small, localized detachment of the retinal pigment epithelium and the neurosensory retina. These detachments produce acute or chronic symptoms of metamorphopsia and blurred vision when the macula is involved. They are difficult to visualize with a direct ophthalmoscope because the detached retina is transparent and only slightly elevated. OCT shows fluid beneath the retina, and fluores­ cein angiography shows dye streaming into the subretinal space. The cause of central serous chorioretinopathy is unknown. Symptoms may resolve spontaneously if the retina reattaches, but recurrent detach­ ment is common. Laser photocoagulation has benefited some patients with this condition. Disorders of the Eye CHAPTER 34 Diabetic Retinopathy  A rare disease until 1921, when the discov­ ery of insulin resulted in a dramatic improvement in life expectancy for patients with diabetes mellitus, diabetic retinopathy is now a leading cause of blindness in the United States. The retinopathy takes years to develop but eventually appears in nearly all cases. Regular surveil­ lance of the dilated fundus is crucial for any patient with diabetes. In advanced diabetic retinopathy, the proliferation of neovascular vessels leads to blindness from vitreous hemorrhage, retinal detachment, and glaucoma (Fig. 34-15). These complications can be avoided in most patients by administration of panretinal laser photocoagulation at the appropriate point in the evolution of the disease. Antivascular endothelial growth factor antibody treatment is equally effective, but intraocular injections must be given repeatedly. For further discussion of the manifestations and management of diabetic retinopathy, see Chaps. 415–417. Retinitis Pigmentosa  This is a general term for a disparate group of rod-cone dystrophies characterized by progressive night blindness, visual field constriction with a ring scotoma, loss of acuity, and an abnormal electroretinogram (ERG). It occurs sporadically or in an autosomal recessive, dominant, or X-linked pattern. Irregular black deposits of clumped pigment in the peripheral retina, called bone spicules because of their vague resemblance to the spicules of FIGURE 34-15  Proliferative diabetic retinopathy in a 25-year-old man with an 18-year history of diabetes, showing neovascular vessels emanating from the optic disc, retinal and vitreous hemorrhage, cotton-wool spots, and macular exudate. Round spots in the periphery represent recently applied panretinal photocoagulation.

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-16  Retinitis pigmentosa with black clumps of pigment known as “bone spicules.” The patient had peripheral visual field loss with sparing of central (macular) vision. cancellous bone, give the disease its name (Fig. 34-16). The name is actually a misnomer because retinitis pigmentosa is not an inflamma­ tory process. Genetic testing usually identifies a mutation in the gene for rhodopsin, the rod photopigment, or in the gene for peripherin, a glycoprotein located in photoreceptor outer segments. Leber’s congenital amaurosis, a rare cone dystrophy, has been treated by replacement of the missing RPE65 protein through gene therapy, resulting in slight improvement in visual function. Some forms of retinitis pigmentosa occur in association with rare, hereditary systemic diseases (olivopontocerebellar degeneration, Bassen-Kornzweig dis­ ease, Kearns-Sayre syndrome, Refsum’s disease). Chronic treatment with chloroquine, hydroxychloroquine, and phenothiazines (especially thioridazine) can produce visual loss from a toxic retinopathy that resembles retinitis pigmentosa. Patients receiving long-term treat­ ment with hydroxychloroquine require regular eye examinations and screening by OCT to monitor for potential development of a bull’s eye maculopathy. Epiretinal Membrane  This is a fibrocellular tissue that grows across the inner surface of the retina, causing metamorphopsia and reduced visual acuity from distortion of the macula. A crinkled, cello­ phane-like membrane is visible on the retinal examination. Epiretinal membrane is most common in patients aged >50 years and is usually unilateral. Most cases are idiopathic, but some occur as a result of hypertensive retinopathy, diabetes, retinal detachment, or trauma. When visual acuity is reduced to the level of about 6/24 (20/80), vitrectomy and surgical peeling of the membrane to relieve macular puckering are recommended. Contraction of an epiretinal membrane sometimes gives rise to a macular hole. Most macular holes, however, are caused by local vitreous traction within the fovea. Vitrectomy can improve acuity in selected cases. Melanoma and Other Tumors  Melanoma is the most common primary intraocular tumor (Fig. 34-17). Approximately 3500 cases occur annually in the United States. It causes photopsia, an enlarg­ ing scotoma, and loss of vision. A small melanoma is often difficult to differentiate from a benign choroidal nevus. Serial examinations are required to document a malignant pattern of growth. Risk factors include light skin, hair, and eyes. Uveal origin accounts for 85% of cases. GNAQ and GNA11 mutations are common. About half metas­ tasize, mainly to the liver. Small and medium-sized tumors may be treated with radiation therapy; enucleation is the best treatment for large tumors. Metastatic tumors to the eye outnumber primary tumors.

FIGURE 34-17  Melanoma of the choroid, appearing as an elevated dark mass in the inferior fundus, with overlying hemorrhage. The black line denotes the plane of the optical coherence tomography scan (below) showing the subretinal tumor. Breast and lung carcinomas have a special propensity to spread to the choroid or iris. Leukemia and lymphoma also commonly invade ocular tissues. Sometimes the only sign on eye examination is cellular debris in the vitreous, which can masquerade as a chronic posterior uveitis. In a patient with vision loss, CT or MR scanning should be consid­ ered if the cause remains unknown after careful review of the history, visual fields, and thorough examination of the eye. Optic nerve sheath meningioma is a common retrobulbar tumor. It produces the classic triad of optociliary shunt vessels, optic atrophy, and progressive visual loss. Optic disc swelling and proptosis are also frequent signs. Optic nerve glioma in young patients is usually a pilocytic astrocytoma and has a good prognosis for preservation of vision, especially in neurofi­ bromatosis type 1 (Chap. 95). In adults, optic nerve glioma is rare and highly malignant. Chiasmal tumors (pituitary adenoma, meningioma, craniopharyngioma) produce visual loss with few objective findings except for optic disc pallor. Loss of the temporal visual field in each eye is typical, but usually patients complain of vision loss in just one eye. OCT shows loss of the retinal nerve fiber layer entering the nasal and temporal sides of the optic discs, as well as thinning of the ganglion cell complex in each nasal retina (Fig. 34-18). A high degree of vigilance is necessary to avoid missing chiasmal tumors. Although symptoms progress gradually, in rare instances, the sudden expansion of a pitu­ itary adenoma from infarction and bleeding (pituitary apoplexy) causes acute severe retrobulbar visual loss, with headache, nausea, and ocular motor nerve palsies. ■ ■PROPTOSIS When the globes appear asymmetric, the clinician must first decide which eye is abnormal. Is one eye recessed within the orbit (enophthal­ mos), or is the other eye protuberant (exophthalmos, or proptosis)? A small globe or Horner’s syndrome can give the appearance of enoph­ thalmos. True enophthalmos occurs commonly after trauma, from atrophy of retrobulbar fat, or from fracture of the orbital floor. The position of the eyes within the orbits is measured by using a Hertel exophthalmometer, a handheld instrument that records the position of the anterior corneal surface relative to the lateral orbital rim. If this instrument is not available, relative eye position can be judged by

FIGURE 34-18  Bitemporal hemianopia (top), with corresponding thinning of the ganglion cell complex in the nasal maculae bilaterally (middle) and reduced retinal nerve fiber layer thickness along the temporal and nasal edges of the optic discs (red zone <1%) from compression of the optic chiasm by a pituitary adenoma (bottom). bending the patient’s head forward and looking down upon the orbits. A proptosis of only 2 mm in one eye is detectable from this perspective. The development of proptosis implies a space-occupying lesion in the orbit and may warrant CT or MR imaging. Graves’ Ophthalmopathy  This is the leading cause of proptosis in adults (Chap. 394). The proptosis is often asymmetric and can even appear to be unilateral. Orbital inflammation and engorgement of the extraocular muscles, particularly the medial rectus and the inferior rectus, account for protrusion of the globe. Corneal exposure, lid retrac­ tion, lid lag on downgaze, conjunctival injection, restriction of gaze, diplopia, and visual loss from optic nerve compression are cardinal symptoms. Graves’ eye disease is a clinical diagnosis, but laboratory testing can be useful. The serum level of thyroid-stimulating immu­ noglobulins is often elevated. Orbital imaging usually reveals enlarged extraocular eye muscles, but not always. Topical lubricants, taping the eyelids closed at night, and moisture chambers are helpful to limit exposure of ocular tissues. Graves’ ophthalmopathy can be treated with oral prednisone (60 mg/d) for 1 month, followed by a taper over several months, but worsening of symptoms upon glucocorticoid withdrawal is common. Infusions of teprotumumab, an inhibitor of the insulinlike growth factor I receptor, reduce proptosis and diplopia. Radiation therapy is not effective. Orbital decompression should be performed for severe, symptomatic exophthalmos or if visual function is reduced by optic nerve compression. In patients with diplopia, prisms or eye muscle surgery can be used to restore ocular alignment in primary gaze. Orbital Pseudotumor  Also known as idiopathic orbital inflam­ matory syndrome, orbital pseudotumor is distinguished from Graves’ ophthalmopathy by the prominent complaint of pain. Other symptoms include diplopia, ptosis, proptosis, and orbital congestion. Evaluation for sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease, and other types of orbital vasculitis or collagen-vascular pathology is negative. Imaging often shows swollen eye muscles (orbital myosi­ tis) with enlarged tendons. By contrast, in Graves’ ophthalmopathy, the tendons of the eye muscles usually are spared. The Tolosa-Hunt syndrome (Chap. 452) may be regarded as an extension of orbital pseudotumor through the superior orbital fissure into the cavernous

sinus. The diagnosis of orbital pseudotumor is difficult. Biopsy of the orbit frequently yields nonspecific evidence of fat infiltration by lymphocytes, plasma cells, and eosinophils. A dramatic response to a therapeutic trial of systemic glucocorticoids indirectly provides the best confirmation of the diagnosis.

Orbital Cellulitis  This causes pain, lid erythema, proptosis, con­ junctival chemosis, restricted motility, decreased acuity, afferent pupil­ lary defect, fever, and leukocytosis. It often arises from the paranasal sinuses, especially by contiguous spread of infection from the ethmoid sinus through the lamina papyracea of the medial orbit. A history of recent upper respiratory tract infection, chronic sinusitis, thick mucus secretions, or dental disease is significant in any patient with suspected orbital cellulitis. Blood cultures should be obtained, but they are usually negative. Most patients respond to empirical therapy with broadspectrum IV antibiotics. Occasionally, orbital cellulitis follows an over­ whelming course, with massive proptosis, blindness, septic cavernous sinus thrombosis, and meningitis. To avert this disaster, orbital celluli­ tis should be managed aggressively in the early stages, with immediate imaging of the orbits and antibiotic therapy that includes coverage of methicillin-resistant Staphylococcus aureus (MRSA). Prompt surgical drainage of an orbital abscess or paranasal sinusitis is indicated if optic nerve function deteriorates despite antibiotics. Disorders of the Eye CHAPTER 34 Tumors  Tumors of the orbit cause painless, progressive propto­ sis. The most common primary tumors are cavernous hemangioma, lymphangioma, neurofibroma, schwannoma, dermoid cyst, adenoid cystic carcinoma, optic nerve glioma, optic nerve meningioma, and benign mixed tumor of the lacrimal gland. Metastatic tumor to the orbit occurs frequently in breast carcinoma, lung carcinoma, and lym­ phoma. Diagnosis by fine-needle aspiration followed by urgent radia­ tion therapy sometimes can preserve vision. Carotid Cavernous Fistulas  With anterior drainage through the orbit, these fistulas produce proptosis, diplopia, glaucoma, and cork­ screw, arterialized conjunctival vessels. Direct fistulas usually result from trauma. They are easily diagnosed because of the prominent signs produced by high-flow, high-pressure shunting. Indirect fistulas, or dural arteriovenous malformations, are more likely to occur spontane­ ously, especially in older women. The signs are more subtle, and the diagnosis frequently is missed. The combination of slight proptosis, diplopia, enlarged muscles, and an injected eye often is mistaken for thyroid ophthalmopathy. A bruit heard upon auscultation of the head or reported by the patient is a valuable diagnostic clue. Imaging shows an enlarged superior ophthalmic vein in the orbits. Carotid cavernous shunts can be eliminated by endovascular embolization. ■ ■PTOSIS Blepharoptosis  This is an abnormal drooping of the eyelid. Unilateral or bilateral ptosis can be congenital, from dysgenesis of the levator palpebrae superioris, or from abnormal insertion of its aponeurosis into the eyelid. Acquired ptosis can develop so gradually that the patient is unaware of the problem. Inspection of old photo­ graphs is helpful in dating the onset. A history of prior trauma, eye surgery, contact lens use, diplopia, systemic symptoms (e.g., dysphagia or peripheral muscle weakness), or a family history of ptosis should be sought. Fluctuating ptosis that worsens late in the day is typical of myasthenia gravis. Ptosis evaluation should focus on evidence for pro­ ptosis, eyelid masses or deformities, inflammation, pupil inequality, or limitation of motility. The width of the palpebral fissures and distance from the upper eyelid margin to corneal light reflex are measured in primary gaze to determine the degree of ptosis. The ptosis will be underestimated if the patient compensates by lifting the brow with the frontalis muscle. Mechanical Ptosis  This occurs in many elderly patients from stretching and redundancy of eyelid skin and subcutaneous fat (dermato­ chalasis). The extra weight of these sagging tissues causes the lid to droop. Enlargement or deformation of the eyelid from infection, tumor, trauma, or inflammation also results in ptosis on a purely mechanical basis.

Aponeurotic Ptosis  This is an acquired dehiscence or stretching of the aponeurotic tendon, which connects the levator muscle to the tarsal plate of the eyelid. It occurs commonly in older patients, presum­ ably from loss of connective tissue elasticity. Aponeurotic ptosis is also a common sequela of eyelid swelling from infection or blunt trauma to the orbit, cataract surgery, or contact lens use.

Myogenic Ptosis  The causes of myogenic ptosis include myasthenia gravis (Chap. 459) and a number of rare myopathies that manifest with ptosis. The term chronic progressive external ophthalmoplegia refers to a spectrum of systemic diseases caused by mutations of mitochondrial DNA. As the name implies, the most prominent findings are symmet­ ric, slowly progressive ptosis and limitation of eye movements. In gen­ eral, diplopia is a late symptom because all eye movements are reduced equally. In the Kearns-Sayre variant, retinal pigmentary changes and abnormalities of cardiac conduction develop. Peripheral muscle biopsy shows characteristic “ragged-red fibers.” Oculopharyngeal dystrophy is a distinct autosomal dominant disease with onset in middle age, charac­ terized by ptosis, limited eye movements, and trouble swallowing. Myo­ tonic dystrophy, another autosomal dominant disorder, causes ptosis, ophthalmoparesis, cataract, and pigmentary retinopathy. Patients have muscle wasting, myotonia, frontal balding, and cardiac abnormalities. PART 2 Cardinal Manifestations and Presentation of Diseases Neurogenic Ptosis  This results from a lesion affecting the inner­ vation to either of the two muscles that open the eyelid: Müller’s muscle or the levator palpebrae superioris. Examination of the pupil helps distinguish between these two possibilities. In Horner’s syndrome, the eye with ptosis has a smaller pupil and the eye movements are full. In an oculomotor nerve palsy, the eye with the ptosis has a larger or a normal pupil. If the pupil is normal but there is limitation of adduc­ tion, elevation, and depression, a pupil-sparing oculomotor nerve palsy is likely (see next section). Rarely, a lesion affecting the small, central subnucleus of the oculomotor complex will cause bilateral ptosis with normal eye movements and pupils. ■ ■DOUBLE VISION (DIPLOPIA) The first point to clarify is whether diplopia persists in either eye after the opposite eye is covered. If it does, the diagnosis is monocular dip­ lopia. The cause is usually intrinsic to the eye and therefore has no dire implications for the patient. Corneal aberrations (e.g., keratoconus, pterygium), uncorrected refractive error, cataract, or foveal traction may give rise to monocular diplopia. Occasionally, it is a symptom of malingering or psychiatric disease. Diplopia alleviated by covering one eye is binocular diplopia and is caused by disruption of ocular align­ ment. Inquiry should be made into the nature of the double vision (purely side-by-side vs partial vertical displacement of images), mode of onset, duration, intermittency, diurnal variation, and associated neu­ rologic or systemic symptoms. If the patient has diplopia while being examined, motility testing should reveal a deficiency corresponding to the patient’s symptoms. However, subtle limitation of ocular excur­ sions is often difficult to detect. For example, a patient with a slight left abducens nerve paresis may appear to have full eye movements despite a complaint of horizontal diplopia upon looking to the left. In this situ­ ation, the cover test provides a more sensitive method for demonstrat­ ing the ocular misalignment. It should be conducted in primary gaze and then with the head turned and tilted in each direction while the patient fixates a central, distant target. In the above example, a cover test with the head turned to the right bringing the eyes into left gaze will maximize the fixation shift evoked by the cover test. Occasionally, a cover test performed in an asymptomatic patient during a routine examination will reveal an ocular deviation. If the eye movements are full and the ocular misalignment is equal in all direc­ tions of gaze (comitant deviation), the diagnosis is strabismus. In this condition, which affects about 1% of the population, fusion is disrupted in infancy or early childhood. To avoid diplopia, retinal input from the nonfixating eye may be partially suppressed. In some children, this leads to impaired vision (amblyopia, or “lazy” eye) in the deviated eye. Binocular diplopia results from a wide range of processes: infec­ tious, neoplastic, metabolic, degenerative, inflammatory, and vascular. One must decide whether the diplopia is neurogenic in origin or is

due to restriction of globe rotation by local disease in the orbit. Orbital pseudotumor, myositis, infection, tumor, thyroid disease, and muscle entrapment (e.g., from a blowout fracture) cause restrictive diplopia. The diagnosis of restriction is usually made by recognizing other associated signs and symptoms of local orbital disease. Dedicated, high-resolution orbital imaging with fat saturation and gadolinium enhancement is helpful when the cause of diplopia is not evident. Myasthenia Gravis  (See also Chap. 459) This is a major cause of painless diplopia. The diplopia is often intermittent, variable, and not confined to any single ocular motor nerve distribution. The pupils are always normal. Serial observation of a fatigable ptosis, often accompa­ nied by diplopia from fluctuating ocular misalignment, establishes the diagnosis. Many patients have a purely ocular form of the disease, with no evidence of systemic muscular weakness. Classically, the diagnosis was confirmed by an IV edrophonium injection, which produces a transient reversal of eyelid or eye muscle weakness, but this drug is discontinued in the United States. Blood tests for antibodies against the acetylcholine receptor or the MuSK protein are frequently negative in the purely ocular form of myasthenia gravis. Botulism from food or wound poisoning can mimic ocular myasthenia. If restrictive orbital disease and myasthenia gravis are excluded, a lesion of a cranial nerve supplying innervation to the extraocular muscles is the most likely cause of binocular diplopia. Oculomotor Nerve  The third cranial nerve innervates the medial, inferior, and superior recti; inferior oblique; levator palpebrae superi­ oris; and the iris sphincter. Total palsy of the oculomotor nerve causes ptosis, a dilated pupil, and leaves the eye “down and out” because of the unopposed action of the lateral rectus and superior oblique. This combination of findings is obvious. More challenging is the diagnosis of early or partial oculomotor nerve palsy. In this setting, any com­ bination of ptosis, pupil dilation, and weakness of the eye muscles supplied by the oculomotor nerve may be encountered. Frequent serial examinations during the rapidly evolving phase of the palsy help ensure that the diagnosis is not missed. The advent of an oculomotor nerve palsy with pupil involvement, especially when accompanied by pain, suggests a compressive lesion, such as a tumor or circle of Willis aneurysm. Urgent neuroimaging should be obtained, along with a CT or MR angiogram. The resolution of these noninvasive techniques has advanced to the point that catheter angiography is rarely necessary to exclude an aneurysm. A lesion of the oculomotor nucleus in the rostral midbrain produces signs that differ from those caused by a lesion of the nerve itself. There is bilateral ptosis because the levator muscle is innervated by a single central subnucleus. There is also weakness of the contralateral superior rectus, because it is supplied by the oculomotor nucleus on the other side. Occasionally both superior recti are weak. Isolated nuclear oculo­ motor palsy is rare. Usually, neurologic examination reveals additional signs that suggest brainstem damage from infarction, hemorrhage, tumor, or infection. Injury to structures surrounding fascicles of the oculomotor nerve descending through the midbrain has given rise to a number of classic eponymic designations. In Nothnagel’s syndrome, injury to the superior cerebellar peduncle causes ipsilateral oculomotor palsy and contralat­ eral cerebellar ataxia. In Benedikt’s syndrome, injury to the red nucleus results in ipsilateral oculomotor palsy and contralateral tremor, chorea, and athetosis. Claude’s syndrome incorporates features of both of these syndromes, by injury to both the red nucleus and the superior cerebel­ lar peduncle. Finally, in Weber’s syndrome, injury to the cerebral pedun­ cle causes ipsilateral oculomotor palsy with contralateral hemiparesis. In the subarachnoid space, the oculomotor nerve is vulnerable to aneurysm, meningitis, tumor, infarction, and compression. In cerebral herniation, the nerve becomes trapped between the edge of the tento­ rium and the uncus of the temporal lobe. Oculomotor palsy also can result from midbrain torsion and hemorrhage during herniation. In the cavernous sinus, oculomotor palsy arises from carotid aneurysm, carotid cavernous fistula, cavernous sinus thrombosis, tumor (pituitary adenoma, meningioma, metastasis), herpes zoster infection, and the Tolosa-Hunt syndrome.

The etiology of an isolated, pupil-sparing oculomotor palsy often remains an enigma even after neuroimaging and extensive laboratory testing. Most cases are thought to result from microvascular ischemia of the nerve somewhere along its course from the brainstem to the orbit. Usually, the patient complains of pain. Diabetes, hypertension, and vascular disease are major risk factors. Spontaneous recovery over a period of months is the rule. If this fails to occur or if new findings develop, the diagnosis of microvascular oculomotor nerve palsy should be reconsidered. Aberrant regeneration is common when the oculo­ motor nerve is injured by trauma or compression (tumor, aneurysm). Miswiring of sprouting fibers to the levator muscle and the rectus mus­ cles results in elevation of the eyelid upon downgaze or adduction. The pupil also constricts upon attempted adduction, elevation, or depres­ sion of the globe. Aberrant regeneration is not seen after oculomotor palsy from microvascular infarct and hence vitiates that diagnosis. Trochlear Nerve  The fourth cranial nerve originates in the mid­ brain, just caudal to the oculomotor nerve complex. Fibers exit the brainstem dorsally and cross to innervate the contralateral superior oblique. The principal actions of this muscle are to depress and intort the globe. A palsy therefore results in hypertropia and excyclotorsion. The cyclotorsion seldom is noticed by patients. Instead, they complain of vertical diplopia, especially upon reading or looking down. Vertical diplopia is exacerbated by tilting the head toward the side with the muscle palsy and alleviated by tilting it away. This “head tilt test” is a cardinal diagnostic feature. Review of old photographs will sometimes reveal a habitual head tilt, signifying a patient with a decompensated, congenital trochlear nerve palsy. New, isolated trochlear nerve palsy results from all the causes listed above for the oculomotor nerve except aneurysm. The trochlear nerve is particularly apt to suffer injury after closed head trauma. The free edge of the tentorium impinges on the nerve during a concussive blow. Most isolated trochlear nerve palsies are idiopathic and hence are diagnosed by exclusion as “microvascular.” Spontaneous improvement occurs over a period of months in most patients. A base-down prism (conveniently applied to the patient’s glasses as a stick-on Fresnel lens) may serve as a temporary measure to alleviate diplopia. If the palsy does not resolve, the eyes can be realigned by weakening the inferior oblique muscle. Abducens Nerve  The sixth cranial nerve innervates the lateral rectus muscle. A palsy produces horizontal diplopia, worse on gaze to the side of the lesion. A nuclear lesion has different consequences, because the abducens nucleus contains interneurons that project via the medial longitudinal fasciculus to the medial rectus subnucleus of the contralateral oculomotor complex. Therefore, an abducens nuclear lesion produces a complete lateral gaze palsy from weakness of both the ipsilateral lateral rectus and the contralateral medial rectus. Foville’s syndrome after dorsal pontine injury includes lateral gaze palsy, ipsilat­ eral facial palsy, and contralateral hemiparesis incurred by damage to descending corticospinal fibers. Millard-Gubler syndrome from ventral pontine injury is similar except for the eye findings. There is lateral rec­ tus weakness only, instead of gaze palsy, because the abducens fascicle is injured rather than the nucleus. Infarct, tumor, hemorrhage, vascular malformation, and multiple sclerosis are the most common etiologies of brainstem abducens palsy. After leaving the ventral pons, the abducens nerve runs forward along the clivus to pierce the dura at the petrous apex, where it enters the cavernous sinus. Along its subarachnoid course, it is susceptible to meningitis, tumor (meningioma, chordoma, carcinomatous meningitis), subarachnoid hemorrhage, trauma, and compression by aneurysm or dolichoectatic vessels. At the petrous apex, mastoiditis can produce deaf­ ness, pain, and ipsilateral abducens palsy (Gradenigo’s syndrome). In the cavernous sinus, the nerve can be affected by carotid aneurysm, carotid cavernous fistula, tumor (pituitary adenoma, meningioma, nasopharyn­ geal carcinoma), herpes infection, and Tolosa-Hunt syndrome. Unilateral or bilateral abducens palsy is a classic sign of raised intracranial pressure. The diagnosis can be confirmed if papilledema is observed on fundus examination. The mechanism is still debated but probably is related to rostral-caudal displacement of the brainstem. The

same phenomenon accounts for abducens palsy from Chiari malfor­ mation or low intracranial pressure (e.g., after lumbar puncture, spinal anesthesia, or spontaneous dural cerebrospinal fluid leak).

Treatment of abducens palsy is aimed at prompt correction of the underlying cause. However, the cause remains obscure in many instances despite diligent evaluation. As was mentioned above for isolated trochlear or oculomotor palsy, most cases are assumed to rep­ resent microvascular infarcts because they often occur in the setting of diabetes or other vascular risk factors. Some cases may develop as a postinfectious mononeuritis (e.g., after a viral flu). Patching one eye, occluding one eyeglass lens with tape, or applying a temporary prism will provide relief of diplopia until the palsy resolves. If recovery is incomplete, eye muscle surgery nearly always can realign the eyes, at least in primary position. A patient with an abducens palsy that fails to improve should be reevaluated for an occult etiology (e.g., chordoma, carcinomatous meningitis, carotid cavernous fistula, myasthenia gra­ vis). Skull base tumors are easily missed even on contrast-enhanced neuroimaging studies. Disorders of the Eye CHAPTER 34 Multiple Ocular Motor Nerve Palsies  These should not be attributed to spontaneous microvascular events affecting more than one cranial nerve at a time. This remarkable coincidence does occur, especially in diabetic patients, but the diagnosis is made only in ret­ rospect after all other diagnostic alternatives have been exhausted. Neuroimaging should focus on the cavernous sinus, superior orbital fissure, and orbital apex, where all three ocular motor nerves are in close proximity. In a diabetic or immunocompromised host, fungal infection (Aspergillus, Mucorales, Cryptococcus) is a common cause of multiple nerve palsies. In a patient with systemic malignancy, carcino­ matous meningitis is a likely diagnosis. Cytologic examination may be negative despite repeated sampling of the cerebrospinal fluid. The can­ cer-associated Lambert-Eaton myasthenic syndrome also can produce ophthalmoplegia. Giant cell (temporal) arteritis occasionally manifests as diplopia from ischemic palsies of extraocular muscles. Fisher’s syn­ drome, an ocular variant of Guillain-Barré, produces ophthalmoplegia with areflexia and ataxia. Often the ataxia is mild, and the reflexes are normal. Antiganglioside antibodies (GQ1b) can be detected in about 50% of cases. Supranuclear Disorders of Gaze  These are often mistaken for multiple ocular motor nerve palsies. For example, Wernicke’s encepha­ lopathy can produce nystagmus and a partial deficit of horizontal and vertical gaze that mimics a combined abducens and oculomotor nerve palsy. The disorder occurs in patients who are malnourished, alco­ holic, or following bariatric surgery, and can be reversed by thiamine. Infarct, hemorrhage, tumor, multiple sclerosis, encephalitis, vasculitis, and Whipple’s disease are other important causes of supranuclear gaze palsy. Disorders of vertical gaze, especially downward saccades, are an early feature of progressive supranuclear palsy. Smooth pursuit is affected later in the course of the disease. Parkinson’s disease, Huntington’s disease, and olivopontocerebellar degeneration also can affect vertical gaze. The frontal eye field of the cerebral cortex is involved in generation of saccades to the contralateral side. After hemispheric stroke, the eyes usually deviate toward the lesioned side because of the unopposed action of the frontal eye field in the normal hemisphere. With time, this deficit resolves. Seizures generally have the opposite effect: the eyes deviate conjugately away from the irritative focus. Parietal lesions disrupt smooth pursuit of targets moving toward the side of the lesion. Bilateral parietal lesions produce Bálint’s syndrome, which is charac­ terized by impaired eye-hand coordination (optic ataxia), difficulty initiating voluntary eye movements (ocular apraxia), and visuospatial disorientation (simultanagnosia). Horizontal Gaze  Descending cortical inputs mediating horizon­ tal gaze ultimately converge at the level of the pons. Neurons in the paramedian pontine reticular formation are responsible for control­ ling conjugate gaze toward the same side. They project directly to the ipsilateral abducens nucleus. A lesion of either the paramedian pon­ tine reticular formation or the abducens nucleus causes an ipsilateral

conjugate gaze palsy. Lesions at either locus produce nearly identical clinical syndromes, with the following exception: vestibular stimula­ tion (oculocephalic maneuver or caloric irrigation) will succeed in driving the eyes conjugately to the side in a patient with a lesion of the paramedian pontine reticular formation but not in a patient with a lesion of the abducens nucleus.

INTERNUCLEAR OPHTHALMOPLEGIA  This results from damage to the medial longitudinal fasciculus ascending from the abducens nucleus in the pons to the oculomotor nucleus in the midbrain (hence, “inter­ nuclear”). Damage to fibers carrying the conjugate signal from abducens interneurons to the contralateral medial rectus motoneurons results in a failure of adduction on attempted lateral gaze. For example, a patient with a left internuclear ophthalmoplegia (INO) will have slowed or absent adducting movements of the left eye (Fig. 34-19). A patient with bilateral injury to the medial longitudinal fasciculus will have bilateral INO. Multiple sclerosis is the most common cause, although tumor, stroke, trauma, or any brainstem process may be responsible. One-anda-half syndrome is due to a lesion of the medial longitudinal fasciculus combined with a lesion of either the abducens nucleus or the paramedian pontine reticular formation on the same side. The patient’s only horizon­ tal eye movement is abduction of the eye on the other side. PART 2 Cardinal Manifestations and Presentation of Diseases Vertical Gaze  Midbrain lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus and the interstitial nucleus of Cajal cause supranuclear paresis of upgaze, downgaze, or all vertical eye movements. Distal basilar artery ischemia is the most common etiol­ ogy. Skew deviation refers to a vertical misalignment of the eyes, usually constant in all positions of gaze. The finding has poor localizing value because skew deviation has been reported after lesions in widespread regions of the brainstem and cerebellum. PARINAUD’S SYNDROME  Also known as dorsal midbrain syndrome, this is a distinct supranuclear vertical gaze disorder caused by damage to the posterior commissure. It is a classic sign of hydrocephalus from aqueductal stenosis. Pineal region or midbrain tumors, cysticercosis, and stroke also cause Parinaud’s syndrome. Features include loss of upgaze (and sometimes downgaze), convergence-retraction nystagmus on attempted upgaze, downward ocular deviation (“setting sun” sign), lid retraction (Collier’s sign), skew deviation, pseudoabducens palsy, and light-near dissociation of the pupils. Nystagmus  This is a rhythmic oscillation of the eyes, occurring physiologically from vestibular and optokinetic stimulation or pathologi­ cally in a wide variety of diseases (Chap. 24). Abnormalities of the eyes or optic nerves, present at birth or acquired in childhood, can produce a complex, searching nystagmus with irregular pendular (sinusoidal) and jerk features. Examples are albinism, Leber’s congenital amaurosis, and bilateral cataract. This nystagmus is commonly referred to as congenital sensory nystagmus. This is a poor term because even in children with congenital lesions, the nystagmus does not appear until weeks after birth. Congenital motor nystagmus, which looks similar to congenital sensory nystagmus, develops in the absence of any abnormality of the sensory visual system. Visual acuity usually is also reduced, probably by the nys­ tagmus itself, but seldom below a level of 20/200. JERK NYSTAGMUS  This is characterized by a slow drift off the target, followed by a fast corrective saccade. By convention, the nystagmus is named after the quick phase. Jerk nystagmus can be downbeat, upbeat, horizontal (left or right), and torsional. The pattern of nystagmus may vary with gaze position. Some patients will be oblivious to their nystag­ mus. Others will complain of blurred vision or a subjective to-and-fro movement of the environment (oscillopsia) corresponding to the nys­ tagmus. Fine nystagmus may be difficult to see on gross examination of the eyes. Observation of nystagmoid movements of the optic disc on ophthalmoscopy is a sensitive way to detect subtle nystagmus. GAZE-EVOKED NYSTAGMUS  This is the most common form of jerk nystagmus. When the eyes are held eccentrically in the orbits, they have a natural tendency to drift back to primary position. The subject compensates by making a corrective saccade to maintain the deviated eye position. Many normal patients have mild gaze-evoked nystagmus.

A B C D FIGURE 34-19  Left internuclear ophthalmoplegia (INO). A. In primary position of gaze, the eyes appear normal. B. Horizontal gaze to the left is intact. C. On attempted horizontal gaze to the right, the left eye fails to adduct. In mildly affected patients, the eye may adduct partially or more slowly than normal. Nystagmus is usually present in the abducted eye. D. T2-weighted axial magnetic resonance image through the pons showing a demyelinating plaque in the left medial longitudinal fasciculus (arrow).