Relative Afferent Pupillary Defect

The swinging flashlight test and the detection and grading of RAPDs are discussed in Chapter 2 . Abnormal visual acuity and color vision, a central scotoma, and an RAPD collectively are highly suggestive of an optic neuropathy, although a large macular or other retinal lesion could produce similar findings. In bilateral optic nerve disease, an RAPD may not be present unless the visual loss is asymmetric. An individual with severe unilateral visual loss, no RAPD, and a normal ocular examination may have nonorganic visual loss. An RAPD is not associated with visual loss due to corneal, lens, and vitreous opacities and refractive errors, but a densely amblyopic eye may have a mild RAPD. Nevertheless, an amblyopic eye with an RAPD generally requires further investigation to exclude an acquired optic neuropathy. When anisocoria is present, care should be taken to avoid overcalling an RAPD. In this setting, a false RAPD can be seen on the side of the smaller pupil as less light enters this eye than the fellow eye.

Asymmetric chiasmal syndromes may be associated with an RAPD, especially if an eye has subnormal visual acuity. Isolated optic tract lesions may have a contralateral RAPD, despite normal visual acuities, because the defective temporal field in the contralateral eye is 61–71% larger than the nasal field of the ipsilateral eye, the nasal retina has a greater photoreceptor density, and the ratio of crossed to uncrossed fibers in the chiasm is 53 : 47. The magnitude of the RAPD in this setting may reflect the relative light sensitivity of the intact temporal versus nasal field. Less commonly, when an optic tract disturbance is associated with an incongruous homonymous hemianopia with greater involvement of the nasal field, the RAPD will be in the eye ipsilateral to the lesion. Behr’s pupil (a large contralateral pupil) and Wernicke’s hemianopic pupil, one which reacts more briskly to light projected from within the intact hemifield than to light within the abnormal field, have been associated with optic tract syndromes. However, in clinical practice they are rarely identified, and the reliability of both signs has been questioned. RAPDs in patients with hemianopias due to retrogeniculate lesions have been reported, but in those cases concomitant optic tract involvement was not convincingly excluded.

Exceptional cases of RAPDs without visual loss can be associated with lesions in the midbrain pretectum, which contains afferent pupillary fibers and the pretectal nuclei, but no visual fibers ( Fig. 13.8 ). Due to more contralateral nasal than ipsilateral temporal fiber involvement of the afferent pathway as in an optic tract lesion, the RAPD is usually contralateral to the lesion. Most of these patients have other signs of dorsal midbrain involvement, such as upgaze paresis, ataxia, or fourth nerve dysfunction.

Axial fluid level attenuated inversion recovery magnetic resonance imaging in a patient with a left afferent pupillary defect due to a tectal glioma, predominantly on the right ( arrow ). The patient’s visual acuity and visual fields were normal.

Pupillometry studies have demonstrated that some individuals with normal visual function can have subtle RAPDs which may fluctuate (up to 0.3 log units) when tested over years. Whether the RAPDs were due to test artifact or were reflective of asymmetry in the visual pathways was unclear.

Amaurotic (Deafferented) Pupil

In the absence of any optic nerve or retinal function, or both, the eye is completely blind (i.e., has no light perception (NLP)), and the pupil will be unreactive to even the brightest direct light stimuli because it is deafferented. If the fellow eye is normal and light is directed at it, the pupillary reaction in the affected eye (consensual) should be intact. An amaurotic pupil confirms blindness if the patient claims not to see anything out of that eye. However, if the pupil reacts to direct light in an eye with purported blindness, the visual loss is either nonorganic or has a cortical basis or the patient is a poor observer. In certain conditions such as Leber’s hereditary optic neuropathy there may be a mismatch with relatively preserved pupillary reaction due to intact ipRGC function and very poor vision. Bilateral deafferentiation will result in an increase in the resting size of both pupils, as less total light is able to reach the midbrain pretectum.

Deafferented pupils can also react during attempted viewing of near targets and thus exhibit light-near dissociation ( Table 13.1 ). Even individuals who are bilaterally blind can attempt to look at their thumb placed a few inches in front of their face and stimulate the near reflex, as this task can be accomplished using proprioceptive clues.

Pretectal Pupils

Lesions affecting the dorsal midbrain, causing the pretectal, or Parinaud, syndrome (see Chapter 16 ), may interfere with pupillary reactivity by disrupting ganglion cell axons entering the pretectal region. The pretectal nuclei may also be involved. Bilaterally the pupils may be midposition to large and exhibit light-near dissociation due to intact supranuclear influences upon midbrain accommodative centers ( Fig. 13.9 ,Video 13.1 ). Usually both pupils are involved, although size and light reactivity may be asymmetric. Occasionally the near response may also be defective, as accommodative and convergence insufficiency can be observed. The diagnosis is suggested when other features of Parinaud syndrome, such as upgaze paresis, convergence retraction saccades, and eyelid retraction, are evident. Common causes include pineal region tumors and hydrocephalus, so abnormal pupils suggestive of a tectal lesion mandate neuroimaging.

Tectal pupils associated with Parinaud syndrome due to a pineal region germinoma. A. On examination this 15-year-old boy was found to have upgaze paresis, ocular tilt reaction (right superior rectus skew deviation and head tilt), papilledema, and anisocoria. The pupils were moderate in size and poorly reactive to light, but when the patient looked at a near target, the pupils constricted ( B ) (light-near dissociation). Sagittal ( C ) and axial ( D ) gadolinium-enhanced magnetic resonance imaging demonstrated hydrocephalus and a large enhancing pineal region mass ( arrows ) compressing the dorsal midbrain.

Argyll Robertson Pupils

Argyll Robertson pupils also exhibit light-near dissociation with a brisk constriction during near viewing but typically are miotic, are slightly irregular, and dilate poorly in the dark ( Fig. 13.10 ). The pupil does not react to light regardless of which eye is stimulated. Technically, to have an Argyll Robertson pupil, the involved eye must have some vision, to ensure the light-near dissociation is not due to a deafferented pupil. This pupillary abnormality is highly suggestive of syphilis and should therefore prompt serologic and fluorescent treponemal antibody absorption (FTA-ABS) testing. However, it is nonspecific and may also be caused by diabetes. The lesion responsible for Argyll Robertson pupils is uncertain but may result either from a disturbance in the midbrain light-reflex pathway between the pretectal and Edinger–Westphal nuclei or from damage to the ciliary ganglia.

Argyll Robertson pupils in tabes dorsalis (absent deep tendon reflexes, loss of vibratory sense and proprioception in the lower extremities, and Charcot joints). The pupils are small (A) and poorly reactive to light (B) but constrict during near viewing (C).

(Courtesy of Dr. J. Lawton Smith.)

Third Nerve Palsy

Because the third nerve carries parasympathetic fibers originating from the Edinger–Westphal nuclei, injury to the third nerve often results in an ipsilateral poorly reactive or unreactive pupil.

Signs and symptoms. In a pupil-involving third nerve palsy, the pupil is large and does not constrict to light, either directly or consensually, or during near viewing (internal ophthalmoplegia) ( Fig. 13.11 ). Usually either ptosis or a deficit in adduction, depression, or elevation of the eye, or a combination of these findings (external ophthalmoplegia), will assist in the diagnosis of a third nerve palsy, but in very rare instances a dilated pupil is the only manifestation. In inferior division third nerve palsies, the pupil and inferior rectus muscles are involved. In a pupil-sparing third nerve palsy, the eye movements or lid are affected, but the pupil retains normal size and reactivity.

Pupil-involving left third nerve palsy due to head trauma. A. The ptotic left eyelid is being elevated, revealing the exotropic and hypotropic left eye and dilated left pupil. The right eyelid is also being elevated for photographic purposes. B. The left pupil is fixed (i.e., it does not react to direct light). Notice the intact right pupil constricts to light shone in the left eye (consensual response).

Because a dilated pupil exposes spherical aberrations of the lens and cornea, some patients with pupil-involving third nerve palsies complain of blurry vision in that eye. Because this is a refractive problem, a pinhole occluder resolves the visual symptom. Abnormal miosis during attempted ocular adduction or depression may be a sign of aberrant regeneration (synkinesis or misdirection) following a third nerve palsy ( Fig. 13.12 andVideo 13.2 ). The phenomenon results when fibers that had previously supplied the medial rectus or inferior rectus regenerate and accidentally reach the ciliary ganglion, then connect with postganglionic neurons, which innervate the pupil. In these situations the pupil does not react to direct or consensual light stimulation but contracts during ocular adduction or depression. Segmental contraction of the iris sphincter during eye movements (Czarnecki’s sign ) may also be observed in these instances. Furthermore, because postganglionic accommodative fibers far outnumber those dedicated to the pupillary light reflex (see Tonic Pupils ), pupillary miosis during near viewing is more likely to recover than constriction to direct light (light-near dissociation). These pupillary signs are sometimes accompanied by other manifestations of aberrant regeneration of the third nerve, such as elevation of the ptotic eyelid during adduction or depression of the eye.

Pupillary constriction in adduction due to aberrant regeneration of the right third nerve. Pituitary apoplexy had caused ptosis and complete ophthalmoplegia of the right eye (see Fig. 7.21 for magnetic resonance imaging of the same patient), which recovered. The right pupil remained slightly enlarged but was reactive to light. When the eyes are in ( A ) primary gaze, ( B ) upgaze, ( C ) rightward gaze, and ( D ) downgaze, the right pupil is larger than the left. However, ( E ) the right pupil constricts during adduction of the right eye and ( F ) constricts more than the left when the patient viewed a near target.

Etiology . Pupil involvement is commonly seen in nuclear, fascicular, and especially subarachnoid third nerve palsies. As alluded to earlier, the external location of the pupillary fibers of the third nerve renders them particularly vulnerable to compression and infiltration in subarachnoid processes such as meningitis, aneurysmal compression (posterior communicating or internal carotid), and uncal herniation (Hutchinson’s pupil). Pupil-sparing third nerve palsies in middle-aged to elderly patients are usually related to diabetes or hypertension but occasionally can be seen even in fascicular or subarachnoid third nerve palsies from other causes. However, an aneurysm that presents initially with external ophthalmoparesis or ptosis alone typically will involve the pupil within several days.

Aberrant regeneration most commonly occurs in traumatic or compressive third nerve palsies, sometimes with congenital or tumor-related third nerve palsies, but almost never in diabetic or hypertensive third nerve palsies.

Pharmacologic testing . A chronically dilated pupil due to a third nerve palsy may be difficult to distinguish from a tonic pupil (see later discussion). Although the latter redilates slowly after constriction, both may exhibit light-near dissociation, segmental paresis of the iris sphincter, and denervation hypersensitivity. The last characteristic, demonstrated by pupillary constriction following instillation of dilute (0.125%) pilocarpine eye drops, does not seem to depend on whether the lesion is anatomically before or after the ciliary ganglion (i.e., preganglionic or postganglionic), or whether there is aberrant regeneration. Jacobson has offered the following explanations for denervation hypersensitivity in preganglionic third nerve lesions: (1) transsynaptic degeneration of postganglionic axons; (2) the greater sensitivity of larger pupils than smaller ones to dilute pilocarpine; and (3) upregulation of acetylcholine receptors because of decreased cholinergic stimulation following third nerve injury. Denervation hypersensitivity in acute pupil-involving third nerve palsies, due to unclear mechanisms, is less common but has been observed.

Management . If the patient has isolated pupillary dilation along with other signs of a third nerve palsy, an aneurysm of the posterior communicating artery should be considered until proven otherwise. To minimize risk and to screen for other possible compressive lesions, noninvasive angiography as well as routine brain imaging should be performed first. Either an emergent computed tomography (CT) and CT angiography or magnetic resonance imaging (MRI) and MRI angiography can be obtained. The choice of CT or MRI depends on which is more rapidly available, whether the patient is allergic to CT contrast, and whether MRI is contraindicated because of a pacemaker or metal in the body. If the scans are negative, conventional angiography may still be necessary as small symptomatic aneurysms can still be missed by CT or MRI angiography. Although CT angiography is emerging as a noninvasive technique for identification of posterior communicating artery aneurysms, the importance of the training and experience of the radiologist interpreting these studies is a critical component. Whether a catheter angiogram should be obtained in the setting of a negative MRI or CT angiogram continues to be a matter of debate and relies heavily on the correct performance and interpretation of the noninvasive study. CT angiography and subsequent catheter angiography can also demonstrate changes in aneurysm morphology occurring between studies, including sudden expansion leading to the acute appearance of a pupil-involving third nerve palsy.

The reader is referred to a more detailed discussion regarding the differential diagnosis and management of third nerve palsies, in addition to issues regarding pupil-involving versus pupil-sparing third nerve palsies and aberrant regeneration, in Chapter 15 .

Tonic Pupils

Clinical symptoms and signs (see Box 13.2 ). Patients with a tonic pupil often discover that they have a unilateral, partially dilated pupil while looking in the mirror, or a friend notices the pupillary inequality. Affected individuals are usually otherwise healthy and more commonly female. They may be symptomatic with photophobia or difficulty reading with that eye. In general, the disorder is painless, although occasionally patients will complain of a cramping sensation in the affected eye from ciliary body spasm.

Characteristically the pupil is initially large, exhibits light-near dissociation ( Fig. 13.13 ), and redilates slowly after constriction after near fixation (hence the term “tonic”). In some patients, especially in early cases, the near response may also be defective, or the individual may have difficulty refixing from near to far visual targets (“tonic” accommodation). Corneal sensation may be depressed. On a slit-lamp examination, the pupil may be irregular, with sectoral paralysis (immobility of parts of the pupil during light stimulation), vermiform movements, and loss of pupillary ruff (the normal border of the pupil). After 1 or 2 months, a tonic pupil may become miotic and smaller than the fellow pupil. In most patients the disorder is unilateral, but in about 10% of cases, the other pupil may become involved months or years later.

Idiopathic right tonic pupil. The right pupil is midposition and larger than the left ( A ), poorly reactive to light, but reactive during near viewing (the examiner’s thumb) ( B ). The patient complained of blurry vision in the right eye while attempting to read, consistent with accommodation paresis. After instillation of 0.125% pilocarpine eye drops at 0 and 5 minutes into both conjunctivae, 30 minutes later the right pupil constricted while the left did not (( C ) compared with ( A )), indicating denervation hypersensitivity on the right.

Pathophysiology . The pupillary abnormality results from damage to the ciliary ganglion or the postganglionic short ciliary nerves (see Fig. 13.3 ), which innervate the pupillary sphincter and ciliary muscles (the latter is important for accommodation). Partial preservation of the pupil’s parasympathetic innervation results in areas of segmental contraction adjacent to sector paralysis. When normal portions of the pupil contract, they pull and twist paralyzed segments towards them. Accommodation paresis accounts for the difficulty with near vision, and the photophobia results from the poor pupillary constriction to light. The light-near dissociation can be explained by the 30 : 1 ratio of accommodative fibers arising from the ciliary ganglion relative to those responsible for pupillary constriction. Hence damage to the ciliary ganglion or short ciliary nerves would have a greater chance of disabling pupillary constriction to light than disrupting miosis during near viewing. Furthermore, as neuronal cell bodies in the ciliary ganglion sprout new axons following injury, postganglionic accommodative fibers may mistakenly reinnervate the iris sphincter. This misdirection results in excess pupillary constriction during accommodation.

Etiology . The causes of tonic pupils fall into four major groups:

• 1.
  

  Adie (or Holmes Adie) syndrome, which is a symptom complex consisting of tonic pupil(s) and absent deep tendon reflexes. The cause has yet to be elucidated, but the disorder may be explained by concurrent involvement of the ciliary and dorsal root ganglia or root entry zone.

  
  
• 2.
  

  Local ocular processes that affect the ciliary ganglion or short ciliary nerves, such as eye or orbital trauma, sarcoidosis, or viral illnesses (e.g., varicella), or ischemia (e.g., giant cell arteritis, other vasculitides, or strabismus surgery). Orbital tumors have also been reported in association with tonic pupils ( Fig. 13.14 ). Panretinal photocoagulation (laser) in patients with proliferative diabetic retinopathy may damage the ciliary nerves underlying the retina. The resultant pupil is typically irregularly shaped and poorly reactive to light ( Fig. 13.15 ). Other factors contributing to a poorly reactive pupil in diabetics can include iris ischemia, iris neovascularization, and associated autonomic neuropathy.

  
  

  
  

  
  

  

  
  

  
  

  Posterolateral orbital mass that caused a tonic pupil in an infant. The lesion, which presumably compressed the ciliary ganglion or short ciliary nerves, was demonstrated to be a glial–neural hamartoma at biopsy. A. Axial contrast-enhanced magnetic resonance imaging (MRI) with fat saturation reveals enhancement on the periphery ( white arrow ) of the mass. There is normal contrast enhancement of the rectus muscles, and thus the right lateral rectus ( black arrows ) can be distinguished from the mass that lies along it. B. Coronal MRI reveals the mass ( white arrow ) in the inferolateral aspect of the right orbit and obscuring the inferior and lateral rectus muscles, which are visible in the normal left orbit. The mass abuts the optic nerve sheath complex ( black arrow ), which is slightly displaced superiorly.

  
  

  (From Brooks-Kayal AR, Liu GT, Menacker SJ, et al. Tonic pupil and orbital glial-neural hamartoma in infancy. Am J Ophthalmol 1995;119:809–811, with permission from Elsevier Science.)

  
  

  
  

  

  
  

  
  

  
  

  

  
  

  
  

  Irregularly shaped pupil in a diabetic patient who had undergone panretinal photocoagulation and whose diabetes was complicated by peripheral and autonomic neuropathy.

  
  
  
  
• 3.
  

  Reflecting autonomic dysfunction, tonic pupils uncommonly may occur in association with neurosyphilis, advanced diabetes mellitus, dysautonomias (e.g., Shy–Drager and Riley–Day syndromes), amyloidosis, Guillain–Barré syndrome, Miller Fisher variant (see below), Charcot–Marie–Tooth and Dejerine–Sottas neuropathies, Lambert–Eaton myasthenic syndrome, and paraneoplastic syndromes. Patients with tonic pupils associated with congenital neuroblastoma, Hirschsprung disease, and central hypoventilation syndrome have also been described.

  
  
• 4.
  

  Idiopathic tonic pupils. Either unilateral or bilateral, these tonic pupils are unassociated with absent deep tendon reflexes, midbrain or orbital lesions, or systemic disorders.

Ross and harlequin syndromes are two rare focal dysautonomias frequently associated with pupillary abnormalities. Ross syndrome is characterized by the triad of tonic pupil, hyporeflexia, and segmental anhidrosis. It is probably related to injury to sympathetic and parasympathetic ganglion cells or their postganglionic projections and rarely can be associated with Horner syndrome. In contrast, harlequin syndrome, in which only half the face flushes or sweats, is more frequently characterized either by normal pupils or oculosympathetic paresis. However, in some instances tonic pupils and areflexia can occur.

Pharmacologic testing . Because of iris sphincter denervation cholinergic hypersensitivity, chronically tonic pupils will constrict following administration of dilute (0.125%) pilocarpine ( Fig. 13.13 ). Pilocarpine is a cholinergic substance that can act directly on the iris sphincter muscle at higher concentrations. However, normal pupils typically have little or no response to dilute pilocarpine. The test should be considered positive when the pupil in question constricts more than the fellow pupil (assuming the fellow pupil is normal). The solution can be premixed or made readily by combining 0.1 ml of 1% pilocarpine with 0.7 ml of sterile saline in a 1-ml tuberculin syringe. With the needle removed, the syringe can be used as a dropper, with care taken to administer the same size drops into each eye. More dilute concentrations of pilocarpine, such as 0.0625%, can be used to reduce the chance of a false-positive result.

Some caution is also necessary in interpreting the dilute pilocarpine test since some patients with preganglionic parasympathetic dysfunction (see previous discussion) will also respond to dilute pilocarpine.

Management . The presence or absence of deep tendon reflexes should be noted. The ocular motility and orbital examination should be done carefully to exclude any evidence of a third nerve palsy or orbital tumor.

Since tonic pupils may be a manifestation of neurosyphilis, FTA-ABS or microhemagglutination assay– Treponema pallidum (MHA-TP) testing should be obtained in those patients without a defined cause for their dilated pupil. In an elderly patient with a new-onset tonic pupil we would suggest obtaining an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to screen for giant cell arteritis. No further laboratory workup is indicated, as tonic pupils otherwise usually have a benign cause.

Symptomatic treatment is sometimes helpful. Refractive correction may be prescribed for reading in those with accommodative insufficiency, for instance. Rarely, some patients find the anisocoria bothersome cosmetically, and these individuals might find pupil-forming contact lenses or dilute pilocarpine helpful. Dilute pilocarpine may also aid accommodation, and in addition may relieve photophobia. However, some patients find the induced pupillary miosis intolerably painful. Darkened lenses may aid photophobia.

Pharmacologically Dilated Pupils

Pupils dilated surreptitiously or as part of an ophthalmic evaluation with anticholinergic agents such as atropine, tropicamide, or cyclopentolate or sympathomimetic agents such as phenylephrine are generally large (>7–8 mm) and do not constrict to light stimulation or during near viewing. Pharmacologically dilated pupils can also occur accidentally in an individual who has contact with atropine-like drugs; a scopolamine patch; ipratropium ; or plants such as jimson weed (“corn picker’s pupil”), blue nightshade, or Angel’s Trumpet who then touches his or her eye or if a nasal vasoconstrictor sprays get into the eye. Other patients may consciously place mydriatic solutions in their eye as part of a functional illness (Munchausen syndrome, for example). In many cases the actual cause of the pharmacologic dilation cannot be identified despite careful review of the patient’s history. Pupils that are overly generous and unreactive but appear normal on slit-lamp examination should suggest pharmacologic dilation, because third nerve–related and tonic pupils tend to be smaller. In addition, unlike tonic pupils, pharmacologically dilated pupils do not constrict during near viewing. The lack of ptosis or ophthalmoplegia would exclude a third nerve palsy.

Pharmacologic testing . One percent pilocarpine drops will fail to constrict pharmacologically dilated pupils (examined after 30 minutes), because the postsynaptic receptors have been blocked. However, 1% pilocarpine would be effective in normal pupils, third nerve–related mydriasis, tonic pupils, and other preganglionic and postganglionic parasympathetic disorders, because in these cases the receptors at the iris constrictor muscle are either normal or hypersensitive. This test should be applied with caution, as pupils that are dilated due to traumatic iridoplegia and acute narrow-angle glaucoma would also fail to constrict with 1% pilocarpine (see later discussion). The 1% pilocarpine test should also be interpreted carefully if it is performed near the termination of pharmacologic blockade, since the affected pupil may constrict.

Neuromuscular Junction Blockade

Patients with botulism, who have defective release of acetylcholine, can develop bilaterally dilated pupils and accommodative paresis with varying degrees of ptosis and ophthalmoparesis. The eye findings are often accompanied by bulbar or generalized weakness. In general, the pupils are unaffected in myasthenia gravis, which affects nicotinic and not muscarinic cholinergic synapses. Both botulism and myasthenia gravis are discussed in more detail in Chapter 14 .

Ocular Causes of Unreactive Pupils

The clinical history or slit-lamp examination may suggest the following conditions. Depending on disease severity, the pupillary constriction with 1% pilocarpine may be defective.

• 1.
  

  Ocular trauma. Following trauma to the eye, the pupil may be fixed and unreactive (traumatic iridoplegia). Responsible mechanisms include tears or trauma to the iris sphincter muscle, tearing of short ciliary nerves, dislocation of the lens into the pupillary plane, or compression of the ciliary nerves or ganglion by blunt trauma or a retrobulbar hemorrhage.

  
  
• 2.
  

  Angle-closure glaucoma. This disorder, an ophthalmic emergency, should be considered when the pupil is middilated and fixed and the patient acutely complains of visual loss, nausea, vomiting, eye pain, and a rainbow-colored halo seen around lights. Ocular pressures can be very high (>60 mmHg), and visual acuity may be markedly impaired. Slit-lamp examination will identify the characteristic shallow anterior chamber, cornea edema, and ciliary or conjunctival injection. Pupillary nonreactivity is the result of sphincter muscle ischemia. If left untreated, the pupil may remain fixed, and the iris can become atrophic.

  
  
• 3.
  

  Iritis. When affected by iritis, the pupil can be small, irregular, or poorly reactive (see Fig. 13.6A ) or demonstrate impaired dilation in the dark. Cells and flare in the anterior chamber, iris synechiae, and keratic precipitates seen on slit-lamp examination help establish the diagnosis. Photophobia is the major complaint, and there is less pain and the onset is more gradual than in angle-closure glaucoma. Because of the synechiae, the pupil dilates poorly and irregularly, even with mydriatics.

  
  
• 4.
  

  Congenital mydriasis. Albeit rare, in this condition children are born with fixed and dilated pupils that are unreactive to dilute or 1% pilocarpine. Accommodation is also affected. The cause is unknown. Congenital mydriasis in association with patent ductus arteriosus and megacystic microcolon have been documented.

Clinical Signs and Symptoms in Horner Syndrome

Because of the lack of sympathetic input to the iris dilator muscle, Horner syndrome is strongly suggested when the anisocoria increases in the dark or if dilation lag of the miotic pupil is observed ( Box 13.4 ,Video 13.3 ). Dilation lag may be demonstrated at the bedside by turning the lights off and observing the pupils with a dim light directed from below the nose. The normal pupil dilates briskly, but it takes time for the sympathetically denervated pupil to reach its final resting state in the dark. Typically, measurements of pupil size are made at 5 and 15 seconds to document this dilation disparity in darkness, and there is usually more anisocoria at the earlier measurement. However, the absence of dilation lag does not exclude Horner syndrome. The pupil in Horner syndrome constricts normally during light stimulation and near viewing.

The upper lid ptosis is always mild and rarely ever covers the visual axis. The lower lid may be slightly elevated (lower eyelid, or upside-down, ptosis). The upper and lower eyelid ptosis (narrow palpebral fissure) may give the false impression that the eye is set back in the orbit (pseudoenophthalmos).

Horner syndrome by itself does not cause visual symptoms. However, disruption in sympathetic input to the eye may produce several other ocular signs. There may be conjunctival congestion or transient ocular hypotony. Because iris melanocytes require oculosympathetic input during development in early infancy, congenital Horner syndromes can be associated with an ipsilateral lighter-colored iris (iris heterochromia) ( Fig. 13.18 ). In rare instances, heterochromia may also result from acquired instances of Horner syndrome (see Fig. 13.17 ). Also, neurotrophic corneal endothelial failure has been reported in association with Horner syndrome.

Iris heterochromia in idiopathic congenital Horner syndrome. The affected left eye has ptosis, miosis, and a lighter colored iris than the right eye. Imaging and urine catecholamine metabolite testing were unremarkable.

Theoretically, lesions of the third-order neuron distal to the carotid bifurcation result in loss of sweating or flushing on just the medial aspect of the forehead and side of the nose, while more proximal lesions, including those of the first- and second-order neurons, decrease sweating or flushing in the whole half of the face ( Fig. 13.19 ). Hemibody sweating would also be anticipated from first-order neuron dysfunction. However, the expected patterns are present inconsistently, and the air conditioning in most hospitals and offices often masks any anhidrosis, making it a less important practical sign of Horner syndrome than the ptosis and miosis.

Right Horner syndrome with right ptosis, miosis, and facial anhidrosis due to right lateral medullary infarction. The patient sweats on the left side of the face but not on the right.

Etiology and Localization of Horner Syndrome

Table 13.3 outlines the causes of Horner syndrome according to localization and frequency. The various causes have been analyzed in large series, and the most common localization varies, most likely due to selection bias. In a study of inpatients with acquired oculosympathetic palsy, 63% had involvement of the first-order neuron, reflecting a large proportion of patients with strokes. The second-order neuron (preganglionic) was the most common lesion site in two other studies, while the third-order neuron (postganglionic) was most frequent in another, reflecting the authors’ interest in headaches. The ganglion referred to is the superior cervical ganglion; thus “preganglionic” refers to the second-order neuron, and “postganglionic” to the third-order neuron.

The presence of other clinical signs or symptoms may help localize the Horner syndrome. Sweat patterns have been mentioned already. Brainstem or spinal cord signs suggest involvement of the first-order neuron. Arm pain or a history of neck or shoulder trauma, surgery, or catheterization point to injury of the second-order neuron. Horner syndrome accompanied by ipsilateral facial pain or headache is characteristic of disorders that affect the third-order neuron.

The ciliospinal reflex may also help with localization in Horner syndrome. The reflex consists of bilateral pupillary dilation in response to a noxious stimulus, such as a pinch, on the face, neck, or upper trunk. Reeves and Posner showed that when there is a lesion of the first-order oculosympathetic neuron, the reflex is still intact. In contrast, in patients with injury to the second- or third-order neurons, which contain the efferent arm of the reflex, the pupil usually fails to dilate ipsilaterally.

Injury of the First-Order Neuron (Central Horner Syndrome)

Central Horner syndrome can be caused by lesions involving the descending oculosympathetic pathway in the hypothalamus, brainstem, or spinal cord.

Hypothalamic lesions . Injury to the neuronal cell bodies in the hypothalamus is a relatively infrequent etiology of Horner syndrome. The most common causes of dysfunction in this area are tumors or hemorrhages involving the thalamus or hypothalamus ( Fig. 13.20 ). Less commonly, a Horner syndrome is the result of hypothalamic infarction, occasionally combined with contralateral ataxic hemiparesis. Isolated infarction of the hypothalamus is an unusual event because of a rich blood supply to the hypothalamus, consisting of branches from the anterior cerebral artery and thalamoperforating arteries arising from the proximal portions of the posterior cerebral arteries near the basilar bifurcation, as well as short hypothalamic arteries that derive from the posterior segment of the posterior communicating artery. However, in some individuals with persistence of the fetal circulation, the hypothalamus is supplied directly by branches of the internal carotid artery. In such cases, large, deep cerebral infarcts may involve the hypothalamus when this artery is occluded, and these patients may have prominent sensory or motor signs or a hemianopia contralateral to the Horner syndrome.

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