Dilator Innervational Problems: Horner Syndrome
Horner syndrome results from disruption of sympathetic innervation to the eye (oculosympathetic disruption). It is characterized clinically by unilateral miosis, facial anhidrosis, ipsilateral upper lid ptosis, and mild lower lid elevation (upside-down ptosis). The ptosis and upside-down ptosis are due to the denervation of Müller muscle of the upper lid and the analogous lower lid muscle, respectively. The combination of upper and lower lid ptosis may create a false impression of enophthalmos. In the acute phase, conjunctival hyperemia and ocular hypotony can also be present.
It can be difficult to differentiate Horner syndrome from physiologic anisocoria since physiologic anisocoria may also be greater in dim light. In both conditions, the pupillary reaction to light is normal. However, pupillary dilation is intact in physiologic anisocoria and is impaired in oculosympathetic disruption, seen as a dilation lag. The characteristic dilation lag of the Horner pupil can be demonstrated in the office by observing the pupils with a hand light shining from below after the lights are turned off. A normal pupil will dilate briskly. The weak dilator muscle of a Horner pupil will dilate more slowly than normal. This asymmetry of pupillary dilation produces an anisocoria that is greatest 4 to 5 seconds after the lights are turned off. The anisocoria is less when the pupils are remeasured at 15 seconds. Video 1 illustrates a dilation lag. The presence of dilation lag is sufficient to differentiate Horner syndrome from physiologic anisocoria. Table 1 summarizes other causes of a small pupil that dilates poorly in dim light.
Pharmacologic Diagnosis of Horner Syndrome
If evaluation for a dilation lag is inconclusive, pharmacologic testing should be used to confirm the diagnosis of Horner syndrome. Cocaine has been the traditional agent used in suspected cases of Horner syndrome. Cocaine blocks the reuptake of norepinephrine at the sympathetic nerve terminal in the iris dilator muscle. As a consequence, a normal pupil will dilate after instillation of cocaine. However, any interruption in the sympathetic pathway results in decreased norepinephrine release so cocaine will have little or no effect. Pupil sizes should be assessed at baseline in room light and 40 to 60 minutes after the instillation of 1 to 2 drops of 4% cocaine in each eye. Cocaine disrupts the corneal epithelium and freely penetrates the cornea. Consequently, contact lens wear or intraocular pressure measurement will not affect the outcome of the cocaine test. If there is at least 0.8 mm of pupillary inequality after cocaine, the presence of a Horner syndrome is highly likely (Figure 2).
In recent years, the use of cocaine has been supplanted by the use of topical 0.5% apraclonidine, an alpha-2 (α2) adrenergic receptor agonist with weak alpha-1 (α1) activity. Unlike cocaine eyedrops, apraclonidine is readily available and has good corneal penetration. Apraclonidine has proven to be a good alternative pharmacologic agent to cocaine. Patients with Horner syndrome have denervation supersensitivity of the α1 receptors on the dilator muscle of the affected eye, making the pupil dilator responsive to the weak α1 effect of apraclonidine. As a result, following the instillation of apraclonidine, the affected pupil dilates and the lid elevates, versus no effect in the contralateral eye (often the normal pupil becomes smaller, most noticeable in dim light). Reversal of anisocoria, with the Horner pupil becoming larger than the normal pupil, is often seen, along with resolution of the ptosis (Figure 3). One drop of apraclonidine is placed in each eye and the patient is reassessed 60 minutes later (though a positive result may often be detected earlier than 60 minutes). The time required for upregulation of iris α1 receptors to produce supersensitivity to apraclonidine after acute injury is on the order of 2 to 5 days. If testing with apraclonidine is performed prior to this upregulation, there will be a false-negative result and an acute Horner syndrome may be missed. Apraclonidine should be used with caution in children younger than 1 year of age, in whom it may cause serious acute respiratory depression due to crossing the blood–brain barrier; young children tested should be monitored for 3 to 4 hours. Cocaine remains a better choice for this age group given its lower risk of adverse events. Brimonidine cannot be used as a substitute for apraclonidine for Horner pharmacologic testing because it is a relatively pure α2 agonist and has no significant α1 adrenergic effect. Interestingly, brimonidine can pharmacologically induce a Horner syndrome due to its α2 agonist effect that inhibits norepinephrine release from the presynaptic sympathetic nerve terminal and is most obvious in patients receiving brimonidine in only one eye.
Localization of Sympathetic Denervation
A good understanding of the anatomy of the oculosympathetic pathway is critical when evaluating a patient with Horner syndrome. The sympathetic outflow to the iris dilator muscle is a paired (right and left), 3-neuron chain without decussation (Figure 4). The first-order neuron (central) originates in the hypothalamus and descends through the brainstem into the lateral column of the spinal cord, where it synapses at the cervicothoracic junction (level C7-T2). The second-order neuron (preganglionic) leaves the spinal cord and travels over the apex of the lung to synapse at the superior cervical ganglion at the level of the carotid artery bifurcation. The third-order neuron (postganglionic) follows a course along the internal carotid artery, passes through the cavernous sinus where the postganglionic fibers are briefly associated with the abducens nerve and then the ophthalmic nerve (V1). The fibers then travel with the long ciliary nerve through the superior orbital fissure, and end within the iris dilator muscle and the retractor muscles of the upper and lower eyelids (Müller muscles).
The long and complicated course of the oculosympathetic pathway predisposes it to a variety of pathological processes, from benign vascular headache to serious conditions such as carotid dissection or malignant neoplasm. One percent hydroxyamphetamine can be used to differentiate pre- versus postganglionic lesions. Hydroxyamphetamine enhances the release of presynaptic norepinephrine from an intact third-order neuron.
Following at least 72 hours after cocaine pharmacologic testing to confirm the diagnosis of Horner syndrome, 1% hydroxyamphetamine is applied topically to both eyes. Since cocaine blocks the reuptake of adrenergic substances into the nerve ending, residual cocaine may block the uptake of hydroxyamphetamine and confound the test if used within 72 hours of the cocaine test. If apraclonidine was initially used to confirm the diagnosis of Horner syndrome, then hydroxyamphetamine testing may be performed in 24 hours. The pupils are measured before and 40 to 60 minutes after the drops. In first- and second-order Horner syndrome, both pupils will dilate, and occasionally the involved pupil will dilate more than the normal one due to supersensitivity. In contrast, in third-order Horner syndrome (postganglionic), the involved pupil dilates less than the normal pupil, which manifests as an increase in the anisocoria post-hydroxyamphetamine. Hydroxyamphetamine may result in a false negative postganglionic result when used in the acute phase since it takes about a week after injury for the synaptic stores of norepinephrine to be depleted at the presynaptic terminal of the sympathetic nerves innervating the iris dilator muscle.
While hydroxyamphetamine may be useful, sometimes the change in anisocoria can be equivocal for localization to the pre- or postganglionic site. A thorough history alone may determine the etiology of Horner syndrome. For example, if there has been previous accidental or surgical trauma to the chest, neck, or upper spine, no further workup is necessary, although it is helpful to document that the Horner syndrome is temporally related to the surgery or trauma by checking old photographs. Associated signs and symptoms might help localize the lesion. In a central Horner syndrome there will often be associated neurological findings. The presence of ataxia, skew deviation, nystagmus, and hemisensory deficit, for example, would strongly suggest a medullary lesion and magnetic resonance imaging (MRI) of the brain would be recommended. An acute Horner syndrome associated with ipsilateral facial or neck pain requires urgent imaging of the neck to exclude a carotid dissection or thrombosis. Trigeminal autonomic syndromes, such as cluster headache, should remain diagnoses of exclusion since carotid dissections can present in a similar fashion. Arm pain, weakness, and numbness would suggest a lesion near the lung apex, brachial plexus, or cervical spine. The presence of an ipsilateral sixth, third, or fourth nerve palsy or trigeminal dysfunction would suggest a lesion in the cavernous sinus and should be further evaluated with MRI. Table 2 summarizes potential causes of Horner syndrome in adults.
If a Horner syndrome is felt to be truly isolated without an accompanying cranial nerve palsy, and pharmacologically localizes to the preganglionic location, then chest and neck imaging should be performed. An adequate neck protocol should go as far up as the skull base. Computed tomography and CT angiography (CTA) of the neck is a good choice since CT offers excellent resolution of the soft tissues of the neck and CTA provides good views of the carotid artery lumen. Alternatively, MRI/MRA of the neck (including the skull base) along with a chest CT would also provide a thorough anatomical evaluation of an isolated Horner syndrome to help determine its cause. While the presence of anisocoria in old photographs can be reassuring, it does not exclude the possibility of underlying pathology.
Pediatric Horner Syndrome
As mentioned earlier, apraclonidine can be associated with CNS and respiratory depression when used in children younger than 1 year of age. In cases of congenital or early onset Horner syndrome, hydroxyamphetamine may yield false localizing results. This is due to orthograde transsynaptic degeneration at the superior cervical ganglion following early damage to the preganglionic neuron. Transsynaptic degeneration results in fewer postganglionic neurons, even in the absence of postganglionic injury, and therefore a false positive postganglionic hydroxyamphetamine test.
A diagnosis of Horner syndrome can be confirmed without pharmacologic testing in a child with suspected Horner syndrome who presents with one of the following: hemifacial flush on the normally innervated side and facial blanching on the side of oculosympathetic defect (can be seen when the child is crying or nursing); naturally curly hair on the normal side and straight hair on the affected side; or iris heterochromia with an ipsilateral lighter colored iris (might not be detected until the age of 9 to 12 months).
These findings are typically seen with congenital Horner syndrome or sympathetic damage within the first year of life, but rarely with oculosympathetic disruption acquired after 1 year of age. While a history of birth trauma or presence of heterochromia suggests a benign etiology, it does not entirely exclude the possibility of an underlying neoplasm. A mass lesion such as neuroblastoma is the main concern in the presence of Horner syndrome in a child of any age without a history of surgery in the area of the sympathetic chain. Urine catecholamine levels alone cannot rule in or out neuroblastoma. Emphasis should be placed on a thorough physical examination and imaging studies of the brain, neck, and chest. MRI is the imaging modality of choice in the pediatric population.
Iris Sphincter Problems: Adie Pupil
Damage to the ciliary ganglion or short ciliary nerves produce a tonic pupil, which is characterized by poor reaction to light with sectoral palsy of the iris sphincter; accommodative paresis during the acute stage; cholinergic supersensitivity during the acute stage; and strong and tonic pupillary response to near (light-near dissociation) in the chronic state, as a result of aberrant regeneration of accommodative neurons innervating the iris sphincter.
A tonic pupil can be caused by local ocular/orbital processes such as surgery, trauma, laser procedure (eg, panretinal photocoagulation), infection, inflammation, or ischemia. Tonic pupils can also be part of widespread autonomic dysfunction: diabetes, dysautonomia, neurosyphilis, amyloidosis, sarcoidosis, Sjögren syndrome, or Charcot-Marie-Tooth disease.
Adie pupil is the most common form of tonic pupil in which no local cause for denervation is evident. Patients are typically young adults and more commonly women than men. When symptomatic, patients may present with a large pupil, blurred vision at near, photophobia, or difficulty focusing from near to distance. An Adie pupil can also be asymptomatic and incidentally noticed by others or on a routine eye exam. At presentation, 10% of patients have bilateral Adie pupils.
Slit lamp examination typically shows segmental denervation of the iris sphincter, with other segments reacting normally creating vermiform movements of the iris to light stimulation. Within a week after onset, supersensitivity of the iris and ciliary muscle to dilute cholinergic agents can be demonstrated (Figure 5). The near reaction is not spared in Adie pupil but later it is restored. Approximately 8 weeks after the onset, nerve regrowth is active and aberrant regeneration takes place. Fibers originally bound to the ciliary muscle (they outnumber the sphincter fibers by 30:1) start arriving at the iris sphincter. The light reaction of the denervated segments does not return, but the reinnervated segments now show contraction to a near stimulus, producing the characteristic light–near dissociation (Figure 6). Video 2 demonstrates an example of bilateral Adie pupil with poor reaction to light but pupillary constriction to a near stimulus (bilateral light–near dissociation). Other causes of light–near dissociation of the pupil include dorsal midbrain syndrome (Parinaud), Argyll-Robertson pupils secondary to neurosyphilis, third nerve aberrant reinnervation, and severe loss of afferent light input secondary to bilateral retinal or anterior visual pathway lesions.
Bilateral Adie Pupil
With time, there is some return of accommodation amplitude. Eventually, the Adie pupil becomes the smaller of the two pupils (termed a little old Adie pupil), especially in dim light. Little old Adie pupil can be mistaken for a Horner syndrome. It is important to remember that unlike Adie pupil, a Horner pupil should react normally to the light.
The presence of clinical findings is often sufficient to support a diagnosis of Adie pupil. However, because of the iris sphincter denervation cholinergic hypersensitivity, pharmacologic testing with pilocarpine 0.125% can be used to help with the diagnosis. Unlike cocaine, anything that might affect corneal permeability may affect the penetration of dilute pilocarpine through the cornea and thereby affect the outcome of the test. Therefore, pharmacologic testing with dilute pilocarpine should not be performed after intraocular pressure measurement or contact lens wear. The test is considered positive when the pupil in question constricts more than the fellow pupil (assuming the fellow pupil is normal), best assessed in dim light with the patient looking in the distance. Clinicians should remember that it takes a few days for the supersensitivity to take place following denervation, and as reinnervation takes place over time, the eye may lose its cholinergic supersensitivity.
A third nerve palsy can be associated with a dilated pupil and the pupillary findings can be difficult to distinguish from a tonic pupil. Third nerve–related mydriasis is nearly always associated with other signs of oculomotor nerve dysfunction such as ocular motility abnormality and ptosis. Acute pupil-involving third nerve palsies do not typically show sectoral sparing of the light reaction, but affect the sphincter muscle symmetrically about its circumference. Sometimes the ocular motility deficit expected with third nerve dysfunction can be subtle. Most cases of acute third nerve–related mydriasis will also respond to a weak concentration of pilocarpine within 3 to 7 days and will also respond to 1% pilocarpine (unlike pharmacologic mydriasis).
Pharmacologic mydriasis can also mimic a tonic pupil. In this situation, the pupil is typically very large and nonreactive to light and near stimulation. The slit lamp examination does not reveal sectoral palsy. One percent pilocarpine will show undersensitivity of a pharmacologically dilated pupil compared to the opposite normal eye, but show enhanced miosis in tonic pupils as well as third nerve–related mydriasis. Other causes of pupillary efferent defects due to iris sphincter dysfunction include acute intraocular pressure elevation causing iris ischemia; pigmentary dispersion syndrome; pseudoexfoliation; iridocorneal endothelial syndrome; blunt trauma; anterior segment surgery; herpes zoster; siderosis; iris ischemia secondary to carotid artery disease; and, rarely, an autoimmune condition such as Miller-Fisher syndrome, which can be segmental and without light–near dissociation.