Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Does the patient have an aneurysm or is it just physiologic anisocoria? The pupil exam is to the eye what the deep tendon reflexes are to the neurologic exam: an objective and easily elicitable measurement. The author discusses causes of anisocoria and abnormal pupillary activity. A “low tech” algorithm leads the clinician through the evaluation process to know whether the patient can be reassured or needs additional testing.
• The pupil examination includes: (1) swinging flashlight test to determine the presence of a relative afferent pupillary defect; and (2) measurement of pupil size in dim illumination and constriction to light and a near target.
• The mydriatic pupil of oculomotor palsy must be distinguished from “isolated” pupil disturbances, including tonic (Adie) pupil and pharmacologic and traumatic (including intraocular surgery) mydriasis.
• The miotic pupil of Horner syndrome should be recognized and confirmed with topical apraclonidine testing.
Around 200 A.D., Galen likened the iris to an elastic circular ring that was passively inflated or deflated by vital spirits sent from the brain to enhance vision. It was not until the first half of the 18th century that it became widely accepted that iris movement and pupil size were due to active interaction of 2 iris muscles: a longitudinal radial dilator and a circular sphincter muscle.
Many contributions to our understanding of pupillary physiology and pathology were made in the 20th century, including the description of the swinging flashlight test for assessing a relative afferent pupillary defect (48).
There are several major types of pupil abnormalities:
• Afferent: relative afferent pupillary defect
- Anisocoria (unequal sized pupils)
- Light-near dissociation
- Irregularly shaped pupil
- Abnormally positioned pupil (corectopia)
- Episodic pupillary abnormalities
The abnormality may be transient or constant. Often pupillary abnormalities are asymptomatic or noticed only by an observer. Occasionally, patients may complain of photophobia in the eye with a large (mydriatic) pupil because increased light reaches the retina through the wider aperture. Because the parasympathetic system innervates the ciliary muscle, which governs accommodation, as well as the iris sphincter muscle, which governs pupil size, patients with oculomotor nerve palsy or short ciliary nerve damage may report blurred near vision while reading.
Prognosis and complications are individually assessed for the specific pupillary abnormality and its etiology.
Case 1. A 68-year-old man with new headache was referred to the emergency eye clinic from the general emergency department to rule out giant cell arteritis. He had no other giant cell arteritis symptoms. Platelet count, erythrocyte sedimentation rate, and C-reactive protein were within normal limits. He had not undergone neck manipulation. Neuro-ophthalmologic examination showed 1 mm of left upper lid ptosis, a miotic left pupil, and anisocoria that worsened in the dark. Both pupils constricted normally to light, but the left pupil dilated relatively slowly when light was withdrawn (“positive dilation lag”). Instillation of topical apraclonidine 0.5% in both eyes produced reversal of the anisocoria, confirming a diagnosis of left Horner syndrome. He had not noticed the ptosis and neither had several physicians in earlier examinations. Because of the combination of new headache and Horner syndrome, the diagnosis of cervical carotid dissection was made presumptively, and the patient was sent for urgent imaging. He declined a CT angiogram, so MRI/MR angiography was performed, showing a left internal carotid artery dissection.
He was treated with anticoagulation. Headache eventually resolved, but the Horner syndrome persisted.
Any process that affects the autonomic innervation of the iris muscles or damages the iris muscles themselves will cause a pupil abnormality.
The pupillary innervation pathway consists of an afferent and an efferent limb. If the afferent limb is damaged asymmetrically, it will result in a relative afferent pupillary defect. The efferent limb has two parts: parasympathetic and sympathetic. The parasympathetic component innervates the iris sphincter muscle; the sympathetic component innervates the iris dilator muscle. If the efferent limb is damaged asymmetrically, anisocoria will result (47).
For example, a stroke in the dorsolateral medulla may injure the central neuron of the oculosympathetic pathway to cause ipsilateral miosis and poor pupillary dilation (Horner syndrome) usually in association with other neurologic symptoms and signs. Local trauma to the iris sphincter muscle may result in mechanical restriction of pupillary movement. Diabetes mellitus or inflammation may damage outflow from the ciliary ganglion, causing a type of pupillary abnormality known as a tonic pupil.
The parasympathetic supply to the iris sphincter muscle consists of a 2-neuron pathway. The impulse originates in the Edinger-Westphal subnucleus of the oculomotor (third) nuclear complex and travels through the oculomotor (third) nerve to synapse in the ciliary ganglion. The postganglionic short ciliary nerves transmit the final parasympathetic impulse to the iris sphincter muscle, which constricts the pupil. The sphincter muscle bundles are made up of 5 to 8 muscle cells located around the pupillary margin, each muscle bundle functioning as a unit.
The sympathetic supply to the iris dilator muscle consists of a 3-neuron pathway. The first (central) neuron travels through the lateral brainstem to synapse in the spinal cord at C8-T2, the ciliospinal center of Budge-Waller. The second (preganglionic) neuron skirts across the lung apex and ascends in the neck to synapse in the superior cervical ganglion. The third (postganglionic) neuron accompanies the internal carotid artery into the skull base and into the cavernous sinus, where it lies just lateral to the carotid artery. After briefly joining with fibers of the abducens nerve, it passes through the superior orbital fissure with the ophthalmic division of the trigeminal (fifth) nerve. It continues in the nasociliary branch of the trigeminal nerve to reach the iris dilator muscle and Muller muscle, a small lid elevator that resides in the upper lid (32; 49).
The pupillary light reflex pathway is composed of afferent and efferent limbs.
The afferent limb begins in the retinal photoreceptors that receive the light impulse (input signal) and transmit it to the optic nerves. Similar to the fibers mediating vision, the fibers from the nasal retina (temporal visual field) decussate at the optic chiasm so that the ipsilateral optic tract carries impulses from the ipsilateral temporal retina and the contralateral nasal retina. The pupillary input signal travels in the optic tract but diverges from the visual fibers to enter the midbrain through the brachium of the superior colliculus, synapsing in the pretectal nuclei. Axons from the pretectal nuclei stimulate both the ipsilateral and contralateral Edinger-Westphal nuclei. Axons from the pretectal nuclei stimulate both the ipsilateral and contralateral Edinger-Westphal nuclei. Thus, under normal conditions, both Edinger-Westphal nuclei receive identical afferent input. The Edinger-Westphal nucleus begins the efferent limb of the pupillary light reflex and provides the output signal that ultimately directs pupilloconstriction. Only about 4% of the efferent output of the Edinger-Westphal nucleus mediates the pupillary light reflex, whereas 96% is concerned with accommodation. Axons from the Edinger-Westphal nucleus travel through the oculomotor (third) nerves and synapse in the ciliary ganglion. The postganglionic short ciliary nerves transmit the final impulse to the pupilloconstrictor muscle (47).
Because both Edinger-Westphal nuclei receive the same afferent input, a lesion in one afferent limb of the pupillary light reflex (eg, optic nerve) decreases the amplitude of pupilloconstriction in both eyes (direct and consensual response) when that eye is stimulated compared to when the eye with the normal afferent limb is stimulated. This phenomenon can be detected clinically during the swinging flashlight test as a relative afferent pupillary defect. Pupil sizes are equal as long as output signals (efferent limb) are equal. Anisocoria is, therefore, never caused by a lesion of the afferent limb of the pupillary reflex arc (08).
A study of 3046 adults 50 to 93 years of age found that larger pupillary diameter was associated with younger age, female sex, lower body mass index, taller body height, and lower systolic blood pressure (52). Ocular parameters influencing larger pupil diameter included longer axial length of the globe, deep anterior chamber, flatter cornea, and higher intraocular pressure.
Physiologic (essential) anisocoria, defined as a difference of 1 mm or less between the two pupils with normal pupil function and a negative apraclonidine test, is the most common pupil abnormality, with an estimated prevalence of up to 20% of the general population (25). The other common cause of anisocoria is damage to the iris sphincter muscle following intraocular surgery, other intraocular trauma, or intraocular inflammation.
Prevention of pupillary abnormalities is directed at prevention of any disease that may affect the eye or the autonomic nervous system (eg, diabetes mellitus).
Relative afferent pupillary defect. The relative afferent pupillary defect is a sensitive sign of optic nerve dysfunction, although other disorders (widespread retinal disease, optic tract lesion) may produce a relative afferent pupillary defect.
Anisocoria. Anisocoria, or unequal pupil size, can be evaluated by first determining the size of the pupils in light and in darkness.
This maneuver reveals whether the anisocoria is greater in darkness or if it is greater in light. Then the light reaction is assessed. If the abnormal pupil does not react to light, check for the presence of near constriction. Sometimes it is difficult to determine whether the abnormal pupil is the smaller one or the larger one.
Anisocoria with normal constriction to light.
Physiologic anisocoria. A study found a 23.8% prevalence of physiologic anisocoria (44). The anisocoria is usually less than 1.0 mm; it is equal in light and darkness and may be intermittent. The larger pupil may episodically change sides. Although reported to be more common in persons with lightly colored irides, it may just be more noticeable in that population. In this condition, pupils are round, react briskly to light, and dilate equally when the lights are turned off (28; 04). The topical apraclonidine test does not produce reversal of anisocoria.
Horner (oculosympathetic) syndrome. The classical triad of Horner syndrome is ptosis, miosis, and anhidrosis. The upper lid ptosis, caused by denervation of Müller muscle, is mild (not more than 3 mm). Lower lid ptosis may also be present, raising the lower lid and creating the false impression of enophthalmos. The anisocoria varies with ambient lighting and may be barely noticeable in bright light. As the Horner pupil does not dilate normally, the anisocoria is greater in darkness. The most specific clinical sign of Horner syndrome is dilation lag of the miotic pupil compared to the normal pupil when viewed over 15 to 20 seconds in darkness (38; 46; 16). Ipsilateral anhidrosis, a phenomenon that is often difficult to detect, is more common in central and preganglionic lesions than in postganglionic lesions.
Horner syndrome that is congenital or acquired in childhood may be associated with iris heterochromia and ipsilateral straight hair. The affected iris is usually lighter in color from failure of pigmentation (congenital lesion) or depigmentation (acquired lesion). Horner syndrome may result from injury at any point along the 3-neuron oculosympathetic pathway. A central (first order) Horner syndrome is always accompanied by signs of hypothalamic, brainstem, or spinal cord dysfunction. A preganglionic (second order) Horner syndrome may occur in isolation or with symptoms and signs of a lower cervical/upper thoracic radiculopathy. A postganglionic Horner syndrome is usually an isolated finding but is sometimes associated with neck pain or headache, ipsilateral cerebral hemispheric dysfunction (from thromboembolic disease related to cervical carotid dissection), or ipsilateral trigeminal or abducens palsy from a cavernous sinus lesion. Distinguishing a preganglionic from a postganglionic Horner syndrome can be challenging. Detection of a preganglionic Horner syndrome requires careful imaging of the chest and neck to exclude a tumor.
In a retrospective chart review of 200 adult patients with pharmacologically confirmed Horner syndrome, only 13% had causative lesions on imaging (42). In that study, 69.0% were deemed idiopathic, but 9.0% had serious pathology, including carotid artery dissection or a brain or neck lesion, of which only a minority had acute symptoms.
In a nationwide, population-based cohort study in Korea, the cumulative incidence of a Horner syndrome was 2.12 out of 100,000 in children, and 2.95 out of 100,000 in adults (17). The most common cause was a surgical procedure. The cause was known before identifying the Horner syndrome in 83.2%, at the time of identifying the Horner syndrome in 9%, and only after diagnosing the Horner syndrome in 7.8%. Neuroblastoma was the most common tumorous cause in children, and thyroid cancer was the most common tumorous cause in adults.
Another study of 318 patients similarly reported that the most common cause was procedures on the neck, chest, and skull base, as well as the paraspinal region, followed by carotid dissection and tumor (41). The cause was almost always known prior to identification of the Horner syndrome. Nevertheless, the finding of Horner syndrome was crucial in identifying carotid dissection and tumor.
In a retrospective case series of 14 children under 14 years of age with Horner syndrome, the most common cause of a congenital Horner syndrome (defined as a diagnosis made before 5 months of age) was tumor, especially neuroblastoma (36). Horner syndrome was the first manifestation in 50% of those cases. Among children with acquired Horner syndrome (defined as a diagnosis made after 5 months of age), cervical and thoracic spine surgery was the most common cause.
Anisocoria with pupils that do not constrict normally to light. The differential diagnosis here includes oculomotor nerve palsy, tonic (Adie) pupil, pharmacologic mydriasis, and iris sphincter damage
Tonic (Adie) pupil. A tonic (Adie) pupil constricts poorly to light, but more completely, albeit slowly, to a near stimulus. This is a benign condition most common in adult women (24). A viral etiology is suspected but has never been proven. Injury to the ciliary ganglion or short ciliary nerves results in postganglionic parasympathetic denervation of the iris sphincter and ciliary muscle. In the acute phase, the affected pupil becomes large and reacts poorly, if at all, to light and a near target. Owing to accommodative paresis, the patient may notice blurred vision when reading and performing other near tasks. After several days, the sphincter develops cholinergic denervation supersensitivity. Instillation of dilute pilocarpine (< 0.10%), a concentration that would not constrict a normal pupil, will constrict a tonic pupil. After several weeks, the injured postganglionic short ciliary nerves begin to sprout collaterals and regenerate. As there are 30 times more axons serving accommodation than pupil constriction, the axons serving accommodation are more likely to survive than the pupilloconstrictor axons. The surviving axons serving accommodation aberrantly reinnervate the iris sphincter. As a result, pupil constriction to a near target will be preserved, but it will slower than normal (hence “tonic light-near dissociation”). This aberrant reinnervation also accounts for slow dilatation of the pupil when the patient shifts gaze from a near to a distant target (“tonic dilatation”). Because the preservation of innervation is typically segmental, it is common to see segmental constriction of the pupil and vermiform movements of the iris margin.
Over months to years, the tonic pupil will often become the smaller pupil. Vermiform iris movements, poor light reaction, slow near constriction, slow redilatation, and cholinergic supersensitivity will persist (30; 31). About 4% of patients develop a tonic pupil in the previously unaffected eye with each passing year.
Deep tendon hyporeflexia or areflexia may be present initially or occur later. The combination of tonic (Adie) pupil and hyporeflexia or areflexia is termed Holmes-Adie syndrome. The hyporeflexia is attributed to dorsal root ganglionopathy (34).
Monocular tonic pupils are mostly of unknown cause. However, they have been reported to occur transiently with migraine attacks (45), giant cell arteritis (40), syphilis (21), COVID-19 infection (15), and paraneoplastic disorders (37). Bilateral tonic pupils have been reported in diabetes, Lyme disease, rabies, Sjögren syndrome, and systemic lupus erythematosus, botulism, alcoholism, Charcot-Marie-Tooth disease, multisystem atrophy, and other neurodegenerative disorders (51). Isolated tonic (Adie) pupils and those that are part of a systemic dysautonomia have the same pupillary features (02).
Mydriasis in oculomotor palsy. The oculomotor nerve is the preganglionic parasympathetic neuron to the iris sphincter and ciliary muscle. It also innervates the levator palpebrae, superior rectus, inferior rectus, medial rectus, and inferior oblique muscles. The clinical features of oculomotor nerve palsy are ptosis, mydriasis, and ophthalmoplegia. The upper lid ptosis can be mild or complete. The pupil is usually larger (mydriasis) than the normal pupil and reacts poorly to light and near stimulation. Preganglionic parasympathetic denervation of the pupil (oculomotor nerve palsy) can sometimes lead to cholinergic supersensitivity of the iris sphincter, much like postganglionic denervation of the pupil (tonic pupil).
Isolated mydriasis with poor constriction to light is never caused by an intracranial process. If intracranial aneurysm or other intracranial abnormality is the cause of oculomotor palsy, ptosis and ophthalmoplegia will usually be present. However, in a comatose patient, assessment of ptosis, eye alignment, and eye movement is difficult; therefore, mydriasis may be the only ophthalmic sign of a compressive oculomotor palsy from transtentorial herniation.
Microvascular ischemia is actually the most common cause of isolated oculomotor palsy in adults over the age of 50, occurring especially in those with small vessel arteriosclerosis (hypertension, diabetes). Although the pupil is often spared, mydriasis with poor constriction to light is reported in two thirds of cases. However, the anisocoria in such cases is generally less than 1 mm (20) and may develop up to 2 weeks after the onset of symptoms (11).
When the oculomotor nerve suffers a nonischemic injury (trauma, compression) that disrupts the Schwann cell tube, the regenerating axons may grow along an aberrant course. For example, axons originally destined to the inferior rectus muscle might instead sprout into the iris sphincter. When the patient attempts to look down, the pupil constricts due to synkinesis. Each of the oculomotor nerve branches that innervate extraocular muscles have been reported to aberrantly innervate the iris sphincter, leading to a variety of synkinetic eye and eyelid movements involving the pupil (09; 29).
Pharmacologic mydriasis or miosis. Topical agents that dilate the pupil fall into 2 classes: sympathomimetics, which stimulate the iris dilator muscle, and anticholinergics, which inhibit the iris sphincter muscle. Topical sympathomimetic agents include phenylephrine and cocaine; anticholinergic agents include atropine, scopolamine, homatropine, cyclopentolate, and tropicamide. Inadvertent exposure to mydriatic agents may occur from over-the-counter eyedrops used for red, irritated, "allergy" eyes, scopolamine skin patches used for motion sickness, anticholinergic agents used for hyperhidrosis, asthma, and respiratory distress, application of phenylephrine-containing topical preparations to reduce eyelid puffiness, or atropinic plants like Jimson weed (14; 39). A mydriatic pupil owing to topical exposure to an anticholinergic agent will not constrict upon topical application of 1% pilocarpine. By contrast, a mydriatic pupil owing to topical application of a sympathomimetic agent will constrict, although less profoundly than an uncontaminated pupil.
Many drugs can affect pupillary size and reactivity. Mydriatics include belladonna alkaloids, atropine, scopolamine, tropicamide, cyclopentolate, intraorbital lidocaine, epinephrine, phenylephrine, ephedrine, cocaine, tricyclic antidepressants, papaverine, and other sympathomimetic agents. Miotics include pilocarpine, carbachol, acetylcholine, physostigmine, topical guanethidine, heroin, morphine, and dapiprazole (“Rev-Eyes”).
Dorsal midbrain (tectal or pretectal) pupils. Lesions of the dorsal midbrain/pretectal region cause large pupils that do not constrict normally to light but often constrict somewhat to a target viewed at close range (“tectal light-near dissociation”). Other signs of dorsal midbrain dysfunction include reduced upgaze, convergence-retraction, lid retraction, and esotropia or exotropia.
Argyll-Robertson pupils. Describing the pupillary sign in 1869 that still bears his name, Douglas Mooray Cooper Lamb Argyll Robertson stated, “I could not observe any contraction of either pupil under the influence of light, but on accommodating the eyes for a near target, both pupils contracted” (35). In dim illumination, Argyll Robertson pupils are small (1 to 2 mm) and irregular, and they display light-near dissociation; they are specific to neurosyphilis (27). Iris atrophy may be visible on the slit lamp examination.
Iris sphincter damage. Anisocoria may be caused by a damaged or anomalous iris from uveitis with synechiae, ocular surgery, or trauma. Slit lamp examination is usually necessary to confirm this diagnosis, showing iris atrophy, a distorted pupillary margin, or heterochromia. The pupil is generally irregular and poorly reactive to light. Confirming these abnormalities on expert slit lamp examination will avoid unnecessary testing (08).
Abnormal pupil position. Corectopia is the displacement of one or both pupils from the center of the iris. It may be congenital or acquired. Acquired corectopia is most frequently caused by asymmetric damage to the pupil sphincter or displacement of the iris by anterior chamber pathology. When it is associated with midbrain lesions, other manifestations of midbrain dysfunction are present, which warrant evaluative neuroimaging studies (07).
Episodic pupillary abnormalities. Transient pupillary abnormalities occur in the following conditions: cyclic oculomotor palsy, recurrent mononeuritis, benign episodic unilateral mydriasis, tadpole pupils, and Harlequin syndrome.
Oculomotor palsy with cyclic spasms. Oculomotor palsy with cyclic spasms is a rare syndrome with onset usually before 2 years of age. The affected child has a congenital unilateral oculomotor palsy with superimposed spasms of hyperfunction of the oculomotor nerve. During the spasms, the eye adducts, the ptotic lid rises, and the mydriatic pupil constricts. The spasms last 10 to 30 seconds, after which the oculomotor palsy returns. The cycles persist in sleep and throughout adulthood (12). These features are most commonly noted in infancy or early childhood and attributed to unstable innervation of the oculomotor nerve.
Recurrent mononeuritis of the oculomotor nerve. Recurrent mononeuritis of the oculomotor nerve, previously termed “ophthalmoplegic migraine” because of the accompanying headache, occurs most often in children and adolescents, with an average age of onset of 10 years, and with a female predominance. There is no association with migraine (13; 43). The oculomotor palsy takes 1 to 4 weeks to resolve. The diagnosis is based on a characteristic history and negative evaluation for other possible causes of an oculomotor palsy. MRI often shows enhancement of the oculomotor nerve in its interpeduncular segment, suggesting that this condition is actually a recurrent mononeuritis (05). Permanent palsy can occur after multiple attacks.
Benign episodic unilateral mydriasis. Benign episodic unilateral mydriasis is characterized by paroxysms of unilateral mydriasis that can alternate between the 2 eyes in different episodes or occur in both eyes at the same time. Often noted in young women with a migraine history, the mydriasis lasts from a few minutes to 48 hours, with an average of 12 hours, and a recurrence of 2 to 3 episodes per month. It may occur concurrently or independently of headache as a manifestation of an idiopathic and limited dysautonomia predominantly affecting the parasympathetic innervation of the iris and ciliary muscle. Neuroimaging is not recommended in the absence of associated symptoms as it is usually normal (19; 33).
Tadpole-shaped pupils are rare and due to intermittent segmental spasm of the dilator muscle lasting a few minutes and recurring several times daily or weekly (23). The episodic distortion eventually resolves spontaneously. Conditions associated with tadpole pupils are Horner syndrome, tonic pupil, and migraine (50). Pharmacologic testing for Horner syndrome is recommended for patients with a history of episodic pupillary distortion as it accounts for nearly half of reported cases of tadpole pupils (01).
Harlequin syndrome. Harlequin syndrome is manifested by the sudden loss of facial flushing on 1 side of the face after exercise, emotional stress, or heat exposure, resulting in a sharp demarcation line between the flushed contralateral side of the face and the pale ipsilateral side. This phenomenon is often caused by underlying birth trauma to the brachial plexus, a systemic dysautonomia, or an apical lung tumor, producing damage to the ipsilateral sympathetic fibers. The most common pupillary abnormality is an ipsilateral Horner syndrome. Tonic pupils occur infrequently (03).
Intracranial hypertension. Intracranial hypertension may influence pupillary reactivity. A pupillometric study of patients with severe traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage found an inverse relationship between pupillary reactivity and intracranial pressure (06). Patients with unreactive pupils had the highest peaks of intracranial pressure.
Examination. A complete pupillary examination consists of 5 parts: inspection, measurement of pupillary size in the light and in the dark, reaction to light, the swinging flashlight test, and the near response.
1. Inspection: The pupils are inspected for evidence of irregularity or iris damage.
2. Measurement of pupillary size: The pupil size is measured in light and darkness using a pupil gauge as the patient fixates in the distance. The pupil size in darkness is obtained by dimly illuminating the eyes from below. Anisocoria of 0.4 mm or more should be clinically visible (25).
3. Constriction to light: The constriction of each pupil to a bright, well-focused light source is assessed.
4. Near response: The pupillary reaction to a near stimulus is clinically relevant when there is a poor light reaction. The patient is asked to look at a distant target as the pupils are illuminated from below. When the patient converges on a near target, such as the examiner’s finger, the pupils will constrict (47). It is normal for the near response to be somewhat better than the light response, especially in patients who converge well. Preservation of constriction to a near target in the absence of constriction to light is termed “light-near dissociation,” a sign present in optic neuropathy, ciliary ganglionopathy, and dorsal midbrain syndrome.
Pharmacologic testing. Two agents are instilled in the eyes to confirm the presence of a Horner syndrome: apraclonidine and cocaine. Dilute pilocarpine instillation has been employed to confirm a tonic (Adie) pupil but has largely fallen out of use because it must be compounded and because supersensitivity to topical cholinergic agent application also occurs in preganglionic (oculomotor nerve) palsies. Pilocarpine 1% may be used to confirm pharmacologic mydriasis or iris sphincter damage.
Apraclonidine test. Commercially available as Iopidine, apraclonidine is a strong alpha 2 receptor agonist and a weak alpha 1 agonist. In normal eyes, its alpha 2 activity down-regulates the production and normal release of norepinephrine. However, with denervation supersensitivity of the iris alpha 1 receptors, apraclonidine causes dilation of the pupil in Horner syndrome due its weak alpha 1 receptor agonist action. Instillation of 1 drop of 0.5% apraclonidine into each eye results in reversal of the anisocoria after 30 minutes (sensitivity 0.91). It has no effect on a normal pupil. There are reports of a positive apraclonidine test as early as 36 hours from the onset of Horner syndrome. (26) False negative results have been reported (10). Apraclonidine should not be instilled in the eyes of children under age 2 because of life-threatening cardiovascular autonomic effects.
Cocaine test. Cocaine inhibits the presynaptic reuptake of released norepinephrine at the neuromuscular junction. When the oculosympathetic pathway is intact, cocaine will dilate the pupil. However, if there is any interruption within the oculosympathetic pathway, there will be no release of norepinephrine, so that cocaine will not dilate the pupil of Horner syndrome. A post-cocaine anisocoria of 0.8 to 1.0 mm or more is considered diagnostic of Horner syndrome (22). After the cocaine test is completed, the examiner should verify that the Horner pupil is capable of full dilation by instilling 1% phenylephrine into both conjunctival sacs. As phenylephrine is a direct sympathomimetic agonist on the pupillodilator muscle, both pupils should now dilate well. This step is important to make sure that the miotic pupil that fails to dilate to cocaine is not due to a "sticky" iris or pupillodilator muscle dysfunction. Cocaine solution is not manufactured for ophthalmic instillation. It may be compounded by the pharmacy from powdered cocaine or buffered from the 4% solution that is commercially available for otolaryngologic use, although a 10% solution is preferable.
Pilocarpine test. Dilute pilocarpine (0.1%) is a pharmacologic test for pupillary cholinergic supersensitivity. A denervated iris constricts to dilute pilocarpine but a normal iris will not. Dilute pilocarpine has traditionally been used as a diagnostic test for a suspected Adie tonic pupil, which usually constricts to dilute pilocarpine. However, the test is neither 100% sensitive nor specific for tonic pupil: only 80% of postganglionic lesions (tonic pupils) demonstrate cholinergic supersensitivity, and a substantial number of nonischemic preganglionic lesions (oculomotor nerve palsy) will also have some degree of cholinergic supersensitivity (30; 18). The testing solution may be prepared using a commercial preparation of pilocarpine mixed with sterile saline. Pilocarpine 1%, the strength commercially prepared, is useful in confirming pharmacologic or traumatic mydriasis.
Management is aimed at the etiology of each specific pupillary abnormality.
Pregnancy itself is not associated with any particular pupillary abnormality, but complications of pregnancy may affect the pupils.
Barbiturate general anesthesia causes progressive constriction of the pupils with loss of responsiveness to light and failure of dilation to sensory stimulation as the coma deepens. The pupils can be used to assess the depth of the patient's barbiturate coma. Opiate analgesics cause miosis but do not block the pupillary light reaction. The iris sphincter may be paralyzed by neuromuscular depolarizing agents used to immobilize patients during surgery and in the intensive care unit.
Danah Albreiki MBBS
Dr. Albreiki of the Ottawa Eye Institute has no relevant financial relationships to disclose.See Profile
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Jun. 20, 2022
Jun. 04, 2022
Jun. 04, 2022
May. 29, 2022
May. 28, 2022
May. 28, 2022
May. 27, 2022
Neuro-Ophthalmology & Neuro-Otology
May. 21, 2022