Horner's Syndrome: What Optometrists Should Know

Miosis, Ptosis, and Anhidrosis! Oh My!

We are all conditioned to remember that rhyming triad, as it was drilled into our heads repeatedly during optometry school. Most of us immediately think of Horner’s Syndrome.

However, recognizing the condition and its appropriate treatment in office is not always as simple as that little verse. This article serves as a reference for optometrists seeking to properly identify and manage a patient with Horner’s Syndrome if they end up in your chair.

What is Horner’s Syndrome?

Horner’s syndrome, also known as oculosympathetic paresis, is a neurologic condition that commonly presents with unilateral miosis (constricted pupil), partial ptosis of the upper lid, and anhidrosis (absence of sweating) all on the affected side (1).

In order to fully understand the causes of Horner’s Syndrome, we unfortunately have to delve into a little anatomy—but we will make it brief!

Neuroanatomy of Horner’s Syndrome

To keep this as painless as possible, we will focus only on the sympathetic pathways relevant to ocular signs and symptoms involved in Horner’s Syndrome. Recall this sympathetic pathway that innervates various aspects of the head, neck, and face:

Preganglionic fibers originate in the hypothalamus and descend through the brainstem to the C8-T2 region of the spinal cord (also known as the Ciliospinal Center of Budge) (1-3)
- Currently a first order neuron prior to any synapse
These fibers then synapse in the Ciliospinal Center of Budge (1,2)
- This is the first synapse in the pathway which results in a second order neuron
The now second order preganglionic fibers exit the spinal cord and travel over the apex of the lung. They join the cervical sympathetic chain of ganglia in the neck region (1,2).
The fibers then ascend and go on to synapse in the superior cervical ganglion (located near the mandible and where the common carotid artery bifurcates)(1,2).
- This is the second synapse in the pathway, so the fibers exit as a postganglionic third order neuron.
The third order postganglionic fibers leave the superior cervical ganglion to form a plexus with the internal carotid artery (ICA). The plexus enters the skull via the carotid canal and travels through the cavernous sinus (1,2).
- Note that the pupillomotor fibers and fibers that innervate sweat glands of the medial forehead travel via the internal carotid with the third order sympathetics. The fibers that supply the sweat glands of the rest of the face as well as the vasomotor and sudomotor fibers travel via the external carotid arteries to branch off more proximally (1,3).
Once within the ocular orbit, the sympathetic fibers may take one of several courses:
- Travel with the superior division of Cranial Nerve 3 (CN III) to innervate the upper eyelid via Mueller’s muscle (4,5)
- Travel with the nasociliary branch of CN V1(ophthalmic branch of the trigeminal nerve) and follow one of its expansions (1,2,5):
  - The Long Posterior Ciliary Nerves (LPCN): The LPCNs carry the sympathetic fibers to innervate the iris dilator muscle. (Note the LPCNs themselves provide sensory innervation to cornea, iris, and ciliary muscle) (1,5)
  - The Short Posterior Ciliary Nerves (SPCN): The sympathetic fibers may exit with SPCNs after leaving the ciliary ganglion and go on to innervate the conjunctival and choroidal blood vessels. (Note the SPCNs themselves are a branch of the inferior division of CN III and innervate the ciliary and iris sphincter muscles via parasympathetic innervation) (1,5)
- Travel with the vidian nerve to innervate the blood vessels of the lacrimal nerve (5).

Whew! We made it through the anatomy. This sympathetic pathway is important because a lesion anywhere along this three-neuron pathway can result in Horner’s Syndrome on the ipsilateral side.

Time to play NAME THAT LESION!

The underlying cause and classification of Horner’s Syndrome varies by location of the lesion. Let’s break down the possible locations and types of lesions along the sympathetic pathway.

First Order Neuron Lesion

First order (central) Horner’s may result from damage to the hypothalamus, brainstem, or lower cervical or upper thoracic spinal cord (2).

Examples of first order lesions include but are not limited to: Intracranial tumors, spinal cord tumors, hemorrhage of the hypothalamus, cerebral vascular accidents, demyelination (such as Multiple Sclerosis), Arnold-Chiari malformation, inflammatory or infectious myelitis, lateral medullary syndrome, encephalitis, syringomyelia, vessel infarction, neoplasms, or trauma to the head or spine (1,2).

Second Order Neuron Lesion

Second Order (preganglionic) Horner’s results from lesions in the thoracic outlet (space between collarbone and first rib), thoracic spinal cord, mediastinum (area between the lungs), lung apex, or neck (2).

Examples of second order lesions include but are not limited to: a subclavian artery aneurysm, Pancoast’s syndrome (most commonly from non-small cell lung carcinoma), metastasis of malignant tumors, thyroid malignancies, trauma to spinal cord or ribs, neck hematoma, or iatrogenic causes (surgical procedures in the spinal cord, neck, or thorax). Many preganglionic Horner’s syndromes also have no identifiable cause (1,2).

Third Order Neuron Lesion

Third Order (postganglionic) Horner’s results from lesions in the superior cervical ganglion, the ICA (neck, base of skull), the cavernous sinus, and sellar/parasellar regions (including the pituitary gland)(2,4).

Note: Sometimes a third order Horner’s is classified as an incomplete Horner’s because it does not always result in full anhidrosis of the face. This is because lesions that affect the sympathetic fibers in the internal carotid plexus do not always affect the external carotid plexus (2). Therefore, damage to the majority of facial sweat glands is spared. This damage to the ICA, usually caused by dissection or trauma, often results in a painful Horner’s Syndrome (2).

Examples of lesions include but are not limited to: Artery dissection or aneurysm, thrombosis, tumors at base of skull, neck, or pituitary, surgical procedures (such as a stent), acute thrombosis, trauma, ectatic jugular veins, malignant tumors or metastasis, and migraine or cluster headaches (1,2).

Lesions in the cavernous sinus that produce a postganglionic Horner’s syndrome may also produce other ocular motor nerve palsies, most notably an abducens nerve palsy (2).

As optometrists we are primarily concerned with sympathetic denervation to the eye (obviously). We know that pupil size is a tug of war battle between the iris dilator muscle (sympathetic innervation) and the iris sphincter muscle (parasympathetic innervation) (3). When the sympathetics are damaged, the dilator can no longer perform its job. Thus, the parasympathetic sphincter muscle takes over, which creates a miotic pupil on the affected side. We also know Muller’s muscle is partially responsible for elevating the upper eyelid and the inferior tarsal muscle functions to retract the lower lid (4). When the sympathetic innervation to these muscles is damaged, we will see a subtle ptosis (approx. 2mm) of the upper lid and reverse ptosis of the lower lid (2).

Diagnosing Horner’s Syndrome

First and foremost, careful observation and a good patient history are the initial steps needed when diagnosing a Horner’s Syndrome.

With classic acquired Horner’s you will see a ptosis and miotic pupil that is more apparent in dim illumination on the affected side. If both these signs are noted, you may inquire about perceived changes in facial sweating, but patients may not always perceive full facial anhidrosis, as earlier mentioned (2).

Other ocular signs of Horner’s Syndrome on the affected side may be an abduction deficit, reverse ptosis of the lower lid (sometimes falsely creating the appearance of enophthalmos), dilation lag, and occasionally an increase in the amplitude of accommodation on the affected side (1-3).

Congenital Horner’s Syndrome often presents with iris heterochromia. The eye on the ipsilateral side may present with an iris lighter in color than the unaffected side due to the sympathetic nervous system’s involvement in the development of iris color. Occasionally, patients with congenital Horner’s Syndrome have straighter hair on the affected side. Congenital Horner’s most often results from birth trauma (2). Note that children who were not born with Horner’s can still develop the condition, often from trauma or malignancies, so it is imperative to ask about the child’s birth history and perform a detail-oriented clinical exam on the child.

On all suspected Horner’s patients, take a thorough history. Ask about surgeries, trauma, new pains and their location, diagnosed malignancies, vascular issues, stroke symptoms or past diagnosis of stroke, diagnosis of demyelinating disease, and history of migraine or cluster headaches (1).

A careful clinical examination is also necessary in suspected Horner’s Syndrome. As always, start with a good visual acuity measurement. Measure pupil sizes in dim and bright illumination and check pupil reactivity to light and accommodation prior to instilling any topical drops. Evaluate extraocular muscles and ask about any diplopia. Take careful note of any signs of ptosis or reverse ptosis, even if they are subtle. Occasionally, Horner’s Syndrome may present with nystagmus. Color vision testing and visual fields can also provide additional information about the type of lesion we are dealing with (1).

Once you suspect an undiagnosed Horner’s syndrome based on the patient’s clinical exam and their history, you need to start thinking about referral. These patients will likely need imaging, and we will typically not be the physicians to order imaging. However, we do have some techniques available to help us reaffirm our diagnosis and localize the site of oculosympathetic damage. We can identify these areas of damage using topical eye drops.

We first use topical pharmacologic agents to determine the presence of Horner’s Syndrome. Cocaine (yes, cocaine) drops instilled in the eye will normally cause the pupil to dilate. One drop of 5% or 10% topical solution may be instilled in both eyes to compare results. The mechanism of action of cocaine involves blocking the re-uptake of norepinephrine released at the neuromuscular junctions of the iris dilator muscle. Thus, there is more norepinephrine available to induce dilation. With damage to the sympathetics in Horner’s syndrome, norepinephrine is unable to be released from the presynaptic nerve endings. Therefore, the pupil will dilate very poorly, if at all, after instilling cocaine drops (1-3).

For most accurate results, it is best to wait at least 45 minutes before assessing the pupil sizes after cocaine drop instillation. Anisocoria of approximately 1mm or more is considered diagnostic of Horner’s syndrome on the side of the miotic pupil (2). Note that on occasion, Horner’s Syndrome can be bilateral, so it is important to measure pupil sizes prior to drop instillation as well as after.

If you don’t have cocaine lying around in your office (but no judgment if you do), you may also use apraclonidine drops. Apraclonidine normally either has no effect on the pupil or causes minimal pupillary constriction. It is primarily an alpha-2 adrenergic agonist, but also a weak alpha-1 agonist. When there is sympathetic damage in Horner’s, the alpha-1 receptors of iris dilator muscle become hypersensitive. Apraclonidine will then dilate the pupil on the affected side and create a reversal in the anisocoria in the presence of Horner’s Syndrome (1-3). A downside of the apraclonidine test is that it can take several hours or even a day or two to produce dilation in a Horner’s pupil (2,7).

Now that we have determined the presence of Horner’s Syndrome with pharmacologic agents, we can determine if the causative lesion is pre- or postganglionic. In order to separate preganglionic lesions (first and second order) from postganglionic lesions (third order), we can instill topical drops of 1% phenylephrine or 0.5% or 1% hydroxyamphetamine (1-3).

Phenylephrine is a direct sympathomimetic drug. It will cause the ipsilateral pupil in a postganglionic Horner’s to dilate due to the denervation hypersensitivity from a lack of norepinephrine present in the postsynaptic terminals (1-3). A normal or preganglionic Horner’s pupil will not dilate with phenylephrine.

Oppositely, hydroxyamphetamine will not dilate the pupil in a postganglionic Horner’s. In normal circumstances, hydroxyamphetamine (an indirect sympathomimetic) causes pupils to dilate by releasing norepinephrine in healthy postganglionic nerve endings. Therefore, preganglionic Horner’s pupils will still dilate since they are unaffected by this. Since there is a reduced amount of norepinephrine in the nerve endings impacted by postganglionic Horner’s, the pupil will not dilate with hydroxyamphetamine in postganglionic lesions (1-3).

Remember that every medication has contraindications and side effects. Ophthalmic drops are no exception.

Any form of cocaine should not be used for patients who have pre-existing heart conditions, hypertension, or epilepsy. The drug can induce tachycardia, seizures, restlessness, anxiety, myocardial infarction, and stroke (6).
Apraclonidine can cause a reduction in intraocular pressure and is contraindicated in patients taking MAO inhibitors (7).
Phenylephrine and hydroxyamphetamine should not be used in patients with heart or thyroid conditions (8,9).

Be wary of using any of these drops in patients with glaucoma, especially narrow angle glaucoma. Do not instill these drops in any patient who has a known allergy or hypersensitivity to them.

To recap:

Step One: Confirm the presence of Horner’s with one of these two drugs:
- Cocaine ophthalmic drops (poor/no dilation in Horner’s pupil)
- Apraclonidine Ophthalmic drops (dilation of Horner’s pupil)
Step Two: Localize the lesion (pre- or postganglionic)
- Phenylephrine (No dilation in preganglionic Horner’s; pupil dilation in postganglionic Horner’s)
- Hydroxyamphetamine (Pupil dilation in preganglionic Horner’s; no dilation in postganglionic Horner’s)

Bear in mind that testing may sometimes be inconclusive or present with false negatives. If testing is inconclusive or not indicative of a Horner’s Syndrome but a patient has new onset symptoms suggesting it is a possibility, do not hesitate to refer anyways. If you do not have the resources in your office to confirm or localize a Horner’s syndrome, again, refer!

Ideally, we would like to refer to a neurologist or neuro-ophthalmologist, but referring to an ophthalmologist, primary care physician, or the emergency room are options as well. Be sure to send a report with all of your exam findings to the provider you have referred your patient to. This helps the receiving provider determine what type of imaging to order and what locations to focus on. Initial testing often includes lab work such as CBC, ESR, urine or blood cultures, or testing specific to infectious or inflammatory disease (1). Imagining is often focused on the head (brain), neck, chest, spine, thorax, or vasculature. Common imaging techniques used to diagnose Horner’s causes are MRI, CT, X-ray, MRA, and carotid ultrasound (1,4).

Treatment and management

Management and prognosis of Horner’s Syndrome depends on the etiology. Our job is to recognize signs of Horner’s syndrome and ensure the patient is appropriately referred for testing and treatment in a timely manner. Sometimes the etiologies of Horner’s are life-threatening. Treatment modalities often involve surgery (sometimes emergent), chemotherapy or radiation, or anticoagulants.

Of particular importance, recognize that the onset of an acute Horner’s Syndrome with head, neck, or face pain is an emergency. This is often the result of an internal carotid artery dissection (2). Skip the drops and send these patients to the emergency room immediately. These patients are also at an increased risk of cerebral infarction.

Differential Diagnosis

As always, even when we think we are certain of a diagnosis, we still need to consider differential diagnosis.

There are several conditions that have an overlap of clinical signs with Horner’s Syndrome. In addition to Horner’s, anisocoria can also be caused by unilateral pharmacologic dilation or constriction, third nerve palsy, tonic pupil, trauma to iris sphincter or dilator, Argyll Robertson pupils, iritis, iris atrophy, or ophthalmic surgery (1). Remember physiological anisocoria occurs in up to 20% of the normal population (10).

A unilateral ptosis also has several causes in addition to Horner’s Syndrome. A unilateral ptosis may be neurologic (such as Myasthenia Gravis), congenital, mechanical (surgical or trauma), myopathic, from eyelid tumors or swelling, from botox injections, or a third nerve palsy (11).

Clinical Pearls and Takeaways in Horner’s Syndrome Management

Take a thorough history and perform a careful clinical examination
- Remember, Horner’s syndrome anisocoria is more evident in dim illumination
- Ask about surgeries, trauma, and long standing medical conditions
An acute onset painful Horner’s is a medical emergency. Refer these patients immediately!
Topical solutions can help us determine the presence of and localize Horner’s lesions
Be aware of the side effects and contraindications of any medication you use in your exam room
Always consider differential diagnosis when you suspect Horner’s Syndrome
Optometrists often have the opportunity to first diagnose Horner’s Syndrome due to the presentation of ocular symptoms. You may be crucial in ensuring the patient gets appropriate and timely treatment
Horner’s Syndrome is a condition is best managed by the collaboration of an interdisciplinary medical team

References:

Khan, Z, et al. “Horner Syndrome” Treasure Island (FL): StatPearls Publishing; PMID: 29763176. 2020 Feb.
Kanagalingam, S, et al. "Horner Syndrome: Clinical Perspectives." Eye Brain. 2015;7:35-46. doi: 10.2147/EB.S63633.
Zwueste, DM, et al. “A Review of Horner’s Syndrome in Small Animals.” Can Vet J. 60(1): 81-88(2019).
Park, JM, et al. “Microscopic Characteristics of the Inferior Tarsal Muscle and Its Surroundings in Korean.” Int J Ophthalmol. 6(2): 126-130(2013). doi: 10.3980/j.issn.2222-3959.2013.02.03.
Cheatham, KM, et al. Part One Applied Science Review Guide Part 1. 7th Ed. KMK Educational Services LLC; (1): 161-163(2014).
Richards, JR, et al. “Cocaine” Treasure Island (FL): StatPearls Publishing; 2020 Feb.
Morales J, Brown SM, Abdul-Rahim AS, Crosson CE. Ocular Effects of Apraclonidine in Horner Syndrome.Arch Ophthalmol. 2000;118(7):951–954. doi:10-1001/pubs.Ophthalmol.-ISSN-0003-9950-118-7-ecs90240
Richards, E, et al. “Phenylephrine” Treasure Island (FL): StatPearls Publishing; 2019 Oct.
LL Simpson. “Blood Pressure and Heart Rate Response Evoked by P-Hydroxyamphetamine and by P-Hydroxynorephedrine II. A Quantitative Assessment of the Role of Amphetamine Metabolites in Acute Responses Evoked by D-Amphetamine.” J Pharmacol Exp Ther. 213(3): 504-8(1980).
Falardeau, Julie. “Anisocoria.” International Ophthalmology Clinics. 59 (3): 125-139 (2019). doi: 10.1097/IIO.0000000000000276.
Finsterer, J. “Ptosis: Causes, Presentation, and Management.” Aesth Plast Surg. 27, 193–204 (2003). https://doi.org/10.1007/s00266-003-0127-5.