Horner syndrome describes the constellation of findings associated with a lesion affecting the oculosympathetic pathway. Clinically, ipsilateral miosis, ptosis, and anhidrosis form the classic triad, with other features potentially being present.
Without getting into too much detail about the sympathetic pathways and differential diagnosis of Horner syndrome (those will be covered in other articles), I will attempt to highlight the 3 pharmaceutical agents used in the diagnosis of Horner syndrome, discuss the tests, and point out the key ideas that often find themselves in tests.
Caveat: Because of the general unavailability of some of these drugs (namely cocaine and hydroxyamphetamine) and the relatively lower cost/availability of neuroimaging, these drugs may not be available to your local neuro-ophthalmologist. There are evolving discussions about navigating the challenges of diagnosis given these limitations (1, 2). Despite these changes to practical clinical evaluation, it remains clinically important to understand the pharmacologic principles involved in the diagnosis of Horner syndrome.
The pharmacologic diagnosis of Horner syndrome can be broken into two major categories:
Confirming the diagnosis of Horner syndrome
Localizing Horner syndrome to preganglionic (1st-/2nd-order) or postganglionic (3rd-order) neuron
The cocaine test for Horner syndrome is often tested in board exam/OKAP settings, most likely because of its understood mechanism of action, its contribution to the understanding/diagnosis of Horner syndrome, and somewhat counterintuitive testing results.
From a practical standpoint, relatively few clinics have cocaine available for Horner syndrome testing, largely due to the unavailability, high cost with no reimbursement, and security requirements for storage. So although cocaine is discussed from a historical context, we unfortunately have to also learn the details of this test so that you can easily answer any questions that might pop up on a test. Just don’t be surprised if you can’t find any doctors who can do a cocaine test for Horner (it might not be necessary anyways).
Mechanism of action: blocks the reuptake of norepinephrine into presynaptic neurons at the synapse of postganglionic sympathetic nerves and muscle (in eye drops, synapse of long ciliary nerves and iris dilator muscle).
Test (3, 4):
Measure pupil size of both eyes
Instill 1 drop of cocaine (4% or 10%) in each eye, wait 5 minutes, then an additional 1 drop of cocaine in each eye
Wait 40-60 minutes
Remeasure pupil size of both eyes
No reaction after 60 minutes: put one more drop of cocaine, wait another 30 minutes
Pupillary inequality ≥ 1.0 mm: positive test for Horner syndrome (the greater the inequality, the more accurate it gets)
Pupillary inequality < 1.0 mm: negative test for Horner syndrome
Urine drug test for cocaine will be positive for a few days after testing (5)
Apraclonidine is the most readily available drug used for confirming Horner syndrome. Because this drop is often available in comprehensive ophthalmology clinics for other uses (it lowers IOP and may be used as a pre- or post-treatment for in-office procedures), knowing how to administer this test may be helpful for confirming Horner syndrome, especially if neuro-ophthalmology is not readily available.
Mechanism of action: α2-adrenergic agonist, weak α1-adrenergic agonist; in Horner syndrome, sympathetic denervation hypersensitivity of α1-receptors occurs within the pupillary dilator muscle.
Note anisocoria (which pupil is small, which pupil is larger)
Instill 1 drop of apraclonidine (0.5% or 1%) in each eye
Wait 40-60 minutes (effects can be quicker)
The smaller pupil dilates, normal pupil stays the same (reversal of anisocoria): positive test for Horner syndrome
No change to pupils: negative test for Horner syndrome
Denervation must be present long enough for receptor upregulation to have occurred (14)
Positive tests have been noted within hours of a carotid dissection but the onset of denervation sensitivity are variable (15)
False negatives can occur in the setting of acute Horner syndrome or in long-standing cases if strict “reversal of anisocoria” criteria used (16, 17)
Apraclonidine has limited use in pediatric Horner syndrome due to the risk of CNS and respiratory depression (18)
Hydroxyamphetamine remains a useful tool for localization of the lesion once a diagnosis of Horner syndrome has been confirmed (20). However, it is limited by accessibility and some considerations detailed below. Since it’s still tested (and important to understand from a mechanistic and historical perspective), you still need to know how it works and what it does.
Mechanism of action: increases the release of norepinephrine from the presynaptic neuron (21). In intact presynaptic (3rd order, postganglionic) neurons, this results in pupil dilation; if this neuron is not intact, the pupil does not dilate.
Note anisocoria (which pupil is small, which pupil is larger)
Instill 1 drop of hydroxyamphetamine (1%) in each eye
Wait 45-60 minutes
In patients with normal pupils, there is a symmetric 2 mm dilation of each pupil (anisocoria remains) (22).
In patients with Horner syndrome, the reaction is based on whether or not there is an intact 3rd-order (postganglionic) neuron (23):
Both pupils dilate: intact 3rd-order neuron (localizes to 1st- or 2nd-order neuron)
Only non-Horner pupil dilates: not intact 3rd-order neuron (localizes to 3rd-order neuron)
Cocaine interferes with the uptake and efficacy of hydroxyamphetaine; as such, if cocaine is used for confirming the diagnosis, at least 72 hours must pass before hydroxyamphetamine testing is done (26).
In cases where there is concern for rapid diagnosis and localization (such as in carotid dissection), don’t delay neuroimaging for the hydroxyamphetamine test!
In acute Horner syndrome, hydroxyamphetamine testing may produce a false-negative result during the first week after injury (27-28).
Dr. Andrew Lee is a highly-regarded neuro-ophthalmologist and a phenomenal educator. He has made some short lecture videos on neuro-ophthalmology available on YouTube!
Video credit: Lee AG. Pharmacologic Testing for Horners. Video. YouTube. Available online. Accessed 02-27-2019.
Basic and Clinical Science Course, Section 5. Neuro-Ophthalmology. San Fransisco: American Academy of Ophthalmology; 2018-2019:257-262.
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Kanagalingam S, Miller NR. Horner syndrome: clinical perspectives. Eye Brain 2015;7:35-46. Available online.
Sadaka A, Schockman SL, Golnik KC. Evaluation of Horner syndrome in the MRI era. J Neuroophthalmol 2017;37:268-272.
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Do you have any tips on how to remember the pharmacologic testing for Horner syndrome? Leave a comment or contact us!