Eyedrop testing

in
Horner
Syndrome

Eugene F. May, MD
Neuro-ophthalmic Consultants Northwest
Seattle Neuroscience Institute at Swedish Medical Center
University of Washington
Seattle, WA
• Horner JF. Über eine Form von
Ptosis. Klinische Monatsblätter
für Augenheilkunde.
1869;7:193-198.
– No references
– Described by Claude
Bernard (1850)
– Described by Francois
Pourfour de Petit (1727)
Anatomy
Pharmacology
 Findings
• Ptosis
– upper eyelid ptosis
– inverse ptosis
– narrowing of the palpebral fissure
• facial anhidrosis
• miosis
– > 1.0 mm
– dilatation lag
• any combination of the above
– van der Wiel HL The diagnosis of Horner’s syndrome. Clin Neurol Neurosurg.
1988;90:103-108.
 Miosis
• Ptosis
– iris constrictor unopposed
– 1 - 1.5 mm miosis
• greatest in dim illumination
• dilation lag
– pupil dilation is passive
Is there a chance combination of
the ptosis and miosis?

• No anhidrosis
• No associated neurologic symptoms
or findings
Historical Background

• Dilute epinephrine test

• Cocaine test
• Hydroxyamphetamine test
• Apraclonidine test
 Cocaine test
• Cocaine hydrochloride, 10%
• one or two drops in each eye
– perhaps several minutes apart
• measure pupil size before and 50-60 minutes
later
– maintain stable ambient lighting (what level?)
– control near response
– ?measure post-drop anisocoria
– ?measure change in anisocoria pre- vs. post-drop
 Cocaine test
• Normal eyes
– post-cocaine anisocoria < 0.5 mm
– pupils of Afro-americans react poorly to cocaine
– Friedman JR et al. The cocaine test in normal patients. Am J
Ophthalmol. 1984;98:808-810

• Horner syndrome
– anisocoria of 1.0 mm or more is consistent
– normal result does not exclude Horner’s
– Van der Wiel HL, Van Gijn J. The diagnosis of Horner’s syndrome:
use and limitations of the cocaine test. J Neurol Sci. 1986;74:311-
316.
 Cocaine test
• Chances of a Horner syndrome increase
with anisocoria
– anisocoria of 0.8 mm = odds ratio of 1050:1
– anisocoria of 1.0 mm = odds ratio of 6000:1
• but measured anisocoria of up to 0.9 mm in normals
• anisocoria as little as 0.3 mm in Horner group

Kardon RH et al. Critical evaluation of the cocaine test in the diagnosis

of Horner’s syndrome. Arch Ophthalmol. 1990;108:384-387.
 Cocaine test
– Absolute anisocoria more predictive than
change in anisocoria
• less overlap between groups
– physiologic anisocoria
• anisocoria actually decreased in most

Kardon RH et al. Critical evaluation of the cocaine test in the diagnosis of

Horner’s syndrome. Arch Ophthalmol. 1990;108:384-387.
 Cocaine test
Alternatives

• Why not cocaine?

– difficult to obtain (?)
– expensive (?)
– short shelf life (?)
– parents hesitant (?)
– positive urine test (?)
 Cocaine test
Alternatives

• Apraclonidine 0.5%, 1% (Iopidine)

– α2 > α1 adrenergic agonist
• approved for treatment of IOP after trabeculoplasty
• receptors upregulate after 5-8 days
– reversal of anisocoria in several studies
• 0.5% and 1.0%
• denervation supersensitivity
– actively dilates the abnormal pupil
 Apraclonidine
• Studies show good sensitivity
– 1.00 (1%) and 0.88 (0.5%)
– Morales J et al. Arch Ophthalmol. 2000;118:951-954.
– Brown SM et al. Arch Ophthalmol. 2003;121:1201-1203.
– physiologic anisocoria: no reversal of anisocoria
• Comparison studies
– 0.5% vs 4% cocaine in children
• equally sensitive
• Chen P et al. J Ocular Pharm and Therapeutics. 2006;22:182-187.
 Apraclonidine
• must have high level of illumination
• sometimes normal pupil dilates
 Apraclonidine
• Side effects
– in children with glaucoma
• apnea, bradycardia, hypotension, somnolence,
fatigue
– in children with Horner syndrome
• conjunctival hyperemia
• sleepiness
Localization
 Hydroxyamphetamine test

• Pivotal study
– more reliable than dilute epinephrine testing
– Thompson HS and Mensher JH. Adrenergic mydriasis in Horner’s
syndrome. Hydroxyamphetamine test for diagnosis of
postganglionic defects. Am J Ophthalmol 1971;72:472-480.
 Hydroxyamphetamine test

• Post-drop anisocoria
– difference in dilation
• 1.0 mm: 85% chance of post-ganglionic lesion
• 1.5 mm: 96% chance of post-ganglionic lesion

Cremer SA, et al. Hydroxyamphetamine mydriasis in Horner’s

syndrome. Am J Ophthalmol. 1990;110:66-70.
 Hydroxyamphetamine test

• Problems
– range of variability exists
• even in normals
– Cremer et al. Hydroxyamphetamine mydriasis in normal
subjects. Am J Ophthalmol. 1990;110:66-70.
• extent of deficit influences test results
– false negative in acute Horner’s
• one week before NE stores are exhausted
– must wait two days after cocaine test
 Hydroxyamphetamine test
• False positive
– if second and third order neuron involved
• extensive tumor
• radiation
– blood supply to the SCG arises lower in the
neck
– congenital
• trans-synaptic degeneration of 2o neuron
 Hydroxyamphetamine test
Alternatives

• Hydroxyamphetamine not always available

• Denervation supersensitivity
– Dilute epinephrine
• 55% false positives
• 61% false negatives
– Hydroxyamphetamine
• 16% false positives
• 4% false negatives
– Maloney WF, et al. Am J Ophthalmol. 1980;90:394-402.
 Hydroxyamphetamine test
Alternatives

• Dilute (1%) phenylephrine

– sensitivity 81%; specificity 100%
– effects vary according to integrity of corneal
epithelium
• hydroxyamphetamine not dose-dependent
– partial postganglionic lesion may not be
distinguished from preganglionic lesion

Danesh-Meyer HV et al. The correlation of phenylephrine 1% with

hydroxyamphetamine 1% in Horner’s syndrome. Br J Ophthalmol. 2004;88:592-
3.
 Hydroxyamphetamine test
Alternatives

• Problems with supersensitivity testing

– dilution of eyedrop
– degree of supersensitivity
• preganglionic lesions cause relative supersensitivity
– dilute solutions more dependent on corneal
parameters
– supersensitivity of the iris dilator increases with
age
 Hydroxyamphetamine test
Alternatives

• Not generally available in US:

– Tyramine hydrochloride (5%)
– Hydroxymethylamphetamine (Pholedrine)
 Conclusions

• A combination of characteristic symptoms and

signs allows a diagnosis of Horner syndrome
 Conclusions
• Cocaine testing is the eyedrop test of choice
for diagnosing anisocoria due to Horner
syndrome
– 1.0 mm anisocoria after the eyedrops is a useful
cutoff
– apraclonidine testing is very helpful and the
eyedrop is more readily available
• bright light
 Conclusions
• Hydroxyamphetamine testing helps localize
the Horner syndrome to the third order
neuron
– 1.0 mm difference in dilation a useful cutoff
– beware of false positives
– dilute phenylephrine if hydroxyamphetamine
not available
Thank you!