A patient presents with anisocoria that is greater in the dark than in the light. You suspect a right-sided Horner's syndrome which is confirmed on cocaine testing. What would be the result of hydroxyamphetamine testing if this was a 3rd order Horner's syndrome?
Episclera / Sclera / Anterior Uvea
Anisocoria that is greater in the dark than the light suggests that there is abnormal dilation under dark conditions. That means that the smaller pupil would be the suspect pupil. This patient would also demonstrate right upper eyelid ptosis in the right eye with the miotic pupil. Together these features are characteristic for Horner syndrome in the right eye.
Technically there are three drops that can aide in the work-up of Horner syndrome; cocaine and apraclonidinecan be used to confirm the diagnosis and hydroxyamphetamine can be used to localize the pathology to either the first/second-order neuron or the third-order neuron. In reality, hydroxyamphetamine drops are no longer available in the US market except from special order pharmacies so this test has been abandoned by most clinicians.
Historically the most commonly utilized drop test for the confirmation of Horner syndrome was cocaine testing although regulations on cocaine have led to more clinicians using apraclonidine drop testing. The response of a normal pupil to cocaine 10% is dilation because cocaine blocks reuptake of norepinephrine at the pre-synaptic cleft allowing more norepinephrine to function in stimulation of the pupillary dilator muscle. The response of a Horner syndrome pupil to cocaine is no or poor dilation due to decreased sympathetic tone to the eye there is a shortage of norepinephrine in the synaptic cleft. Despite blockage of pre-synaptic norepinephrine reuptake by cocaine in a Horner syndrome eye, there is limited norepinephrine in the synaptic cleft to cause dilation. If anisocoria is physiologic both pupils will dilate equally (or nearly equally) leading to less than 1 mm anisocoria 30 minutes following instillation of cocaine 10% in both eyes. In this patient with a right Horner syndrome, a cocaine test would have resulted in an increase in the anisocoria with the left eye dilating and the right eye staying about the same size.
Apraclonidine is an alpha-adrenergic receptor agonist that has more effect on alpha-2 receptors than alpha-1 receptors. It is not completely clear how it functions in the diagnosis of Horner syndrome but the current theory revolves around up-regulation of post-synaptic alpha-1 receptors in Horner syndrome. The belief is that as early as 36 hours following disruption of sympathetic fibers to the eye, the pupillary dilator muscle experiences up-regulation of alpha-1 receptors in response to sympathetic denervation. A normal pupillary response to apraclonidine (trade name Iopidine) is mild constriction due to action of the medication on pre-synaptic alpha-2 receptors which act to decrease release of norepinephrine to the dilator muscle. In patients with Horner syndrome, however, the action of apraclonidine on up-regulated alpha-1 receptors predominates over the presynaptic alpha-2 effect resulting in dilation. In an individual with unilateral Horner syndrome who has apraclonidine drops applied bilaterally, the abnormal eye dilates and the normal eye constricts leading to reversal of anisocoria.
Lastly, hydroxyamphetamine causes active release of stored norepinephrine from the presyntaptic nerve ending which will cause dilation of the pupil as long as the 3rd order neuron is intact. However, in a 3rd-order Horner's syndrome, there will be no change in pupil size on the affected side, while the contralateral normal pupil will dilate. Therefore in the above scenario, the right pupil will not change while the left pupil will dilate (Answer "A").