Correct! Because both pupils constrict normally to light, there are only four possible causes: 1) Horner syndrome; 2) topical adrenergic-induced mydriasis; 3) episodic mydriasis; and 4) physiologic anisocoria.

If apraclonidine instillation causes the relatively miotic pupil to become the relatively mydriatic (dilated) pupil, you have diagnosed Horner syndrome, which can exist even without ipsilateral ptosis (or ipsilateral hypohidrosis).

Topical instillation of cocaine 10% was formerly the standard way to test for a Horner syndrome, but it has been displaced by apraclonidine, which is more reliable and available. Cocaine is still used in ruling out Horner syndrome in children aged 2 years or younger because apraclonidine instillation in that age group is contraindicated.

If apraclonidine does not reverse the anisocoria, you are left with the other three possibilities, none of which is medically important. If the patient tells you that she has used a nasal spray or eyedrop to “get the red out,” you can diagnose adrenergic-induced mydriasis, which often does NOT disturb pupil constriction to light.

Episodic mydriasis typically shows reduced constriction to light in the eye with the larger pupil, so that diagnosis would not really apply here. You will have to wait to confirm that diagnosis when you re-examine the patient the next morning and find that the pupils have become equal in size and normal in constriction. By the way, episodic mydriasis is sometimes associated with migraine, seizure, or manifestations of a dysautonomia.

Physiologic anisocoria is the last—but most common-- possibility. In that case, you can confidently reassure the patient that the condition is benign, that the anisocoria will often come and go, and that the larger pupil may even jump from one eye to the other!.

With regard to the other answers here: topical pilocarpine 1% is used when there is anisocoria, the mydriatic pupil fails to constrict normally to light or a near target, and there is no pupil ovality or tonicity. In that case, you would be suspecting topical pharmacologic (parasympatholytic) mydriasis. Failure of the affected pupil to constrict to pilocarpine 1% (in the presence of intense constriction of the unaffected pupil) would confirm that diagnosis. Pilocarpine 0.1% is used when you have found features of a tonic pupil. You could confirm a postganglionic (ciliary) lesion by finding constriction of the affected pupil but no constriction of the unaffected pupil. However, pilocarpine 0.1% is no longer available, so you would have to compound it yourself—not an easy task. You do not really need that confirmation if the tonic features are unequivocal.