The diagnosis of pupil abnormalities tends to be related mostly to pupil reaction and not so much to difference in size (anisocoria).  Pupils that are dilated but equal in size and which react normally are common, particularly in young women.  There is a series of diagnoses to consider when there is anisocoria but normal function.  If there is no more than 0.5 mm difference, it may be called physiologic but beware of such a simple answer.  Unless you can verify this difference by longstanding pictures, thereby ruling out a recent event, you must explain the difference in pupil size some other way.  The best old pictures are those used for identification (job, drivers license or military).   Also useful are school year books, wedding pictures, etc.

When you are presented with anisocoria as the only presenting sign, the first question to be considered is which is the abnormal pupil; the larger or smaller one.  The larger one can be due to an aneurysm, a recovered Horner's that is more sensitive to its effector substance or occasionally it may be idiopathic.  The location of the aneurysm causing anisocoria is at the junction of the internal carotid and posterior communicating arteries.  The aneurysm is usually superior to the third nerve pressing on the superior part of the nerve where the pupil fibers are located.  If the aneurysm just touches this region then anisocoria without pupiloplegia will result.  Unless there are other symptoms suggesting an aneursym, then an MRA with particular views of that junction of arteries is indicated. MRA is not the "gold standard" like arteriography, but it has a 95% accuracy.  Even if diplopia is not a complaint, the patient should be examined in up gaze particularly where a small vertical deviation may exist but is not noticed by the patient.

Pupil area depends on square of the radius meaning in the above example 0.5 mm less. Pupil diameter means 12% less pupil area.

Occasionally, patients have periodic pupil dilatation and the cause is unknown.  This is only a diagnosis of exclusion or last resort.

A rare diagnosis is the Claude Bernard syndrome.  In this case, a lesion barely touches the sympathetic chain and stimulates it.  This lesion is a precursor to injury of the sympathetic chain eventually causing a Horner's syndrome.  It is an extremely rare syndrome reported and mostly seen by Claude Bernard.

Systemic drugs can cause mydriasis on rare occasion but they are not a frequent solution to anisocoria.  However, this possibility needs to be kept in mind.

The smaller pupil syndrome is usually a Horner's syndrome even without the other parts of the syndrome.In the absence of trauma to the neck or neck surgery a Horner's syndrome may be partial with no ptosis.  If Horner's syndrome occurs without obvious reason such as vascular disease, then a tumor has to be considered.  In this case it is important to differentiate between a peripheral 3^rd neuron lesion and a 1^st or 2^nd neuron lesion which could point to the possibility of tumor.  This can be done with the hydroxyamphetamine test. If the lesion is in the 3^rd neuron, the hydroxyamphetamine eye drop won't dilate the smaller pupil; this localizes it to the 1^st or 2^nd neuron.  This raises the question of tumor if the pupil dilates with hydroxyamphetamine the lesion is in the 3^rd neuron and is more likely benign.  There are no accurate chemical tests to directly identify a 1^st or 2^nd neuron location. If the patient fails to dilate with hydroxyamphetamine and is middle aged, you must consider a 2^nd neuron location and a tumor of the apex of the lung.

Diagnose Horner

Cocaine (2-10%) will dilate non-Horner pupil - but will not dilate Horner pupil

1% hydroxyamphetamine (Paradrine) will dilate pupil with 1^st or 2^nd  order neuron lesion and not dilate 3^rd order neuron lesion. 

Another cause of a smaller pupil may be due to a mild iritis that does not present with the usual external sign of a red eye.  If one has Posner-Schlossman syndrome, the iritis may be mild by slit lamp examination and show no injection of the eye.  The intraocular pressure is usually very high without the pain and inflammation that combination usually produces.

Another cause of anisocoria may not be found in the pupil but in the angle.  Gonioscopy of the angle may demonstrate a tear at the base of the iris from previous trauma.  This defect would not be seen with a routine slit lamp exam but requires gonioscopy.

Thomas J. Walsh, M.D.