There is continued interest in the underlying pathophysiology, but the scarcity of cases makes ongoing research difficult.

The pathophysiologic mechanism which produces an Argyll Robertson pupil is unclear, but is believed to be the result of bilateral damage to the pretectal nuclei in the midbrain.

Research has implicated the rostral midbrain in the vicinity of the cerebral aqueduct of the third ventricle as the most likely region of damage.

"[5] The causes of Parinaud syndrome include brain tumors (pinealomas), multiple sclerosis and brainstem infarction.

Due to the lack of detail in the older literature and the scarcity of AR pupils at the present time, it is not known whether syphilis can cause Parinaud syndrome.

[6] When penicillin became widely available in the 1940s, the prevalence of AR pupils (which develop only after decades of untreated infection) decreased dramatically.