Nearly a century and a half ago, Argyll Robertson pointed out that some patients with tabes dorsalis had small pupils that constricted poorly if at all to light yet constricted promptly when the patients viewed a near object (“light-near dissociation”). This observation was soon confirmed at a rate of three to four publications per year and was pronounced a useful clinical sign for syphilis (1). After 1908, when Wassermann's serologic test for syphilis became available and was found to be frequently positive in patients with Argyll Robertson (AR) pupils, the popularity of Argyll Robertson's pupillary sign increased.
In the twentieth century, it became apparent to Adie and others (2) that some young patients without clinical or serologic signs of syphilis had this pupillary light-near dissociation and also an abnormally slow (“tonic”) pupillary constriction when changing fixation from a distant to a near target and back again. By mid-century, many of the tonic light-near dissociated pupils that had previously been called AR pupils (3) were being called “Adie's tonic pupils.”
TWO TYPES OF LIGHT-NEAR DISSOCIATION
There appeared to be two different kinds of pupillary light-near dissociation in patients with good vision and normal eye movements and alignment-AR pupils and tonic pupils:
- AR pupils. These were frequently associated with syphilis, tended to be small, almost always bilateral, with little or no constriction to direct light, but prompt, apparently normal, pupil constriction to near targets.
- Tonic pupils. The tonic response to near came in three varieties, all apparently orbital:
a) Adie tonic pupil. These were not clinically associated with syphilis. Usually at first, only one pupil was affected. The pupil was large, and accommodative power was diminished. Close examination showed segmental paralysis of the iris sphincter with the intact segments constricting to light, a feature that ruled out pharmacologic mydriasis. After some weeks, the constriction to a near stimulus would return, but it was strong and long-lasting (“tonic”), and with time the second eye would often become involved with the same process. Both pupils would eventually become small. When the ciliary ganglia of some of these patients with Adie syndrome were examined, a loss of ciliary ganglion cells was demonstrated (4).
b) Neuropathic tonic pupils (5). Patients with various kinds of peripheral neuropathy also damage the innervation of their intraocular muscles in both eyes, including the sympathetic innervation to the dilator muscle (6).
c) Local tonic pupils (5). These were associated with local damage to orbital nerves (penetrating wounds, surgery, hemorrhage, orbital tumors, or infections).
It was eventually recognized that the tonicity of the pupil reaction to a near target seen in these three groups of patients was the result of aberrant regeneration into the iris sphincter of fibers that had been originally destined for the ciliary muscle (7). The slowness and tonicity of this restored near response could be taken as an indicator of aberrant regeneration of orbital peripheral nerves (7).
LOCALIZING THE LESION CAUSING THE ARGYLL ROBERTSON PUPIL
There are two schools of thought about the location of the lesion that causes the AR pupil. The first school suggests that a lesion in the midbrain knocks out the light reaction by damaging the interneuron that bridges the connection between the retinal ganglion cells and the Edinger-Westphal nucleus but does not affect the more ventral pathway mediating the near reaction. The second school suggests that the lesion lies in the ciliary ganglion or nerves in the orbit and that we have been fixating on the midbrain and searching there in vain for pathology for a hundred years because little was known of peripheral misdirection syndromes when the AR pupil was first described.
THE CASE FOR A MIDBRAIN CAUSE FOR THE ARGYLL ROBERTSON PUPIL
Loewenfeld (8,9) has strongly favored the idea that syphilis usually produces a pupillary light-near dissociation of a “central” (midbrain) variety by damaging the pupillary light reaction pathway and sparing the near reaction pathway and that the resulting light-near dissociation without tonicity of the near reaction was what we called the AR pupil. Using pupillography, Lowenstein (10) documented a number of such cases in patients with syphilis and argued that it was natural to think that different kinds of light-near dissociation should have different mechanisms, probably in different locations.
In 1921, Kinnier Wilson started using the term “dissociation” to refer to the pupil reactions in syphilis and clearly favored a midbrain mechanism for AR pupils because he had seen pupillary light-near dissociation in patients with dorsal midbrain tumors (11) and, during the 1918 influenza pandemic, in patients with an acute encephalitis (12). Unfortunately, he called every light-near dissociated pupil an AR pupil and did not look closely at the iris sphincter. Because he made no effort to distinguish between tonic and normal constriction to a near target, his rich clinical experience with neurosyphilis and AR pupils is not relevant to our discussion of the location of the lesion.
THE CASE FOR AN ORBITAL CAUSE FOR THE ARGYLL ROBERTSON PUPIL
The counter argument suggests that Treponema pallidum, or the body's immune reaction to it, has a predilection for the meninges and blood vessels and that in tabes dorsalis, the target is the dorsal root ganglion (part of the peripheral nervous system). Peripheral nervous system damage leads to the radiculopathy that accounts for the typical symptoms in tabes. Since syphilis is a famously versatile disease, why can't it also damage the ciliary ganglion or short ciliary nerves? The aberrant regeneration process would then produce a tonic pupillary light-near dissociation. This hypothesis would eliminate the need to invoke an anatomically murky midbrain cause for pupillary light-near dissociation in the AR pupil.
However, a traditionally strong argument against a peripheral origin for the abnormal pupil in syphilis is that syphilis does not commonly produce tonic pupils because it does not produce a peripheral neuropathy. Yet, two studies (5,13) have shown that a small number of patients with tonic pupils in both eyes have (or have had) syphilis. One series (5), published in 1977, followed 150 patients with tonic pupils and segmental iris palsy. Of these patients, 21 had bilateral tonic pupils in the context of a widespread peripheral neuropathy. This subgroup (neuropathic tonic pupils) was older (63 years old at time of examination) than the group of Adie tonic pupils without the neuropathy (32 years old at onset of symptoms). Seventy-seven of these 150 patients were tested for syphilis (VDRL, FTA-ABS). No patient with only one eye involved was positive, but one-third of the older group with both eyes involved (7/21) were positive.
The other series (13) involved 60 patients with tonic pupils and segmental iris palsy. Five of the 29 patients tested (VDRL, FTA-ABS) had a positive serology (17%). All five patients had bilateral tonic pupils and were appropriately pursued for evidence of treatable neurosyphilis. In four of these five patients, the same tests were positive in the spinal fluid.
Although the authors of these series of tonic pupils suggested that the syphilis caused the orbital damage to the pupillary pathways, we now think it more likely that the tonic pupils were merely an expression of the patients' established peripheral neuropathy.
Certain features of a peripherally denervated iris sphincter-irregularity of the pupil margin and segmental damage-have occasionally appeared in older descriptions of the AR pupil. For example, the Hamblin drawings in McGrath's 1932 paper, reprinted in Duke-Elder (14-16), show a tight miosis with some wrinkling of the pupillary margin in one patient and an apparent segmental iris atrophy of the stroma in another. These iris abnormalities were blamed on the patient's syphilis, but they are the very features often seen in old Adie tonic pupils.
Another strong argument against a peripheral (orbital) cause of the AR pupil in syphilis is that pathologic study of the ciliary ganglia in these patients has invariably been normal. After Marina (17) argued for a peripheral cause in 1910, there appeared a cluster of five publications on postmortem studies of the ciliary ganglia in 40 syphilitic patients with AR pupils and age-matched controls (18). The ciliary ganglia were invariably normal.
We believe that the evidence supports a midbrain cause of the AR pupil, provided one follows Loewenfeld's definition of the AR pupil as small pupils that react very poorly to light and yet seem to retain a normal pupillary near response that is definitely not tonic.
We support our position with the following arguments:
- A tumor growing in the dorsal midbrain is known to be capable of producing pupillary light-near dissociation, although usually in association with upgaze difficulties;
- The increased third ventricle pressure that occurs when a ventricular drain or shunt has failed can also produce a pupillary light-near dissociation.
- Tonic pupils are common in patients with a widespread peripheral neuropathy. They are usually bilateral and have sector sphincter palsies and a tonic light-near dissociation. If a patient with a diabetic neuropathy is found to have bilateral tonic pupils, it would be wise to assume that this is simply a manifestation of the diabetic neuropathy. A minority of such patients may also have syphilis (5,13), and their unrelated peripheral neuropathy might obscure a midbrain mechanism for the AR pupils. For this reason, we favor checking the blood for syphilis in patients with bilateral neuropathic tonic pupils.
- There is a very long and well-established tradition, dating from the late nineteenth century when neurosyphilis was common, that syphilis does not cause a “polyneuritis.”
- Patients with AR pupils often have a considerable amount of subependymal gliosis in the area where the third ventricle narrows into the Sylvian aqueduct, at or near the posterior commissure. Loewenfeld (19) cites 20 papers remarking on a combination of ependymitis and subependymal gliosis. For example, Warkany (20), in 1924, studied the brains of 10 tabetic patients with a pupillary light-near dissociation and compared them with non-syphilitic patients of a similar age. All of the patients with syphilis and a light-near dissociation had a striking gliosis just outside the ependyma that lined the top end of the aqueduct of Sylvius. Could this kind of periaqueductal subependymal gliosis and associated nerve fiber loss, by itself, be enough to interfere with the pupillary light reflex pathways from both eyes while sparing the pupil response to a near effort as suggested by Warkany (20)? The iris sphincter is a very small muscle, and it probably does not take very many nerve fibers to make it contract. It is not known whether these few fibers of the interneuron controlling the pupillary light reflex in both eyes could be taken out of action by subependymal gliosis in the right location, leaving the pupillary near reaction intact.
DETECTING SEGMENTAL IRIS SPHINCTER PALSY
In our slit-lamp (21) and infrared iris transillumination (22-24) examinations of the iris sphincter in patients with Adie tonic pupil, we have consistently found evidence of segmental iris sphincter palsies. When the lights are turned on, the video monitor will show segmental iris sphincter palsy as a darkening of the parts of the iris sphincter that are still wired up to the pupillary light reflex (see boxed text below). With a near effort, there will often be a thickening/darkening of other parts of the iris sphincter, sometimes in the very sectors that failed to darken in light.
Even if examiners lack the equipment for iris infrared transillumination, they should inspect the remaining movements of the iris sphincter at the slit-lamp, looking for sectoral sphincter palsies. Our working assumption is that when a patient has a sectoral sphincter palsy, light-near dissociation is of orbital origin.
To settle the question of whether the AR pupil is of central or peripheral origin, it will be necessary to perform iris transillumination (or a magnified slit-lamp examination) in a substantial number of patients who have a pupillary light-near dissociation (with and without tonicity of the near reaction), perhaps in many parts of the world.
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