VIEWPOINT

The Argyll Robertson Pupil

H. Stanley Thompson, MD and Randy H. Kardon, MD, PhD

Abstract: The Argyll Robertson (AR) pupil has been dened as a pupil that is small and constricts poorly to direct light but briskly when a target within reading distance is viewed (light-near dissociation). Most descriptions of the AR pupil do not mention segmental iris sphincter constriction, or slow, sustained constriction with a near vision effort. Such features are considered typical of the light-near dissociation of Adie syndrome and of neuropathic tonic pupils, where damage to the ciliary ganglion or ciliary nerves is believed to be the mechanism. Because the AR pupil lacks these features, it has been attributed to a dorsal midbrain lesion that interrupts the pupillary light reex pathway but spares the more ventral pupillary near reex pathway. However, lesions in this region have not been reliably demonstrated in syphilis. Resolving the issue about the location of the syphilitic lesion that produces the AR pupil will depend on careful examination of patients with techniques designed to disclose segmental palsy of the iris. If segmental iris sphincter palsy is found and the light-near dissociation has tonic features, one must conclude that the mechanism of the pupil disorder is a ciliary (peripheral) rather than a midbrain (central) denervation. Until better evidence settles the localization of the AR pupil, it is appropriate to screen patients with bilateral tonic pupils for syphilis. (J Neuro-Ophthalmol 2006;26:134138)

became available and was found to be frequently positive in patients with Argyll Robertson (AR) pupils, the popularity of Argyll Robertsons 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 xation 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 Adies 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 alignmentAR pupils and tonic pupils: 1. 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. 2. 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 rst, 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 longlasting (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).
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early 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 conrmed at a rate of three to four publications per year and was pronounced a useful clinical sign for syphilis (1). After 1908, when Wassermanns serologic test for syphilis

Neuro-ophthalmology Unit, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa. Address correspondence to H. Stanley Thompson, MD, Ginniff Brooks 2096 Krestel Ridge SW, Oxford, IA 52322; E-mail: thompson@ ginniff.com

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FIG. 1. Pupillogram of Argyll Robertson pupils showing a weak (low amplitude) light reaction and a strong near pupil constriction, which dilates promptly with a change in focus to a far object. Adapted from Reference 1.

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 bers 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 rst 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 EdingerWestphal 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 xating 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 rst described.

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 inuenza 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 bodys 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 cant 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

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

FIG. 2. Aqueduct of Sylvius in a normal patient (A) and in a patient with tabes dorsalis and Argyll Robertson pupils (B) showing subependymal gliosis as a dark line around the lining of the aqueduct. Adapted from Reference 20.

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FIG. 3. Pupillary light-near dissociation in a patient with neurosyphilis who had smallish pupils in dark (top) and light (bottom). There was very prompt miosis with a near effort. Inset shows that this patient had a normal iris sphincter with no signs of sector palsy.

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 ve patients had bilateral tonic pupils and were appropriately pursued for evidence of treatable neurosyphilis. In four of these ve patients, the same tests were positive in the spinal uid. 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 sphincterirregularity of the pupil margin and segmental damagehave occasionally appeared in older descriptions of the AR pupil. For example, the Hamblin drawings in McGraths 1932 paper, reprinted in Duke-Elder (1416), 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 patients 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 ve 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.

OUR POSITION
We believe that the evidence supports a midbrain cause of the AR pupil, provided one follows Loewenfelds denition 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 denitely not tonic.
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We support our position with the following arguments: 1. A tumor growing in the dorsal midbrain is known to be capable of producing pupillary light-near dissociation, although usually in association with upgaze difculties; 2. The increased third ventricle pressure that occurs when a ventricular drain or shunt has failed can also produce a pupillary light-near dissociation. 3. 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. 4. 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. 5. 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 ber loss, by itself, be enough to interfere with the pupillary light reex 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 bers to make it contract. It is not known whether these few bers of the interneuron controlling the pupillary light reex in both eyes could be taken out of action by subependymal gliosis in the right location, leaving the pupillary near reaction intact.

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 reex (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 magnied 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.

REFERENCES
1. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993:9778. 2. Lowenstein O, Loewenfeld IE. Pupillotonic pseudotabes: the syndrome of Markus-Weill & Reys-Holmes-Adie: a critical review of the literature. Surv Ophthalmol 1965;10:12985. 3. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993:984. 4. Harriman DG, Garland H. The pathology of Adie syndrome. Brain 1968;91:40118. 5. Thompson HS. Adie syndrome: some new observations. Trans Am Ophthalmol Soc 1977;75:587626. 6. Koc F, Kansu T, Kavuncu S, et al. Topical apraclonidine testing discloses pupillary sympathetic denervation in diabetic patients. J Neuroophthalmol 2006;26:259. 7. Loewenfeld IE, Thompson HS. The tonic pupil: a re-evaluation. Am J Ophthalmol 1967;63:4687. 8. Loewenfeld IE. Midbrain syndrome: Argyll Robertson pupils. In: Loewenfeld IE. The Pupil. Ames, Iowa: Iowa State University Press; 1993:9561001 9. Loewenfeld IE. Lesions in the ciliary ganglion and short ciliary nerves: the tonic pupil Adie syndrome. In: Loewenfeld IE. The Pupil. Ames, Iowa: Iowa State University Press; 1993:1080 130. 10. Lowenstein O. The Argyll Robertson pupillary syndrome: mechanism and localization. Am J Ophthalmol 1956;42:10521. 11. Wilson SAK, Gerstle M Jr. The Argyll Robertson sign in mesen-cephalic tumors. Arch Neurol Psychiat (Chicago) 1929; 22:918. 12. Kinnier Wilson SA. Some problems in neurology: the Argyll Robertson pupil. J Neurol Psychpath 1921;2:125. 13. Fletcher WA, Sharpe JA. Tonic pupils in neurosyphilis. Neurology 1986;36:18892. 14. Duke-Elder WS. Text-Book of Ophthalmology, vol. IV. St. Louis: C.V. Mosby Co.; 1949:3785. 15. Duke-Elder WS, Scott GI. System of Ophthalmology, vol XII. St. Louis: C.V. Mosby Co.; 1971:663. 16. McGrath WM. Observations on abnormalities of the pupils and iris in tabes dorsalis, general paralysis and tabo-paresis. J Ment Sci 1932;78: 36273.

DETECTING SEGMENTAL IRIS SPHINCTER PALSY

In our slit-lamp (21) and infrared iris transillumination (2224) examinations of the iris sphincter in patients with Adie tonic pupil, we have consistently found evidence

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17. Marina A. Le ganglion ciliare comme centre peripherique de la reaction pupillaire a la lumiere et la phenomene dArgyll Robertson. ` Presse Med 1910;18:4801. 18. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993:994. 19. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993:997. 20. Warkany J. Studien ueber das Verhalten der Glia im Mittelhirn bei reektorischer Pupillenstarre. Arbeit Neurol Inst Wien Univ (Obersteiner) 1924;26:45569.

21. Thompson HS. Segmental palsy of the iris sphincter in Adie syndrome. Arch Ophthalmol 1978;96:161520. 22. Kardon RH, Corbett JJ, Thompson HS. Segmental denervation and reinnervation of the iris sphincter as shown by infrared videographic transillumination. Ophthalmology 1998;105;31321. 23. Alward WL, Munden PM, Verdick RE, et al. Use of infrared videography to detect and record iris transillumination defects. Arch Ophthalmol 1990;108:74850. 24. Verdick RE, Thompson HS. Infrared videography of the eyes. J Ophthalmic Photography 1991;13:1921.

HOW TO TRANSILLUMINATE THE IRIS

The image on the screen shows the typical segmental iris sphincter palsy of Adie syndrome. The patients head is supported by the chin rest. The sensitive camera is focused on the iris. The transilluminating light shines into the globe through the lower lid and uvea, and the reected light emerges through the iris, outlining its structures. Even an eye with a heavily pigmented uvea can be penetrated with sufcient light to show the sphincter muscle. By turning the transilluminating light off and on at a remote switch, one can obtain a sense of the mobility of various iris sphincter segments. The resting position of the muscles in the dark can be seen during the latent period of the light reaction (2224).

Equipment Used
1. A small, low-light video camera. These security cameras have been greatly improved in the last few years. Choose one that is sensitive to near infrared wavelengths and very sensitive to low light levels. We have clamped this camera to a table with a Bogen No. 3265 tripod head. 2. A macro close-up zoom lens that has no coated elements designed to block infrared wavelengths can focus on the eye from just a few inches away and still leave enough room to move the transilluminator in front of the patients face. 3. A monitor on which the image can be displayed. 4. A recording device (S-VHS tape recorder, DVD recorder, or a digital tape). 5. A transilluminating light source. Since this hand light is applied to the patients skin, it should not become uncomfortably hot. We use a standard Welch-Allyn Finhof transilluminator with a halogen source, which produces a bright, visible light that is rich in infrared. It is held on the lower lid laterally and aimed at the posterior pole of the eye.

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