Argyll Robertson Pupil

Key Points at a Glance

Key Points of This Disease

• Argyll Robertson (AR) pupil is a pupillary abnormality characterized by the triad of miosis, loss of light reflex, and preserved near reflex (light-near dissociation).
• The classic cause is neurosyphilis (tabes dorsalis), but in modern times it is often associated with diabetes, cerebrovascular disease, and demyelinating diseases.
• Usually bilateral, with irregular pupil shape.
• Light-near dissociation without miosis is distinguished as “pseudo AR pupil”.
• Lack of response to low-concentration pilocarpine (0.1%) is an important differentiating point from Adie pupil.
• Syphilis serology (TPHA, RPR) is essential for diagnosis.
• Treatment is directed at the underlying disease (neurosyphilis, diabetes, multiple sclerosis, etc.), and recovery of pupillary findings is usually difficult.

1. What is Argyll Robertson Pupil?

Argyll Robertson (AR) pupil is a clinical entity characterized by miosis, loss of the light reflex, and preservation of the near reflex (light-near dissociation)^1,5). It is often accompanied by irregular pupil shape. It is usually bilateral and not associated with visual pathway defects¹⁾.

The condition is named after Scottish ophthalmologist Douglas Moray Cooper Lamb Argyll Robertson, who first described it in 1869 in patients with neurosyphilis²⁾. At that time, it was recognized as an important ocular sign of tabes dorsalis.

Conceptual distinction from pseudo AR pupil: Cases showing light-near dissociation without miosis are termed “pseudo Argyll Robertson pupil” and are used as one of the disease concepts indicating neurological abnormalities. True AR pupil and pseudo AR pupil differ in underlying causes and pathophysiology, making differential diagnosis important^3,5).

Q Does AR pupil always occur in both eyes?

A

It is usually bilateral, but may initially present asymmetrically depending on the underlying disease. In classic neurosyphilis, bilaterality is typical and is an important diagnostic criterion.

2. Main Symptoms and Clinical Findings

Diagnosis of AR pupil is based on confirmation of the following three main signs.

Three Main Signs (Clinical Findings)

1. Miosis Small pupils bilaterally even in dim light. Marked miosis is characteristic, with persistent pupillary constriction regardless of illumination. The combination of light-near dissociation and miosis distinguishes AR pupil from other light-near dissociation disorders.

2. Loss of light reflex Both direct and indirect (convergence) light reflexes are absent or markedly diminished. No pupillary response is observed with a penlight during routine light testing.

3. Preservation of near reflex Constriction during convergence and accommodation is preserved. When the patient fixates on a near object, the pupil constricts, and this dissociation between light and near reflexes (light-near dissociation) serves as a diagnostic criterion.

Additional Findings

• Pupil shape abnormality: Often irregularly round
• Bilaterality: Usually symmetric or asymmetric bilateral involvement
• Visual acuity: Generally preserved (without visual pathway involvement)

Differences from Pseudo AR Pupil

Finding	True AR Pupil	Pseudo AR Pupil
Pupil size	Miosis (small pupil)	Normal to mild mydriasis
Light reflex	Absent	Absent
Near reflex	Preserved	Preserved
Typical causes	Neurosyphilis, diabetes mellitus	Tectal pupil, Parinaud syndrome

Q Is vision normal even with an AR pupil?

A

The AR pupil itself does not affect the visual pathway (optic nerve, optic radiation, visual cortex), so vision is usually preserved. However, if the underlying disease (neurosyphilis, diabetes, multiple sclerosis, etc.) affects the optic nerve or other structures, visual impairment may occur.

3. Causes and Risk Factors

The lesion responsible for the AR pupil is thought to be in the dorsal midbrain, particularly the pretectal area. Lesions in this area selectively damage the light reflex pathway.

Classic causes

Neurosyphilis (tabes dorsalis, general paresis) is historically the most famous cause and is almost synonymous with the AR pupil ^1,2). In tabes dorsalis, demyelination of the posterior columns and posterior roots occurs, and as part of the central nervous system lesions associated with tabes dorsalis, the pretectal area of the midbrain is affected ²⁾. In the era before antibiotics, neurosyphilis often had severe outcomes, and the AR pupil was an important physical sign.

Modern causes

In recent years, causes other than neurosyphilis have become more common.

• Diabetes mellitus: As part of diabetic autonomic neuropathy, an AR-like pupil may appear.
• Cerebrovascular disorders: Infarction or hemorrhage around the midbrain that damages the pretectal area
• Demyelinating diseases: Demyelinating lesions such as multiple sclerosis (MS) that extend to the midbrain

Special Findings in Advanced Cases

In advanced paralysis, if the lesion extends ventrally beyond the responsible lesion for AR pupil, the near reflex pathway may also be affected. As a result, both the light reflex and near reflex disappear, and “spastic miosis” may occur. This finding indicates ventral extension of the lesion and has important prognostic significance.

Q Can AR pupil occur due to causes other than syphilis?

A

In modern times, diabetes, cerebrovascular disorders, and demyelinating diseases (such as multiple sclerosis) are the main causes. Although syphilis is certainly suspected as an etiology, even if syphilis serology is negative, other causative diseases should be investigated.

4. Diagnosis and Examination Methods

In diagnosing AR pupil, it is important to confirm miosis and light-near dissociation, and to search for the underlying cause.

Essential Examinations

1. Pupillary examination

   • Measurement of pupil diameter in bright and dark rooms
   • Assessment of direct and consensual light reflex (penlight test)
   • Assessment of near reflex (convergence test: have the patient fixate on a near object and observe pupillary constriction)

2. Syphilis serology (TPHA, RPR): Essential test in all cases where AR pupil is suspected

3. Blood glucose and HbA1c: To rule out or evaluate diabetes

4. MRI (brain, midbrain): Evaluation of tumors, demyelination, and vascular lesions around the cerebral aqueduct and pretectal area

Pharmacological Diagnosis (Low-concentration Pilocarpine Test)

The low-concentration pilocarpine test is useful for differentiating between AR pupil and Adie pupil (tonic pupil)³⁾.

• AR pupil: No constriction to 0.1% pilocarpine instillation³⁾
• Adie pupil: Constriction to 0.1% pilocarpine instillation (due to denervation supersensitivity)³⁾

Diagnostic Note

In tonic pupil (Adie pupil), denervation supersensitivity is observed, and constriction occurs with low concentrations of parasympathomimetic agents (0.1% pilocarpine or 2.5% mecholyl) that normally have no pharmacological effect. The AR pupil does not show such a pharmacological response, which is an important distinguishing feature.

Differential Diagnosis

Representative diseases showing light-near dissociation are compared below.

AR Pupil

Lesion: Pretectal area of the midbrain

Pupil size: Miosis, bilateral

Light reflex: Absent

Near reflex: Preserved

Low-concentration pilocarpine: No response

Complications: Syphilis, diabetes, demyelination

Adie pupil (tonic pupil)

Lesion: Ciliary ganglion (peripheral)

Pupil size: Mydriasis, often unilateral

Light reflex: Absent or reduced

Near response: Preserved (tonic, slow)

Low-concentration pilocarpine: Miosis (hypersensitivity)

Complications: Loss of tendon reflexes

Tectal pupil

Lesion: Pretectal area of midbrain to posterior commissure

Pupil size: Moderate mydriasis, bilateral

Light reflex: Absent

Near response: Preserved

Low-concentration pilocarpine: No response

Complications: Often associated with Parinaud syndrome

Argyll Robertson pupil occurs with midbrain dorsal lesions such as pineal tumors or multiple sclerosis. Unlike AR pupil, it presents with moderate mydriasis rather than miosis, and is often accompanied by eye movement disorders (Parinaud syndrome such as upward gaze palsy).

Adie pupil is a disorder of the ciliary ganglion (peripheral), typically unilateral with mydriasis, and hypersensitivity to low-concentration pilocarpine (denervation supersensitivity) is key for differentiation.

Q How is AR pupil different from Adie pupil?

A

The three main differentiating points are pupil size (miosis vs mydriasis), laterality (bilateral vs often unilateral), and response to low-concentration pilocarpine (no response vs constriction). The lesion sites also differ: AR pupil is central (midbrain pretectal area), while Adie pupil is peripheral (ciliary ganglion).

5. Standard Treatment

There is no direct treatment for AR pupil itself; the basic approach is to treat the underlying disease.

Treatment by Cause

For neurosyphilis High-dose intravenous penicillin G is the standard treatment. Inpatient treatment is performed in collaboration with neurology and infectious disease departments. Treatment can halt the progression of syphilis, but recovery of the pupil findings themselves is unlikely.

For diabetes Strict glycemic control suppresses the progression of diabetic autonomic neuropathy. It is important to continue treatment according to the target HbA1c level.

For demyelinating diseases (e.g., multiple sclerosis) High-dose steroid therapy for acute exacerbations, and disease-modifying therapies (DMTs: interferon beta, fingolimod, etc.) for long-term management. Collaboration with neurology is essential.

Important Points in Treatment

Treatment of the underlying disease can prevent progression of the lesion, but the pupil findings (miosis, loss of light reflex) that appear as AR pupil often persist after treatment. When explaining to patients, it is important to convey in advance that “the pupil is unlikely to return to normal even with treatment.”

Q Will the pupil return to normal with treatment?

A

Treatment of the underlying disease can prevent progression of the lesion, but the miosis and loss of light reflex that occur as AR pupil usually do not recover. Even after treatment for neurosyphilis (penicillin G), pupil findings often persist, and it is not realistic to aim for normalization of pupil findings as a treatment goal.

6. Pathophysiology and Detailed Mechanism

To understand the pathogenesis of AR pupil, it is important to grasp the anatomical background of the light reflex pathway and the near reflex pathway.

Light Reflex Pathway

The neural circuit of the light reflex follows the following pathway.

Retina → Optic nerve → Optic chiasm → Optic tract → Pretectal nucleus of the midbrain → Edinger-Westphal (EW) nucleus → Ciliary ganglion → Short posterior ciliary nerves → Sphincter pupillae muscle

In this pathway, signal transmission from the pretectal nucleus to the EW nucleus serves as the central relay point of the light reflex.

Near Reflex Pathway

The circuit of the near reflex (miosis associated with convergence and accommodation) runs from the cerebral cortex (visual cortex and frontal lobe) to the midbrain, but its descending pathway travels slightly ventral to the pretectal nucleus to reach the EW nucleus.

Pathogenesis of AR Pupil

The responsible lesion for AR pupil is located in the dorsal midbrain and pretectal area. This lesion causes the following changes.

Mechanism of light reflex loss Because the signal from the pretectal nucleus to the EW nucleus is blocked, the EW nucleus is not activated by light stimulation, and the sphincter pupillae muscle does not contract^2,3).

Mechanism of miosis At the same time, the supranuclear inhibitory fibers to the EW nucleus are also damaged. Normally, supranuclear inhibition from the cerebral cortex regulates the activity of the EW nucleus, but when this inhibition is removed, the EW nucleus becomes continuously excited, causing sustained contraction of the sphincter pupillae muscle, resulting in miosis²⁾.

Reason for preserved near reflex The near reflex pathway runs slightly ventral to the pretectal area, so it is spared from lesions in the pretectal area. Therefore, signals to the EW nucleus associated with convergence and accommodation are preserved, allowing miosis in response to near stimuli^2,5).

Mechanism of Spastic Miosis

When the lesion extends ventrally, as in general paresis, the near reflex pathway is also damaged. Both the light reflex and near reflex are lost, and only the impairment of supranuclear inhibition to the EW nucleus remains, resulting in sustained miosis (spastic miosis).

Mechanism of Diabetic AR-like Pupil

In AR-like pupil associated with diabetic autonomic neuropathy, in addition to widespread peripheral autonomic nerve damage, functional abnormalities of the central autonomic nervous system are thought to be involved. The degree of miosis is often milder.

7. Latest Research and Future Perspectives (Research-stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or based on case reports, and is not standard treatment available at general hospitals. It is reference information for future medical development.

Renewed Attention to AR Pupil Due to Resurgence of Syphilis

In recent years, a global resurgence of syphilis has been reported, and with it, cases of AR pupil caused by neurosyphilis are attracting renewed attention ^1,4). Compared to the era when syphilis was thought to be declining, the diagnostic significance of AR pupil is being reevaluated by modern ophthalmologists and neurologists. Lemarie et al. (2019) reported a case of a 57-year-old man who had been diagnosed with hysteria for five years due to gait disturbance, but later presented with paraplegia, neuropathic pain, and pressure ulcers, and was definitively diagnosed with neurosyphilis triggered by left AR pupil, indicating that this disease is still easily overlooked in modern times ⁴⁾.

Diabetic Autonomic Neuropathy and AR-like Pupil

The concept of AR-like pupil associated with diabetic autonomic neuropathy is being organized. It may differ pathologically from classic AR pupil, and establishing systematic evaluation criteria for pupillary autonomic neuropathy in diabetes is a challenge.

Need for Systematic Differentiation of Pseudo AR Pupil

There is a need to develop systematic differential diagnosis algorithms for diseases presenting with pseudo AR pupil, such as midbrain lesions, tectal pupil, and Parinaud syndrome ^2,3). In particular, combination with imaging diagnosis for early detection of pineal tumors, germ cell tumors, etc., is important, and the development of future diagnostic guidelines is expected.

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8. References

1. Dichter SL, Khan Suheb MZ, Shubert GS. Argyll Robertson Pupil. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024 [Updated 2024 Jan 31]. PMID: 30725864. Bookshelf ID: NBK537179.

2. Thompson HS, Kardon RH. The Argyll Robertson pupil. J Neuroophthalmol. 2006;26(2):134-138. PMID: 16845316. doi:10.1097/01.wno.0000222971.09745.91

3. Kawasaki AK. Diagnostic Approach to Pupillary Abnormalities. Continuum (Minneap Minn). 2014;20(4 Neuro-ophthalmology):1008-1022. PMID: 25099106. PMCID: PMC10563972. doi:10.1212/01.CON.0000453306.42981.94

4. Lemarie B, Matt M, Deconinck L, Perronne C, Dinh A, Davido B. All eyes on him: Argyll Robertson pupil in late syphilis. Int J Infect Dis. 2019;83:1-2. PMID: 30904677. doi:10.1016/j.ijid.2019.03.023

5. Thompson HS. Light-near dissociation of the pupil. Ophthalmologica. 1984;189(1-2):21-23. PMID: 6472802.