Adie's Pupil (Tonic Pupil)

Key Points at a Glance

Highlights of This Disease

• Adie pupil is a condition caused by parasympathetic denervation of the ciliary ganglion, resulting in loss or reduction of the light reflex while the near reflex is preserved.
• Approximately 80% of cases are unilateral, and it is more common in young women (20–40 years old).
• Segmental palsy of the iris sphincter causing “vermiform movements” and light-near dissociation are key diagnostic features.
• The low-concentration pilocarpine (0.125%) test shows miosis, and about 80% of cases are positive.
• It is a benign condition; observation is the basic management unless severe photophobia is present.
• If accompanied by loss of deep tendon reflexes, it is diagnosed as Holmes-Adie syndrome; if also with sweating abnormalities, it is Ross syndrome.
• Accommodative paresis may improve over months to years, but recovery of the light reflex is usually not expected.

1. What is Adie Pupil?

Adie tonic pupil is a condition in which, due to parasympathetic denervation, the light reflex of the affected pupil is lost or diminished, while the near reflex shows a good and tonic constriction.

The disease is named after William John Adie, and was independently reported around the same time in 1931 by Adie, Morgan, Symons, and Holmes. The prevalence is 2 per 1,000 population, with a female-to-male ratio of 2.6:1 (about 70% are female), and the average age of onset is 32 years. About 80% are unilateral, and progression to bilateral occurs at a rate of 4% per year.

Related syndromes include the following two important conditions:

• Holmes-Adie syndrome: Adie pupil combined with loss or reduction of deep tendon reflexes. It is considered the complete form.
• Ross syndrome: A rare peripheral autonomic nervous system disorder involving Adie pupil, loss of tendon reflexes, and autonomic symptoms such as orthostatic hypotension and sweating abnormalities. To date, only about 60 cases have been reported in the literature³⁾.

Q Does Adie's pupil occur in only one eye?

A

Approximately 80% of cases are unilateral. However, progression to bilateral involvement occurs at a rate of 4% per year, so attention should also be paid to pupillary changes in the contralateral eye during follow-up.

2. Main symptoms and clinical findings

Clinical photograph of Adie's pupil. Shows dilated pupil, reduced light response, miosis during near vision, and miosis after dilute pilocarpine.

Penney DC, et al. Abnormal pupils at the bedside: rapid recognition of neurologic and systemic emergencies in acute care settings. Int J Emerg Med. 2026. Figure 2. PMCID: PMC13015004. License: CC BY.

Four clinical photographs compare the dilated pupil at rest, reduced response to light stimulation, miosis during near vision, and miosis after dilute pilocarpine. This image helps visually understand the light-near dissociation and denervation supersensitivity characteristic of Adie’s pupil.

Subjective symptoms

• Photophobia (glare): Because the light reflex is impaired, discomfort occurs in bright environments.
• Blurred vision, eye strain, difficulty with near work: Often accompanied by accommodative paralysis, causing decreased vision during near vision or when switching focus.
• Anisocoria: Many patients notice it themselves when looking in a mirror, or are pointed out by others and seek medical attention.
• Difficulty adapting to darkness: Due to dilation of the affected pupil, adaptation to changes in light and dark environments is delayed.

Clinical findings (findings confirmed by the physician during examination)

• Moderate dilation and irregular shape of the pupil: Anisocoria becomes prominent in bright light. Segmental paralysis of the iris sphincter causes the pupil to become irregularly shaped.
• Worm-like movements: A characteristic finding observed under a slit lamp. Because the remaining healthy segments of the sphincter contract segmentally, the iris undulates like a crawling worm.
• Light-near dissociation: The light reflex is diminished or absent, but the near response (convergence miosis) is preserved. The most tonic pupillary response is easily observed during dilation after the near response.
• Tonic reaction: Once the pupil constricts, it takes time to dilate, and the constricted state is maintained for a long time. This is the origin of the name “tonic.”
• Chronic phase changes: Initially, mydriasis is prominent, but in the chronic phase, as abnormal regeneration progresses, the pupil of the affected eye tends to become smaller instead.

Q What happens to the pupil when it becomes chronic?

A

Initially, the affected eye is dilated and anisocoria is marked compared to the contralateral side, but in the chronic course, the affected pupil tends to constrict. This is thought to be due to aberrant regeneration of parasympathetic nerve fibers from the ciliary body innervating the sphincter pupillae muscle.

3. Causes and Risk Factors

Most cases are idiopathic (unknown cause), and the responsible lesion is in the peripheral ciliary ganglion and short posterior ciliary nerves.

Identifiable causes include the following:

• Infections: Viral infections (herpes zoster, varicella, influenza, etc.), bacterial infections (neurosyphilis)
• Trauma/Surgery: Ophthalmic surgery, orbital trauma
• Association with systemic diseases: Fisher syndrome, encephalitis, spinocerebellar degeneration, diabetes, collagen disease, multiple sclerosis
• Others: Vasospasm due to migraine, tumors (orbital tumor, paraneoplastic)

Regarding the pathogenesis of Ross syndrome, a theory has been proposed that genetic predisposition combined with environmental factors (such as viral infection) contributes. There are reports of Ross syndrome in monozygotic twins and cases following cytomegalovirus infection, suggesting both genetic and infectious factors may be involved³⁾.

Regarding tonic pupil after COVID-19 infection, multiple cases of immune-mediated onset have been reported since the COVID-19 pandemic, and it is increasingly recognized as a neuro-ophthalmic complication after infection^{1, 2)}.

Expert Supplement

When associated with polyneuritis, it is often bilateral. If bilateral Adie’s pupils are confirmed, systemic diseases such as diabetes, alcoholism, syphilis, amyloidosis, and paraneoplastic autonomic neuropathy should be actively investigated.

4. Diagnosis and Examination Methods

Diagnosis is easy when typical symptoms (segmental palsy, vermiform movements, light-near dissociation) are present.

Pharmacological Diagnosis

The low-concentration pilocarpine test is most widely used.

• Concentration: 0.125% (prepared by diluting 1% solution with sterile saline) or 0.1%
• Assessment: Check for miosis 30–60 minutes after instillation
• Principle: Due to denervation supersensitivity, the affected eye constricts even at low concentrations that do not affect normal eyes.
• Sensitivity: Positive in about 80% of cases

Cautions

In the acute phase, denervation supersensitivity may not yet have developed, so the test may be negative. Also, since hypersensitivity can occur not only peripherally but also centrally, this test is considered only an adjunct. 2.5% mecholyl (methacholine chloride) is also used similarly for diagnosis.

Differential Diagnosis

Differential diagnosis is needed, focusing on diseases that present with light-near dissociation.

Adie Pupil

Lesion: Ciliary ganglion (peripheral)

Pupil size: Moderate dilation, irregular shape

Laterality: Usually unilateral (about 80%)

Tonic: Present (miosis persists for a long time)

Pilocarpine response: Miosis with low concentration

Argyll Robertson pupil

Lesion: Midbrain pretectal area (syphilis)

Pupil size: Bilateral severe miosis

Laterality: Bilateral

Tonic: None

Pilocarpine response: No response to low concentration

Tectal pupil

Lesion: Dorsal midbrain (e.g., pineal tumor)

Pupil size: Moderate mydriasis

Laterality: Bilateral

Parinaud syndrome: Frequently associated

Tonic: None

Other differential diagnoses include aberrant regeneration of the oculomotor nerve after palsy, orbital trauma/tumor, varicella-zoster infection, Fisher syndrome, Charcot-Marie-Tooth disease, and neurosarcoidosis.

Syphilis serology (RPR), and history of diabetes, trauma, or neurological disease can aid diagnosis. If Ross syndrome is suspected, Minor’s test (iodine-starch test) can detect anhidrotic areas ³⁾.

Q If the pilocarpine instillation test is negative, can Adie's pupil be ruled out?

A

It cannot be ruled out. In the acute phase, denervation supersensitivity may not yet be established, so the test can be negative. If clinical findings (vermiform movements, segmental palsy) are typical, Adie’s pupil can be diagnosed clinically even with a negative test. Serial testing is also useful.

5. Standard Treatment

Adie’s pupil is a benign condition. For most patients, the basic approach is to explain that it is benign and to observe over time.

• Management of photophobia: For severe photophobia, topical 0.125–0.25% pilocarpine can reduce symptoms. Topical physostigmine is also an option. Sunglasses or iris-colored contact lenses can also help alleviate photophobia.
• Management of accommodative paresis: For patients with persistent accommodative paresis, near-vision glasses or bifocal lenses with frosted segments can be helpful.
• Adie syndrome (with areflexia): In Holmes-Adie syndrome with areflexia, consider referral to a neurologist.
• When systemic disease is present: If an underlying cause (e.g., diabetes, syphilis) is identified, treatment should focus on that condition.

Treatment Precautions

Continuous use of 0.125% pilocarpine eye drops may cause ciliary muscle spasm, brow pain, worsening anisocoria, or induced myopia. The frequency of use should be adjusted according to symptoms.

Prognosis: Accommodative paresis may improve over months to years. However, the pupillary light reflex usually does not recover. When associated with systemic disease, the prognosis is not necessarily favorable, and management of the underlying condition is important.

Treatment of compensatory hyperhidrosis in Ross syndrome: Topical glycopyrrolate, aluminum chloride cream, and botulinum toxin injections are used. For severe cases where surgery is desired, thoracic sympathectomy is an option ³⁾.

Q Will vision recover without treatment?

A

Blurred vision and difficulty with near vision due to accommodative paresis may improve over months to years. However, the pupillary light reflex usually does not recover, so normalization of the pupillary response to light cannot be expected. This condition rarely leads to severe visual impairment and is a benign condition that can be safely observed.

6. Pathophysiology and Detailed Mechanism

Two main mechanisms play a central role in the pathogenesis of Adie’s pupil: “denervation supersensitivity” and “aberrant regeneration.”

Parasympathetic neuroanatomy: 95% of parasympathetic fibers from the Edinger-Westphal (EW) nucleus of the oculomotor nerve innervate the ciliary muscle (involved in accommodation), and 5% innervate the sphincter pupillae (involved in the light reflex). The ratio of neurons in the ciliary ganglion related to the light reflex versus accommodation is 3:97, indicating that fibers for the light reflex are originally few.

The course of onset progresses in the following order:

1. Damage to the ciliary ganglion: The ciliary ganglion or short posterior ciliary nerves are damaged due to viral infection, trauma, idiopathic causes, etc.
2. Development of denervation supersensitivity: After injury, upregulation of postsynaptic receptors occurs, leading to hypersensitivity to low concentrations of cholinergic agents. This is the basis for pharmacological diagnosis.
3. Aberrant regeneration: When damaged parasympathetic fibers regenerate, fibers that should originally target the ciliary muscle (the majority) instead innervate the sphincter pupillae. Since the number of fibers to the ciliary muscle is about 30 times that to the iris, after aberrant regeneration, fibers from the ciliary muscle dominate the pupil, causing strong miosis during near stimulation, while the light reflex does not recover. This is the mechanism of light-near dissociation.

Neuroanatomical explanation of light-near dissociation: The supranuclear fibers for the near response to the EW nucleus run more ventrally than the midbrain pretectal area and posterior commissure, through which the afferent fibers of the light reflex pass. Therefore, damage to the pretectal area (central) can also cause similar dissociation, but in Adie’s pupil, the lesion is in the ciliary ganglion (peripheral), which is key for differentiation.

COVID-19-related mechanism: In tonic pupils after SARS-CoV-2 infection, three mechanisms have been proposed: direct viral neural invasion, endothelial dysfunction, and neurotoxicity due to excessive inflammation and cytokine release¹⁾.

Pathophysiology of Ross syndrome: Dorsal root ganglion neurons and the parasympathetic nervous system are thought to share a common origin from neural crest cells, which is proposed as a hypothesis to explain the loss of tendon reflexes in Ross syndrome³⁾.

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

For patients: Please read this

The following content is currently at the research stage or under clinical trials, and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Tonic pupil after COVID-19 infection

Since the COVID-19 pandemic, there have been successive case reports of tonic pupil as a neuro-ophthalmic complication after infection.

Quijano-Nieto et al. (2021) reported a case of a 36-year-old woman who developed bilateral tonic pupil 17 days after COVID-19 infection (PCR positive)¹⁾. Brain MRI, blood tests, and cerebrospinal fluid tests were all normal. Strong miosis was confirmed in both eyes with 0.125% pilocarpine eye drops. An immune-mediated mechanism is presumed.

Gopal et al. (2021) reported a case of a 37-year-old woman who developed tonic pupil in the right eye 3 weeks after COVID-19 infection²⁾. Right pupil diameter was 5.5 mm, with vermiform movement and segmental constriction. Miosis was confirmed with 0.1% pilocarpine eye drops. No significant findings on brain and orbital MRI, and post-infection immune response is suspected as the cause.

Ross syndrome and synucleinopathy

Ahmad et al. (2022) reported two cases of Ross syndrome diagnosed within one month at the same institution³⁾. Case 1 (24-year-old woman) showed the triad of left tonic pupil, loss of right ankle jerk, and segmental anhidrosis up to T4 level. Case 2 (42-year-old woman) was “Ross syndrome plus” with bilateral tonic pupil, loss of lower limb tendon reflexes, and Horner syndrome.

It has been proposed that Ross syndrome may be a synucleinopathy, like Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy³⁾. It has also been suggested that Ross syndrome, Holmes-Adie syndrome, and Harlequin syndrome may be different phenotypes of the same disease process, and integration of these disease concepts is expected in the future.

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8. References

1. Quijano-Nieto BA, Córdoba-Ortega CM. Tonic pupil after COVID-19 infection. Arch Soc Esp Oftalmol. 2021;96(7):353-355.

2. Gopal M, Ambika S, Padmalakshmi K. Tonic Pupil Following COVID-19. J Neuroophthalmol. 2021;41:e764-e766.

3. Ahmad R, Saurabh K. Two Cases of Tonic Pupil: Ross and Ross Syndrome Plus. Cureus. 2022;14(2):e22305.