Pupillary reactions are caused by contraction of the sphincter pupillae and dilator pupillae muscles, resulting in miosis and mydriasis, respectively. The former is excited by the parasympathetic and inhibited by the sympathetic nervous system, while the latter is inhibited by the parasympathetic and excited by the sympathetic, receiving dual innervation.
Normally, the pupil is located inferonasally in the iris, is nearly round and equal in size bilaterally, and changes occur simultaneously in both eyes. In bright light, it constricts (about 2–3 mm); in darkness, it dilates (about 5–8 mm). However, reactivity changes with age and medication.
Physiological and Pathological Anisocoria
Anisocoria refers to a difference in pupil size between the left and right eyes. Even in normal individuals, a physiological anisocoria of 1.0 mm or less may exist. A difference exceeding 1.0 mm is generally considered pathological and requires investigation of the cause.
Epidemiology
Scope of this article
This article comprehensively covers the overall picture of pupillary abnormalities (from innervation to differential diagnosis and treatment of miosis and mydriasis). Details of intraoperative floppy iris syndrome (IFIS) are left to the “IFIS specialist article,” and details of pupil dilation device techniques are left to the “Pupil dilation device article.”
If the difference is 1.0 mm or less, it is within the range of physiological anisocoria and usually not urgent. However, if the difference exceeds 1.0 mm, or if anisocoria occurs suddenly (especially when accompanied by eye movement disorder or ptosis on the dilated side), there is a possibility of serious diseases such as aneurysm, so prompt consultation with an ophthalmologist or neurosurgeon is necessary.
Miosis (small pupil) causes decreased vision in dark places (due to poor pupil dilation) and difficulty in dilating with mydriatic agents. This is particularly problematic during preoperative examination and cataract surgery.
Mydriasis causes photophobia (glare) and decreased near vision (when accompanied by accommodative dysfunction). Anisocoria itself is often noticed by patients as a cosmetic issue or asymmetry in photographs.
Horner syndrome
Degree of miosis: Moderate (appears prominently in dim light)
Associated findings: Mild ptosis, elevation of the lower eyelid (inverse ptosis), narrowing of the palpebral fissure, abnormal sweating on the affected side
Characteristics: Disorder of the sympathetic efferent pathway. Can occur with damage to any of the three-neuron pathway.
Argyll Robertson Pupil
Degree of miosis: Marked miosis, irregular shape
Associated findings: Loss of light reflex, preserved near response (light-near dissociation)
Characteristics: Dorsal midbrain lesion. Main causes: syphilis, diabetes, multiple sclerosis.
Pontine Miosis
Degree of miosis: Pin-point pupil of about 1 mm
Associated findings: Light reflex is preserved (observed under slit-lamp magnification)
Characteristics: Pontine lesion such as pontine hemorrhage. Characterized by bilateral severe miosis.
Congenital Miosis
Degree of miosis: 2 mm or less. Poor dilation even under distant vision in a bright room.
Associated findings: Bilateral. Markedly poor response to mydriatic agents.
Characteristics: Caused by hypoplasia of the pupillary dilator muscle. Pupil dilation is essential during cataract surgery.
Poor mydriasis (small pupil) significantly increases the difficulty of cataract surgery. Causes of poor preoperative mydriasis include posterior synechiae (after uveitis), exfoliation syndrome (often combined with poor mydriasis and zonular weakness)1), diabetic autonomic neuropathy, long-term use of miotics (glaucoma treatment), and congenital miosis.
First, observe pupil size and anisocoria under both light and dark conditions. If anisocoria is more pronounced in the dark, the miotic side (sympathetic defect side) is abnormal. Next, perform a pharmacologic test (1% apraclonidine eye drops) to confirm Horner syndrome. If Horner syndrome is diagnosed, perform systemic evaluation including MRI/CT, chest imaging, and carotid ultrasound according to the lesion site.
| Category | Disease/Condition | Main Mechanism |
|---|---|---|
| Neurologic (Sympathetic Defect) | Horner syndrome | Lesion anywhere in the 3-neuron pathway |
| Nervous system (central) | Argyll Robertson pupil | Lesion of the dorsal midbrain (pretectal area → Edinger-Westphal nucleus) |
| Nervous system (central) | Pontine miosis | Pontine hemorrhage/infarction |
| Ocular local | Posterior synechiae | Mechanical miosis after uveitis |
| Ocular local | Exfoliation syndrome | Deposition of exfoliation material on the iris sphincter |
| Drugs | Organophosphate poisoning | Cholinesterase (AChE) inhibition |
| Medications | Miotics such as pilocarpine | Parasympathetic stimulation |
| Systemic diseases | Diabetic neuropathy | Poor response to mydriatics due to autonomic neuropathy |
| Congenital | Congenital miosis | Hypoplasia of the dilator pupillae muscle |
| Cause category | Disease/Condition | Notes |
|---|---|---|
| Nervous system (parasympathetic dysfunction) | Oculomotor nerve palsy | Emergency exclusion of aneurysm is top priority |
| Nervous system (postganglionic fiber disorder) | Tonic pupil (Adie pupil) | Ciliary ganglion / postganglionic fiber disorder |
| Medication | Atropine, tropicamide, phenylephrine, etc. | History of eye drops or oral medications must be checked |
| Trauma | Traumatic mydriasis | Rupture/degeneration of iris sphincter |
| Functional | Recurrent episodic unilateral mydriasis | Young women, associated with headache. Sympathetic attack |
Poor mydriasis during cataract surgery often involves multiple factors.
Although the risk of IFIS is increased, surgery is possible in most cases if the medication history is obtained preoperatively and appropriate measures are taken. Since discontinuation of the drug alone does not prevent IFIS, it is essential to check the medication history before surgery and prepare measures such as use of dispersive viscoelastic devices, intracameral phenylephrine, and appropriate fluidics settings. For details, refer to the dedicated article on IFIS.
The most important aspect of pupil observation is to perform it under both light and dark conditions.
In a dark room, alternately stimulate the right and left eyes with a penlight and observe changes in pupil diameter. If dilation is observed upon stimulation, a relative afferent pupillary defect (RAPD) is present on that side. This test is useful for diagnosing optic nerve diseases and severe retinal diseases.
Instillation of 1% apraclonidine hydrochloride (Iopidine®) is used for diagnosis (off-label). It utilizes the paradoxical response where the affected miotic pupil dilates due to denervation supersensitivity. A sensitivity of 93% has been reported 2). 5% cocaine instillation dilates the normal pupil but does not affect the Horner side; however, it is often difficult to obtain nowadays.
The following instillation tests are used to determine the lesion site:
| Instillation drug | Normal side | Central | Preganglionic | Postganglionic |
|---|---|---|---|---|
| 5% cocaine (mydriasis) | ++ | + | − | − |
| 5% tyramine (mydriasis) | + | + | + | − |
| 1.25% adrenaline (mydriasis) | − | − | + | ++ |
The 0.125% pilocarpine hydrochloride eye drop test is useful. Due to denervation supersensitivity, miosis occurs even at low concentrations that normally do not elicit a response. Since normal eyes do not respond to 0.125%, miosis only in the affected eye confirms the diagnosis of tonic pupil.
Differential diagnosis of miosis:
Differential diagnosis of mydriasis:
If the pupil diameter is 5 mm or less on preoperative mydriasis testing, intraoperative pupil dilation maneuvers are required. The following should be confirmed in preoperative evaluation:
Infrared measurement with an automated pupillometer enables objective and quantitative pupil measurement, and its application for consciousness level assessment in the ICU and neurology is advancing 4).
Observation in light and dark rooms is key to differentiation. If the difference increases in the dark, the smaller pupil is abnormal, suggesting sympathetic nerve disorder (e.g., Horner syndrome). If the difference increases in the light, the larger pupil is abnormal, suggesting parasympathetic nerve disorder (e.g., oculomotor nerve palsy, tonic pupil).
In many cases, observation alone is sufficient. If symptoms are severe, consider the following:
The prognosis is benign, and most cases recover spontaneously. Over time, the pupil tends to become miotic. In cases associated with systemic diseases (e.g., Shy-Drager syndrome), the prognosis may be unfavorable.
Treatment of the underlying disease is prioritized. If there are no other systemic findings, the condition is benign and observation is sufficient.
Treatment is primarily directed at the underlying cause, such as neurosyphilis, diabetes, or multiple sclerosis. Direct treatment for the pupillary abnormality itself is not established.
No specific treatment is necessary; symptomatic management is sufficient. If needed, treat the headache.
Preoperative Pharmacological Mydriasis
Standard preoperative eye drops are a combination of tropicamide 1% and phenylephrine 2.5%. Preoperative NSAID eye drops (diclofenac, ketorolac, etc.) are also useful as an adjunct to prevent intraoperative miosis 1). Intracameral injection of phenylephrine 1% and ketorolac 0.3% is also an effective option for maintaining mydriasis 1).
Intraoperative Pupil Dilation Techniques
When pupil dilation is required with a pupil diameter of 5 mm or less, select from the methods listed in the table below according to the situation.
| Method | Characteristics | Indications/Precautions |
|---|---|---|
| OVD viscodilation | Dilation with high molecular weight OVD (e.g., Healon V®). Least invasive. | Effective for mild poor mydriasis. Effect is temporary 1). |
| Iris retractors (iris hooks) | Reliable dilation to any size. Inserted through side incisions in 4 directions. | Risk of pupillary margin tear if pulled too hard. Target 4–5 mm 7). |
| Pupil expansion ring (e.g., Malyugin ring) | Uniform pupil dilation. Easy insertion and removal. | Widely used. Can be used in IFIS 6). |
| Sphincterotomy | Circumferential short radial incisions of about 0.5 mm at the pupillary margin | Not indicated for IFIS or uveitis. Leaves permanent mydriasis 8) |
| Capsule expander (CE) | Placed over the CCC edge, also provides capsular support | Useful for small pupil with zonular weakness |
For device selection and procedural details, refer to the dedicated article on “Pupil expansion devices and mechanical dilation.”
IFIS management (overview)
Preoperative identification of α1-blocker use is most important 5). In small pupil cases, complications such as posterior capsule rupture and postoperative inflammation are more likely; use pupil expansion devices as needed 9). Management includes use of dispersive viscoelastic, long corneal tunnel incision, fluidics setting adjustment, and intracameral phenylephrine administration 1). See dedicated IFIS article for details.
With appropriate measures, surgery can be performed safely. Preoperative evaluation should identify the cause of poor dilation (posterior synechiae, exfoliation syndrome, α-blocker use), and intraoperative pupil dilation methods (viscoelastic dilation, iris retractors, Malyugin ring, etc.) should be prepared. In cases with zonular weakness, planning must consider the risk of lens nucleus drop.
Miosis is caused by parasympathetic excitation.
Pupillary light reflex pathway (afferent): Retina (especially intrinsically photosensitive retinal ganglion cells: ipRGCs) → optic nerve → optic chiasm (partial decussation) → pretectal area of midbrain → bilateral EW nuclei → ciliary ganglion → sphincter pupillae muscle. Constriction occurs in both eyes (direct and consensual response).
Mydriasis is controlled by a three-neuron sympathetic pathway.
Horner syndrome is classified as central, preganglionic, or postganglionic depending on the site of the lesion. Preganglionic (second neuron) lesions require differentiation from apical lung tumors and mediastinal lesions; postganglionic lesions require differentiation from internal carotid artery dissection and cavernous sinus lesions.
The near response (triad of convergence, accommodation, and miosis) uses a pathway anatomically distinct from the pupillary light reflex. The near response is controlled by the pathway from the cerebral cortex (occipital lobe) to the EW nucleus.
Light-near dissociation in Argyll Robertson pupil: The pupillary light reflex pathway from the pretectal area to the EW nucleus is selectively damaged, while the near response pathway from the cerebral cortex to the EW nucleus is preserved. This results in loss of the light reflex but preservation of the near response (light-near dissociation).
Light-near dissociation also occurs in tonic pupil, but both the light reflex and near response are absent or markedly delayed, with segmental palsy (vermiform movements) being a characteristic finding.
Damage to the ciliary ganglion or postganglionic fibers leads to upregulation of muscarinic receptors in the denervated sphincter pupillae muscle. As a result, even a low concentration (0.125%) of pilocarpine, which normally does not cause miosis, produces constriction. This is the pathophysiological basis of the 0.125% pilocarpine test for tonic pupil.
A similar mechanism is applied in the 1% apraclonidine test for Horner syndrome. Postganglionic fiber damage causes upregulation of adrenergic receptors in the dilator pupillae muscle, leading to an exaggerated response on the affected side even to low concentrations of the drug that are usually ineffective.
Deposition of exfoliation material (abnormal fibrillar material) on the pupillary margin, iris stroma, and ciliary body leads to fibrosis and sclerosis of the pupillary sphincter and iris stroma. This markedly reduces responsiveness to mydriatic agents. In exfoliation syndrome, in addition to poor mydriasis, zonular weakness due to exfoliation material deposition on the zonules occurs at a high rate, further increasing the complexity of cataract surgery1).
International standardization of pupillometry
The International Pupil Colloquium (IPC) has established international standards for pupillography (Standards in Pupillography), providing recommended standards for data collection, processing, and reporting4). This is enabling data comparison across different facilities and devices.
Chromatic pupillometry
This method uses light stimuli of different wavelengths (red and blue) to separately evaluate the function of the inner retina (melanopsin-containing ipRGCs) and outer retina (cones and rods). Its potential as a biomarker for glaucoma and Alzheimer’s disease has been suggested4).
Expanding clinical applications of automated pupillometers
Objective and quantitative pupillary measurement using infrared automated pupillometers is advancing in applications for consciousness level assessment and severity monitoring of brain injury in ICU and neurology settings. Its use as a prognostic indicator in neurocritical care is being investigated.
Advances in pharmacological mydriasis maintenance during cataract surgery
Intracameral use of a combination of phenylephrine 1% and ketorolac 0.3% has been reported to be effective in maintaining intraoperative mydriasis1), and is expected to reduce the need for mechanical dilation in cases of small pupils.
