Physiology and Abnormalities of the Pupil

The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. The afferent pathway for visual function starts from the retina and moves through the optic tracts and lateral geniculate nuclei, terminating in the visual cortex. Light stimulus is conducted by the parasympathetic system to the midbrain, while psychosensory reaction is processed by the sympathetic system. Efferent pathways produce the appropriate response: miosis and mydriasis from the parasympathetic and sympathetic innervations, respectively. Pupillary disorders result from defects in areas of the visual afferent and efferent pathways. Presentation varies with pupillary size along with response to light and medication.

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Overview

Pupil

  • Opening in the center of the iris
  • Space within the eye that allows light to enter and stimulate the retina

Adjacent structures

  • Cornea:
    • In front of the pupil 
    • Transparent structure that provides fixed refraction to focus light onto the retina
    • Primary site of refraction
  • Lens: 
    • Behind the pupil 
    • Transparent structure that provides adjustable refraction to focus light onto the retina
  • Iris:
    • Surrounding the pupil 
    • Colored portion of the eye, composed of contractile smooth muscle to control the size of the pupil
    • Circular muscle group: 
      • Sphincter pupillae for contraction (miosis)
      • Innervation: parasympathetic nervous system
    • Radial muscle group: 
      • Dilator pupillae for dilation (mydriasis)
      • Innervation: sympathetic nervous system

Physiology of the Pupil

Visual pathway

  • Afferent: Sensory neurons carry impulses from sensory stimuli to the central nervous system (CNS).
  • Efferent: Motor neurons carry impulses away from the CNS toward the effector organs.

Afferent pathway

From stimuli to the primary visual cortex:

  • Retina
    • Photoreceptors and bipolar cells
    • Light stimulates retinal photoreceptors → signal goes to bipolar cells, then reaches ganglion cells
  • Optic nerve to optic tract
    • Optic nerve: Axons of the ganglion cells converge, forming the optic nerve.
    • Optic chiasm: where hemidecussation of optic nerve fibers occurs
    • Optic tract:
      • Nasal fibers from left eye decussate to join the temporal fibers of the right eye → right optic tract
      • Nasal fibers from right eye decussate to join the temporal fibers of the left eye → left optic tract
  • Lateral geniculate nucleus (LGN): synaptic relay in the midbrain
    • Majority of the fibers pass posteriorly → genico-calcarine tracts → terminate in the primary visual cortex
    • Minority of fibers pass into the superior colliculus and Edinger-Westphal nuclei (for parasympathetic innervation of the pupil).
Visual system

Illustration of the visual pathway from the eye to the cortex. Vision starts from the retina, then moves to the optic nerve and optic chiasm (where hemidecussation occurs). From this point, fibers synapse with the lateral geniculate nucleus, where most of the fibers proceed to the primary visual cortex posteriorly. Some fibers go to the Edinger-Westphal nuclei (for the parasympathetic visual pathway).

Image by Lecturio.

Parasympathetic innervation pathway (pupillary light reflex)

  • Light stimuli → starts the afferent pathway from the retina, with impulses going to the pretectal nucleus (at the level of the superior colliculus)
  • Protection from increased light intensity by diminishing the amount of light entering the eye
  • Part of the “rest and digest” response
  • Efferent pathway:
    • 1st-order neuron: 
      • Pretectal nucleus projects bilaterally to the Edinger-Westphal nucleus, where the efferent limb begins (preganglionic parasympathetic) → CN III parasympathetic fibers → ciliary ganglion 
    • 2nd-order neuron: 
      • From the ciliary ganglion (postganglionic) → short ciliary nerve fibers synapse on sphincter pupillae → miosis
  • Consensual light reflex:
    • Pretectal nucleus supplies the Edinger-Westphal nucleus bilaterally.
    • Shining light in 1 eye → bilateral constriction of the pupils (miosis)
Pupillary reflex pathways

Pupillary light reflex pathway: from light stimulation of the retina to the midbrain. Afferent pathway (red and blue lines): Left light stimulus goes from the left retina to the optic chiasm to the optic tract, ending at the ipsilateral pretectal nucleus. The pretectal nucleus supplies both left and right Edinger-Westphal nuclei. Yellow lines show impulse from both nuclei reaching both ciliary ganglia and resulting in bilateral miosis.

Image by Lecturio.

Sympathetic innervation pathway

  • Psychosensory or physical stimuli (darkness) → sympathetic response, stimulating the retina and optic tracts to send signal to the hypothalamus
  • Part of the “fight or flight” response
  • Efferent pathway:
    • 3-neuron chain originating from the hypothalamus
    • 1st-order (central neuron): 
      • Neurons from the posterior hypothalamus → spinal cord at C8–T2 (ciliospinal center of Budge) 
    • 2nd-order (preganglionic neuron): 
      • Passes out of the spinal cord → cervical sympathetic chain (through the brachial plexus, over the lung apex) 
      • From the sympathetic chain (going superiorly) → superior cervical ganglion 
    • 3rd-order (postganglionic neuron): 
      • From the superior cervical ganglion → oculosympathetic pathway joins the ophthalmic division of the trigeminal nerve (CN V) 
      • Oculosympathetic fibers synapse on the dilator pupillae (mydriasis) and superior tarsal muscle/Müller’s muscle (upper lid elevation).
Sympathetic innervation pathway

Image of the sympathetic innervation pathway:
1st-order neuron: starts from the hypothalamus to the center of Budge (spinal cord C8–T2)
2nd-order neuron: passes out of the spinal cord going superiorly to the superior cervical ganglion
3rd-order neuron: joins the trigeminal nerve and oculosympathetic fibers, synapses on the dilator pupillae and Müller’s muscle, causing mydriasis and eyelid opening.

Image by Lecturio.

Near response

Consists of 3 responses:

  • Convergence
    • Medial eye movement to track object
    • Oculomotor nucleus stimulates contraction of bilateral medial rectus muscles.
  • Contraction of the ciliary muscles
    • Alteration of lens shape to maintain focus on the retina
    • Initially, ciliary muscles are relaxed, with eyes focused on distant objects.
    • With near objects, parasympathetic pathway stimulates the ciliary muscles → lens thickening → ↑ refractive power (lens accommodation)
  • Constriction of the pupils
    • Adjustment of light to focus on near objects
    • Parasympathetic pathway stimulates the sphincter pupillae.

Examination of the Pupil

Light and near response

  • Examination in dim light
    • Direct response: Pupil constricts on direct illumination.
    • Consensual response: constriction on illumination of the contralateral eye
    • Without light or in the dark: Pupils dilate. 
    • Abnormal response: Pupil fails to dilate to the dark or fails to constrict to light or accommodation (near response).
  • Note the speed of response:
    • 4 +: brisk response 
    • 3 +: a moderate response
    • 2 +: a small, slowed response
    • 1 +: represents a tiny/just visible response
    • 0: indicates unresponsive pupils

Pupil size

  • Normal: 2–4 mm (bright), 4–8 mm (dark)
  • Isocoria: same size of pupils
  • Anisocoria: difference in size of pupils

Swinging-flashlight test

  • In a dark room, the patient fixates on a distant object.
  • With light source below the line of sight, confirm pupils are isocoric.
  • Shift illumination after 3 seconds from 1 eye to the other.
  • Normal response:
    • Shine light in 1 eye → equal bilateral constriction
    • During transfer, there is dilation.
    • Swing light to other eye → similar equal bilateral constriction 
    • Expected in an intact retina and/or optic nerve

Slit-lamp examination

  • Examines the surface of the iris and pupillary margin
  • Irregularities, raised lesion, and pigment abnormalities can be seen.

Pharmacologic tests

  • Pharmacologic agents (topical cocaine, apraclonidine, pilocarpine or hydroxyamphetamine) utilized to check pupillary reactivity
  • Work-up for Horner’s syndrome, tonic pupil, or pharmacologic mydriasis

Disorders of the Afferent Pathway

Relative afferent pupillary defect

  • Also called Marcus Gunn pupil
  • Pathophysiology: caused by unilateral or asymmetrical disease of the optic nerve or retina
  • Presentation:
    • Impaired direct pupillary reflex in the affected eye and impaired indirect pupillary reflex in the normal eye
  • Swinging-flashlight test:
    • Abnormal response: paradoxical dilation or weak constriction when light shines into the affected eye (Marcus Gunn pupil)
  • Associated conditions:
    • Optic neuritis 
    • Traumatic optic neuropathy
    • Ischemic optic disease or retinal disease
    • Glaucoma causing optic nerve damage
    • Retinal detachment
    • Severe macular degeneration
    • Retinitis (cytomegalovirus (CMV), herpes)
    • Optic nerve tumors
    • Other optic neuropathies

Anisocoria

Physiologic anisocoria

  • Difference between the pupil size remains the same regardless of illumination.
  • Affects 20% of normal individuals 
  • Difference in size: typically < 1 mm
  • No damage to the sphincter and dilator pupillae innervation
  • Normal pupillary reactions to light and darkness 
  • Review of old photographs or driver’s license helps with diagnosis.

Pathologic anisocoria

  • Pathophysiology:
    • Neural defect of the efferent pupillomotor pathways innervating the iris muscles in 1 or both eyes
    • Structural defect of 1 or both irides 
  • Presentation:
    • Pathologically small pupil: in darkness, usually remains small while the normal pupil dilates
    • Pathologically large pupil: in bright light, remains large while the normal pupil constricts
    • Difference usually > 1 mm
  • Associated conditions:
    • Horner’s syndrome
    • CN III palsy with pupillary involvement
    • Adie tonic pupil
    • Anterior uveitis
    • Acute angle closure glaucoma
    • Trauma or surgery
    • Congenital defects (coloboma or heterochromia iridis)
Evident right mydriasis

Anisocoria with right mydriasis

Image: “Evident right mydriasis” by U,O,C Pediatria Generale Dipartimento di Medicina Pediatrica, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Roma, Italy. License: CC BY 2.0

Disorders of the Efferent Pathway

Adie tonic pupil

  • Large pupil, impaired light reaction
  • Presentation:
    • Tonic, usually unilateral mydriasis 
    • Has light-near dissociation: 
      • No or poor constriction on illumination 
      • Positive near response (constriction) but slow redilation
    • More common in women 30–40 years of age
    • Holmes-Adie syndrome: loss of deep tendon reflexes
  • Pathophysiology: degeneration of the ciliary ganglion and postganglionic parasympathetic denervation of the affected pupil
  • Associated conditions:
    • Idiopathic (most cases)
    • Infection (viral or bacterial)
    • Trauma or surgery
    • Tumors
    • Ross syndrome: tonic pupil, hyporeflexia, sudomotor disturbances
  • Pilocarpine test:
    • Tonic pupil: 
      • Has cholinergic supersensitivity
      • Will constrict; more miotic response than normal pupil
Tonic right pupil

Tonic right pupil: unresponsive to light stimulation

Image: “Holmes-Adie’s Syndrome” by US National Library of Medicine. License: CC BY 4.0

Argyll Robertson pupil

  • Small bilateral pupils, impaired light reaction
  • Presentation:
    • Always bilateral, may be asymmetric
    • Light-near dissociation: 
      • Pupils do not constrict to illumination
      • Positive constriction to accommodation/near response
  • Pathophysiology: result of dorsal midbrain lesion (damages nerve fibers that control pupillary reflex but spares more ventral nerve fibers that control accommodation reflex)
  • Associated with late-stage syphilis:
    • Other symptoms: sensory ataxia and lancinating pains in tabes dorsalis
    • Treatment: penicillin regimen for neurosyphilis
Argyll Robertson Pupil

Argyll Robertson pupil with bilateral miosis that do not constrict to light, but do constrict to accommodation

Image by Lecturio.

Horner’s syndrome

  • Small pupil, normal light reaction
  • Anisocoria more noted in the dark (abnormal pupil with dilation lag)
  • Presentation:
    • Ptosis: paresis of Müller’s muscle
    • Anhidrosis: damage proximal to fibers mediating sweat and temperature
    • Miosis: loss of innervation to dilator pupillae 
  • Pathophysiology: results from disruption of sympathetic chain 
  • Associated conditions:
    • 1st-order neuron: lateral medullary syndrome (Wallenberg’s syndrome) or tumors or strokes affecting 1st-order sympathetic tract 
    • 2nd-order neuron: trauma or tumors in spinal cord, thoracic outlet, or lung apex (pancoast tumor)
    • 3rd-order neuron: carotid dissection, thrombosis, cavernous sinus aneurysm
  • Pharmacologic tests:
    • Cocaine solution: 
      • Blocks reuptake of norepinephrine and dilates the eye with intact sympathetic innervation  
      • Horner’s syndrome: poor-to-no dilation (impaired sympathetic innervation)
    • Apraclonidine (0.5%–1% solution):
      • A weak alpha-1 agonist and strong alpha-2 agonist
      • Horner’s syndrome (dominant supersensitivity to alpha-1 receptor): Affected pupil dilates. 
    • Localization with topical hydroxyamphetamine:
      • Hydroxyamphetamine releases norepinephrine from intact postganglionic fibers (this test helps to localize the lesion).
      • Horner’s syndrome with intact postganglionic fibers: dilate affected pupil ≥ normal pupil
      • Horner’s syndrome with damaged postganglionic fibers: no pupil dilation

Pharmacology and Pupillary Effects

MedicationMydriasisMiosis
Ophthalmic medications
  • Anticholinergic
    • Atropine
    • Cyclopentolate
  • Mydriatic
    • Tropicamide
  • Alpha-adrenergic agonist
    • Phenylephrine
    • Clonidine
    • Apraclonidine
  • Miotic/anti-glaucoma
    • Pilocarpine
    • Carbachol
  • Anticholinesterase inhibitor
    • Physostigmine
Illicit drugs
  • Cocaine
  • Amphetamine
  • Lysergic acid diethylamide (LSD)
Heroin
Other medications
  • Antihistamine
    • Diphenhydramine
  • Anticholinergic
    • Ipratropium
    • Scopolamine
  • Tricyclic antidepressant
    • Desipramine
  • Anti-Parkinson’s
    • Carbidopa-levodopa
Opioid
  • Morphine
  • Codeine
  • Hydrocodone
HerbalJimsonweed (with anticholinergic properties)

Differential Diagnosis

  • Glaucoma: an optic neuropathy with distinctive changes in the optic cup and visual field defect. Glaucoma is often associated with increased pressure within the eyeball (commonly within the anterior and posterior chambers), which results in gradual vision loss. This can occur acutely due to a blockage of the aqueous humor drainage (acute angle-closure glaucoma) and presents as a mid-dilated pupil. Diagnosis is critical, as acute angle-closure glaucoma is an emergency. Gonioscopy is utilized to visualize the angle. Treatment of choice is peripheral iridotomy.
  • Multiple sclerosis (MS): a chronic inflammatory autoimmune demyelinating disease of the central nervous system. Multiple sclerosis causes acute demyelinating optic neuropathy. Patients report acute-to-subacute vision loss with pain on eye movements. Detection of relative afferent pupillary defect (RAPD) is suggestive of optic neuropathy. Internuclear ophthalmoplegia can also result from MS, exhibited as diplopia, nystagmus, and loss of depth perception. Magnetic resonance imaging helps detect the demyelinating plaques on the affected nervous system. Treatment involves immunomodulation and symptomatic relief.
  • 3rd nerve palsy: neurologic deficit characterized by a large, sluggishly reactive to unreactive pupil, ptosis, and paralysis of eye movement (adduction, elevation, and depression) resulting from lesions along its path from the oculomotor nucleus in the midbrain to the orbit. Causes include aneurysm, ischemia, and trauma. Magnetic resonance imaging with angiography helps evaluate the etiology. Treatment is directed toward the underlying condition causing the palsy.
  • Retinal detachment: separation of the retina from the retinal pigment epithelium resulting in rapid photoreceptor damage. Symptoms include painless vision changes such as sudden flashes of light, floaters, worsening peripheral vision, or having a shadow in the field of vision. Vision is described as curtain-like. Macular involvement would present as rapid afferent pupillary defect due to photoreceptor degeneration caused by the detachment. Acute visual loss from retinal detachment is an emergency requiring corrective surgery.
  • Hutchinson’s pupil: dilated pupil that occurs due to compression of the ipsilateral 3rd cranial nerve arising from trauma, tumor, or aneurysm. Irritation on the nerve initially leads to pupillary constriction of the affected eye. As the nerve is mechanically compressed, the superficially located parasympathetic nerve fibers on the oculomotor nerve are paralyzed, so isolated mydriasis follows. Further increases in intracranial pressure leads to bilateral pupillary dilation. This dilation is associated with uncal herniation. Brain imaging is necessary to determine etiology.

References

  1. American Academy of Ophthalmology. Pupillary examination. Retrieved 9 Oct 2020, from https://www.aao.org/bcscsnippetdetail.aspx?id=ce5e4e47-1d5f-4a06-b1c9-22c23879114a
  2. Belliveau, A., Somani, A., Dossani R. (2020) Pupillary light reflex. StatPearls. Retrieved 10 Oct 2020, from https://www.ncbi.nlm.nih.gov/books/NBK537180/#_NBK537180_pubdet_  
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  4. Dichter, S., Shubert, G. (2020). Argyll Robertson Pupil. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK537179/
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  7. Kedar, S., Biousse, V., Newman, N. (2018). Horner Syndrome. UpToDate. Retrieved 11 Oct 2020, from https://www.uptodate.com/contents/horner-syndrome
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