Pupillary Abnormalities in Internal Medicine: A Comprehensive Review

Dr Neeraj Manikath , claude.ai

Abstract

Pupillary examination remains one of the most valuable clinical skills in internal medicine, providing critical diagnostic information across a spectrum of neurological, pharmacological, and systemic disorders. This review synthesizes current understanding of pupillary anatomy, physiology, and pathology, with emphasis on clinical pearls that enhance diagnostic accuracy. We discuss common and rare pupillary abnormalities, their underlying mechanisms, and systematic approaches to evaluation. Understanding pupillary signs can expedite diagnosis in emergency settings and guide management of complex medical conditions.

Keywords: Pupil abnormalities, anisocoria, Horner syndrome, Adie's pupil, internal medicine, neurological examination

Introduction

The pupillary examination, while taking mere seconds, can provide invaluable diagnostic insights spanning neurology, ophthalmology, toxicology, and critical care medicine. Despite advances in neuroimaging and laboratory diagnostics, the bedside pupillary examination remains irreplaceable for real-time assessment of brainstem function, autonomic integrity, and presence of focal neurological lesions.

This review provides a structured approach to pupillary abnormalities relevant to internal medicine practice, emphasizing diagnostic reasoning, clinical pearls, and practical management strategies.

Anatomy and Physiology

Neural Pathways

Sympathetic Pathway (Mydriasis)

The sympathetic pathway involves a three-neuron arc:

First-order neurons: Originate in the posterolateral hypothalamus, descend through the brainstem to the ciliospinal center of Budge (C8-T2)
Second-order neurons: Exit the spinal cord, ascend over the lung apex, and synapse at the superior cervical ganglion
Third-order neurons: Ascend along the internal carotid artery, join the ophthalmic division of the trigeminal nerve, and innervate the iris dilator muscle and Müller's muscle

Parasympathetic Pathway (Miosis)

The parasympathetic pathway consists of:

Afferent limb: Retinal ganglion cells → optic nerve → pretectal nucleus
Efferent limb: Edinger-Westphal nucleus → oculomotor nerve (CN III) → ciliary ganglion → short ciliary nerves → iris sphincter muscle

Normal Pupillary Response

Normal pupils are round, equal (anisocoria <0.4 mm in 20% of population), and reactive to light and accommodation. Pupil size ranges from 2-8 mm, influenced by age, ambient light, emotional state, and medications.

Clinical Pearl #1: The "reverse relative afferent pupillary defect" - When examining for RAPD, if you're uncertain, repeat the test in darkness. A true RAPD becomes more apparent as the baseline pupil size increases.

Systematic Approach to Pupillary Examination

The Five-Step Examination

Size assessment (ambient lighting)
Shape evaluation (round vs. irregular)
Direct light response (each eye individually)
Consensual light response (contralateral pupil)
Accommodation reflex (near response)

Clinical Pearl #2: The "dim and bright" rule - Always examine pupils in both dim and bright lighting. Anisocoria that is worse in darkness suggests sympathetic dysfunction (Horner syndrome), while anisocoria worse in bright light suggests parasympathetic dysfunction (Adie's pupil, CN III palsy).

Pharmacological Testing

Cocaine 4-10%: Confirms Horner syndrome (affected pupil fails to dilate)

Apraclonidine 0.5-1%: Reverses anisocoria in Horner syndrome due to denervation supersensitivity (affected pupil dilates more than normal pupil)

Hydroxyamphetamine 1%: Differentiates preganglionic from postganglionic Horner syndrome (postganglionic lesions fail to dilate)

Pilocarpine 0.125%: Supersensitivity in Adie's pupil causes constriction; normal pupils don't respond to this dilute concentration

Clinical Pearl #3: Apraclonidine has largely replaced cocaine testing - It's more readily available, safer, and reverses the anisocoria rather than accentuating it, making the diagnosis visually obvious even to patients.

Classification of Pupillary Abnormalities

Anisocoria (Unequal Pupils)

Anisocoria affects 10-20% of the normal population (physiologic anisocoria). Pathological anisocoria requires systematic evaluation.

Approach to Anisocoria

Step 1: Determine which pupil is abnormal

Anisocoria greater in darkness → smaller pupil is abnormal (sympathetic dysfunction)
Anisocoria greater in light → larger pupil is abnormal (parasympathetic dysfunction)

Step 2: Assess associated signs

Ptosis, anhidrosis → Horner syndrome
Ophthalmoplegia, headache → CN III palsy
Light-near dissociation → Adie's pupil, Argyll Robertson pupil

Clinical Pearl #4: The "smartphone flashlight test" - In suspected Horner syndrome, use your smartphone flashlight to illuminate the face from below in a dark room. The affected side will show less iris illumination (transillumination deficit) due to less pupillary dilation.

Horner Syndrome

Horner syndrome results from disruption of the oculosympathetic pathway, characterized by:

Miosis (affected pupil smaller)
Ptosis (1-2 mm, due to denervation of Müller's muscle)
Anhidrosis (variable distribution depending on lesion location)
Apparent enophthalmos
Iris heterochromia (in congenital cases)

Etiology by Location:

First-order (Central):

Stroke (lateral medullary/Wallenberg syndrome)
Multiple sclerosis
Cervical spinal cord lesions
Syringomyelia

Second-order (Preganglionic):

Pancoast tumor (most important to exclude)
Thyroid carcinoma
Mediastinal masses
Thoracic aortic aneurysm
Neck trauma/surgery

Third-order (Postganglionic):

Carotid artery dissection (most common acute cause)
Cavernous sinus lesions
Cluster headache
Herpes zoster

Clinical Pearl #5: Acute painful Horner syndrome = carotid dissection until proven otherwise - These patients require immediate vascular imaging (CTA or MRA). The combination of neck/facial pain with Horner syndrome is carotid dissection until you prove it's not.

"Oyster" (Hidden Finding): Harlequin sign - Some patients with Horner syndrome develop hemifacial flushing on the affected side during exercise or heat exposure due to preserved cholinergic sweating but absent sympathetic vasoconstriction. This can be the first clue to the diagnosis.

Workup for Horner Syndrome:

Confirm diagnosis: Apraclonidine or cocaine test
Localize lesion: Hydroxyamphetamine test (if available)
First-order: Brain and cervical spine MRI
Second-order: CT chest, neck imaging
Third-order: Carotid imaging (CTA/MRA)

Third Nerve Palsy

CN III palsy presents with:

Large, non-reactive (or poorly reactive) pupil
Ptosis (complete, involving levator palpebrae)
Ophthalmoplegia (down and out position)
Loss of accommodation

Critical Distinction: Pupil-Involving vs. Pupil-Sparing

Pupil-involving (surgical/compressive):

Posterior communicating artery aneurysm (25-30%)
Uncal herniation
Cavernous sinus masses
Requires urgent neurosurgical evaluation

Pupil-sparing (medical/ischemic):

Diabetic mononeuropathy (most common)
Hypertensive vasculopathy
Giant cell arteritis
Collagen vascular disease

Clinical Pearl #6: The "rule of the pupil" - A pupil-involving CN III palsy must be considered a surgical emergency (aneurysm) until proven otherwise. Pupil-sparing CN III palsy that doesn't improve within 3 months requires imaging regardless, as 10-15% may still have compressive lesions.

"Oyster": Aberrant regeneration - After CN III injury, misdirected nerve growth can cause paradoxical pupillary constriction with adduction or elevation (pseudo-Argyll Robertson). This strongly suggests a compressive rather than ischemic lesion.

Clinical Hack: The "elevator lag" test - Ask the patient to look down then up. In true CN III palsy, the ptotic lid won't retract with upgaze. In myasthenia gravis mimicking CN III palsy, the lid may show transient improvement with ice pack application (ice test).

Adie's Tonic Pupil

Adie's pupil results from postganglionic parasympathetic denervation of the iris sphincter and ciliary muscle, typically affecting young women (age 20-40, female:male ratio 2.6:1).

Characteristics:

Unilateral mydriasis (70%)
Minimal or absent light response
Slow, tonic constriction to near effort
Light-near dissociation
Sector palsy (vermiform movements on slit-lamp)
Hypersensitivity to dilute pilocarpine (0.125%)

Associated Features:

Absent deep tendon reflexes (Holmes-Adie syndrome)
Segmental sudomotor abnormalities (Ross syndrome)

Clinical Pearl #7: The "tonic re-dilation" - After near effort, the Adie's pupil re-dilates very slowly (taking minutes), unlike the brisk re-dilation of a normal pupil. This is pathognomonic and can be observed at the bedside.

Workup: Generally benign and self-limited. Rule out syphilis (RPR/VDRL), paraneoplastic syndrome (if bilateral), and autonomic neuropathy (if systemic symptoms present).

Argyll Robertson Pupil

The classic pupillary sign of neurosyphilis, though now rare in developed countries.

Features:

Bilateral small, irregular pupils
Absent light reflex
Preserved near reflex (light-near dissociation)
Poor dilation to mydriatics

Mnemonic: Argyll Robertson pupils are "Accommodations Reflex Present" but light reaction absent - like a "prostitute" who "accommodates but reacts to no light" (historically used but culturally insensitive).

Modern Differential for Light-Near Dissociation:

Neurosyphilis (rare)
Diabetic autonomic neuropathy (common)
Adie's pupil (common)
Parinaud syndrome (dorsal midbrain)
Aberrant CN III regeneration
Amyloidosis

Clinical Pearl #8: True Argyll Robertson pupils are bilateral, irregular, and extremely miotic (1-2 mm). Adie's pupil is typically unilateral, larger (4-6 mm), and regular until chronic stages.

Relative Afferent Pupillary Defect (RAPD)

RAPD, or Marcus Gunn pupil, indicates asymmetric afferent pathway dysfunction anterior to the optic chiasm.

Swinging Flashlight Test

Shine light in normal eye: both pupils constrict
Swing light to affected eye: both pupils dilate paradoxically
Grading: 1+ to 4+ based on degree of dilation

Clinical Pearl #9: RAPD quantification - Use neutral density filters to quantify RAPD severity. A 0.3 log unit RAPD correlates with significant optic nerve dysfunction and should prompt urgent ophthalmologic evaluation.

Common Causes:

Optic neuritis (multiple sclerosis)
Ischemic optic neuropathy (giant cell arteritis)
Severe glaucoma (asymmetric)
Optic nerve compression (tumor, aneurysm)
Extensive retinal disease (detachment, central retinal artery occlusion)
Traumatic optic neuropathy

Clinical Pearl #10: RAPD never occurs from cortical blindness - The pretectal pathway is intact, so bilateral occipital lobe lesions causing complete blindness will still have normal pupillary responses. Use this to distinguish cortical from ocular/nerve blindness.

"Hack": The "reverse RAPD" - In extremely asymmetric cataracts, the eye with the dense cataract may have a subtle RAPD due to reduced light transmission. However, true optic nerve disease causes a much more pronounced RAPD than any media opacity.

Bilateral Pupillary Abnormalities

Bilateral Mydriasis (Large Pupils)

Pharmacological:

Anticholinergics (atropine, scopolamine, antihistamines)
Sympathomimetics (cocaine, amphetamines)
Topical medications (inadvertent contamination)

Neurological:

Bilateral CN III dysfunction
Severe cerebral hypoxia/ischemia
Brain death (mid-position to dilated, fixed)
Status epilepticus (postictal)
Severe trauma

Clinical Pearl #11: The "Nasal decongestant sign" - Patients with bilateral mydriasis from nasal spray contamination (containing sympathomimetics) often have a history of recent upper respiratory infection. Ask specifically about over-the-counter medications.

"Oyster": Pretectal pupils - Dorsal midbrain syndrome (Parinaud syndrome) causes mid-dilated pupils (4-6 mm) that are light-near dissociated, with impaired upgaze. Consider hydrocephalus, pineal tumors, or stroke in the appropriate clinical context.

Bilateral Miosis (Small Pupils)

Pharmacological:

Opioids (pinpoint pupils are classic)
Cholinergics (pilocarpine, organophosphates)
Alpha-2 agonists (clonidine, dexmedetomidine)
Pontine hemorrhage (pinpoint, reactive)

Neurological:

Pontine lesions (hemorrhage, infarction)
Metabolic encephalopathy (various)
Argyll Robertson pupils (neurosyphilis)
Bilateral Horner syndrome (rare)

Clinical Pearl #12: Pontine vs. opioid pupils - Both cause pinpoint pupils, but pontine pupils may still be minimally reactive with a bright light and magnification, while opioid pupils have preserved hippus (rhythmic variations). More importantly, pontine hemorrhage presents with coma, quadriplegia, and abnormal respirations.

"Hack": The naloxone test - In suspected opioid overdose with pinpoint pupils, pupillary dilation after naloxone administration can be diagnostic and therapeutic simultaneously. Document pupil size before and after administration.

Pupillary Abnormalities in Systemic Disease

Diabetes Mellitus

Diabetic autonomic neuropathy commonly affects pupillary function:

Smaller baseline pupil size
Reduced light response amplitude
Slower constriction and reddilation
Light-near dissociation (in advanced cases)
Increased risk of Adie's tonic pupil
Pupil-sparing CN III palsy (microvascular ischemia)

Clinical Pearl #13: Diabetic pupillary dysfunction correlates with systemic autonomic neuropathy - Patients with impaired pupillary responses often have gastroparesis, erectile dysfunction, or orthostatic hypotension. Document pupillary findings as part of diabetic neuropathy assessment.

Pharmacology and Toxicology

Understanding pupillary responses to drugs is crucial in toxicology:

Miosis:

Opioids (morphine, heroin, fentanyl)
Organophosphates
Clonidine
Phenothiazines
Nicotine

Mydriasis:

Anticholinergics (antihistamines, TCAs)
Sympathomimetics (cocaine, amphetamines, MDMA)
Serotonin syndrome (with hyperthermia, clonus)
Withdrawal states (alcohol, benzodiazepines, opioids)

Clinical Pearl #14: Pupil size in toxidromes - Pupillary examination is one of the most reliable physical findings in toxicology. When combined with vital signs and mental status, it narrows the differential dramatically:

Hot, dry, dilated pupils + delirium = anticholinergic
Pinpoint pupils + respiratory depression = opioid
Dilated pupils + hypertension + agitation = sympathomimetic

Critical Care Applications

Brain Death Determination:

Pupils must be fixed and non-reactive
Mid-position (4-6 mm) or dilated
No confounding drugs (avoid mydriatics for 24h before testing)

Traumatic Brain Injury:

Unilateral dilated pupil = uncal herniation (medical emergency)
Bilateral dilated pupils = severe brainstem injury or bilateral herniation
Improving pupillary responses = favorable prognostic sign

Clinical Pearl #15: The "fixed, dilated pupil in trauma" - Not all fixed, dilated pupils in trauma indicate herniation. Direct ocular trauma, commotio retinae, or traumatic mydriasis can cause a fixed pupil without intracranial pathology. Always correlate with CT findings and neurological exam.

Unusual Pupillary Syndromes

Tadpole Pupil

Intermittent segmental iris sphincter spasm causing a teardrop shape lasting seconds to minutes. Benign but can be alarming to patients.

"Oyster": Often associated with migraine, though usually benign. Document with photography if possible.

Springing Pupil

Alternating dilation and constriction, seen in:

Aberrant CN III regeneration
Midbrain lesions
Seizure disorders

Paradoxical Pupillary Response

Pupillary dilation to light instead of constriction, seen in:

Congenital stationary night blindness
Melanoma-associated retinopathy
Severe retinal disease

Hippus

Rhythmic pupillary oscillations (dilation-constriction), exaggerated in:

Fatigue
Multiple sclerosis
Metabolic encephalopathy
Normal finding in some individuals

Clinical Pearl #16: Benign hippus vs. pathologic oscillations - Benign hippus is symmetric, regular, and low amplitude. Pathologic causes show irregular, asymmetric, or high-amplitude changes.

Diagnostic Approach: Clinical Algorithms

Algorithm for Anisocoria

Anisocoria → Assess in dim and bright light

Worse in DIM light (small pupil abnormal):
├─ Associated ptosis/anhidrosis? → Horner syndrome
│  └─ Pharmacologic testing, imaging per localization
└─ No other signs → Physiologic anisocoria

Worse in BRIGHT light (large pupil abnormal):
├─ Ophthalmoplegia? → CN III palsy
│  ├─ Pupil involved → Urgent imaging (aneurysm)
│  └─ Pupil spared → Medical workup (DM, GCA)
├─ Light-near dissociation? → Adie's pupil
│  └─ Pilocarpine test, rule out systemic causes
└─ Irregular pupil → Iris trauma, inflammation, synechiae

Red Flags Requiring Urgent Evaluation

Acute painful Horner syndrome → Carotid dissection
Pupil-involving CN III palsy → Aneurysm
Fixed, dilated pupil + altered consciousness → Herniation
RAPD + vision loss → Optic neuritis, ischemic optic neuropathy (GCA)
Bilateral fixed pupils + coma → Brain death evaluation, severe anoxic injury

Pearls and Pitfalls Summary

Top 10 Clinical Pearls

Lighting matters: Always examine in both dim and bright light
Acute painful Horner = dissection: Emergent vascular imaging required
Pupil-involving CN III = aneurysm: Urgent neurosurgical consultation
Apraclonidine over cocaine: Easier, safer, and reverses anisocoria
Smartphone flashlight: Useful bedside tool for assessing anisocoria
RAPD excludes cortical blindness: Differentiates ocular from cortical causes
Pilocarpine supersensitivity: Confirms Adie's pupil (0.125% causes constriction)
Light-near dissociation: Think Adie's, Argyll Robertson, diabetes, or dorsal midbrain
Opioid pupils react minimally: Unlike pontine pupils, which may show minimal reactivity
Document pupil size numerically: Use pupil gauge or calipers for accuracy

Common Pitfalls to Avoid

Mistaking physiologic for pathologic anisocoria: 20% of population has <0.4mm difference
Missing subtle Horner syndrome: Look for dilation lag (affected pupil dilates slower in darkness)
Over-imaging pupil-sparing CN III palsy: Medical causes likely, but image if no improvement in 3 months
Forgetting about pharmacologic mydriasis: Ask about eye drops, nasal sprays, patches
Not recognizing aberrant regeneration: Suggests compressive lesion, not ischemic
Missing bilateral Adie's pupils: Consider paraneoplastic syndrome
Inadequate lighting during examination: Need very bright light to assess light reflex properly
Ignoring age-related changes: Pupils become smaller and less reactive with age
Mistaking sector palsy for synechiae: Adie's shows vermiform movements on slit-lamp
Not correlating with clinical context: Pupillary findings must fit the clinical picture

Practical Examination Hacks

The "swinging flashlight" enhancement: Use a dim red light to observe the affected pupil during RAPD testing - makes the paradoxical dilation more visible
The "near-far-near": Test accommodation three times - Adie's pupil shows progressive fatigue and slower responses
The "dilation lag" test: In suspected Horner, turn lights off for 15 seconds, then on - affected pupil lags in dilation and may still be smaller at 15 seconds
The "ice pack test": Apply ice to ptotic lid for 2 minutes - improvement suggests myasthenia gravis, not CN III palsy
Photography: Use smartphone to document pupil size, shape, and reactions - invaluable for serial comparisons
The "ambient light trick": Examine pupils near a window with natural light - provides ideal illumination without flashlight artifacts

Special Populations

Pediatric Considerations

Physiologic anisocoria more common in children
Congenital Horner syndrome causes iris heterochromia
Tonic pupil rare before adolescence
Neuroblastoma can present with Horner syndrome (opsoclonus-myoclonus syndrome)
Birth trauma may cause Horner syndrome or CN III palsy

Clinical Pearl #17: Iris heterochromia in a child with ptosis = congenital Horner - The affected iris is lighter (hypopigmented) due to sympathetic denervation during development. This is irreversible even if the Horner resolves.

Geriatric Considerations

Age-related miosis (senile miosis)
Decreased light reflex amplitude and speed
Increased prevalence of pharmacologic mydriasis (anticholinergic medications)
Higher risk of ischemic CN III palsy
Cataract surgery may alter pupillary anatomy

Pregnancy-Related Changes

Benign episodic mydriasis reported
Gestational diabetes may cause pupillary dysfunction
Eclampsia can present with anisocoria
Carotid dissection risk increased (especially postpartum)

Emerging Concepts and Technology

Pupillometry

Automated pupillometry provides objective measurements:

Pupil size and shape
Light reflex parameters (latency, amplitude, velocity)
Neurological pupil index (NPi) for intracranial pressure monitoring
Research applications in Alzheimer's disease, autism spectrum disorder

Clinical Application: Quantitative pupillometry is increasingly used in ICU settings to detect early neurological deterioration and guide management of intracranial hypertension.

Artificial Intelligence

Machine learning algorithms are being developed for:

Automated RAPD detection
Quantification of pupillary light reflex abnormalities
Prediction of neurological outcomes in critical care
Screening for systemic autonomic dysfunction

Case-Based Teaching Points

Case 1: The Subtle Horner

A 45-year-old woman presents with mild headache and slight drooping of her right eyelid noticed by her husband. On examination, you note subtle ptosis and miosis on the right.

Teaching Point: In acute Horner syndrome with pain, always consider carotid dissection. The patient requires urgent CTA or MRA of the neck vessels. Don't be reassured by mild symptoms - dissection can present subtly before catastrophic progression.

Case 2: The Dilated Pupil in ICU

A 62-year-old man with diabetic ketoacidosis develops a dilated right pupil on ICU day 2. CT head is normal. He has had multiple finger-stick blood glucose checks.

Teaching Point: Always consider pharmacologic mydriasis from inadvertent contamination. Healthcare workers handling medications can transfer sympathomimetics or anticholinergics to patients. Pilocarpine 1% should constrict a truly dilated pupil from CN III palsy but not a pharmacologically dilated one.

Case 3: The "Normal" MRI

A 28-year-old woman presents with unilateral pupillary dilation and light-near dissociation. Brain and orbital MRI are normal. She's been told "it's nothing to worry about."

Teaching Point: Adie's tonic pupil is a clinical diagnosis. Imaging is normal by definition. Confirm with dilute pilocarpine test. Reassure patient it's benign, though depth perception may be affected. Check for associated areflexia (Holmes-Adie syndrome).

Conclusion

Pupillary examination remains an essential clinical skill for internists, providing immediate diagnostic information that guides urgent decision-making and long-term management. Mastery requires understanding anatomical pathways, systematic examination techniques, and recognition of subtle findings that distinguish benign from dangerous conditions.

The key principles are:

Systematic examination in varied lighting
Localization of lesions through associated findings
Recognition of red flags requiring urgent action
Judicious use of pharmacologic testing
Integration with clinical context

As technology advances, automated pupillometry and AI-assisted diagnostics will complement but not replace the skilled clinical examination. The ability to recognize an acute Horner syndrome, differentiate pupil-involving from pupil-sparing CN III palsy, or detect a subtle RAPD remains fundamental to excellent patient care.

Future directions include standardization of quantitative pupillometry, development of portable diagnostic devices, and integration of pupillary findings into predictive algorithms for neurological outcomes. However, the foundation remains the careful, systematic bedside examination taught to generations of physicians.

References

Kawasaki A, Borruat FX. Neurological examination of the pupils. J Neuroophthalmol. 2005;25(2):125-134.
Thompson HS, Pilley SF. Unequal pupils: a flow chart for sorting out the anisocorias. Surv Ophthalmol. 1976;21(1):45-48.
Jacobson DM. Pupil involvement in patients with diabetes-associated oculomotor nerve palsy. Arch Ophthalmol. 1998;116(6):723-727.
Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine test in the diagnosis of Horner's syndrome. Arch Ophthalmol. 1990;108(3):384-387.
Biousse V, Newman NJ. Third nerve disorders. Semin Neurol. 2000;20(1):55-74.
Lee AG, Brazis PW. Clinical Pathways in Neuro-ophthalmology: An Evidence-Based Approach. 2nd ed. Thieme; 2003.
Wilhelm H, Wilhelm B, Schiefer U. Mydriasis caused by plant contact. Fortschr Ophthalmol. 1991;88(5):588-591.
Cox TA, Corbett JJ, Thompson HS, Lennarson L. Upside-down reversal of the upper eyelid: a new sign of Horner's syndrome. Ann Neurol. 1979;6(6):574-575.
Pilley SF, Thompson HS. Pupillary "dilatation lag" in Horner's syndrome. Br J Ophthalmol. 1975;59(12):731-735.
Jacobson DM, Vierkant RA. Comparison of cholinergic supersensitivity in third nerve palsy and Adie's syndrome. J Neuroophthalmol. 1998;18(3):171-175.
Thompson HS. Adie's syndrome: some new observations. Trans Am Ophthalmol Soc. 1977;75:587-626.
Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Iowa State University Press; 1993.
Gladstone JP, Dodick DW. Painful Horner's syndrome. Headache. 2004;44(8):840-841.
Keane JR. Third nerve palsy: analysis of 1400 personally-examined inpatients. Can J Neurol Sci. 2010;37(5):662-670.
Chen JJ, Thurtell MJ, Longmuir RA, et al. Causes and prognosis of sixth nerve palsy in young adults. J Neuroophthalmol. 2011;31(2):182-186.
Flaharty PM, Lieb WE, Sergott RC, et al. Color Doppler imaging: a new noninvasive technique to diagnose and monitor carotid cavernous sinus fistulas. Arch Ophthalmol. 1991;109(4):522-526.
Maloney WF, Younge BR, Moyer NJ. Evaluation of the causes and accuracy of pharmacologic localization in Horner's syndrome. Am J Ophthalmol. 1980;90(3):394-402.
Kawasaki A. Physiology, assessment, and disorders of the pupil. Curr Opin Ophthalmol. 1999;10(6):394-400.
Wilhelm H, Peters A, Ludtke H, Wilhelm B. The prevalence of relative afferent pupillary defects in normal subjects. J Neuroophthalmol. 2007;27(4):263-267.
Czyz CN, Petrie TP, Cahill KV, Karanfilov B. Apraclonidine in the diagnosis of Horner syndrome. J Neuroophthalmol. 2018;38(2):217-220.
Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A. Chromatic pupillometry in patients with retinitis pigmentosa. Ophthalmology. 2011;118(2):376-381.
Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. 2005;140(3):517-523.
Cremer SA, Thompson HS, Digre KB, Kardon RH. Hydroxyamphetamine mydriasis in Horner's syndrome. Am J Ophthalmol. 1990;110(1):71-76.
Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT. Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm. Eye (Lond). 2013;27(3):291-298.
Sadun AA. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc. 1998;96:881-923.

Disclosure: The author has no financial conflicts of interest relevant to this article.