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Pupil Anomalies: Reaction and Red Flags

Weon Jun, OD, FAAO

 

Contents

 

Clinical Manifestations of the Pupillary Anomalies (Types of Pupillary Anomalies)

Congenital defects of the ocular structures happen due to developmental anomalies and intrauterine insults such as infections and drugs during pregnancy.  During an exam, misplaced or ectopic pupils are frequently observed in clinic.  Polycoria is used to describe multiple pupils.  Ectopia describes displaced pupil.  Corectopia refers to displacement of the pupil.  Dyscoria refers to an abnormal shape of the pupil.  Aniridia implies total absence of the iris, but some iris tissue usually remains.  Both iris dilator and sphincter muscles are usually absent.  Abnormalities in iris color could result from albinism.  Heterochromia is used to describe a difference in color between two eyes.  Iris coloboma implies a defect in the structure of the lower part of the iris.  It is also described as keyhole pupil.  Congenital miosis and mydriasis could be present at birth.  

Anisocoria


Anisocoria is defined by a difference in the size of the two pupils of 0.4 mm or greater.   Roughly one fifth of the normal population has an anisocoria, but the difference in size is not more than 1mm. (9)  Anisocoria or a difference in pupil size may be normal but may be a sign of ocular or neurologic disease.  It should be considered a neurosurgical emergency if a patient has anisocoria with acute onset of third-nerve palsy and associated with headache or trauma.  It is also important to note that symmetrically rapid constriction in pupillary light response indicates that the anisocoria is not due to third-nerve palsy.       

 

To evaluate anisocoria, the examiner must determine which pupil is abnormal by noting pupil size under light and dark illumination.  If the difference in pupil size in both light and dark illumination is constant, then it is called physiologic or essential anisocoria.  Physiologic anisocoria could also vary in pupil size from day to day and it could switch sides.  When there is an imbalance of parasympathetic (efferent) and sympathetic innervations, an acquired anisocoria will be present.  The presence of anisocoria may help differentiate and localize a lesion to one of the parasympathetic (efferent) and sympathetic pupillary pathways, but does not localize the lesion’s location within those pathways.  Based on the anatomy and physiology of the pupillary pathways, lesions of the retina, optic nerve, chiasm, and optic tract do not cause anisocoria.  A lesion in the midbrain produces a subtle and transient anisocoria.  However, most neurologic causes of anisocoria involve lesions in the parasympathetic (efferent) and sympathetic pupillary pathways. 

If an anisocoria is noted, then one must measure pupil size under both dim and bright illumination in order help differentiate between the sympathetic pupillary pathway defects from the parasympathetic pupillary pathway defects. (Figure 3)  If the larger pupil is abnormal (poor constriction), the anisocoria is greatest in bright illumination, as the normal pupil becomes small.  This is caused from the disruption of the parasympathetic (efferent) pupillary pathway.  If the smaller pupil is abnormal (poor dilation), the anisocoria is greatest in dark illumination, as the normal pupil becomes large.  It is caused from the disruption of the sympathetic pupillary pathway.   

 

Disorders Characterized by Anisocoria (10)


Physiologic (essential) anisocoria
Alternating contraction anisocoria
Bernard’s syndrome
Horner’s syndrome
Episodic unilateral mydriasis
Adie’s tonic syndrome
Third-nerve palsy
Adrenergic mydriasis
Anticholinergic mydriasis
Argyll Robertson pupils
Local iris disease (e.g., sphincter atrophy, posterior synechiae, pseudoexofoliation syndrome)
Hutchinson’s pupil
Angle-closure glaucoma

 

Figure 3

Figure 3.  Flow chart of evaluation of anisocoria.  Image from http://www.opt.indiana.edu/riley/HomePage/Pupil_Abnormal/Graphics/2_anisocoria.GIF

 

Afferent Pupillary Defects


An afferent pupillary defect test is an important physical sign in an evaluation for neurologic disease.  A relative afferent pupillary defect (RAPD) is an objective sign of unilateral or asymmetric disease of the optic nerve head or retina.  The visual acuity does not necessarily correlate with an RAPD.  If there is an RAPD with good central vision, you are likely dealing with optic nerve diseases and not retinal diseases.  Usually retinal disease has to be quite severe for an RAPD to be clinically evident.  In addition, there are many conditions with a severe vision loss, but without an RAPD, such conditions are a complete vitreous hemorrhage and hyphema.  

     

When performing an afferent pupillary defect test, it is important to move the light away from one eye to the other eye quickly within 1 second and holding a 3-second pause in each eye.  This technique is reliable in detecting and quantifying the relative afferent pupillary defects, especially a subtle RAPD.  Also, using a 0.3 log unit neural density filter over the suspected subtle RAPD eye will help in enhancing the RAPD.  In a normal pupil, using a 0.3 log unit neural density filter does not enhance or change it.   It is also critical to have the same amount of light into each eye in approximately the same retinal area and same amount of time exposed to eliminate to any induced pseudo-afferent pupillary defect.  Sometimes, it is difficult to differentiate an RAPD from hippus, which is a normal fluctuation in pupillary size under steady illumination.  Importantly, the hippus should be equal in amplitude between two eyes to qualify as a normal variant.  If there is any difference in hippus amplitude between two eyes, then this may indicate a trace RAPD.    

     

Cox (11) concluded that the most sensitive criterion for detection of RAPD is difference in amplitude of initial consensual pupillary constriction versus the initial direct pupillary constriction.  An examiner should diagnose an RAPD when the consensual pupillary response is greater than the direct response.  This is opposite in a patient who has a non-reactive pupil with an RAPD.  A non-reactive pupil could be caused from dilation, constriction or trauma.  An examiner can test the non-reactive pupil for an RAPD by observing the direct response of the reactive pupil and the consensual response of the non-reactive pupil.  This method is known as reserve RAPD testing.  An RAPD is present if the direct pupillary response of the reactive pupil is greater than consensual pupillary response of the non-reactive pupil.       

There are many different methods to measure an RAPD in clinic.  A common method is using a qualitative 1-4+ grading scale.   

Grading Scale:  RAPD

Grade 1+:  A weak initial pupillary constriction followed by greater redilation
Grade 2+:  An initial pupillary stall followed by greater redilation
Grade 3+:  An immediate pupillary dilation
Grade 4+:  No reaction to light – Amaurotic pupil

However, this method lacks the quantitation that is necessary for comparison in follow ups.  The use of neutral density filters and crossed polarized filters provide a way to quantify the RAPD.  Using neutral density filters, an RAPD can be quantified by sequentially placing optical filters of increasing density from 0.3 to 1.6 log units in front of the normal eye until both pupils response equally to a light source as an examiner alternates the light source between the pupils.  The crossed polarized filters provide narrower scale ranges from 0.02 to 0.9 log units and the ranges could be increased by placing a standard neutral density filter over the polarized filter.  For example, using a 0.3 log unit density filter over the polarized filter, you could increase the range from 0.3 log unit (at 0 degrees) to 1.2 log units (at 90 degrees). (8) 

If there is a poor direct pupillary response, the lesions could be any location along the visual pathway from optic nerve to two-third of the optic tract.  They could also be located in the pretectal area, the ipsilateral parasympathetic pathway traveling in CN III, or the iris sphincter.  In addition, failure of the pupil to constrict to both direct and consensual stimuli indicates dysfunction of the efferent (parasympathetic) pupillary pathway.  Also, you should expect an afferent pupillary pathway interruption if a patient has a poor direct pupillary response, but the preservation of the consensual light reflex in the same eye.  An eye with no light perception should have no pupillary response to direct light stimulation as well.  This is called an amaurotic pupil.  The consensual response defect could arise from lesions of the contralateral optic nerve, the pretectal area, the ipsilateral parasympathetic traveling in CN III, or the iris sphincter. 

An RAPD could be presented in a hemianoptic visual field loss if the lesion is along the afferent pupillary pathway.  The RAPD will be found in the eye contralateral to the side of the lesion because 54% of the nasal fibers cross to the contralateral tract and 47% of the temporal fibers remain ipsilateral.  However, an RAPD would not be present when the hemianoptic lesions are beyond the lateral geniculate nucleus body, because the pupillary fibers are not involved.  There is also a greater pupillary escape with central visual field loss compared to peripheral visual field loss due to more concentrated afferent neurons in the central retina. (12) 

An RAPD does not cause anisocoria; however, anisocoria may cause an apparent RAPD in the smaller pupil due to more shading of the retina compared to the larger pupil.  This is more apparent when anisocoria is 2 mm or greater, or the pupil is very small.  Amblyopia may cause a mild RAPD, rarely exceeding 0.6 log units, mostly 0.3 or less. (13)  It has been also documented that RAPD is more likely to occur in anisometropic than strabismic amblyopia.  Usually the visual acuity would be 20/200, or worse.  However, in the presence of an RAPD, the diagnosis amblyopia should be made with caution, especially if an RAPD is greater than a mild grading.  Cataracts and other opacities in the ocular media generally do not produce an RAPD.  However, it has been reported that opaque white cataracts may produce a contralateral RAPD from excess retinal stimulation from light scatter. (14)

There are many different ocular or neurologic conditions which could cause an RAPD.  The following are a list of common ocular conditions causing an RAPD:

Unilateral optic nerve diseases:
Anterior ischemic optic neuropathy: 
Arteritic (Giant Cell Arteritis) and Non-arteritic
Optic neuritis
Central retinal arterial occlusion
Compressive optic neuropathy:

Optic nerve tumor            
Traumatic optic neuropathy
Asymmetric glaucoma
Homonymous hemianopsia (Lesions involving pupillary pathway)

Retinal conditions:
Branch retinal arterial occlusion

Ischemic central retinal vein occlusion
Retinal detachment, greater RAPD if involving macula
Asymmetric macular disease with VA <20/200
Unilateral panretinal photocoagulation 

Clinical Pearls:

Efferent Pupillary Defects (Parasympathetic)


Efferent pupillary defects will occur if there is any disruption along the parasympathetic pupillary fibers from E-W nuclei to iris sphincter via third cranial nerve.  An abnormal dilated pupil could be due to iris sphincter damage from trauma, pharmacologic agents or parasympathetic pupillary pathway defects.  In addition, traumatic iritis, uveitis, angle-closure glaucoma, and recent eye surgery can cause an abnormal dilated pupil.  The following is a list of etiologies for efferent pupillary defects:

Efferent Pupillary Defect Etiologies:

An abnormal dilated pupil could be alarming to an examiner because you must rule out third-nerve palsy from pharmacologic pupil dilation and traumatic dilated pupil.  A traumatic dilated pupil could be ruled out clinically by careful history and biomicroscopic examination.  A patient with traumatic iris sphincter damage will present with torn pupillary margin or iris illumination defects seen on biomicroscopic examination.  With a careful examination for ptosis and abnormal extraocular muscle restrictions, an examiner should also be able to differentiate third-nerve palsy from pharmacologic pupil dilation.  Furthermore, pilocarpine may help differentiate the pharmacologic pupil dilation from other causes of an abnormally dilated pupil, such as third-nerve palsy, tonic pupil and iris sphincter damage.  With a lower concentration of 0.125% pilocarpine, a tonic pupil will constrict significantly more than the unaffected pupil because of the denervation supersensitivity.  With a higher concentration of 1% pilocarpine, even third-nerve palsy related pupil will constrict.  If the dilated pupil fails to constrict with 1% pilocarpine, an examiner could localize the problem at the iris sphincter muscles. (Figure 4)  The cause of problems could arise from pharmacologic dilation (Figure 5), synechiae, iritis, and traumatic iris sphincter damage.      

  

Figure 4

Figure 4.  1 % pilocarpine testing.  Image from http://www.jeffmann.net/NeuroGuidemaps/anisocoria.htm

 

Figure 5

Figure 5.  Left pharmacologic mydriasis:  no response to light and near reflex in the left eye, the left pupil remains dilated after instillation of 1 % pilocarpine in the left eye.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5820&locale=en

 

Tonic Pupil


The tonic pupil is sometimes called Adie’s tonic pupil or Adie’s pupil.  Adie’s tonic pupil refers to an idiopathetic tonic pupil and the term is mistakenly overused.  Adie’s pupil is used when there is only tonic pupil without association of the diminished deep tendon reflexes of the knee and ankle (hyporeflexia).  The term Adie’s syndrome is applied when both tonic pupil and associated hyporeflexia are present. (10)  Most cases of the tonic pupil are idiopathic or caused by trauma; however, the tonic pupil can be caused by local disorders such as tumor, inflammation, trauma, surgery or infection within the orbit affecting the ciliary ganglion.  In addition, systemic (autonomic or peripheral) neuropathies such as diabetes, Guillain-Barre syndrome, Ross’ syndrome and Riley-Day syndrome can also cause tonic pupil. (7)  An acute tonic pupil in patients over 60 years of age warrants an erythrocyte sedimentation rate to rule out giant cell arteritis.      

Adie’s pupil is usually unilateral in 80% to 90% of cases and may become bilateral at a rate of 4% per year. (16)  Adie’s pupil results from damage to the ciliary ganglion or postganglion fibers of the short posterior ciliary nerves.  This subsequently leads to dilated pupil and anisocoria (greater in light illumination than dark illumination). (Figure 6)  It has minimal or no reaction to light but slow reaction to accommodative response due to damage to the parasympathetic innervation to the eye.  An intact near pupillary reflex is believed to be due to the ratio of fibers that control the near pupillary reflex is much greater as compared to those that control the light pupillary reflex.  Furthermore, preservation of the pupil constriction in accommodation may be result of accommodative fiber aberrant regeneration.  Some accommodative fibers formerly destined for the ciliary body now travel to the pupil becoming misdirected and supply the iris sphincter.  This is why a lesion in the ciliary ganglion or short ciliary nerves shows a light-near dissociation (Figure 7), even though both light and near innervation of the iris sphincter follow an identical final common pathway. 

 

Figure 6

Figure 6.  Left tonic pupil: greater anisocoria in light illumination (above) than dark illumination (below).  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5832&locale=en

 

Figure 7

Figure 7.  Right tonic pupil (light-near dissociation from aberrant degeneration):  the dilated right pupil (above) constricts slowly and progressively until it becomes slightly smaller (below) than the simultaneously constricted left pupil.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5833&locale=en

 

Adie’s Pupil:

Symptoms: 

Critical Signs:

Other Characteristics:

Pharmacologic testing:

Syphilis needs to be worked up if a patient is male, and has bilateral tonic pupils.  An examiner should order a specific (FTA-ABS) and non-specific treponemal (RPR) test.  While syphilis may infrequently cause the tonic pupil, late syphilis is more commonly associated with the Argyll Robertson pupil.  Adie’s pupil initially is dilated but may become miotic over time.  Thus, the tonic pupil may look like Argyll Robertson pupil.  The difference is that the Argyll Robertson pupils are not tonic.  The Argyll Robertson pupils constrict quickly to near response and redilate quickly when removed from the near stimulus.  

Pharmacological testing helps in the diagnosis of Adie’s tonic pupil.  In 80-90% of patients with Adie’s tonic pupil, 0.125% pilocarpine (Figure 8) or 2.5% methacholine causes denervation supersensitivity. (7)  The concentration is too weak to cause constriction of the normal pupil. 

Pharmacologic testing steps:

 

Figure 8

Figure 8.  Right tonic pupil:  dilated pupil with minimal reaction to light (above); the right pupil constriction (denervation supersensitivity) and no left pupil constriction with 0.125 % pilocarpine.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5831&locale=en

 

Clinical Pearls:

  1. With a higher concentration of 1% pilocarpine, even third-nerve palsy related pupil will constrict.
  2. Most cases of the tonic pupil are idiopathic or caused by trauma.
  3. An acute tonic pupil in patients over 60 years of age warrants an erythrocyte sedimentation rate to rule out giant cell arteritis. 
  4. Syphilis needs to be worked up if a patient is male, and has bilateral tonic pupils.    
  5. The tonic pupil is distinguished from other causes of light-near dissociation by the presents of TONIC near response. 
  6. Pharmacological testing, 0.125% pilocarpine or 2.5% methacholine causes denervation supersensitivity.

Oculomotor Nerve (CN III) Palsy with or without Pupil Involvement

It should be considered a neurosurgical emergency if a patient has anisocoria with acute onset of third-nerve palsy and associated with headache or trauma.  Third cranial nerve palsy generally presents with a complete or partial palsy with or without pupil involvement.  It also presents with a complete or partial ptosis, which may mask symptoms of diplopia.  Its clinical presentation depends on the location of the dysfunction along the pathway between the oculomotor nucleus in the midbrain and its branches of the oculomotor nerve.  The inferior branch of the oculomotor nerve supplies the medial and inferior rectus muscles, the inferior oblique, and the pupillary sphincter via parasympathetic pupillary pathway.  It is crucial to differentiate the cause of the third-nerve palsy.  The clinical challenge of third nerve palsy is to determine the etiology.  There are various differential diagnoses: ischemia, aneurysm, tumor, trauma, infection, inflammation or congenital anomalies.  The diagnosis and management of third-nerve palsy becomes critical when there is presence of pupil involvement (Figure 9).  Sparing of the pupil is an important diagnostic sign for ruling out a more serious etiology such as aneurysm or tumor.  Most pupil sparing cases are microvascular in origin such as diabetes or hypertension. 

 

Figure 9

Figure 9.  Third-nerve palsy with pupil involvement in the right eye:  the right pupil is non-reactive; complete ptosis, hypoexotropia, impaired adduction, elevation and depression in the right eye.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5830&locale=en

 

As a rule of thumb, a patient with sudden onset of painful third-nerve palsy with pupil involvement and no history of trauma or vascular disease should assume an intracranial aneurysm until proven otherwise.  The most common site of an intracranial aneurysm causing third-nerve palsy is the posterior communicating artery; however, the internal carotid artery and basilar artery aneurysms are reported to produce third nerve palsies as well. (17)  This is a life-threatening emergency because there is a potential of rupturing and leading to subarachnoid hemorrhage (within hours or days), so the patient needs emergency neurological imaging and hospitalization. 

In most cases, third-nerve palsy improved with resolution of diplopia and ptosis over several weeks to months.  If there is no improvement of third-nerve palsy within 3 months, an examiner needs to order imaging study to rule out intracranial aneurysm or mass.  Also, it is important to monitor and follow up third-nerve palsy patients daily for 5-7 days from the onset of third-nerve palsy to check for delayed pupil involvement.  There may be slow growing mass or aneurysm.   


Evaluation of the pupil in third-nerve palsy patients involve checking for anisocoria (asymmetry greater in light than in dark) and pupil light reflex.  If a pupil is involved, the pupil will be fixed, dilated and minimally reactive to light.  If a pupil is spared, the pupil is not dilated and has normal reaction to light.  It is also possible to have relative pupil sparing where the pupil is partially dilated and sluggish in light reflex.  If there is unilateral compression on the pupillary fibers of the acute third-nerve palsy, the affected side of the pupil will not response to both direct and consensual pupillary reflex with no accommodative response; however, the non-affected side pupil will response to both direct and consensual stimulation due to the parasympathetic pathway arrangements (bilateral innervation of E-W nuclei).


Aberrant regeneration of the third-nerve palsy may occur and cause pupil anomalies in 3 months.  Aberrant regeneration could result from trauma, aneurysm, tumor, congenital, but not in microvascular. (18)  A pseudo-Argyll Robertson pupil (light-near dissociation) may develop from the aberrant regeneration, which displays a fixed and dilated pupil.  The pupil will not react to light, but it will constrict on convergence due to misdirection of fibers from the medial rectus to the pupil.

Clinical Pearls:

Sympathetic Pupillary Defects


Sympathetic pupillary defects will occur if there is any disruption along the sympathetic pupillary fibers from hypothalamus to iris dilator.  The following are some of the causes of miotic pupils. 

Causes of Miotic Pupils:

Horner’s Syndrome (Oculosympathetic Paresis)


The clinical signs of Horner’s syndrome are miosis, ptosis, anhidrosis and apparent enophthalmos.  The etiology of Horner’s syndrome could range from benign to serious neurological conditions.  In one large case study, 40 % of cases of Horner’s syndrome had an unknown diagnosis.  In the remaining 270 patients, 13 % were related to a first-order (central) lesion, 44 % to a second-order (preganglionic) lesion, and 43 % to a third-order (postganglionic) lesion. (19)  The common etiologies of acquired Horner’s syndrome include but are not limited to (Table 1):  cerebral vascular accident, demyelination, tumor including thyroid adenoma and Pancoast tumor, tuberculosis, aortic dissection, trauma (neck/head including surgery), internal carotid dissection, herpes zoster virus, and headache syndrome (Cluster/migraine headaches). (18)


Table 1.  Causes of Horner’s syndrome.  Table modified from http://www.emedicine.com/oph/topic336.htm


First-order neuron lesions
  • Arnold-Chiari malformation
  • Basal meningitis (e.g., syphilis)
  • Basal skull tumors
  • Cerebral vascular accident (CVA)/Wallenberg syndrome (lateral medullary syndrome)
  • Demyelinating disease (e.g., multiple sclerosis)
  • Intrapontine hemorrhage
  • Neck trauma (e.g., traumatic dislocation of cervical vertebrae, traumatic dissection of the vertebral artery)
  • Pituitary tumor
  • Syringomyelia

 

Second-order neuron lesions

  • Pancoast tumor (tumor in the apex of the lung - most commonly squamous cell carcinoma)
  • Birth trauma with injury to lower brachial plexus
  • Cervical rib
  • Aneurysm/dissection of aorta
  • Subclavian or common carotid artery
  • Central venous catheterization
  • Trauma/surgical injury (radical neck dissection, thyroidectomy, carotid angiography, coronary artery bypass graft)
  • Chest tubes
  • Lymphadenopathy (Hodgkin disease, leukemia, tuberculosis, mediastinal tumors)
  • Mandibular tooth abscess
  • Lesions of the middle ear (e.g., acute otitis media)
  • Neuroblastoma

 

Third-order neuron lesions

  • Internal carotid artery dissection (associated with sudden ipsilateral face and/or neck pain)
  • Raeder syndrome (paratrigeminal syndrome) - Oculosympathetic paresis and ipsilateral facial pain with variable involvement of the trigeminal and oculomotor nerves
  • Carotid cavernous fistula
  • Cluster/migraine headaches
  • Herpes zoster

 

Patients with Horner’s syndrome are often asymptomatic, but sometimes they may complain of difference in the size of the pupils with droopy eyelid. (Figure 10)  The Horner’s pupil is miotic and the light and near pupillary reflex is intact.  In addition, the Horner’s pupil has a dilation lag in dark compared to the unaffected pupil.  This is due to a passive release of the sphincter muscles rather than active dilation from the pupillodilator muscles since it is damaged to the sympathetic nerve.  Other clinic features include a mild ptosis (less than 2mm) as a result of paralysis of the Muller’s muscle and anhidrosis if involves central and preganglionic neurons (first and second-order). 

 

Figure 10

Figure 10.  Right Horner’s syndrome:  miosis with approximately 2 mm of RUL ptosis.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5822&locale=en

 

It is important to take a good case history on Horner’s syndrome patients to help with the differential diagnosis of acquired Horner’s syndrome as mentioned above.  If a patient has Horner’s syndrome with other accompanying neurologic symptoms and signs, the patient should be referred for an emergent neurological work up including imaging studies.  It also helps to localize the lesion of the Horner’s syndrome from their associated neurologic symptoms and signs.  An isolated Horner’s syndrome accompanied by neck or head pain suggests an internal carotid dissection.  A Horner’s syndrome patient with arm pain and/or hand weakness suggests a lesion in the lung apex, Pancoast tumor.  If a patient has diplopia, vertigo, ataxia and lateralized weakness suggests brainstem localization.  A congenital Horner’s syndrome will present with heterochromia. (Figure 11)

 

Figure 11

Figure 11.  Right congenital Horner’s syndrome:  miosis, mild ptosis and hypochromic iris.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5821&locale=en

 

Horner’s Syndrome (Oculosympathetic Paresis)

Symptoms: 

Etiologies:

Critical Signs:

Other Characteristics:

Pharmacologic Testing:

Figure 12

Figure 12.  Left Horner’s syndrome:  under dark illumination, the right pupil noticeably dilates while the left pupil remains unchanged (below).  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5824&locale=en

 

Figure 13.  Left Horner’s syndrome:  enophthalmos, miosis and ptosis.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=4174&locale=en

 

Pharmacologic testing is used to confirm the diagnosis of Horner’s syndrome and to determine the location of the lesion in the sympathetic pupillary pathway. (Figure 14)  Cocaine is applied to confirm the diagnosis of Horner’s syndrome and hydroxyamphetamine serve to differentiate a preganglionic lesion (first and second-order neuron) from a postganglionic lesion (third-order neuron).  It was found in one of the clinical studies that 0.5 % apraclonidine could potentially be used in replace of 4 % or 10 % in confirming the diagnosis of Horner’s syndrome.  The study showed that all pediatric patients showed reversal of anisocoria (Horner’s pupil was larger than the normal pupil) under high ambient illumination after the instillation of apraclonidine (1 hour later) and the physiologic anisocoria patients showed no reversal of anisocoria. (20)  The dilation of Horner’s pupil is due to the denervation hypersensitivity of the postsynaptic alpha-1 receptor in the pupil dilator muscles. 

 

Figure 14

Figure 14.  Differentiation between physiological anisocoria and Horner's syndrome.  Image from http://www.jeffmann.net/NeuroGuidemaps/anisocoria.htm

 

The neurotransmitter released at the pupillodilator muscle fiber is norepinephrine and the Horner’s pupil has decreased output of norepinephrine in the synaptic cleft of the pupillodilator fibers.  Cocaine blocks the reuptake of norepinephrine at the sympathetic nerve synapse and causes pupillary dilation with intact sympathetic innervation.  Thus, 4 % or 10 % cocaine will cause pupillary dilation in normal pupils and no pupillary dilation in impaired sympathetic innervation, regardless of the lesion location (Figure 15).  It only confirms Horner’s syndrome, but does not differentiate the location of the lesion along the sympathetic pupillary pathway.  1% hydroxyamphetamine eye drops is instilled to distinguish the preganglionic lesion (first and second-order neuron) from the postganglionic lesion (third-order neuron). 

Hydroxyamphetamine releases stored norepinephrine from the postganglionic adrenergic nerve endings.  There is no pharmacologic test to differentiate between first and second-order neuron lesions.  In a preganglionic lesion, the pupils will dilate with 1% hydroxyamphetamine, whereas in a postganglionic lesion will not dilate. (Figure 16)  The test is positive for postganglionic Horner’s lesions when the post-anisocoria increases by at least 1 mm.  This has a sensitivity of 93-96 % and a specificity of 84 % for detecting postganglionic lesions. (19) 

 

Figure 15

Figure 15.  Right Horner’s syndrome:  the right pupil failed to dilate while the left eye dilated to 7 mm with 10 % cocaine.  Image from

http://www.atlasophthalmology.com/atlas/photo.jsf?node=5829&locale=en

 

Figure 16

Figure 16.  Left Horner’s syndrome with a postganglionic (third-neuron order) lesion:  the left pupil failed to dilated white the right eye dilated with 1% hydroxyamphetamine.  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5825&locale=en

 

Horner’s Syndrome (Oculosympathetic Paresis)

Pharmacologic Testing Steps:

Clinical Pearls:

Pupillary Light-Near Dissociation and the Argyll Robertson Pupil


In 1869, Douglas Argyll Robertson was first to describe several patients with tabes dorsalis, a manifestation of neurosyphilis, whose pupils reacted poorly to light with a normal near response. (1)  Light-near dissociation (LND) is an important finding that is common in patients with different pupillary anomalies. (Figure 6)  LND could be manifested due the anatomical arrangements of the light reflex fibers and near reflex fibers.  In the pupillary pathways, the near reflex fibers are more ventrally located than the light reflex fibers, thus the near reflex fibers are spared even with afferent light reflex fiber lesions.  It is important to note if the pupillary light-near dissociation is unilateral or bilateral and it’s associated ocular manifestations such as extra-ocular muscle abnormalities and nystagmus (Parinaud’s syndrome). (Figure 17)  

 

Figure 17

 

Today, light-near dissociation is used as a generic term that includes not only Argyll Robertson pupils, but pupils that has a poor light reaction with retention of the near response.   The following are the causes of LND: (21)

Figure 18

Figure 18.  Bilateral light-near dissociation caused by the dorsal midbrain syndrome:  moderately dilated pupils (above) with brisk near reflex (below).  Image from http://www.atlasophthalmology.com/atlas/photo.jsf?node=5834&locale=en

 

It is common to see miotic pupils in long-standing diabetic patients and usually they are difficult to pharmacologically dilate the pupils for fundus examination.  These patients may need to 2 sets of dilation drops (1% tropicamide and 2.5% phenylephrine) if they are not contraindicated.

Argyll Robertson Pupils


Argyll Robertson pupils are miotic pupils with irregular in shape.  It is usually bilateral, but asymmetric.  The light reflex is absent or very sluggish, but the near reflex is normal (light-near dissociation).  Tertiary syphilis is the most common cause of Argyll Robertson pupils.  An examiner must rule out tertiary syphilis with suspected Argyll Robertson pupils and should at least order a serum fluorescent treponemal antibody test.     

   

Argyll Robertson Pupils

Symptoms: 

Etiology: 

Critical Signs:

Clinical Pearls:

Summary table:


Pupil Anomalies

Anisocoria

Light reaction

Near reaction

0.125 % pilocarpine

4 % or 10% Cocaine

1% hydroxyamphetamine

1 % pilocarpine

Tonic pupil

(+)

(-) or minimal

(+)

(+)

No indication

No indication

No indication

Acute third-nerve palsy

(+)

(-)

(-)

No indication

No indication

No indication

(+)

Pharmacologic dilation

(+)

(-)

(-)

No indication

No indication

No indication

(-)

Horner’s Syndrome

(+)

(+)

(+)

No indication

(-)

(+) 1st or 2nd order neurons
(-) 3rd order neuron

No indication

Argyll Robertson pupils

(+)

(-)

(+)

No indication

No indication

No indication

No indication

 

Conclusion


It is imperative to proceed logically and systemically when examining the pupils.  Fully understanding the mechanisms of actions, neuroanatomy and physiology of the pupillary pathways should assist examiners in recognizing true emergencies from less serious conditions.  It also prevent from ordering invasive and costly testing.       

 

References

  1. Thompson H: The pupil. In: Hart MH, ed. Adler’s physiology of the eye. 9th ed. St Louis: Mosby, 412–441, 1992.
  2. Isenberg SJ, Molarte A, Vasquez M: The fixed and dilated pupils of premature neonates, Am J Ophthalmol 110: 168-71, 1990. 
  3. Lind N, et al: Adrenergic neurone and receptor activity in the iris of the neonate, Pediatrics 47: 105, 1971.
  4. Isenberg SJ, Dang Y, Jotterand V: The pupils of term and preterm infants, Am J Ophthalmol 108: 75-9, 1989.
  5. Pavan-Langston D: Neuroophthalmology: Visual Fields, Optic Nerve, and Pupil. Manual of Ocular Diagnosis & Therapy, 5th ed. St Louis: Williams & Wilkins, 394-397, 1992.
  6. Remington LA: Autonomic Innervation of Ocular Structures: Clinical Anatomy of the Visual System. 1st ed. Boston: Butterworth-Heinemann, 1998:  216.
  7. Slamovits TL, Glasser JS. The pupils and accommodation. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology (CD-ROM).  Philadelphia:  J.B. Lippincott, 1-24, 1998.
  8. Rosenberg ML, Olivia AO: The used of crossed polarized filters in the measurement of the relative afferent pupillary defect. Am J Ophthalmol 110: 62-65, 1990.
  9. Lam BL, Thompson HS, Corbet J: The Prevalence of simple anisocoria, Am J Ophthalmol 104: 69, 1987.
  10.   Skorin L. Jr, Muchnick BG: Neuro-ophthalmic Disorders.  In Bartlett JD, Jaanus SD, ed: Clinical Ocular Pharmacology, 4th ed. Boston: Butterworth-Heinmann, 433-452, 2001.
  11.   Cox TA: Pupillographic characteristics of simulated relative afferent pupillary defect, Invest Ophthalmol Vis Sci 30: 1127-1131, 1989.
  12.   Bergamin O, Kardon RH: Greater pupillary escape differentiates central from peripheral visual field loss, Ophthalmology 109: 771-780, 2002.
  13.   Firth AY: Pupillary responses in amblyopia, Br J Ophthalmol 74: 676-680, 1990.
  14.   Lam BL, Thompson HS: A unilateral cataract produces a relative afferent pupillary defect in the contralateral eye, Ophthalmology 97: 334-338, 1990.
  15.   Kolecki P: Toxicity, Sympathomimetic, emedicince.com 2003.
  16.   Thompson HS: Adie’s syndrome: some new observations, Trans Am Ophthalmol Soc 75: 587-626, 1977. 
  17.   Lustbader JM, Miller NR: Painless, pupil-sparing but otherwise complete oculomotor nerve paresis caused by basilar artery aneurysm, case report, Arch Ophthalmol 106: 583, 1988.
  18.   Rhee DJ, Pyfer MF. Neuro-ophthalmology: Isolated third-nerve palsy. In: Rhee DJ, Pyfer MF, eds. The Wills Eye Manual, 3rd ed. Williams & Wilkins, Philadelphia; 281-283, 1999.  
  19.   Maloney WF, Younge BR, Moyer NJ: Evaluation of the causes and accuracy of pharmacologic localization in Horner’s syndrome, Am J Ophthalmol 90: 394, 1980.
  20.   Chen PL, Hsiao CH, Chen JT, et al. Efficacy of Apraclonidine 0.5% in the Diagnosis of Horner Syndrome in Pediatric Under Low or High Illumination, Am J Ophthalmol 142: 469, 2006.
  21.   Nyman J. Pupillary Anomalies. In: Blaustein BH, eds. Ocular Manifestations of Neurologic Disease. Mosby, St. Louis; 71-93, 1996.

 


 

 

 

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