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History of the present illness
Medical decision-making/treatment
Algorithm number 1 - Smaller pupil = abnormal pupil
Algorithm number 2 - Larger pupil = abnormal pupil
| Introduction |
- anisocoria (pupillary inequality) can be due to serious pathology and a systematic approach is required to elucidate the diagnosis
- this guidemap will enable an ED physician to determine the likely cause of anisocoria, and allow for the expeditious and selective referral to the appropriate specialist
Emergency physicians, who do not have the time and/or the interest, to investigate the cause of anisocoria should immediately consult a neurologist for appropriate triage instructions + additional advice regarding timely diagnostic neuro-imaging studies
| History of the present illness |
- first try and determine if the patient is aware of the anisocoria, and when the patient first became aware of the anisocoria (? physiological vs acquired anisocoria – old photographs may be very useful in helping make this distinction)
- inquire about any previous eye/head injury (traumatic mydriasis) or eye surgery (glaucoma, cataract) or previous eye disease (iritis or glaucoma) which may have produced pupillary inequality
- determine whether the patient has any eye pain or discomfort or any visual changes
- eye pain + "red eye" + blurred vision + halo's around bright lights (angle-closure glaucoma)- inquire about headache or face pain or neck pain- eye pain + "red eye" + blurred vision (iritis)
- photophobia + difficulty with near-focusing (Adie's tonic pupil)
- peri-orbital pain, especially when moving the eyes + limitation of eye movements (cavernous sinus syndrome)
- headache + a dilated unresponsive pupil => ? aneurysm compressing the third cranial nerve- inquire carefully about possible eye contact or po ingestion of drugs/toxins- face or anterior neck pain + a miotic pupil => ? Horner's syndrome secondary to carotid artery dissection
- neck pain + neck swelling + hoarseness + miosis => ? Horner's syndrome secondary to thyroid or other malignancy
- lower neck or shoulder pain + miosis => ? Horners syndrome secondary to Pancoast's tumor at the lung apex
- cocaine or amphetamine powder- inquire about abnormal neurological symtoms- atropine eyedrops
- ipratropium or albuterol nebuliser solution
- scopolamine patches ("cruise ship" anisocoria)
- neosynephrine nasal sprays or eyedrops
- flea collar powders (anti-cholinesterases)
- focal weakness or sensory deficits(* Horner's syndrome may be associated with brain stem pathology, posterior circulation stroke syndromes, spinal cord pathology, or brachial plexus pathology; while 3rd cranial nerve dysfunction may be associated with other cranial nerve dysfunction - 2nd and 4th and 5th and 6th - when the lesion is in the cavernous sinus, superior orbital fissure or orbital apex)- dysarthria or dysphagia or diploplia
- ataxia or vertigo
- face paresthesia or hyperalgesia
| Examination |
- first examine the patient's pupils under normal room light conditions
(* the patient should stare into the distance to avoid the accomodation reflex constricting the pupils)
- then shine a bright light in each eye and determine whether both pupils respond to light (direct and consensually)
- then determine whether the anisocoria is greater in bright light or in the dark (shine an opthalmoscope's light beam - using a low intensity beam - tangentially across the front of the face with just enough illumination to be able to see the pupils when evaluating the pupillary response in the dark)
- evaluate the patient's accomodative pupillary response to near vision (patient looks at the end of his nose, or examiner's finger is brought in from below the level of the nose) to determine whether the patient has near-light dissociation
(* patients with an Adie's tonic pupil may have a delayed miotic response when accomodating during near fixation and it may take > 45 seconds for the pupil to constrict - there is also a re-dilation delay when the patient then quickly looks into the far distance => causing a temporary reverse anisocoria)
- check for visual acuity (impaired by ocular and orbital pathology affecting the optic nerve)
- check for any limitation of extra-ocular eye movements (or subtle diploplia in certain directions of gaze) due to pathology of the extraocular nerves (3rd, 4th and/or 6th cranial nerves)
- examine the anterior chamber and the iris and the pupillary responses with a slit lamp
- segmental paralysis of the iris => wiggling and undulating movements of the iris (Adie's tonic pupil, botulism)- measure the intra-ocular pressure (high pressure = glaucoma)- signs of iritis (posterior synechiae can cause a fixed and irregular pupil)
- narrow anterior chamber and cloudy cornea (angle-closure glaucoma)
- iris 'holes' or tears (trauma or previous surgery)
- check for ptosis
- ptosis is usually determined by checking how far the lower margin of the upper eyelid overlaps the superior edge of the cornea or by measuring (in mm's) the distance of the lower margin of the upper eyelid from the center of the pupil with the patient looking straight ahead (compare both sides)- check for any neurological dysfunction - cranial nerve dysfunction, focal sensorimotor deficits, dysarthria,- also check for reverse ptosis of the lower eyelid by comparing both eyes (lower eyelid ptosis occurs in ptosis secondary to Horner's syndrome and contributes to narrowing of the palpebral fissure => giving the impression of "apparent" enopthalmos)
- check for strength of the the levator palbebrae muscle by having the patient gently close the eye and then hold a ruler vertically across the front of the ipsilateral orbit => ask the patient to look upwards as much as possible (while holding the eyebrow in a fixed position by abutting the ruler against the eyebrow so as to prevent eyebrow elevation) => measure the amount of elevation of the lower margin of the upper eyelid in mm's (normal eyelid elevation = 12mm)
- decreased eyelid elevation suggests myopathic conditions (eg. myasthenia) or third nerve palsy, while the degree of eyelid retraction is normal in Horner's syndrome (even when ptosis is present)
cerebellar dysfunction (brain stem pathology, or vertebro-basilar artery insufficiency, or carotid artery dissection, or third cranial nerve compression syndromes, or cavernous sinus syndromes, or spinal cord syndromes)
- check for neck bruits (carotid artery dissection => Horner's syndrome) and neck masses (pressing on the sympathetic chain/stellate ganglion => Horner's syndrome)
| Medical decision-making |
Step 1:- The first decision that has to be made in a patient with anisocoria => which is the abnormal pupil?
- the abnormal pupil is the pupil that does not respond at all (or well) to direct bright light shone directly into the pupil
Step 2:- Secondly, determine when the anisocoria is greatest - in the dark or under bright light conditions
1) When the anisocoria is greater in bright light conditions => the larger pupil = the abnormal pupil
2) When the anisocoria is greater in the dark => the smaller pupil = the abnormal pupil
(* the results of step1 should be physiologically consistent with the results of step 2 when determining which is the abnormal pupil - the larger pupil (under bright room light conditions) also should not constrict in response to a direct bright light shone directly into the eye, and the smaller pupil (in dim light conditions) should still respond to bright light shone directly into the eye – sympathetic denervation does not alter pupillary reactivity to light)
- patients with local eye pathology (eg. iritis with secondary posterior synechiae) may have a 'fixed' pupil, which does not change in size in response to light or dark conditions
- use the following two algorithms - depending on which pupil is abnormal - to determine the cause of the anisocoria
Another approach is to only use the algorithms if the patient does not have opthalmologic anisocoria due to structural damage of the eye eg. iris damage which can be suggested by marked irregularity of the pupillary margin or unusual distortions of pupillary shape => the algorithm would then only be applied to structurally normal eyes with healthy irises
Algorithm number 1: For patients with a normal light reaction and whose anisocoria is greatest in the dark => the smaller pupil in the dark is the abnormal pupil (dilation problem with the smaller pupil)
- there are two major conditions to clinically differentiate:- physiological anisocoria and Horner's syndrome
- patients with physiological anisocoria have:-
- always less than 1.0 mm difference, and usually < 0.5mm difference, in size between the pupils (the amplitude of the difference may/may not vary greatly under dim or bright light conditions, but may vary in amplitude from hour-to-hour)
- pupillary constriction is normal to light and during near vision
- both pupils respond equally promptly to direct light, and the smaller pupil usually still dilates equally promptly in the dark
- occasionally the anisocoria may switch sides (called "alternating" or "seesaw" anisocoria)
- the patient with Horner's syndrome may also have ipsilateral upper and lower lid ptosis, or delayed eyelid elevation on testing, "apparent" enopthalmos with a narrowed palbebral fissure +/- ipsilateral hypohidrosis
- the upper lid ptosis is usually mild and can be voluntarily overcome if the patient uses the levator palpebrae and frontalis muscles, as these lid elevators are not innervated by the efferent oculosympathetic nervous system
(* the unilateral ptosis may not be readily noticeable in elderly patients with droopy upper eyelids)
- the lower lid ptosis is best detected by asking the patient to look slightly upward until the inferior corneal margin (limbus) of the eye with suspected Horner's syndrome is aligned on the lower lid margin => if sclera is visible between the inferior corneal and lower lid margin in the normal eye, then the lower lid in the suspected eye is ptotic (called "reverse" or "upside-down" ptosis)
- the degree of miosis varies considerably in patients with Horner's syndrome, because of variable factors
- the resting size of the pupils
- the completeness of the injury
- the extent of reinnervation of the pupillary dilator muscle
- the degree of denervation supersensitivity
- the concentration of circulating adrenergic agents in the blood eg. when the patient is anxious => increased adrenergic state => normal pupil is more dilated => anisocoria is more obvious
- the alertness of the patient eg. when the patient is fatigued or drowsy => diminished sympathetic outflow from the hypothalamus => normal pupil is less dilated => less obvious anisocoria
(* use topical ophthalmic anesthetic drops to first anesthetize the eyes because cocaine administration produces transient burning pain; only use 1 - 2 drops of 10% cocaine because cocaine is toxic to the corneal stroma)
- differentiation between pre-ganglionic Horner's syndrome and post-ganglionic Horner's syndrome is made by instilling two drops of hydroxyamphetamine hydrobromide (paredrine) eyedrops into the eyes and checking for a dilatory response, which only occurs in pre-ganglionic Horner's syndrome and normal pupils
(* because the test has to be performed >72 hours after the cocaine test, this test can be performed by a neuro-opthalmology specialist in the outpatient setting - paredrine can be obtained from Leiter's Park Avenue Pharmacy in San Jose, California 408-292-6772 or Thayer's Colonial Pharmacy in Orlando, Florida 407-896-7000)
- if hydroxyamphetamine hydrobromide is not readily available, a weak 1% solution of phenylephrine hydrochlodide can be used to demonstrate that the pupil in post-ganglionic Horner's syndrome has denervation sensitivity => the Horner's pupil will dilate and end up even larger than the normal pupil
(* denervation sensitivity does not occur acutely and may take 14 days to develop)
Differentiation between physiological anisocoria and Horner's syndrome
Clues to the cause of the Horner's syndrome are based on the location of the lesion
- Horner's syndrome + brain stem/cerebellar signs => suspect a brain stem or cerebellar stroke syndrome affecting the first neuron eg. Wallenberg' syndrome
(* a "central" Horner's syndrome affecting the first neuron does not respond to cocaine and the diagnosis must be made by the associated neurological signs - nearly always associated with pain and temperature loss on the opposite side of the body)
- Horner's syndrome + sensory and/or motor deficit of the limbs => suspect cervical spinal cord pathology affecting the first neuron
- Horner's syndrome + hoarseness => compressive lesion in the chest or neck affecting the second neuron and recurrent laryngeal nerve
- Horner's syndrome + paralysis of the ipsilateral phrenic, vagus and recurrent layngeal nerve => tumor behind the carotid sheath at the C6 level affecting the second neuron
All patients with an unexplained unilateral Horner's syndrome + face/head pain should be presumed to have a carotid artery dissection until proved otherwise
- the sympathetic nerves to the eye travel with the ophthalmic nerve (V1) and a lesion affecting V1 in the region of the orbit is also likely to affect to neighbouring nerves
- Horner's syndrome + cranial nerve 3 and/or 4 and/or 6 and/or V1/V2 dysfunction (and not affecting V3) => suspect cavernous sinus pathology
- Horner's syndrome + cranial nerves 3 and/or 4 and/or 6 and/or V1 (and not affecting V2 and V3) dysfunction => suspect superior orbital fissure pathology
- Horner's syndrome + cranial nerves 2 (optic nerve), 3, and/or 4 and/or 6 and V1 (and not affecting V2 and V3) dysfunction => suspect orbital apex pathology
- Horner's syndrome + optic nerve II dysfunction +/- incomplete cranial nerve 3 dysfunction (and not affecting cranial nerves 3, 4 and 6 and V2 and V3) => suspect posterior orbit pathology
- all patients with an asymptomatic, unexplained Horner's syndrome (especially if they have ipsilateral anhidrosis of the face and neck, which implies a preganglionic Horner's syndrome), who are going to be discharged from the ED for pre-arranged follow-up as an outpatient, should have a chest X-ray performed prior to ED discharge - to exclude a mediastinal or apical lung tumor (Pancoast's tumor) or thoracic aneurysm affecting the second neuron
(* central lesions involving the first neuron usually affect sweating
over the entire head, neck, arm and upper trunk on the same side - total
ipsilateral anhidrosis; lesions in the lower neck affect sweating
over the face - partial ipsilateral anhidrosis; while lesions above the
superior cervical ganglion in the upper neck may only affect sweating
of the forehead because the sympathetic fibres accompanying the internal
carotid artery to the eye do not contain postganglionic sudomotor fibres
to the face, which travel with the external carotid artery to the face
- the superior cervical ganglion is situated at the bifurcation of the
carotid artery in the upper neck)
| Causes of Horner's syndrome |
| Central | Preganglionic | Postganglionic |
| Hypothalamus
- infarct - tumor Brainstem
Cervical cord
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Cervico-thoracic spinal roots
- trauma - intramedullary or paravertebral tumor - syrinx - AVM - spondylosis - epidural anesthesia Lower brachial plexus
Pulmonary apex (under subclavian artery)
Anterior neck
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Superior cervical ganglion
- iatrogenic (tonsillectomy) - trauma Internal carotid artery
Base of skull/carotid canal
Middle ear
Cavernous sinus
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- further workup of a Horner's syndrome may include:-
Preganglionic Horner's syndrome - imaging (CT or MRI) of the neck and chest if brainstem signs are absent, neuroimaging of the head if brainstem signs are present
Postganglionic Horner's syndrome - head and neck MRI; angiography may be required if carotid artery dissection is a diagnostic possibility
Algorithm number 2: For patients with an abnormal light reaction and whose anisocoria is greatest in bright light conditions => the larger pupil is the abnormal pupil (constriction problem with the larger pupil)
- the pathology lies at 4 potential levels - i) the midbrain, ii) the pre-ganglionic parasympathetic pathway (ocolomotor nerve), iii) the post-ganglionic parasypathetic pathway (ciliary ganglion and ciliary nerves) or iv) the iris
- if the light reaction and the near-reaction are impaired to the same extent (no near-light dissociation) => iris problem (adhesions secondary to iritis or glaucoma) or oculomotor nerve palsy (preganglionic parasympathetic pathway problem) or secondary to an anti-cholinergic/sympathomimetic drug effect
- if the near reaction is markedly better than the light reaction (near-light dissociation) => post-ganglionic parasympathetic pathology (eg. Adie's tonic pupil) or a midbrain lesion limited to the pre-tectal area of the dorsal midbrain (Parinaud's syndrome)
- causes of Parinaud's syndrome include pinealomas, brainstem encephalitis, brainstem infarction and multiple sclerosis
- the pupil in Parinaud's syndrome is usually mid-sized with an absent light reflex, but retained near response; and the patient may variably have associated vertical gaze palsy, skew deviation of the eys, impaired vergence movements of the eyes, lid retraction and convergence-retraction nystagmus on attempted upgaze
(* usually both pupils are affected in Parinaud's syndrome and there may be no difference in pupillary size => anisocoria is therefore not frequently present)
- a patient with Argyll-Robertson pupils may also have near-light dissociation, but both pupils are usually small and similar in size and dilate poorly in the dark; anisocoria is not always present
(* a patient with Argyll Robertson pupils often has bilateral ptosis and marked overaction of the frontalis muscle to compensate => furrowed brow; the pupils are also often irregular in shape - horizontally or vertically ovoid, tear-dropped shape, serrated or eccentric)
Pupillary response to direct bright light
- further discrimination of a patient's pupil is based on first testing the affected pupil's response to dilute pilocarpine eyedrops (two drops of 0.1% solution = dilute the standard 1% solution 1:10 with water) => and then, if no response to dilute pilocarpine within 30 minutes => use standard dose (1% solution) pilocarpine eyedrops
- 0.1% pilocarpine eyedrops => pupillary constriction => suggests a tonic pupil (which has supersensitivity to dilute pilocarpine)
(* cholinergic supersensitivity exists if the larger pupil becomes the smaller pupil when observed in dim lighting, or if it constricts more than the normal pupil by 1.0 mm or greater; some patients with a 3rd cranial nerve dysfunction also have denervation hypersensitivity and respond to dilute pilocarpine (0.1% sol) in the same way => pupillary constriction)
- tonic pupils are divided into 3 subtypes:- local, neuropathic and Adie' syndrome
- a local tonic pupil may occur following inflammatory processes - herpes zoster, chicken pox, measles, scarlet fever, diptheria, syphilis, pertussis, viral hepatitis, sarcoidosis, lupus; or following blunt or penetrating injury of the globe
- a neuropathic tonic pupil occurs in patients with a generalized autonomic neuropathy eg. syphilis, chronic alcoholism, diabetes mellitus, paraneoplastic syndrome, Sjogrens syndrome, Shy-Drager syndrome and Ross syndrome (hyporeflexia + hypohydrosis + tonic pupil)
- Adie's syndrome consists of unilateral or bilateral tonic pupils +/- depressed deep tendon reflexes with no evidence of ocular pathology or autonomic neuropathy
(* slit lamp examination in Adie's syndrome may not only show segmental paralysis of the iris, but also 'vermiform' movements of the iris)
- if the pupil does not respond to 0.1% pilocarpine eyedrops => administer 1% pilocapine eyedrops
- patients with a 3rd cranial nerve palsy usually not only have a dilated pupil (which constricts in response to 1% pilocarpine eyedrops), but they usually have associated ptosis + extra-ocular muscle palsies
- mild oculomotor nerve EOM palsy may only manifest itself with slight diploplia in all directions of gaze (except laterally), while the patient with a complete oculomotor nerve EOM palsy will have an eye that is looking down and to the side on primary forward gaze
All patients with a new-onset 3rd cranial nerve palsy with pupillary involvement should be presumed to have a cerebral artery aneurysm until proved otherwise => require an expeditious MRI angiogram or four-vessel angiography (emergently if a headache is also present)
(* remember that a patient with an early 3rd cranial nerve palsy
secondary to aneurysmal compression may only have abnormal pupillary signs
- and no ptosis or EOM deficits - for the first few days)
| Findings | Light reaction | Near reaction | 1% pilocarpine |
| Tonic pupil | - | + | + |
| 3rd nerve palsy | - | - | + |
| Mydriatic eyedrops | - | - | - |
| Parinaud syndrome | - | + | + |
| Argyll Robertson pupil | - | + | + |
| Sympathomimetic drugs | (-) + | (-) + | + |
(* topical sympathomimetic drugs may also cause conjunctival blanching and eyelid retraction, and strong light can still induce a pupillary constrictor response; atropinic mydriasis may last 1 - 2 weeks and strong light may only induce a pupillary constrictor response when the drug effect is wearing off)
- if there is a ptosis of the eyelid on the side of the small pupil => the patient has a Horner's syndrome on that side
- if there is a ptosis of the eyelid on the side of the large pupil => the patient has a partial third nerve lesion on that side
- with a lesion in the region of the cavernous sinus, there may actually be a reversal of the anisocoria in going from dark to light as a result of unilateral involvement of both parasympathetic and sympathetic axons
- a patient with a very small unilateral miotic pupil, that does not decrease in size in response to direct bright light, or dilate in response to dim light => probably has unilateral pharmacolgical miosis secondary to a cholinergic glaucoma drug (eg. pilocarpine) or an anti-cholinesterase agent ("flea collar" anisocoria)
- a mydriatic pupil that does not respond to light may appear to be due to 3rd cranial nerve pathology, but it could just be a tonic pupil - the only difference between the two may be that the tonic pupil does eventually constrict slowly on prolonged near fixation
- a patient with uncal herniation causing a compressive 3rd cranial nerve palsy, always has some degree of impairment of LOC and is never fully alert
- a patient with "apparent" physiological anisocoria may have simple anisocoria secondary to the effect of certain drugs eg. pseudo-ephedrine or serotonin reuptake inhibitors, and the anisocoria (like physiological anisocoria) is also eliminated by the instillation of cocaine eyedrops
- blindness in one eye (even if total) never causes anisocoria
- retinal pathology (even if very severe) never causes anisocoria
Disclaimer: My EM guidemaps reflect my personal approach to problem-solving/managing clinical cases in an ED setting and they should not be regarded as the standard of care. They merely represent the personal opinions of the author and they should only be used in clinical practice if the reader-user has substantial reason to believe that the clinical advice contained in the guidemaps is valid and accurate. The guidemaps are not meant to be "authoritative" and the reader-user should consult standard medical textbooks and expert opinion articles/guidelines for more authoritative advice. The reader-user should particularly confirm all drug doses, their indications and contra-indications, prior to their use.