01 pupil 4-19-16 - nc state universityintrinsically photosensitive retinal ganglion cells (iprgc)...
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Comparative Neuro-Ophthalmology
Michael Davidson, D.V.M.Diplomate, American College of
Veterinary Ophthalmologists
Department of Clinical SciencesCollege of Veterinary MedicineNorth Carolina State UniversityRaleigh, North Carolina, USA
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Suggested Reading Webb A, Cullen C. Neuro-ophthalmology. In Veterinary
Ophthalmology. (5th ed) Gelatt KN ed. Wiley-Blackwell, Ames, Iowa, 1820-1896, 2013.
*Shamir MH, Ofri R. Comparative Neuro-ophthalmology. In Veterinary Ophthalmology, (4th ed). Gelatt KN ed. Blackwell Publishing, Oxford, UK, 1406-1469, 2007.
Visual System. In Veterinary Neuroanatomy and Clinical Neurology. Delahunta and Glass ed. Saunders and Elsevier. 2009, p 389.
Walsh and Hoyt’s Clinical Neuro-Ophthalmology: The Essentials. Miller NR, Newman NJ, eds. 7th Edition Williams and Wilkins, Philadelphia, 2007.
Scagliotti, RH. Comparative Neuro-ophthalmology. In Veterinary Ophthalmology (3rd ed) Gelatt KN ed. Lippincott, Williams and Wilkins, Philadelphia, 1307-1400, 1999.
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Neuroophthalmology
I. The PupilII. Visual PathwaysIII. Ocular MovementIV. Eyelid and Nictitans MovementV. Lacrimation
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Anatomic Pathways: Afferent Arm of PLR
Retina Optic nerve Optic chiasm Optic tract Pretectal nuclei CNIII
parasympathetic nuclei
Optic Nerve
Optic TractOptic
Chiasm
LGB
PTN
CNIII parasympathetic nuclei
Retina
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AFFERENT ARM OF PLR: RETINA:
rod/cone photoreceptors retinal bipolar cells retinal ganglion cells and axons
intrinsically photosensitive RGCs*
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Afferent Arm of PLR: Optic Chiasm optic nerve fibers converge at
chiasm species dependent differential
decussation (crossing-over) of fibers correlating with frontal position of eyes:- primate 50%- feline 65%- canine 75%- equine, bovine,
porcine 80-90%- rodents 97%- most
submammals 100%*
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Afferent Arm of PLR: Optic Tract
Post-chiasmal fibers:- ~80% of fibers synapse
in dorsal lateral geniculate body (LGB) (thalamus) = visual fibers
- ~20% of fibers bypass LGB:
• Many synapse in pretectal nuclei (PTN)
Optic tract
LGBPTN80%
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Intrinsically Photosensitive Retinal Ganglion Cells (ipRGC)
Subset of RCG (2%) that are photosensitive (melanopsin) Project to brain centers that control non-visual functions
including circadian related behavior (hypothalamus) and PLR (pretectal nuclei)
RGCs regulate acute changes in pupil size; ipRGC control sustained pupil size in response to environmental light levels
In normal retina, input to ipRGC predominately from rod/cones
ipRGC capable of generating PLR (and reportedly dazzle reflex) without rod/cone input, requires high intensity light in ~480nm wavelengths (blue)
Berson, DM, Dunn FA, Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002; 295: 1070-3.
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20% Optic Tract Fibers Bypassing Lateral Geniculate Body
Synapse in hypothalamus (base of diencephalon) to regulate circadian rhythm
Synapse in pretectal nuclei (at junction of diencephalon and tectum) to elicit PLR
Synapse in rostral colliculi (tectum):
- dazzle reflex- redirection of
gaze and movement of head and neck in response to visual stimuli
Synapse in rostral colliculi to project to the reticular activating system
(Thalamus)
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20% Optic Tract Fibers Bypassing Lateral Geniculate Body
Synapse in hypothalamus (base of diencephalon) to regulate circadian rhythm
Synapse in pretectal nuclei (at junction of diencephalon and tectum) to elicit PLR
Synapse in rostral colliculi (tectum):
- dazzle reflex- redirection of
gaze and movement of head and neck in response to visual stimuli
Synapse in rostral colliculi to project to the reticular activating system
(Thalamus)
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II
LG Body
PTN; R. Colliculus
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Afferent Arm of PLR: Pretectal Nuclear Fibers
at caudal commissure, some fibers stay ipsilateral, others cross over to contralateral CNIII nuclei, (second decussation proportional to first at chiasm):
• Unilateral afferent stimuli results in bilateral efferent effect…. basis for consensual PLR
• Humans:– 50% decussation at each
juncture– direct PLR = indirect PLR– no anisocoria in ambient light
with afferent arm defect • Sub-primate mammals:
– >50% decussation at each juncture
– “dynamic contraction anisicoria”
– direct PLR > indirect PLR– anisocoria with unilateral
afferent arm defect• Most submammals:
– 100% decussation– no indirect PLR
Central decussation CNII nuclei
PTN
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Efferent PLR Pathway Pupillomotor (preganglionic) fibers
originate parasympathetic nuclei of CN III (Edinger-Westphal nucleus), join with motor fibers of CN III
CNIII courses ventrally through midbrain, through cavernous sinus and out orbital fissure, diverge from motor fibers off ventral ramus of CNIII in orbital cone near ciliary ganglion
Orbital fissure
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Postganglionic Efferent Synapse in ciliary ganglion Short ciliary nerves
Dog = 5-8 short ciliary nerves….mixed fibers with parasympathetic, sensory afferent from CNV (nasociliary nerve)
Cat = 2 short ciliary nerves (malar and nasal), only parasympathetic
en.wikipedia.org
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Postganglionic, Parasympathetic Cat
medialmedial
laterallateral
Nasal N.Nasal N.
Malar N.Malar N.
Ciliary GanglionCiliary Ganglion
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Iris Musculature Neurophysiology
Mammals: - Smooth muscle - Sphincter mm = cholinergic (parasympathetic), through
short ciliary nerves; acetylcholine- Dilator mm. = adrenergic (sympathetic), through long ciliary
nerves; norepinephrine- Reciprocal innervation with inhibition of antagonist iris mm.
Most sub-mammals: - Skeletal muscle- Degree of voluntary control of pupillary movement- Parasympatholytic mydriatics not effective
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Ciliary Body Innervation and Accommodation
Efferent parasympathetic through CNIII, short ciliary nerves
Efferent sympathetic through long ciliary nerves (disaccomodation)
Longitudinal, radial, circular ciliary body mm.
Primates=cholinergic stimulation ciliary mm. contraction relaxation of zonules increased axial distance/curvature (disaccomodation occurs through adrenergic stimulation)
Carnivores (cat, raccoon, groundsquirrel)=accommodation through anterior change in lens position within eye (“translation” accommodation”, preponderance of longitudinal mm. in subprimate mammals)
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Other Pupillary Reflexes: Accommodation Reflex
“Accommodation-convergence reflex” or “near reflex”
Afferent = CNII Efferent = CNIII (also
inhibition of CN VI)
Stimuli = focusing on near object Effect =
- accommodation (change in lens shape)
- constriction of pupil (increase depth of focus)
- medial convergence of eyes (medial rectus with inhibition of lateral rectus)
Video
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Other Pupillary Reflexes: Ciliospinal Reflex (Pupillary-Skin Reflex)
Afferent = CNV Efferent = oculosympathetic pathway 1-2 mm dilation of the ipsilateral pupil in
response to pain applied to the ipsilateral neck, face, and upper trunk
Absent in Horner’s syndrome
Video
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Axon “Reflex” “Sensory activity ascends a branch of nerve until bifurcation,
then retrograde transmission, causing a neuroeffector response without passing through the brain stem or spinal cord” - Prodromic axoplasmic flow/transmission- Antidromic axoplasmic flow/transmission
www.zantag.com
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Axon “Reflex” - Reflex Uveitis stimulation of ophthalmic division of CN V (cornea,
conjunctiva, eyelids)- prodromic transmission until bifurcation at iris/ciliary body- antidromic transmission to iris/ciliary body
Effect = release of prostaglandins, substance P, vasoactive compounds, other inflammatory mediators, AcH
Outcome = miosis, ciliary body spasm, disruption of blood-aqueous barrier, ocular hypertension in some species
Bito, LZ. Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research. Exp Eye Res 1984 Dec;39(6):807-29
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Other Factors Modifying the Pupil and PLR
PLRs present at opening of eyelids, but may be sluggish until maturation of retina (28 days dog)
active = direct adrenergic input from psychosensory stimulation (fear)
passive = supranuclear inhibition of parasympathetic fibers of CN III- descending, inhibitory pathways from cortex to CNIII
parasymphathetic nuclei - this inhibition lost with sleep, anesthesia, opiodes,
extensive cerebral cortical lesion….resulting in miosis
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Evaluating Pupillary Light Reflexes Evaluate resting pupil size in room and dim light
Evaluate direct and indirect or consensual PLR (indirect = PLR to fellow eye…denote as “consensual response from OD to OS” or “…..OS to OD”):- in sub-primate mammals, direct PLR > indirect PLR- in most submammals, no consensual PLR due to complete
decussation at chiasm - note pseudo-indirect PLR in birds resulting from scatter illumination
from illuminated eye to non-illuminated eye eliciting a direct PLR
Swinging Flashlight Test and Cover/Uncover Test
Chromatic PLR testing (ipRGCs)
Dark adaptation testing
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Swinging Flashlight Test
Light alternately shifted from one pupil to other, with 2-3 seconds of direct stimulation in each eye
Normal...both pupils constrict to equal degree when stimulated, illuminated eye produces slightly more constriction
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Swinging Flashlight Test “Positive” test (Marcus-Gunn pupil)…illuminated eye
dilates:- “Relative Afferent Pupillary Defect” (RAPD)- unilateral prechiasmal lesion (optic nerve or retina) in humans- can be associated with either pre-and post-chiasmal afferent arm
lesions in sub-primate mammals
”Pupillary escape” (dilate slightly after initial contraction):- can be normal (adaptation of stimulated retina) - may result from incomplete unilateral, afferent arm lesion, results
from scatter illumination entering (fellow) normal eye, causing an initial indirect PLR
Therefore, “positive” test followed by “cover-uncover” test…(cover each eye with hand and ambient light is stimuli) to eliminate influence of scatter illumination
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©Webvision
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480 nm 630 nm
Slide Courtesy of Dr. Andras Komaromy
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Chromatic Testing of PLR Normal:
- Positive red light- Positive blue light
Photoreceptor disease (SARDS, PRA, acute retinal detachment)- Negative red light- Positive blue light
Retinal ganglion cell disease (optic neuritis, ON neoplasia, ON hypoplasia, ON avulsion)- Negative red light- Negative blue light
*White light contains all wavelengths in visible spectrum incl. blue….positive PLR with bright white light does not rule out photoreceptor disease
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Dark Adaptation Test
assessment of pupillary size after 5 minutes in dark
examine with direct ophthalmoscope at an arm’s distance, turned on immediately prior to assessment so as not to stimulate PLR
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Dark Adaptation Test normal = both pupils dilate fully and
symmetrically afferent and efferent lesions = both pupils dilate mechanical restriction problems (e.g. synechiae)
= affected pupil fails to dilate sympathetic denervation = affected pupil fails to
dilate, anisocoria accentuated by dark adaptation
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Afferent Lesion (before LGB)=vision AND PLR AND dazzle reflex abnormal
Efferent Lesions=PLR abnormal, vision and dazzle reflex normal
Cortical Lesion=Vision abnormal, PLR and dazzle reflex normal
Cortex
General Principles of Lesion Localization
*objective assessment of vision and PLR*partial lesions*ipRCGs
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Unilateral Retinal Chain, Intraocular Retinal Ganglion Cell Lesions
anisocoria in ambient light with larger pupil ipsilateral to lesion (subprimate mammals)
deficit of direct and consensual PLR in affected eye
positive swinging flashlight test and cover-uncover test
normal dark adaptation test
visual deficits
*PLRs and dazzle reflex may persist with advanced (outer) retinal disease with visual deficits (ipRCGs)
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Unilateral Prechiasmal Optic Nerve Lesions
signs identical to retinal disorders
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Unilateral Optic Tract Lesions (Anterior to Lateral Geniculate Body)
similar to unilateral prechiasmal lesion but dilated pupil contralateral to lesion
more subtle anisocoria v. prechiasmal lesion
positive swinging flashlight test contralateral to lesion (*see notes for proof, B. Blacklock)
more miotic pupil persists in the same eye (ipsilateral to lesion) regardless of which eye is stimulated
visual field contralateral to affected tract is diminished or lost - contralateral homonymous
hemianopia (vision loss most obvious in eye contralateral to lesion)
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Bilateral Retina, Optic Nerve or Tract, Optic Chiasm or Caudal Commissure Lesions
bilateral mydriasis, PLR deficits, visual deficits commiserate with severity of lesion
lesions in both retinas more common than (>) chiasm > bilateral optic nerves > bilateral caudal commissure > bilateral optic tracts
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Efferent Arm Lesions ipsilateral dilated pupil,
anisocoria often more pronounced than afferent arm lesion
nonreactive (ipsilateral) pupil to direct and indirect light….i.e. negative direct PLR, negative consensual PLR from normal eye to affected eye (side)
normal dark adaptation test
normal optic dazzle reflex and menace response
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Efferent Arm Lesions Preganglionic (ciliary ganglion):
- in non-humans, almost always CNIII motor and pupillomotor (total ophthalmoplegia)
Postganglionic:- pupillomotor fibers only
(internal ophthalmoplegia) as motor fibers diverge from pupillomotor fibers in orbit shortly before ciliary ganglion
- hemipupil in cats if affecting only one short ciliary nerve
- supersensitivity to parasympathomimetics
ciliary ganglion
CNIII
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Internal Ophthalmoplegia “Impairment of pupillary function (sphincter
m, atropine, parasympathetic innervation) Parasympathetic efferent denervation
(pupillomotor fibers), ocular movement (motor fibers) unaffected
Almost always post-ganglionic, often idiopathic and self-resolving (analogous to “Adie Tonic Pupil” in humans)
D or Reverse D shaped pupil in cats if only one short ciliary artery affected
Pupillomotor fibers superficial (medial) and smaller in diameter in CNIII- In humans, may be preferentially
affected with compressive lesions (e.g. aneurism)
- In humans, preferentially spared with microvascular diseases (e.g. diabetes, hypertension)
www.vettimes.co.uk
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External Ophthalmoplegia
motor denervation of CNIII In dogs/cats, isolated
external ophthalmoplegia (without pupillomotor signs) is rare, associated with discrete central lesions affecting (motor) nucleus of CNIII
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Total Ophthalmoplegia internal and external ophthalmoplegia by definition, a preganglionic lesion (re: ciliary ganglion),
- generally, intracranial lesion, as pupillomotor and motor fibers of the ventral ramus of CNIII diverge about mid-orbit
- i.e. intraorbital cause of total ophthalmoplegia uncommon and caused by lesion in caudal orbit
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Pharmacologic Localization of Lesions of Autonomic Innervation to Eye
Direct testing stimulates receptor
Indirect testing affects release or reuptake of neurotransmittor
Direct testing stimulates receptor
Indirect testing affects release or reuptake of neurotransmittor preganglionic postganglionic
Parasympathetic
Sympathetic
Effector
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Limitations/Caveats in Pharmacologic Testing for Autonomic Disorders
requires normal, control eye quantity of absorbed drug affected by volume,
corneal epithelium, etc. prior drug action (wait 24 hours minimum)
acute lesion, denervation hypersensitivity may not have yet developed
partial lesions, partial denervation hypersensitivity
pre-ganglionic lesion, partial denervation hypersensitivity
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Pharmacologic Testing with Parasympathetic Denervation
denervation hypersensitivity > with ganglionic or postganglionic lesions
0.5% physostigmine (indirect parasympathomimetic, allows buildup of acetylcholine at synaptic fissure):
• postganglionic = no constriction (no AcH at synaptic fissure)
• preganglionic = constriction before normal, control eye (basal release of AcH occurs, partial denervation hypersensitivity)
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Pharmacologic Testing with Parasympathetic Denervation
2% pilocarpine (direct parasympathomimetic):• 24 hours post indirect agent testing• postganglionic lesion constricts sooner than
normal eye• preganglionic lesion constricts similar timeframe
to normal eye**
some clinicians use 0.05% pilocarpine, no effect on normal eye
failure to respond to both tests indicates pharmacologic blockade or iridal disease (atrophy, synechia)
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Oculosympathetic Pathway
sympathetic efferent:- central- preganglionic- postganglionic
Cranial cervical ganglion
Cervical sympathetic trunk
Iris dilator mm.
Thoracic spinal cord T1-T3
Lateral tecto-tegmental tract
Cervical spinal cord
A. Iris sphincter mm.
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Efferent Sympathetic Pathway: 1st Order Neurons
sympathetic fibers arise from hypothalamus lateral tectotegmentospinal tract descend ipsilaterally through brain stem
and lateral funiculus of spinal cord synapse in preganglionic cell bodies in gray
matter of intermediolateral column of spinal cord T1-T4
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Efferent Sympathetic Pathway: 2nd Order Neurons
rami communicans through ventral roots thoracic sympathetic trunk cervicothoracic and middle cervical
ganglia, cervical sympathetic trunk synapse in cranial cervical ganglion
(caudomedial to tympanic bullae) with postganglionic sympathetic neurons
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Efferent Sympathetic Pathway: 3rd Order Neurons
postganglionic fibers join tympanic branch of CN IX (glossopharyngeal n.) to form caroticotympanic nerves
over promontory of middle ear exit middle ear and enter cavernous sinus join CN V most fibers pass through ophthalmic division of CNV, to
nasociliary nerve (to levator mm., smooth mm. of orbit) and then continue into globe via the long ciliary neve in the suprachoroidal space to iris dilator m.
some fibers through maxillary division of CNV to infraorbital/zygomatic nerve to supply lower eyelid and nictitans
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Efferent Sympathetic Pathway: 3rd Order Neurons
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Horner Syndrome
protrusion of nictitans ptosis miosis enophthalmos
cutaneous facial and cervial hyperthermia and decreased sweating (peripheral vasodilitation)
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Efferent Sympathetic: Horner Syndrome
cutaneous facial and cervical hyperthermia and conjunctival hyperemia (peripheral vasodilation)
anisocoria (dark adaptation, and excitement accentuate)
ptosis and “reverse ptosis”
enophthalmos variably present……narrowed palpebral fissure (ptosis and reverse ptosis) creates impression of “apparent” enophthalmos even if not present
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Horner Syndrome in Large Animals signs more subtle than dogs/cats ptosis most consistent finding, miosis inconsistent ipsilateral cutaneous facial and cervical hyperthermia
cattle = ipsilateral lack of sweating (anhydrosis, detected in nose), vascular engorgement of pinna (sweating mediated by alpha adrenegic receptors)
horse = ipsilateral facial sweating (vasodilatation and increased blood flow from decreased vasomotor tonus)- entire ipsilateral head and body = first order lesion- ipsilateral head and neck = second or third order lesion
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Pourfour du Petit Syndrome
Mydriasis, widened palpebral fissure, exophthalmos (opposite of Horner)
Oculosympathetic hyperactivity (irritative lesion)
Reported in 3 cats following ear flushing
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Pharmacologic Testing for Horner Syndrome
6% cocaine…blocks reuptake of norepinephrine- no mydriasis confirms Horner’s syndrome
1% hydroxyamphetamine…causes norepinephrine release- postganglionic = no or incomplete mydriasis- preganglionic = normal mydriasis
10% phenylephrine- hypersensitivity with postganglionic- mydriasis in 5-8 minutes- retraction of nictitans and resolution of ptosis also
occurs- some clinicians use 1% phenylephrine
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Apraclonidine (0.5-1%) Testing
Used in lieu of cocaine to establish diagnosis of Horner syndrome in humans
Strong alpha 2 agonist, weak alpha 1 agonist, produces slight miosis in normal human eye
Denervation hypersensitivity causes proliferation of alpha-1 receptors in the dilator muscle
The denervated pupil dilates, slight miosis in normal eye Reportedly does not distinguish pre vs. post ganglionic
lesion
Apraclonidine induces moderate mydriasis (30%) in normal dogs, moderate miosis in normal cats
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Localization of Pupillary Abnormalities First rule out non-neurologic conditions:
- psychosensory stimulation- axon reflex or anterior uveitis- mechanical iris lesion (e.g. glaucoma, lens luxation) - structural iris lesion (e.g. synechia or iris atrophy)- pharmacologic blockade
If neurologic disorder, define effects on:- pupillary diameter or shape- pupillary light reflex using swinging flashlight test- response to dark adaptation testing
Concurrently evaluate:- menace response and dazzle reflex (localizing for afferent arm lesion)- ocular position and motility (motor deficit CNIII, using vestibulo-ocular reflex and
redirection of gaze)- funduscopic exam- complete cranial nerve and neurologic exam
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Special Notes on Pupil Size and PLR and Intracranial Lesions
Cerebellar lesions may cause unilateral (contralateral) or bilateral mydriasis with normal PLR
Acute cerebral or brainstem swelling may cause ipsilateral or bilateral mydriasis/PLR deficit from compression of CNIII
Extensive cerebro-cortical lesion may be associated with bilateral miosis (loss of supranuclear inhibition of CNIII)
Experimental rostral colliculi lesions in dogs associated with bilateral miosis
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Feline Spastic Pupil Syndrome
Inconsistent or alternating anisocoria which persist with dark adaptation
FeLV neuritis of sympathetic, parasympathetic or both
Risk factor for development of lymphoproliferative disease
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Feline Dysautonomia (Key-Gaskell Syndrome)
Idiopathic, diffuse polyneuropathy of autonomic nervous system (r/o toxic or environmental)
Mydriatic, unresponsive pupils Anisicoria Prolapsed nictitans Decreased tear production
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Questions?
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Index: Summary of Localization of Pupillary Abnormalities
Anisocoria- unilateral mydriasis- unilateral miosis
Bilateral mydriasis Bilateral miosis
Adapted from Shamir MH, Ofri R. Comparative Neuro-ophthalmology. In Veterinary Ophthalmology, Gelatt KN ed. Blackwell Publishing, Oxford, UK, 1406-1469, 2007.
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Anisicoria: Unilateral Mydriasis
Efferent arm lesions:- more obvious anisocoria than afferent arm lesion- absent direct PLR, normal indirect PLR from
affected eye to fellow eye- concurrent external ophthalmoplegia if intracranial
lesion- may have “D” and “reverse D” in cat if
postganglionic- supersensitivity to parasympathomimetics esp. if
postganglionic
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Anisicoria: Unilateral Mydriasis
Afferent arm lesions:- less obvious anisocoria (from bilateral afferent
input)- absent direct PLR and indirect PLR from
affected eye/side to fellow eye if prechiasmal- more mydriatic pupil and PLR deficit
contralateral to lesion if postchiasmal (optic tract)- positive swinging flashlight test with pre and post
chiasmal lesion in dogs/cats (only with prechiasmal lesion in humans)
- menace response and dazzle reflex deficits
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Anisicoria: Unilateral Mydriasis
Cerebellar lesions- generally contralateral mydriasis +/-
ipsilateral nictitans protrusion- both pupils respond to light stimuli
Acute cerebral swelling- ipsilateral mydriasis from compression of
CN III
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Anisicoria: Unilateral Miosis
Efferent sympathetic- ipsilateral miosis
- anisocoria accentuated by dark adaptation
- further constriction on light stimulation
- other clinical findings of Horner’s syndrome
- pharmacologic localization
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Localizing Horner’s Syndrome with Other Neurologic Signs
cervical spinal cord= tetraparesis
C6-T2 spinal segments = forelimb monoparesis with reduced spinal reflexes
cervical sympathetic trunk = no other deficits
inner/middle ear = possible CN V, VI, VII, VIII, IX deficits
cavernous sinus = possible CN III, IV, V, VI deficits
retrobulbar space = concurrent parasympathetic denervation, possible CN II, III, IV, V, VI
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Bilateral Mydriasis
Bilateral afferent- retinal disease more common than (>) optic
chiasm > bilateral optic nerve > bilateral optic tract
- concurrent menace/dazzle deficits Bilateral efferent
- bilateral CNIII rare- e.g. brainstem lesions affecting
parasympathetic nucleus of CNIII
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Bilateral Miosis
Loss of supranuclear inhibition of CNIII- Sleep, opioids, general anesthesia- Extensive cerebral cortical lesion
Experimentally, reported with rostral collicular lesions in dogs