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Home , Anisocoria, Miosis, Mydriasis, Synechia (eye)

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The Practitioner’s Guide to NEUROLOGIC CAUSES OF CANINE Heidi Barnes Heller, DVM, Diplomate ACVIM (), and Ellison Bentley, DVM, Diplomate ACVO University of Wisconsin–Madison

Anisocoria is defi ned as asymmetry, photoreceptors. This information travels along and may be seen with ocular or neurologic cranial nerve (CN) II via the optic chiasm to the dysfunction (Figure 1).1 When anisocoria is optic tracts and then the LGN. Optic radiations caused by neurologic , unequal pupil size relay the visual information from the LGN to the may result from malfunction of the sympathetic, occipital cortex. In dogs, about 75% of parasympathetic, or visual systems. fi bers cross to the opposite cerebral cortex at the When evaluating patients with asymmetric , optic chiasm.1 the practitioner needs to: 1. Determine whether one or both pupils are Parasympathetic Function: Pupil Constriction abnormal in size The parasympathetic pathway to the (Figure 2. Localize the lesion responsible for anisocoria. 3, page 78) is a short, 2-neuron pathway Relevant to refers to smaller than normal pupil size, that originates in the . The paired while refers to larger than normal pupil size. parasympathetic nuclei of cranial nerve III (PSN Anisocoria CN III), along with the somatic nerves from the CN II Optic nerve NEUROANATOMY (CN III), send fi bers—called fi rst CN III Oculomotor Visual Pathway order neurons, or preganglionic fi bers—to the eye. nerve The visual pathway (Figure 2 ) is composed of the After synapsing in the , the short, PSN Parasympa- CN III , optic nerve (also known as cranial nerve II), postganglionic fi bers course to the sphincter thetic nucleus lateral geniculate nuclei (LGN) in the thalamus, and muscle and cause pupil constriction. of cranial nerve III occipital cortex in the cerebrum. (previously When enters the eye, it activates the retinal Edinger- Westphal nucleus) CN V Trigeminal nerve CN VII Facial nerve

FIGURE 2. Visual pathway from the ventral aspect of the brain. The blue and orange lines represent visual fi elds from each eye. White FIGURE 1. Representation of a dog with arrow—optic chiasm. Black arrows—lateral anisocoria. geniculate nuclei in the thalamus.

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• The second order neuron exits the spinal cord between T1 and T3, courses cranially through the thoracic cavity, out the thoracic inlet, and along the jugular groove to the cranial cervical ganglion. • The third order neuron exits the cranial cervical ganglion, runs through the middle ear, then

TABLE 1. Anisocoria of Neurologic Origin: Key Neurologic Tests LESION NORMAL LOCALIZATION TEST FIGURE 3. The parasympathetic pathway. The REACTION (if abnormal fi rst order neuron is depicted in orange and the response) second order neuron is depicted in yellow. Visual Pathway Menace Blinking of • Cerebellum The parasympathetic pathway is best assessed response • Cerebrum using the pupillary light refl ex (PLR): • CN II • CN VII • When a bright light enters the eye, a proportion • Eyelid of crossed CN II fibers enter the pretectal nucleus • (exoph- in the midbrain to synapse with neurons which, in thalmos) turn, synapse with efferent parasympathetic fibers • Retina* • Thalamus in PSN CN III. Visual Following a • Brainstem • These parasympathetic fibers transmit this tracking soundless, • Cerebrum information to the eye, resulting in pupillary (cotton odorless object • CN II constriction. ball test) with /head • Retina • A relay between the paired PSN CN III in the Pupillary Pupil constriction • CN II midbrain results in indirect (or consensual) PLR. light refl ex with direct bright • CN III • Clinically, this can be observed when a bright light • Iris • Midbrain light is shone in one eye and the opposite eye also • Retina constricts. The degree of constriction is lesser in the opposite eye. Sympathetic Pathway Dark room Dilation of pupil • CN II • Iris Sympathetic Function: Pupil Dilation • Retina The opposing system is the sympathetic system, • Sympathetic which is responsible for pupillary dilation. The pathway

sympathetic pathway (Figure 4) is a 3-neuron Parasympathetic Pathway pathway that takes a longer course to the eye Pupillary Ipsilateral and • Brainstem compared with the parasympathetic system. light refl ex contralateral • CN II • Sympathetic function originates in the hypothalamus pupil constriction • CN III of the brain and courses as the first order neuron with direct bright • Iris light • Optic chiasm through the brainstem and cervical spinal cord to • Retina thoracic spinal cord segments T1 to T3. Swinging Ipsilateral and • CN II light test contralateral • Retina (indirect) pupil In a patient with left eye miosis, left thoracic limb paresis, and absent constriction with to decreased left thoracic limb refl exes and postural reactions, the bright light as it practitioner would localize the lesion to a site that would affect all these is quickly moved between eyes structures simultaneously. In this patient, loss of left brachial plexus function and sympathetic innervation to the left eye could be explained by * An unobstructed or minimally obstructed optical pathway is required for menace response. For example, lenticular pa- a single lesion at the brachial plexus, which is located between spinal cord thology may obstruct the patient’s visual eld suf ciently to segments C6 and T2. reduce the response to menace. Maze test or visual tracking may be useful in this situation.

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in a comparatively miotic pupil, which results from failure of the iris to dilate in reduced ambient light, typically accompanied by , , and third eyelid protrusion over the .

LESION LOCALIZATION Neurologic Examination The neurologic examination allows the practitioner to localize the lesion to the visual, sympathetic, or parasympathetic pathways (Table 1). Since each neurologic test has a sensory (afferent) and a motor (efferent) component, the examiner must determine which component is affected. Table 2 lists the tests most commonly used to evaluate the neuro-ophthalmic system. A detailed description of how to perform each test can be found elsewhere.2

FIGURE 4. The sympathetic pathway. The fi rst Pharmacologic Testing order neuron is depicted in purple, the second Pharmacologic testing can aid the practitioner order neuron is depicted in blue, and the third with lesion localization within the sympathetic or order neuron is depicted in teal. parasympathetic system. (0.5%) is a cholinesterase alongside the ophthalmic branch of the trigeminal inhibitor and, thus, requires an intact postganglionic nerve (CN V), and ends in the periorbital neuron to induce miosis. muscles, third eyelid, and iris dilator muscles. • Topical administration differentiates between pregan- Dysfunction anywhere along this pathway results glionic and postganglionic parasympathetic lesions.

TABLE 2. Lesion Localization for a Dog with Anisocoria PUPILLARY LIGHT VISUAL DARK ROOM LESION LOCATION MENACE REFLEX MENTATION TRACKING (Pupil Dilation) (Direct & Indirect) Direct (−) Iris + + − Normal Indirect (+) Retina − − − − Normal CN II − − − − Normal Thalamus − − + + Abnormal − ± + + Abnormal CN VII − + + + Normal Cerebellum +/− + + + Normal Normal or First sympathetic neuron + + + − abnormal Second sympathetic + + + − Normal neuron Third sympathetic + + + − Normal neuron First parasympathetic Normal or + + − + neuron abnormal Second parasympathetic + + − + Normal neuron

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• When administered to both eyes, if a parasympathetic system. preganglionic lesion is present, it causes (relative • Animals with ocular parasympathetic dysfunction to the normal eye) rapid pupil constriction. have rapid pupillary constriction following the • In a normal eye, administration of physostigmine administration of . (and pilocarpine, below) causes slow or delayed • Those with iris atrophy demonstrate only partial constriction of the pupil. constriction. Dilute pilocarpine (0.2%−1% solution) is a • Posterior results in no or minimal parasympathomimetic alkaloid that may be used response to pilocarpine, but the patient should to differentiate iris atrophy and other lesions of the also have a dyscoric pupil and other signs of past iris, such as posterior synechia, from a lesion of the or current inflammation.

TABLE 3. Differential Diagnoses Using the DAMNITV Schema

CAUSE LOCATION AFFECTED AFFECTED PUPIL SIZE

Degenerative Intervertebral disk herniation Cervicothoracic cord Miosis Iris atrophy Iris Mydriasis

Anomalous Hydrocephalus Cerebrum, thalamus Miosis or mydriasis

Metabolic Hepatic encephalopathy Cerebrum, thalamus Miosis

Nutritional Thiamine Cerebrum, brainstem Miosis or mydriasis

Neoplastic Neoplasia Any Miosis or mydriasis

Infectious/Infl ammatory Meningitis and encephalitis Intracranial structures, optic nerve Miosis or mydriasis Myelitis Cervicothoracic cord Miosis Iris sphincter Miosis Middle ear infection Second order sympathetic neuron Miosis

Idiopathic Iris sphincter, CN II Mydriasis Sympathetic dysfunction Sympathetic pathway Miosis Dysautonomia Parasympathetic or sympathetic Mydriasis pathway

Traumatic Head trauma CN II, cerebrum, thalamus, brainstem Miosis or mydriasis Brachial plexus avulsion Brachial plexus Miosis Jugular venipuncture Second order sympathetic neuron Miosis Aggressive deep ear fl ush Third order sympathetic neuron Miosis Neck trauma secondary to choke Second order sympathetic neuron Miosis chain or strangulation

Vascular Ischemic brain disease Cerebrum, thalamus Miosis Fibrocartilagenous embolism Cervicothoracic cord Miosis

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consensual (indirect) refl ex in the contralateral eye should be normal.

Neoplasia Neoplasia may occur anywhere throughout the central or peripheral nervous system.

Intracranial Neoplasia The most common intracranial neoplasm in dogs and cats is meningioma. Anisocoria may result from disruption of either the afferent or efferent pathways of pupil innervation. Meningioma routinely occurs in the CN II, cerebrum, brainstem, and spinal cord. FIGURE 5. A 9-year-old, castrated male Glioma, lymphoma, peripheral nerve sheath tumors, dachshund exhibiting anisocoria secondary to and cranial thoracic masses may cause anisocoria but iris atrophy of the right eye. are less common.

• Pilocarpine can cause mild uveitis, resulting in Iris & Neoplasia blepharospasm, redness, and aqueous flare for up Neoplasia of the iris and ciliary body can also cause to 24 hours after administration. anisocoria, through -mediated uveitis Dilute (1%) can be used to test (miosis), secondary glaucoma (mydriasis), synechia the sympathetic system. formation (miosis, mydriasis, or dyscoria), or mass • When applied topically to both eyes, it should infi ltration of the iris with subsequent physical cause rapid (typically 20 minutes or less) dilation obstruction of the pupil. in an eye with a postganglionic sympathetic neuron dysfunction. Idiopathic • Administration in the normal eye has no effect. Sympathetic Dysfunction Approximately 50% of dogs with sympathetic DIFFERENTIAL DIAGNOSIS dysfunction (commonly termed Horner’s syndrome) 3 Lesion localization permits the clinician to assemble are diagnosed with idiopathic dysfunction. The an appropriately ranked list of potential causes lesion may be located in the second or third order (Table 3). Common differential diagnoses are sympathetic neuron based on pharmacologic discussed below using the DAMNITV schema. testing.4-6 No treatment is indicated for these animals and many spontaneously recover.6 Iris Atrophy Iris atrophy—thinning of the iris stroma, especially Dysautonomia at the pupillary margin where the iris sphincter Dysautonomia is an idiopathic disease that affects muscle is located—is a common fi nding in older both branches of the autonomic system. Risk factors dogs. This condition may result in anisocoria and/ for development of dysautonomia include young to or PLR abnormalities if dysfunction of the sphincter middle age, medium to large breed dogs, and living muscle is notably asymmetric (Figure 5). in rural housing.7 Diagnosis is made by careful examination of the Many affected animals are visual, but demonstrate pupillary margin. mydriasis with absent PLR, along with other systemic • Iris atrophy appears as scalloping along the edge signs of autonomic dysfunction. Dysautonomia is of the pupil and/or thinning of the tissue, which not treatable; therefore, humane euthanasia is usually allows light reflected from the tapetum to pass recommended due to poor quality of life. through the translucent, atrophied areas. • In very early iris atrophy, loss of the iris stroma Infectious/In ammatory may expose the posterior pigmented epithelium Otitis Media of the iris, resulting in the darker areas in the Otitis media accounts for 1% to 4% of the cases of pupillary margin, which are actually iris atrophy. sympathetic dysfunction in dogs and cats.3,8 While A direct PLR will be slow or absent, while the management of otitis is important, miosis often persists.

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Uveitis prognosis varies depending on the cause of the Uveitis (intraocular infl ammation) can also cause infection. anisocoria. Although this can occur as a result of iridal swelling, more commonly, Glaucoma active within the eye during acute infl ammation act Glaucoma (increased ) can cause directly on the to cause miosis. a unilateral mydriasis. The mechanism by which Thus, a unilateral or asymmetric uveitis can lead to mydriasis occurs in glaucoma is not entirely clear, anisocoria.9 but likely involves iris or optic nerve dysfunction Additional signs of uveitis include blepharospasm, associated with elevated intraocular pressure. episcleral hyperemia, deep corneal vascularization, Other signs may include blepharospasm, episcleral diffuse corneal edema, aqueous fl are, swollen and/or hyperemia, deep corneal vascularization, and diffuse hyperemic iris, and decreased intraocular pressure. corneal edema. These should be assessed before a neurologic cause of anisocoria is investigated. Trauma Brachial Plexus Avulsion Posterior Synechia Brachial plexus avulsion is a common cause of Posterior synechia—adherence of the iris to the damage to the second order sympathetic neurons —can result in a fi xed, nonmobile pupil that can between T1 and T3. Brachial plexus either be relatively miotic, mydriatic, or abnormally commonly occurs after vehicular trauma and may shaped. result in partial or complete loss of the affected nerve roots. Amputation of the affected limb may Immune-Mediated or Infectious Disease be indicated if recovery is not likely; however, ocular Immune-mediated or infectious disease can affect sympathetic dysfunction does not resolve with any portion of the (CNS), amputation of the limb. causing visual, sympathetic, or parasympathetic dysfunction in any combination. Head Trauma The majority of dogs with immune-mediated Head trauma is a common cause of CNS disease require immunosuppressive therapy to parasympathetic dysfunction due to compression control their clinical signs; this, however, requires of the midbrain at the level of the PSN CN III. that infectious and neoplastic causes are fi rst Compression occurs secondary to hemorrhage eliminated.10,11 or increased , resulting in Infectious agents implicated as causes of CNS herniation of the brain. disease include viruses, bacteria, fungi, protozoa, Elevated intracranial pressure, with damage to and, rarely, rickettsial infections. Treatment and the cerebrum or diencephalon, results in miosis due to disinhibition of the parasympathetic fi bers and, possibly, damage to the sympathetic fi bers. As HEIDI BARNES HELLER brainstem compression occurs, miosis progresses to Heidi Barnes Heller, DVM, Diplomate ACVIM (Neurology), is a clinical assistant professor at University of Wisconsin–Madison. Her research mydriasis with absent PLR. interests include feline seizure disorders and the development of anti- Prognosis is guarded when miosis is detected, epileptic , brain and spinal cord surgery, and infl ammatory CNS disease. She received her DVM from Michigan State University, completed and grave after mydriasis, with absent PLR, is a rotating internship at University of Illinois, and completed a combined identifi ed.1 Treatment to decrease intracranial neurology and neurosurgery residency at University of Florida. pressure should be started as soon as possible. ELLISON BENTLEY Ellison Bentley, DVM, Diplomate ACVO, is a clinical professor and section Jugular Venipuncture head of comparative ophthalmology at University of Wisconsin–Madison. Jugular venipuncture can cause anisocoria due to Her research interests include ocular applications of high resolution ultrasound, glaucoma, management of ocular pain, and non-healing iatrogenic damage to the second order sympathetic corneal erosions in dogs. She received her DVM from University of neuron as it courses through the jugular groove, Florida and completed a small animal internship at North Carolina State University and a residency in comparative ophthalmology at University of deep to the jugular vein. Excessive probing for the Wisconsin–Madison. vein may result in damage to this nerve. Care should be exercised when attempting jugular venipuncture,

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performing deep ear fl ushes, and using choke chains to ers and dogs of other breeds. Vet Ophthalmol minimize risk of trauma to the surrounding structures. 2015; 18(1):1-5. 6. Morgan RV, Zanotti SW. Horner’s syndrome in dogs and cats: 49 cases. (1980-1986). Vascular JAVMA 1984; 194(8):1096-1099. 7. Berghaus RD, O’Brien DP, Johnson GC, Disruption of Blood Flow Thorne JG. Risk factors for development Disruption of blood fl ow to any part of the autonomic or of dysautonomia in dogs. JAVMA 2001; may result in compromised function. The cause 218(8):1285-1290. 8. Van den Broek AHM. Horner’s syndrome in is unknown in almost 50% of dogs with cerebrovascular cats and dogs: A review. J Small Anim Pract disease, therefore, treatment is supportive.12 Treatment 1987; 28(10):929-940. should be directed at the underlying cause in dogs for which 9. Yoshitomi T, Ito Y. Effects of indomethacin and prostaglandins on the dog iris sphincter a diagnosis is obtained. and dilator muscles. Invest Ophthal Vis Sci 1988; 29:127-132. Fibrocartilagenous Embolism 10. Talarico LR, Schatzberg SJ. Idiopathic granulomatous and necrotizing infl ammatory Fibrocartilagenous embolism (FCE) is a common cause of disorders of the canine central nervous spinal cord dysfunction in dogs. Miosis may occur following system: A review and future perspectives. J a FCE in the cervicothoracic spine due to interruption of the Small Anim Pract 2010; 51(3):138-149. 11. Granger N, Smith PM, Jeffery ND. Clinical cervical sympathetic fi bers. fi ndings and treatment of non-infectious meningoencephalomyelitis in dogs: A IN SUMMARY systematic review of 457 published cases from 1962 to 2008. Vet J 2010; 184:290-297. Anisocoria may occur secondary to disease of the eye, optic 12. Garosi L, McConnell JF, Platt SR, et al. Results nerve, and central and . Lesion of diagnostic investigations and long-term outcome of 33 dog brain infarction (2000- localization is critical to developing an appropriate differential 2004). J Vet Intern Med 2005; 19:725-731. diagnosis list. This can often be effectively conducted using knowledge of the neuroanatomical pathways, along with standard cranial nerve testing. Pharmacologic testing may help further isolate sites of dysfunction within the autonomic system. Further diagnostic testing should aim for an etiologic diagnosis and can be chosen based upon neuroanatomical localization. Treatment should always be directed at the underlying cause of anisocoria.

CN = cranial nerve; CNS = central nervous system; FCE = fi brocartilagenous embolism; LGN = lateral geniculate nuclei; PLR = pupillary light refl ex; PSN CN III = parasympathetic nuclei of cranial nerve III

Figures 1–4 Illustrations courtesy Pamela Boutilier, DVM, MVSc, Diplomate ACVIM (Small Animal Internal ), SAA.

References 1. deLahunta A, Glass E. Lower : General visceral efferent system. In deLahunta A, Glass E (eds): Veterinary Neuroanatomy and Clinical Neurology, 3rd ed. St Louis: Saunders, 2009, pp 182-184. 2. Rylander H. The neurologic examination in companion animals. Today Vet Pract 2013; 3(1):18-22. 3. Kern TJ, Aromando MS, Erb HN. Horner’s syndrome in dogs and cats: 100 cases (1975-1985). JAVMA 1989; 195(3):369-373. 4. Boydell P. Idiopathic Horner’s syndrome in the golden retriever. J Small Anim Pract 1995; 36(9):382-384. 5. Simpson KM, Williams DL, Cherubini GB. Neuropharmacological lesion localization in idiopathic Horner’s syndrome in golden retriev-

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