Proceedings 36th Symposium ESVN-ECVN 12th-14th September 2024

The European College of Veterinary Neurology (ECVN) Symposium and the Journal of Veterinary Internal Medicine (JVIM) are not responsible for the content or dosage recommendations in the abstracts. The abstracts are not peer reviewed before publication. The opinions expressed in the abstracts are those of the author(s) and may not represent the views or position of the ECVN. The authors are solely responsible for the content of the abstracts.

RESIDENTS DAY PROGRAM

12 SEP 2024 | THURSDAY

ESVN-ECVN 36th Symposium: Neuro-Ophthalmology

PROGRAM

13 SEP 2024 | FRIDAY

Consensus Statements of the European College of Veterinary Neurology (ECVN) provide the veterinary community with up-to-date information on the pathophysiology, diagnosis, and treatment of clinically important animal diseases. The ECVN Board oversees selection of relevant topics, identification of panel members for each topic with the expertise to draft the statements, and other aspects of assuring the integrity of the process. The statements are derived from evidence-based medicine whenever possible and the panel offers interpretive comments when such evidence is inadequate or contradictory. A draft is prepared by the panel, followed by solicitation of input by the ECVN membership which may be incorporated into the statement. It is then submitted to the Journal of Veterinary Internal Medicine, where it is edited prior to publication. The authors are solely responsible for the content of the statements.

Royal (Dick) School of Veterinary Medicine, University of Edinburgh, Easter Bush Campus, EH25 9RG

This talk will focus on ocular and orbital causes of blindness (i.e., excluding central causes of acute blindness).

This will need to be severe to cause blindness (as opposed to visual deficits). Infectious causes include: Prototheca, Cryptococcosis, Histoplasma, Blastomycosis, Coccidiomycosis, Aspergillosis, Leishmania, Rabies, Distemper, FeLV/FIV, Toxoplasma, Neospora, Ehrlichia, Rickettsia, Babesia, Bartonella. Inflammatory or immune mediated causes include: a septic focus (e.g., pyometra), hyphaema (e.g., traumatic, Angiostrongylus, systemic hypertension, anti-coagulant poisoning), diabetes mellitus (e.g., acute cataract formation), Neoplasia—primary/secondary and Feline Infectious Peritonitis (FIP).

Hyperglycaemia associated with diabetes, and as glucose is a small molecule it will pass into the lens (along with all other tissues). Here it overwhelms the normal hexokinase pathway and excess is shunted to aldose reductase pathway where the end product is sorbitol (a large molecule and therefore trapped within lens capsule) resulting in osmotic draw and tumescent cataract formation. This can be exceptionally rapid where glycaemic control is poor, and may even result in lens capsule rupture and phacoclastic uveitis (requiring emergency intervention to save the globe).

Persistent hyperplastic primary vitreous or persistence of foetal hyaloid system may result in intralenticular hemorrhage and can be associated with retinal detachment.

May be classified as primary (inherited, no antecedent ocular disease) or secondary (e.g., chronic uveitis or lens luxation). Tonometry is essential for diagnosis (see Investigation of Acute Blindness). In dogs the classic presentation is diffuse corneal oedema with dilated pupil and absent menace response. In contrast, with cats the presentation can be more subtle with merely a dilated pupil (anisocoria) and little corneal oedema. They may also retain vision for longer.

Vision loss in not usually acute, however, some owners may not notice until move house/furniture as dog/cat has adapted. Initial presenting sign is usually nyctalopia (most start with rod de.g.eneration followed by cones). Some cases will develop secondary cataract. Funduscopic signs are tapetal hyperreflectivity and vascular attenuation as the disease progresses. Initially may require ERG to diagnose (see Investigation of Acute Blindness).

Acute & permanent vision loss so clinical presentation is typically menace negative, mydriatic pupils with sluggish PLR (N.B. may have positive dazzle and PLRs [esp early]). Mean age at onset is 8.5–10 years (usually 7–-10 years range). Typically older spayed females (60%–90% in some studies, others found no predisposition Heller et al 2017), and small breed dogs (42% Heller et al 2017). A seasonal onset has been reported (46% of cases in Dec & Jan). Retinal examination is usually normal in the acute phase with diffuse signs of atrophy as degeneration continues (6–8 weeks) similar to those seen with PRA.

Some (40%–60%) cases have a history of Cushingoid like signs (PU/PD/PP, wt gain, and skin/hair coat changes), but can be negative/equivocal on testing (only 12%–17% positive). These signs often precede vision loss, and these usually resolve (PP may increase over first year before recedes). Hypothyroidism and diabetes mellitus are reported co-morbidities in some (Stuckey et al. 2013).

Some reports of cases with concurrent hearing loss, sense of smell reduction (Abrams et al. 2023), and/or change in behavior.

Blood biochemistry abnormalities include: increased serum cortisol in 9/11 cases, increased in one or more 1 sex hormones in 11/13 cases in one study, raised cholesterol and/or ALKP was reported in 68% of cases.

Histopathology has revealed the first lesion is a loss of photoreceptor (PhR) outer segments, followed by apoptosis of PhRs and finally full retinal thickness atrophy.

Aetiopathogenesis has not been fully elucidated but an immune-mediated basis has been proposed. Anti-retinal antibodies have been found in SARDS patients but there are contradictory studies with some reporting no higher incidence of anti-retinal antibodies in SARDS vs healthy patients. Immunohistochemistry has revealed immunoglobulin producing plasma cells in affected retinas, and complement activity suggestive of antibody-mediated neuronal damage has been proposed as a mechanism of the syndrome (Grozdanic et al 2008 Vet Clin N Am). In humans, autoimmune retinopathy (AIR) has been described, and a sub-group of this population—‘paraneoplastic AIR’ or ‘Cancer-associated retinopathy (CAR)’ however, there is no evidence to support this in canine SARDS patients.

A neuroendocrine etiology has also been proposed due to concurrent reports of loss of sense of smell, and a pituitary derived factor has been suggested.

The prognosis for vision is grave and treatments reported (including immunosuppression—mycophenolate mofetil—no benefit (Young et al 2018) after 6 weeks therapy, or combination immunosuppressive meds (lifelong)—no controlled prospective studies) are not currently supported by scientific evidence. Most dogs do adjust (Stuckey et al 2013) with good QoL; ‘Living with Blind Dogs’ is a good resource for owners.

A nice review paper summarizing the current knowledge of SARDS (Komaromy et al 2015 Vet. Ophth).

Drug/Chemical-induced retinotoxicity has been reported with enrofloxacin in cats (especially elderly and/or renally impaired, and especially at doses >5 mg/kg), closantel (anthelmintic used predominantly in farm animals) overdose in farm species and dogs with accidental exposure, ivermectin (commonly dogs exposed via equine wormers [can be after eating horse stools], but can be for some mange treatments). Other drugs include: rafoxanide, quinine (RGC loss, optic atrophy), chlorquine (RGC damage), digoxin (reversible cone dysfunction), metal-chelating agents (diphenylthiocarbazone, hydroxpyridinethione).

Phototoxicity (o2 free radicals) is also capable of causing retinal degeneration, as well as high oxygen tensions (human retinopathy of prematurity [ROP]). Radiation induced retinopathy (degenerative angiopathy, multifocal retinal hemorrhages, retinal degeneration usually starting in outer retina)—NB cataracts may obscure fundus examination.

Causes of retinal detachment include: immune mediated (steroid responsive serous), rhegmatogenous, systemic hypertension, subretinal infection or neoplastic infiltration and traumatic (often rhegmatogenous).

Intraocular optic neuritis or retrobulbar (orbital) optic neuritis. Funduscopic changes optic nerve head swelling, retinal vascular engorgement, and peripapillary retinal oedema and/or separation. Foci of chorioretinitis (especially peripapillary) are seen in some cases.

Optic neuropathy can result from trauma to optic nerve and shearing forces within the optic canal. These injuries may be associated with optic nerve avulsion (avulsed posteriorly), basal skull fractures and other cranial nerve deficits, and/or brain stem injuries.

Optic neuropathy can be encountered secondary to proptosis. The trauma required to proptose the brachycephalic globe can be relatively minor, whilst this is not the case in dolicocephalic breeds or cats where extensive trauma is usually required. Prognosis for vision is generally poor at roughly 20%, however the globe can often be salvaged for cosmetic purposes by early intervention and treatment. Multiple extraocular muscle avulsion and total hyphaema cases have a poorer prognosis. The medial rectus muscle is the shortest muscle—first to be avulsed. Pupil size is not a prognostic indicator for vision, although those eyes with a direct and/or indirect pupillary light reflex (PLR) and/or a positive menace response obviously have a better prognosis for vision.

Vision at last recheck was not correlated with breed, cause or duration of proptosis, or post-operative medications (P > .05), but was correlated with presence of direct and indirect pupillary light reflexes (PLRs) on admission (P = .001 and .02, respectively), and with assessment and surgery performed by veterinary ophthalmologists rather than surgery or emergency personnel (P = .015).

Optic neuropathy can also be seen due to ischaemia associated with interrupted vascular supply (more common in humans)—massive blood loss or ligation of carotid arteries (esp. horses).

Compression of the optic nerve due to retrobulbar disease (severe orbital cellulitis, neoplastic infiltration/mass effect) may result in blindness.

In humans this is a more common condition secondary to Graves' disease (hyperthyroidism)—relative proptosis, eyelids that are difficult to open with finger pressure, and the presence of an RAPD (Relative Afferent Pupillary Defect) in the traumatized eye are surgical decompression emergencies (BJ Oral & Maxfac Surg 2020). The coronal approach has been reported as the best for post op visual acuity in humans.

Royal (Dick) School of Veterinary Medicine, University of Edinburgh, Easter Bush Campus, EH25 9RG

History, Signalment & Ophthalmic examination (see resident's day notes)

It is essential when handling cases of suspected glaucoma. Normal in cats and dogs 10–25 mmHg, horses 15–30 mmHg. Tonometry is also useful when monitoring uveitis cases—these can develop glaucoma as a complication, and the intraocular pressure also reduces in many cases of uncomplicated uveitis.

Schiøtz tonometer This is an indentation tonometer and inexpensive. The patient's head is positioned vertically (nose to ceiling) and the Schiotz footplate is placed on the anesthetized cornea. Multiple readings are taken to obtain an average/fairly consistent reading. Different weights may need to be added to neck of the plunger if the IOP is elevated. The IOP is read from a conversion chart. There are drawbacks to the technique; it is not entirely accurate and should not be used after intraocular surgery or diseased corneas. It requires topical anesthesia and a compliant patient. It cannot be used on horses (getting the head vertical not possible). Corneal oedema also artificially lowers the IOP reading.

Applanation tonometry using for example, the “Tonopen” (Carleton Optical) tonometer is one of the methods of choice. The technique measures the force required to flatten a given, small area of the corneal surface. It is fairly accurate for use in small animals and the patient can be examined in a normal sitting position (head horizontal). A Tonopen cover must be used on the tip at all times as service/repair is often only just short of the purchase price. Topical anesthesia is required and it is important not to press on the globe through the eyelids (easy to do in horses and cattle when restraining) as an artificially increased reading will be obtained. Increased systolic blood pressure (fear, stress) or pressure on the jugular veins and carotid arteries (N.B. restraint of patient) may also result in an increased reading. General anesthesia may reduce IOP readings (usually by reducing systolic BP).

Rebound tonometry (e.g., “TonoVet”—iCARE) is a technique in which a small probe is fired from an instrument held close to the eye and perpendicular to the un-anesthetized cornea (needs to be in a horizontal (or near horizontal) plane. The deceleration of the probe as it returns into the instrument is proportional to the intraocular pressure. The technique is accurate, and has been calibrated for the dog/cat and horse (separate settings). As the probe is small, it is ideal for use in small eyes and does not require topical anesthesia. Does not require topical anesthesia and less risk of an iatrogenic corneal ulcer (especially if repeated measurements).

Melanopsin containing RGCs subpopulation which are photosensitive to short wavelength light (480 nm, blue) whereas red light (630 nm) reflects functional photoreceptors and their ganglion cells. SARDS cases would be expected to have a positive blue light reflex but negative red light reflex; whereas optic nerve disease would be expected to have negative blue light and red light reflexes. However, Terakado et al (2013) reported 75% SARDS cases responded as predicted, with 12.5% weak red light PLR, positive blue light and 12.5% weak blue light PLR negative red light PLR, so ERG remains the gold standard for diagnosis of SARDS.

An ERG involves measurement of retinal generated electrical activity in response to light stimuli. The technique is usually performed on an anesthetized patient using standardized conditions (dark and light adaptation for set periods) and recording equipment when documenting retinal degenerations or functional defects—if requiring objective measurements (ISCEV standardized protocol: Robson et al 2022). More sophisticated measurements using light of varying intensity, wavelength and flashing flicker frequency are more often used in research environments.

Clinically however, it can be useful for crudely assessing retinal function in the presence of clouded ocular media (e.g., cataract) prior to surgery, to rule out retinal degeneration that would make the surgery pointless. Under these circumstances a response to a bright white light flash/flashes is measured and can be performed conscious in most amenable dogs and cats.

Patient preparation requires mydriasis, topical anesthesia, ± sedation/anesthesia, dark adaptation (20 min). It is important to avoid retinal photography/indirect ophthalmoscopy before (min 1 h wait) as bright lights will reduce ERG responses for a prolonged period. For equine ERG—auriculopalpebral nerve block for eyelid akinesia, detomidine sedation, eye lubricant.

A Ganzfeld or mini-Ganzfeld stimulator is used to create light stimulation—these require calibration/validation (LEDs) and provide uniform retinal stimulation for reliable/reproducible results. The electrodes required are:

Retinal—JET*/DTL (positive)—topical anesthesia Reference—3 cm behind canthus (negative) Ground—nuchal crest/forehead (common).

Two channels will allow simultaneous bilateral measurements if you using a Ganzfeld or have two mini-Ganzfeld for each eye. An impedance meter (<5 kΩ) is present with most system that informs on electrode placement and good contact.

There are ISCEV ERG experimental protocols—as differing anesthetic drugs may influence the amplitudes and implicit times. Anesthesia/sedation will generate reduce muscle movement ‘noise’. A Faraday cage—keep away from high-powered electric motors (AC interference) can be useful but expensive and limited to certain facilities. Signal averaging increases signal to noise ratio, especially when using low-intensity flashes and expected lower amplitude recordings.

These can provide geographic mapping of retinal activity. Uses a light stimulus displayed as hexagons in different sizes over 20–30′ retinal surface. Each hexagon flickers—black-white. This modality is generally used in experimental set ups—requiring advanced training, expensive equipment, and needs GA for patient.

The electrodes are placed as for fERG and there is no change in light intensity, but uses alternating high-contrast checkerboard/gratings—with variation in alternate rate. Requires fixation (humans)—so necessitates anesthesia in our patients (conscious = unreliable). Classically used to evaluate glaucoma damage—RGCs and ON function.

VEPs represent the electrical activity generated in the visual cortex during light stimulation of the visual pathways. Reliability/reproducibility can be a problem with the technique and anesthesia is required. Largely this is reserved for experimental studies and investigations of visual deficits in humans.

Measures summed electrical potentials in visual cortex in response to visual stimulation. Recorded on scalp (midline)—recording electrode (nuchal crest), reference (forehead), ground electrodes (vertex) Very small amplitudes (~15 uV) expected so susceptible to signal to noise ratio errors. Used in experimental set ups and single channel most practical (multiple channel requires expensive advanced equipment and training but can assess chiasmal and retrochiasmal activity).

IV fluorescein is administered and serial retinal photography (blue light illumination, specialist camera) undertaken. There are different phases of fluorescein flow through fundus—retinal vessels, choroidal vessels and optic nerve vessels. Very sensitive indicator of vascular permeability changes. May assist in investigation of optic neuritis and chorioretinitis.

OCT is a non-invasive imaging technique that uses light to create high-resolution cross-sectional images of tissue. Within ophthalmology it can assist with investigations of retinal and optic disc disease, providing an in vivo and longitudinal high resolution of tissues (comparable to histopathology sections).

This has been covered elsewhere by (see ‘What Imaging Modality to do for Investigation of Blindness’ by Fraser McConnell in residents day program) but we will briefly consider its application to ophthalmic and retrobulbar disease causes of blindness. Recent advances in MRI (7 T) have afforded fantastic resolution of the ocular structures and optic nerve sheath, as well as orbital structures. Neuromuscular blockade is required to avoid eye saccades and artifacts so is largely reserved to experimental protocols currently.

As of 2024, we have crossed 6 of the 9 planetary boundaries which define a safe operating space for humanity. Climate change is a global medical and veterinary healthcare crisis and threatens our ability to continue providing quality of care to our patients. But how can I change anything significant in my clinical practice? What should I focus on? This presentation will provide a brief overview of the state-of- play in veterinary sustainability and focus on a few key areas in which veterinary professionals can make a significant difference in their daily clinical life. Be prepared to think global, and act local.

Pressure of fluid and flow are closely related and there is a close relationship between intracranial pressure and blood/CSF/lymph flow. The appearance of flowing liquids on MRI is complex and varies with pulse sequence, flow velocity and direction and pulse sequence options chosen. Recognition of flow artifacts or absence of artifacts can be helpful in detection of vascular pathology eg thrombi. Venous thrombi in particular are easily overlooked and possibly overlooked in veterinary medicine. Blood flow at the capillary level can be estimated using perfusion-weighted imaging (PWI) which is simple to perform. Alteration in PWI can potentially give additional information in patients with abnormal CSF flow or intracranial pressure. Assessment of increased intracranial pressure is simple in late stages using MRI, for example, brain herniation but in early/mild cases may be challenging and requires GA. Transocular ultrasonography offers the possibility to measure optic nerve sheath diameter without need for sedation/GA and can act as a surrogate marker for intracranial pressure. In the last decade there has been many developments in the understanding of normal CSF flow which challenges the classical theory. The proof of presence of meningeal lymphatics and recognition of the complexity of normal CSF production, resorption and flow has been aided by MRI CSF flow assessment. MRI flow studies in veterinary medicine is at the early stages and may give insights into many challenging pathologies, for example, normal pressure hydrocephalus. MRI assessment of normal lymph flow is challenging whilst described is unlikely to be clinically applicable in most cases.

Inflammatory optic neuropthies in humans constitute a growing subclass of acquired optic neuropathies.

Over the last 2 decades, new antibodies associated with the presence of optic neuropathy have been discovered, including myelin oligodendrocyte glycoprotein (MOG) antibody and aquoporin 4 (AQ4) antibody.

Importantly, new and more efficient treatments have become available, both for multiple slcerosis- related optic neuritis and MOG- and AQ4-related optic neuritis.

In this session we will present an update review on the diagnosis, management and prognosis of inflammatory optic neuropathies in humans.

The diagnosis of abnormal eye movements constitutes a challenging task for the clinician, as these reflect the dysfunction of several brain networks and their complex interaction.

Indeed, supranuclear, nuclear and/or internuclear disorders might occur simultaneously in the same individual.

In this session we will highlight the most common eye movement disorders encountered in the clinic, using a structured approach, by spanning ocular fixation, pursuit, saccades and vergence disorders.

The investigation and treatment of the above conditions will also be briefly discussed.

Nystagmus is characterized by rhythmic and involuntary eye movement oscillations, usually comprising a slow eye movement (“slow phase”), followed by a corrective fast movement (“fast phase”). This type of nystagmus is classicaly associated with vestibular disorders. Less often, oscillations might comprise only slow eye movements (“pendular oscillations”). Here, a congenital origin is usually the culprit.

Importantly, the direction of the fast phase of nystagmus, along with its accompaning features, including head impulse response, beahviour of eccentric nystagmus, and presence of vertical strabismus are critical steps in evaluating a patient with nystagmus and further differentiate between a peripheral and central vestibular disorder.

In this session we will review the most common phenotypes of nystagmus, both in central and peripheral vestibular disorders. Congenital nystagmus and rare form of nystagmus will also be addressed.

The investigation and treatment of nystagmus will also be briefly discussed.

The visual system is an important part of the neural function in our patients, allowing a wider peripheral vision when compared to humans when both eyes are used. The structures that we will discuss through this lecture will include the pathways for visual perception including retina, the optic nerve, the optic chiasm ad the optic tract, the lateral geniculate nucleus, the optic radiation and the visual cortex. We will also discussed the pathways for visual reflexes (body and ocular reflex, pupillary constriction and pupillary dilation).

In cats and dogs, the retina is histologically divided into 10 layers (Parry, 1953). Nine layers form the neurosensory retina (embryonic derivative of the diencephalon, neuroectoderm) and the tenth and most external layer (on the scleral surface and closest to the choroid) is the supportive retinal pigmented epithelium. The central area of this tenth layer has no pigment to allow tapetum to show through; the other nine layers of the retina are transparent with the exception of the blood vessels.

The nine identifiable layers of the neurosensory retina, from the outer (scleral) surface to the inner (vitreal) surface, comprise: the photoreceptor layer; the external limiting membrane; the external nuclear layer; the external plexiform layer; the internal nuclear layer; the internal plexiform layer; the retinal ganglion cell layer; the nerve fiber layer (NFL); and the internal limiting membrane. The neurosensory retina layers contain seven types of major cells (six neuronal and one glial): the outer retinal photoreceptors (rods and cones), bipolar neurons, horizontal neurons, amacrine cells, retinal ganglion cells (RGCs) and the Müller cells (glial cells). These cells convert light into electrical impulses, which are sent, via the optic nerve, to the visual cortex (to be transformed into images) and to the brainstem to elicit reflex pathways that coordinate pupil size, head, neck, eyeball movements in response to visual stimuli and synchronize the animal's biological clock.

The ganglion cell layer contains the cell bodies of the RGCs. There is a new subgroup of RGCs identified called melanopsin-containing RGCs (intrinsically photosensitive RGCs [ipRGCs]) that are also photosensitive with melanopsin as the photosensitive pigment. This subgroup of RGCs can respond to changes in light without the input of the outer photoreceptors (cones and rods) and contribute to the regulation of circadian behavior, seasonal reproductive rhythm and to the PLR.

The area in the retina with the highest number of photoreceptors and RGCs is called the area centralis (Mowat et al., 2008); this is specialized for high resolution with maximal visual acuity, comparable to the human macula.

The NFL is mainly formed by axons of the RGCs, which course on the vitreal surface of the retina to the optic disc (optic nerve head or optic papilla) and this point is the origin of the optic nerve (cranial nerve [CN] II). Myelination starts at different levels across the species, which account for the different shapes, colors and position between cats and dogs.

The optic nerve is a white matter tract formed by RGC axons and glial cells. Optic nerve is a misnomer, as a nerve involves a bundle of axons in the peripheral nervous system (PNS) and is myelinated by Schwann cells; however, the optic nerve is a tract of the central nervous system (CNS) and is myelinated by oligodendrocytes. After the lamina cribrosa, the optic nerve is surrounded by meninges (dura mater, arachnoid membrane and pia mater) with a cerebrospinal fluid (CSF) filled subarachnoid space. The RGC axons in the optic nerve are arranged in a retinotopic manner to maintain the spatial arrangement of the retina. The RGC axons course caudally and enter the skull through the optic canals, located in the presphenoid bone at the level of the rostral cranial fossa, to merge into the optic chiasm. The presphenoid bone in the cat but not in the dog contains a sinus (known as the presphenoid sinus). Lesions at the level of the presphenoid bone (e.g., severe presphenoid sinusitis in a cat) can damage the optic nerve and compromise vision (Beltran et al., 2010; Busse et al., 2009).

The proportion of decussating axons varies between species and correlates with the degree of binocular vision. Species with more binocular fields of view have a smaller percentage of axons crossing at the level of the optic chiasm. Around 66% and 75% of the RGC axons decussate at the optic chiasm in cats and dogs respectively, and the rest remain ipsilateral (around 34% in cats, around 25% in dogs, around 80%–90% in horses and cows) (Boire et al., 1995; Jacqmot et al., 2020). The axons that decussate come from the RGCs in the medial aspect of the retina (which provides the lateral field of view), while the ipsilateral axons come from the RGCs in the lateral aspect of the retina (which provides the medial field of view). The optic chiasm is located intracranially on the floor of the rostral cranial fossa (presphenoid bone) and rostral to the pituitary gland. After the optic chiasm, the RGC axons continue as the optic tract and course caudal dorsolateral over the side of the thalamus. The majority of the optic tract axons synapse in the lateral geniculate nucleus (LGN), located caudal dorsolateral in the thalamus. Some of the optic tract axons (including melanopsin-containing RGC axons) leave the optic tract before reaching the LGN to relay information to extracortical nuclei in the brainstem (pretectal nucleus, rostral colliculus, and suprachiasmatic nucleus). The axons from the neuronal cell bodies in the LGN project into the internal capsule and course caudally as the optic radiation to terminate in the visual cortex and produce the visual perception of images (conscious). A recent study identified the Meyer's and Baum's loops in the canine visual pathway (Jacqmot et al., 2020). These loops are axons from optic radiation and therefore contribute to the visual system. The axons of Meyer's loop pass near the temporal lobe to project themselves into the occipital cortex. The axons of Baum's loop make a caudomedial path to project at the level of the parietal cortex before reaching the occipital cortex. This is important neuroanatomy that might need to be considered to prevent damage to the visual system when neurosurgical or radiotherapeutic procedures are planned (Jacqmot et al., 2020).

The autonomic innervation to the eye has central and peripheral components, including higher centres in the hypothalamus and midbrain and axons and nuclei in the pons, medulla oblongata and spinal cord. The autonomic system has mainly two components: the general visceral afferent system and the general visceral efferent system with its parasympathetic and sympathetic divisions. The parasympathetic innervation to the eye regulates the iris muscle response (pupil size) to the amount of environmental light, while the sympathetic innervation to the eye regulates the iris muscle response (pupil size) to central factors such as emotion, pain and distress. The iris sphincter muscle is primarily under the control of the parasympathetic nervous system while the iris dilator muscle is primarily under the control of the sympathetic system. Iris muscle constriction (miosis) is produced by contraction of the iris sphincter muscle and relaxation of its antagonist muscle (iris dilator muscle). On the other hand, iris muscle dilatation (mydriasis) is produced by contraction of the iris dilator muscle and relaxation of its antagonist muscle (iris sphincter muscle). This is referred to as reciprocal innervation(Yoshitomi and Ito, 1986). Therefore, pupillary size (under even illumination conditions) is an indicator of the autonomic nervous system tone to the eye.

The afferent pathways that contribute to the parasympathetic innervation to the eye arise from the retina, where the impulses originate after light stimulation to the photoreceptors (rods, cones and intrinsically photosensitive RGCs [ipRGCs]). These impulses travel within the RGC axons (optic nerve) and reach the optic chiasm. The majority of the RGC axons decussate at the level of the optic chiasm (around 66% in cats and around 75% in dogs) and continue as part of the optic tract; the rest of the axons remain ipsilateral. Some of the optic tract RGC axons (around 20%) bypass the LGN and course caudally to synapse in the pretectal nucleus (PN) (de Lahunta et al., 2021).

The PN is located rostrally in the midbrain tectum and contributes to the PLR pathway. From the contralateral PN, the majority of the axons (around 66% in cats and around 75% in dogs) cross over again through the caudal commissure and reach the parasympathetic nucleus of the oculomotor nerve (ipsilateral side to the eye where the light stimulus is given). The parasympathetic oculomotor nucleus (preganglionic nucleus, known as Edinger Westphal nucleus in human neuroanatomy) is located in the rostral part of the midbrain and very close to the midline. The remaining axons from the PN (around 34% in cats and around 25% in dogs) remain ipsilateral to the PN, reaching the contralateral parasympathetic nucleus of the oculomotor nerve to the eye where the light stimulus is given.

The efferent parasympathetic axons (preganglionic fibers) from the parasympathetic oculomotor nucleus travel with the motor fibers of the oculomotor nerve, coursing ventrally and emerging on the medial side of the crus cerebri. The parasympathetic axons are located medially to the motor fibers of the oculomotor nerve on the floor of the middle cranial fossa and therefore they are the first to be affected when a structural lesion (such as a pituitary gland mass) arises and extends laterally from the midline.

The parasympathetic axons leave the cranial cavity through the orbital fissure and synapse in the ciliary ganglion (postganglionic neuron) caudal and lateral to the eyeball. These postganglionic parasympathetic axons (five to eight short ciliary nerves in dogs; two short ciliary nerves in cats, nasal (medial) and malar (lateral) nerves) innervate the ciliary body and the iridial sphincter pupillae muscle of the iris to control ocular accommodation and pupil constriction and also give reciprocal cholinergic inhibition to the iridal dilator muscle, causing iridal sphincter contraction and dilator muscle relaxation (pupillary constriction). The reflex in the illuminated eye is considered as the direct PLR, whereas the reflex in the contralateral eye is the indirect, or consensual, PLR.

The sympathetic innervation to the eye is described as a three-order neuron pathway. The cell bodies of the first order neurons are in the caudal nuclei of the hypothalamus, which are activated by emotional factors or noxious stimuli. These first order neurons project caudally and ipsilaterally via the lateral tectotegmental spinal tract (located in the brainstem and deep in the lateral funiculus of the spinal cord) to the preganglionic cell bodies (second order neurons), which are in the lateral gray column at the level of T1 to T3 spinal cord segments. The axons from the preganglionic neurons join the ventral roots of the segmental spinal nerves at the same level, emerge through the intervertebral foramina and leave the spinal nerves in the segmental ramus communicans to join the thoracic sympathetic trunk. The preganglionic axons continue cranially as part of the cervical vagosympathetic trunk. This sympathetic trunk is associated with the vagus nerve (CN X) and located in the carotid sheath. At the level of the cranial cervical area and caudomedial to the tympanic bulla, the preganglionic fibers terminate in the cranial cervical ganglion (CCG) where they synapse with the postganglionic neurons (third order neurons). The exact route of these postganglionic axons to reach the smooth muscles of the iris remains undefined. One of the recent reported possible routes describes that the postganglionic axons leave the CCG and course cranially through the tympano-occipital fissure to enter the cranial cavity joining the ophthalmic branch of CN V, coursing on the floor of the middle cranial fossa and emerging through the orbital fissure. The postganglionic sympathetic fibers innervate the smooth muscles of the periorbita, superior and inferior (Müller's) tarsal muscles of the eyelid and the dilator muscles of the iris. The sympathetic input to the dilator muscle causes contraction of this muscle and therefore mydriasis. As previously described in the parasympathetic innervation (see above), the sympathetic innervation also causes a reciprocal inhibition of the other antagonist muscle (iris dilator muscle) and therefore further relaxation of the iris sphincter muscle.

The pathways of visual perception previously described, and a lesion at any level can cause visual deficits. The clinical assessment of the visual system (in dim and bright light conditions) is mainly performed by observing the animal moving in an unfamiliar environment and negotiating an obstacle course (maze test), and by assessing the menace response. Unilateral visual deficits may be difficult to detect and requires blindfolding each eye in turn.

The menace response is elicited by making a threatening gesture to the eye involving the visual fields (medial and lateral) and observing closure of the eyelids. In cats, the most reliable examination mode for the menace response was achieved standing behind the cat (Quitt et al., 2019). It is important to avoid touching the eye/eyelashes or creating excessive air currents as this can trigger the palpebral and/or corneal reflex and therefore a false positive menace response. The menace response should also be undertaken in both the medial and the lateral visual fields, when possible, as depending on where the lesion is located, specific types of deficits affecting the visual fields might be present. The menace response requires an intact sensory pathway as previously described (optic nerve, optic chiasm, contralateral optic tract, contralateral LGN, contralateral optic radiation and contralateral visual cortex) and an intact motor pathway to elicit the expected response (closure of the eyelids).

From the visual cortex (mainly from the contralateral occipital cortex) the impulses are transmitted by association fibers to the primary motor cortex (frontal cortex), where the motor pathway of the menace response begins. This pathway has not yet been fully described. The axons from the motor cortex reach the pontine nucleus via projection fibers within the crus cerebri and the longitudinal fibers of the pons. The axons from the pontine nucleus decussate by the transverse fibers of the pons and enter the cerebellum via the middle cerebellar peduncle, reaching the cerebellar cortex, which is ipsilateral to the eye where the menace response is elicited.

The cerebellum then coordinates this response by efferent cerebellar pathways that activate the facial nuclei in the ventrolateral part of the rostral medulla oblongata. A recent study has demonstrated, by transsynaptic tracing in mice, that Purkinje cells in the cerebellar cortex project to the cerebellar interpositus nucleus (CIN), which sends projection fibers to the red nuclei in the midbrain (mainly to the red nucleus contralateral to the eye tested) and the red nuclei send projections to the facial nucleus (mainly ipsilateral to the eye tested) in the medulla oblongata. The axons emerge from the medulla oblongata and leave the cranial cavity via the internal acoustic meatus.

At the base of the internal acoustic meatus, the facial nerve continues laterally through the facial canal of the petrous temporal bone and then curves caudoventrally in the caudal wall of the tympanum to exit the skull through the stylomastoid foramen. The facial nerve (CN VII) innervates the orbicularis oculi muscle eliciting a blink (menace response) (de Lahunta et al., 2021). If the menace response is decreased or absent, the facial nerve needs to be evaluated with the palpebral reflex because facial nerve paresis/paralysis may result in a reduced/absent menace response without involving deficits of visual perception. Cerebellar lesions, particularly lesions affecting the interpositus and lateral cerebellar nuclei, can also result in a lack of ipsilateral menace response without involving a deficit of visual perception; however, other clinical signs of cerebellar dysfunction will also be present. It is important therefore, to understand the difference between vision and the menace response. A dog or a cat can be visual with an absent menace response if there is a dysfunction of the cerebellum and/or facial nerve; however, the menace response is also absent if the cat or dog has absent vision.

The menace response is a learned response and therefore is usually absent during the first 10–12 weeks of age in cats and dogs and the first 2 weeks in horses and cows. It is important to remember that the menace response is a cortically mediated response, which needs to be consciously perceived; therefore, animals that have a decreased level of consciousness, are stressed, lethargic or disorientated may have an abnormal menace response without necessarily having a lesion in the menace response pathway.

The pathways of the PLR, and a lesion at any level of these pathways can cause PLR deficits. The PLR is a subcortical reflex that regulates the pupil size in response to the intensity of light that falls on the retina. This reflex assists in adaptation to various levels of darkness/brightness and is driven by the activation of the photoreceptor rods, cones and melanopsin-containing RCGs, with different degrees of contribution. Qualitative PLR is evaluated by shining a bright light into the eye and assessing the ipsilateral (direct PLR) and the contralateral (indirect or consensual PLR) pupillary constriction. The PLR is present as soon as the eyes are open; however, the PLR may be sluggish until the normal retinal structure has developed (from 6 to 10 weeks old in cats and dogs). The assessment of the consensual PLR is not necessary if the menace response and the direct PLRs are present in both eyes. However, the consensual PLR can be of a great value when assessing the afferent pathways (optic nerve and optic chiasm) in an eye where the posterior segment cannot be visualized, resulting in a direct PLR that cannot then be assessed (such as with severe corneal oedema). A recording system and protocol has been developed in dogs to reliably quantify the PLR; however, further studies are needed to evaluate if quantitative PLR abnormalities can be associated with specific diseases(Whiting et al., 2013; Kim et al., 2015). Stressful environments and noxious stimulation can result in pupil dilatation (with little effect on the PLR) due to the influence of the locus coeruleus on pupillary control via sympathetic activation and parasympathetic inhibition. The locus coeruleus is a nucleus located at the level of the pons and is involved with physiological and psychological responses to stress and pain. Other factors that may cause the PLR to be reduced/absent include a low intensity light source, iris atrophy, posterior synechiae, and prior topical administration of a mydriatic agent. Severe retinal, optic nerve, optic chiasm or optic tract lesions are necessary to cause an absent PLR, therefore with only mild retina, optic nerve, optic chiasm or optic tract dysfunction, there is loss of vision, but the PLR could be normal.

Retinal pathology detection may benefit from chromatic PLR (cPLR), which can distinguish between disorders affecting the outer (closer to the scleral surface) photoreceptors (rods and cones) (as seen in sudden acquired retinal degeneration syndrome, SARDS) and the melanopsin-containing RCG (ipRCG) (Grozdanic et al., 2007; Grozdanic et al., 2013; Yeh et al., 2017; Grozdanic et al., 2021). This test is performed using a cPLR device (such as Melan-100®; BioMed Vision Technologies, Ames IA, U.S.A.). This cPLR device is based on the principle that ipRCG can be stimulated with strong blue light (wavelength of 420–440 nm [nanometers]) and induce the PLR. A red light (wavelength of 630 nm) stimulates only the photoreceptors to induce the PLR. Optic nerve lesions may have a decreased to absent PLR regardless of the type of light stimulus used for testing. However, if the disease affects only the photoreceptors (such as in SARDS, immune-mediated retinitis or retinal degeneration), the patient presents with an absent or decreased cPLR using red light and an intact cPLR using blue light. Therefore, cPLR may be a useful method for screening patients that present with loss of vision and PLR with normal mental status, to determine whether further diagnostic tests to evaluate the retina (such as electroretinography (ERG)) should be performed.

The anatomical pathway of this test follows the same course as the PLR. This test is performed using a bright light into one eye and, after the direct PLR is achieved (pupillary constriction), the light source is quickly pointed to the other eye in which further pupillary constriction is expected. The test is then performed in a reversed and repeated manner (swinging movements). A normal reflex is characterized by both pupils constricting to an equal degree when receiving the light stimulus, with the illuminated eye causing further constriction. A mild pupillary escape can be seen when the illuminated eye dilates slightly after an initial contraction; this is a normal reflex, which represents an adaptation of a stimulated retina mainly when using weak light sources. A positive swinging flashing test is considered if the pupil significantly dilates when the light reaches the eye. This pathological pupillary escape (known in humans as Marcus-Gunn sign/pupil) indicates an ipsilateral afferent optic pathway dysfunction (retina or optic nerve).

The dazzle reflex is another subcortical reflex induced by stimulating the eye with a very strong light, which causes an eyelid blink. This reflex is present from birth in puppies and kittens. The afferent arm of this reflex is similar to the PLR; however, the efferent arm is mediated via CN VII. Optic tract axons synapse in the rostral colliculus and then tectonuclear axons synapse in the facial nucleus at the level the medulla oblongata to elicit an eyelid blink. This reflex can be useful when the pupils cannot be visualized to evaluate PLR, such as in patients with severe corneal oedema. However, the exact anatomical pathways have not yet been fully elucidated and therefore this reflex cannot be used on its own to localize subcortical lesions.

Fundic examination is an important part of a neuro-ophthalmic examination, and it should be routinely performed in patients with vision loss, anisocoria, or systemic disease (for instance in systemic hypertension, infectious diseases, storage disease or nutritional deficiencies). The fundus includes all the structures in the posterior portion of the eye globe that can be evaluated with the ophthalmoscope (directly or indirectly). Direct ophthalmoscopy provides an upright evaluation of the fundus; however, it provides a highly magnified small field of view, and it might be a difficult technique to use for general screening of the fundus when compared with the indirect ophthalmoscope. There is also a higher risk for the examiner given the proximity to the patient's head. Indirect ophthalmoscopy provides an inverted evaluation of the fundus with a larger field of view but less magnification. It can be performed using a magnifying lens (20—30D [diopter] lens; the less magnification the greater field of view) and a transilluminator without the necessity to use commercial indirect ophthalmoscopes that are expensive.

Retinal detachment can also be diagnosed with fundoscopy or, in severe cases, by shining a light into the patient's eye and observing a veil of tissue posterior to the lens. Retinal detachment is a clinical sign with several possible underlying causes, including systemic hypertension, neoplasia, inflammation, infectious disease or even congenital abnormalities.

Electrophysiological evaluation of the visual system largely comprises electroretinography and visual evoked potentials (VEPs, also called visual evoked responses). It still has a valued role in the era of advanced imaging (magnetic resonance imaging (MRI)/computed tomography (CT)) in both clinical and research neuro-ophthalmology.

Electroretinography (ERG) evaluates retinal function and assesses the retinal cellular responses to a light stimulus. It is useful for the identification of vision loss due to retinal disease including SARDS, or progressive retinal atrophy (Pasmanter and Petersen-Jones, 2020). ERG can be performed under general anesthesia, or under sedation in a cooperative patient, and it requires the time of dark pupil adaptation (patient placed in a dark room to allow retina to become maximally sensitive to light) as this can affect the ERG results (Lee et al., 2009). Conventional ERG recording uses a corneal contact lens electrode, a skin reference and a ground electrode to record retinal voltage changes that occur in response to a defined flash, or repeated flashes, of light. The response is expressed as a waveform, with a- and b-waves being the most commonly recorded. The waveform and the amplitude and latency of the a- and b-waves are measured. The amplitude of the a-wave and the b-wave increase with the strength of the light stimulus strength, which can be used to evaluate retinal sensitivity(Pasmanter and Petersen-Jones, 2020). The a- and b-waves are the primary ERG components used for assessing retinal function using conventional ERG. However, other waveforms are recognized and used to evaluate retinal function (Pasmanter and Petersen-Jones, 2020).

VEPs are recordings which arise in response to brief flashes of light. VEPs are recorded using electrodes attached to the scalp and signal averaging techniques. The resulting waveform can be used to assess the function of the central retinal region and post-retinal structures, including the optic nerve, optic chiasm, optic tracts, lateral geniculate nucleus, optic radiation and visual cortex. Obtaining VEPs is largely a research procedure and its use in clinical neuro-ophthalmology is limited, but in generalized CNS disorders the VEP may be used to infer white matter conduction velocity within the CNS by determining conduction velocity within the optic nerve (Maehara et al., 2018a; Maehara et al., 2018).

Cross-sectional imaging can provide an excellent complementary diagnostic modality to investigate the dysfunction of the neuro-ophthalmological structures in cats and dogs.

Optic nerve sheath diameter ultrasonography (ONSD-US) is used in human critical care units to assess intracranial pressure (ICP) and to monitor patients during hospitalization that could develop raised ICP (Koziarz et al., 2019). Recent studies in dogs have shown the feasibility of performing this technique and that the measurement of the maximum ONSD-US may provide a noninvasively monitoring tool for evaluation of ICP (Ilie et al., 2015; Smith et al., 2018). Clinical research is required to further evaluate this technique.

Other visual structures accessible by ultrasound include the extraocular muscles (Penninck et al., 2001), which could contribute to the diagnosis of extraocular myopathies in dogs (for instance, extraocular myositis) (Allgoewer et al., 2000; Williams, 2008).

CT allows detailed information of the bones of the skull, including the orbit, and sphenoid bones (presphenoid and basisphenoid) to be visualized. This is especially useful in cases with traumatic brain injury affecting the visual pathways.

MRI allows investigation of the possible relationship between clinical signs and structural lesions along neuro-ophthalmological pathways. However, prior to interpretation of MRI structural abnormalities, it is important that the MRI appearance of the normal anatomy of the visual pathways and the surrounding structures are well known.

CSF analysis could be of diagnostic utility in cases of meningoencephalitis; however, it is unclear of its value in cases of isolated optic neuropathy. The CSF dynamics between the optic nerve subarachnoid space and the CSF is not fully understood. It is possible that there is a free flow of CSF in the subarachnoid space of the optic nerve, creating an optic nerve compartment syndrome, limiting the value of CSF analysis in these patients (Hao et al., 2020).