Neuro-Ophthalmology in Medicine

Optic Neuropathy

The optic nerve is approximately 50 mm in length and is anatomically separated into intraocular, intraorbital, intracanalicular, and intracranial portions. Damage to the optic nerve can occur anywhere along its course, and optic neuropathy may result from ischemic, demyelinating, compressive, genetic, infiltrative, nutritional, traumatic, or toxic causes ( Table 24-2 ).

The term “optic neuritis” should not be used to describe any type of optic neuropathy, but should be reserved to denote the inflammatory, demyelinating optic neuropathy that is either idiopathic or related to demyelinating disease such as multiple sclerosis (MS) or neuromyelitis optica (NMO). Inflammatory or infectious optic neuropathies from other known etiologies are best described in specific terms (e.g., sarcoid or syphilitic optic neuropathy).

Optic neuropathy may be classified anatomically as bulbar/anterior (usually associated with acute disc edema) or retrobulbar (i.e., posterior to the globe without disc swelling) ( Fig. 24-1 ). Any cause of optic neuropathy that results in loss of axons will eventually produce optic atrophy, appearing on funduscopic examination as visible nerve fiber layer loss and disc pallor ( Fig. 24-2 ). Optical coherence tomography is a noninvasive means of quantifying retinal nerve fiber layer atrophy or elevation and is more sensitive to detect axonal loss of the optic nerve. The presence of a relative afferent pupillary defect on the swinging flashlight test can be an important clue to the presence of optic nerve dysfunction, although this finding can also occur with significant asymmetric retinal dysfunction. Bilateral symmetric optic nerve dysfunction does not produce a relative afferent pupillary defect as there is no difference in light transmission in the optic nerve of each eye, although both pupils will react sluggishly.

Inflammatory Demyelinating Optic Neuritis

Optic neuritis may be idiopathic or associated with demyelinating disease, most commonly MS. The clinical course is characterized by a relatively sudden onset of typically unilateral visual loss. The condition worsens to a nadir over several days, and then recovery begins, typically within several weeks, independent of corticosteroid treatment (although intravenous corticosteroids given in a 3-day course followed by a 2-week oral prednisone course and taper is a frequently used therapy). Visual acuity at nadir ranges from 20/20 to no light perception. Pain occurs in more than 90 percent of cases, and often worsens with eye movement. Although centrocecal scotomas are classically associated with demyelinating optic neuritis, other types of field defects (e.g., central, altitudinal, diffuse, paracentral, and arcuate) frequently occur.

Demyelinating optic neuritis is retrobulbar in two-thirds of instances and the optic disc appears normal in the acute phase; the remainder of cases display mild disc edema acutely (“papillitis”). Magnetic resonance imaging (MRI) demonstrates contrast enhancement of the optic nerve in at least 90 percent of cases of demyelinating optic neuritis within the first several weeks, especially when fat-suppressed orbital sequences are obtained ( Fig. 24-3 ). Between 3 and 6 months after optic neuritis, optic atrophy becomes visible if there is nerve fiber loss, and visual evoked potentials may document delayed latencies. Not all cases of optic neuritis result in such optic atrophy.

While the overall prognosis of visual recovery from optic neuritis is good, it is common for many patients to have residual deficits ranging from mildly reduced contrast sensitivity to more significantly reduced acuity. The Optic Neuritis Treatment Trial followed patients with optic neuritis longitudinally and found that 72 percent of subjects had recovered visual acuity to at least 20/20, and 85 percent had acuity of at least 20/25 at 15 years after onset. If the initial visual acuity was limited to counting fingers or worse, there was a decreased chance of 20/20 (49%) or 20/25 (63%) visual recovery at 15 years. There was only a weak correlation between the severity of visual loss at baseline and recovery of vision in patients with an initial visual acuity between 20/20 and 20/200.

The baseline brain MRI predicts the risk of developing MS in the decades following optic neuritis, and accordingly is an important test following a first attack of optic neuritis. The number of T2-weighted hyperintensities at least 3 mm in size on baseline MRI reflects the likelihood that a patient with optic neuritis will develop clinically definite MS as defined by a second subsequent relapse. A normal baseline MRI is associated with a 25 percent chance of developing MS in 15 years. The presence of just one lesion increases the 15-year cumulative probability of MS to 60 percent, while three or more lesions on the baseline brain MRI increase the likelihood to approximately 80 percent. Optic nerve enhancement itself is not counted as a lesion. The overall risk of developing MS within 15 years after optic neuritis is 50 percent, independent of MRI findings, a figure that can be used to counsel those patients who cannot obtain an MRI. The majority of patients developing MS do so within the first 5 years. MRI characteristics also predict future disability in patients with optic neuritis. Spinal cord and infratentorial lesions are associated with a higher future disability.

Neuromyelitis Optica

NMO is an antibody-mediated inflammatory disease of the central nervous system (CNS) with a predilection for the optic nerves, spinal cord, and certain brain regions. While NMO was previously considered a variant of MS, it is now known to have distinct clinical, pathologic, and immunologic features. AQP4-IgG, a pathogenic antibody against aquaporin-4 (AQP4), has been shown to have high specificity to delineate NMO from presentations consistent with MS. More recently, a subset of patients with an NMO phenotype has been found to have autoantibodies targeting myelin oligodendrocyte glycoprotein.

Optic neuritis from NMO is often bilateral and frequently results in severe vision loss. MRI features of NMO include involvement of greater than half the length of the optic nerve and involvement of the chiasm ( Fig. 24-4 ). NMO-related optic neuritis is associated with greater retinal nerve fiber layer loss than MS, which can be measured by optical coherence tomography ( Fig. 24-5 ).

Early treatment of NMO-associated optic neuritis with high-dose corticosteroids is associated with better visual outcomes and preservation of retinal nerve fiber layer. In cases where corticosteroids are ineffective or only transiently helpful, plasma exchange can be utilized; the effectiveness may depend on how early treatment is initiated. Consequently, it is imperative to attempt to distinguish MS from NMO in the acute stage; bilaterality, severe visual acuity loss at onset, and recurrent visual decline following corticosteroid treatment are factors suggestive of NMO.

Ischemic Optic Neuropathy

Ischemic optic neuropathy presents with acute visual loss due to impaired circulation to the optic disc or retrobulbar optic nerve. It may be divided into arteritic (e.g., giant-cell arteritis) and nonarteritic varieties ( Table 24-3 ). Nonarteritic anterior ischemic optic neuropathy (NAION) is always associated with disc edema acutely; the pathophysiologic mechanism of cell death is presumed to be mainly ischemia from impaired perfusion supplied by the network of short posterior ciliary arteries. Individuals with a crowded optic disc (small cup-to-disc ratio) are predisposed to developing NAION. It is believed that an episode of hypoperfusion to the optic disc can invoke a cycle whereby local ischemia gives rise to swelling of the crowded optic disc, which further compromises the circulation and leads to further swelling.

Table 24-3

Neuro-Ophthalmologic Disorders due to Ischemic Disease

Category	Funduscopic Features	Systemic Associations
Nonarteritic anterior ischemic optic neuropathy (NAION)	Generalized or sectoral disc edema, flame-shaped peripapillary hemorrhages, disc-at-risk in opposite eye	Diabetes, nocturnal hypotension, antihypertensive medications, sleep apnea
Nonarteritic posterior ischemic optic neuropathy	Normal in acute stage. May result in disc atrophy chronically	Severe systemic hypotension or anemia, sepsis
Arteritic ischemic optic neuropathy	Papilledema, evidence of choroidal ischemia, infarction in distribution of cilio-retinal artery, if present	Giant-cell arteritis, polymyalgia rheumatica, thrombocytosis, inflammatory aortitis
Diabetic papillopathy	Similar in appearance to NAION, but severity of fundus appearance may be out of proportion to relative sparing of visual function	Diabetes mellitus, diabetic retinopathy
Central retinal artery occlusion	Normal optic disc, but with generalized retinal edema with cherry-red macular spot	Carotid atherosclerosis, hypertension, tobacco use, hyperhomocysteinemia
Branch retinal artery occlusion	Normal optic disc with focal area of retinal edema, sometimes associated with a visible occlusive plaque	Carotid atherosclerosis, hypertension, tobacco use

NAION typically presents with sudden, painless, unilateral vision loss, often with an altitudinal visual field defect ( Fig. 24-6 ). Acutely disc edema may be focal or diffuse. Because the affected optic disc is swollen, the characteristic risk factor of a crowded optic disc is best observed in the opposite eye in the acute phase. Treatment for NAION is limited—systemic high-dose corticosteroids, intravitreal bevacizumab, and optic nerve decompression surgery are not effective. The risk to the opposite eye is approximately 15 percent over the next several years, and efforts should be made to address vascular risk factors such as hypertension, hyperlipidemia, and tobacco abuse. In addition, it is important to take measures to avoid nocturnal hypotension and treat obstructive sleep apnea if it is present.

Giant-cell arteritis (arteritic anterior ischemic optic neuropathy) is a neuro-ophthalmic emergency which may cause ischemia to the eye and optic nerve, leading to permanent visual loss. In addition, it can affect extraocular muscles and present with diplopia. Systemic symptoms such as jaw claudication, headache, scalp tenderness, fever, anorexia, weight loss, or polymyalgia rheumatica can be important clues to the diagnosis. Laboratory abnormalities include elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as thrombocytosis; a normal ESR may be present in up to one-third of patients, but ESR and CRP together have a combined sensitivity of 99 percent. Immediate treatment with corticosteroids is indicated when giant-cell arteritis is suspected and should be initiated even before biopsy, as histopathologic findings will persist for some time following corticosteroid exposure. For patients with difficulty weaning the dose of corticosteroids, tocilizumab has emerged as an effective immunotherapy targeting the IL6 receptor. Temporal artery biopsy often demonstrates characteristic giant cells, noninfectious granulomas, inflammatory infiltrates, and interruption of the internal elastic lamina, although the phenomenon of skip lesions accounts for some biopsy-negative cases.

Posterior ischemic optic neuropathy is extremely rare and usually follows profound hypotension as a complication of surgery (especially prolonged spinal surgeries in the prone position), an episode of severe anemia, or as a result of giant-cell arteritis. Because the responsible lesion occurs distal to the lamina cribrosa of the optic nerve, the disc is not swollen (thus “posterior”).

Compressive Optic Neuropathy

Compressive optic neuropathies are usually painless (unless other cranial nerves are affected) and subacutely progressive ( Table 24-4 ). When the lesion is intraorbital, associated features may include proptosis and optic disc swelling. Diplopia may be present, owing to restricted extraocular muscles or ocular motor nerve involvement. In contrast, retro-orbital lesions such as pituitary macroadenoma or intracranial meningioma cause visual loss and progressive optic disc pallor, but not optic disc edema. MRI including fat-saturated postgadolinium images is often the diagnostic tool of choice and coronal sequences are particularly helpful to delineate the relevant anatomy ( Fig. 24-7 ).

Table 24-4

Compressive Optic Neuropathy Locations and Etiology

Orbit	Sellar Region
Optic nerve sheath meningioma	Pituitary adenoma
Orbital metastases	Craniopharyngioma
Graves ophthalmopathy	Meningioma
Idiopathic orbital inflammatory pseudotumor	Internal carotid aneurysm
Primary bone lesions (e.g., fibrous dysplasia, Paget disease)	Histiocytosis
Orbital fracture or hemorrhage

Papilledema

The term papilledema is meant to specifically refer to optic disc edema caused by elevated intracranial pressure (ICP), in contrast to the broader term optic disc edema, which also encompasses causes such as local ischemic, infiltrative, and inflammatory causes of optic neuropathy. Papilledema is nearly always bilateral, but can be asymmetric. It can range in appearance from mild to severe, described by using the Frisén scale ( Fig. 24-8 ; Table 24-5 ). Peripapillary hemorrhages can be seen acutely but generally resolve once papilledema becomes chronic. Patients with papilledema often report other symptoms of elevated ICP, including headache, diplopia related to abducens neuropathy, and transient visual obscurations. In contrast to the significant central visual loss that can accompany other intrinsic causes of optic disc edema, the visual loss caused by papilledema often spares the central visual field. Visual loss caused by papilledema often starts with an enlarging blind spot and progresses to arcuate nerve fiber layer defects that may advance toward central visual loss when particularly severe. The most common causes of papilledema are listed in Table 24-6 .

Table 24-5

Frisén Scale for Rating Papilledema

Frisen Grade	Funduscopic Features
0	Normal except for mild blurring of the nasal and temporal disc
1	C-shaped peripapillary gray halo sparing temporal quadrant
2	360-degree gray peripapillary halo, nasal elevation
3	Obscuration of ≥1 major vessel segment at disc border, 360-degree elevation
4	Total obscuration of a major vessel on the disc
5	Partial obscuration of all vessels on the disc

Table 24-6

Causes of Increased Intracranial Pressure Resulting in Papilledema

Etiology	Concomitant Features
Space-occupying brain lesion	Subacutely worsening headache. Various neurologic defects depending on location
Meningoencephalitis	Meningismus, abnormal cerebrospinal fluid chemistries
Subarachnoid hemorrhage	Terson syndrome (intravitreal hemorrhage)
Cerebral edema	Vasogenic (due to loss of intracranial capillary integrity), cytotoxic (due to cell death, often as a result of ischemic stroke), or interstitial edema
Venous sinus thrombosis	Triad of seizure, encephalopathy, and headache is classic acute presentation
Cerebral aqueductal stenosis	May be asymptomatic until critical stenosis causes drowsiness and stupor
Superior vena cava syndrome	Dyspnea, face and arm swelling, Pemberton sign
Right heart failure	Peripheral edema, ascites, hepatomegaly
Sleep apnea	Hypertension, frequent napping, crowded oropharynx
Pulmonary hypertension	Parasternal heave, jugular venous distention, clubbing
Idiopathic intracranial hypertension	Obesity, female sex, childbearing age

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is most characteristically a syndrome of obese females of childbearing age. Pediatric IIH is distinct in that the predisposition for obesity and female sex does not apply. The clinical characteristics of IIH include headache, pulsatile tinnitus, transient visual obscurations, and diplopia related to abducens nerve palsy. Patients with IIH may have variable Frisén grades of optic disc edema. The pathophysiology of IIH is not fully understood, but vitamin A metabolism, endocrine-secreting adipose tissue, and cerebral venous dysregulation are all proposed possibilities. An emerging hypothesis is that cerebral venous sinus stenosis may be an important factor contributing to the pathophysiology of this condition in some patients. Once the homeostatic mechanisms maintaining normal ICP have become impaired, elevated ICP can possibly create or worsen stenosis of the venous sinus, potentially causing a hemodynamically significant trans-stenotic pressure gradient. Higher pressure in the venous sinus may cause impaired function of the arachnoid villi that normally drain CSF into the venous sinuses, thereby perpetuating the cycle of events leading to elevated ICP.

The diagnostic evaluation of IIH requires brain imaging to exclude other etiologies of papilledema including venous sinus thrombosis and mass lesions; this is best accomplished with MRI and MRV. Radiologic features of IIH that are supportive of the diagnosis include an enlarged optic nerve sheath, optic nerve tortuosity, protrusion of the optic nerve head, an empty sella, and concavity or flattening of the posterior globes ( Fig. 24-9 ).

Initial treatment for IIH may include weight loss, low-salt diet, and pharmacotherapy with acetazolamide. In cases relating to predisposing factors such as obstructive sleep apnea, excess vitamin A intake, tetracycline and related compounds, or chronic anemia, the underlying cause must be addressed. When visual loss is severe and progressive despite medical management, surgical options include optic nerve sheath fenestration, lumboperitoneal or ventriculoperitoneal shunting, or stenting of a hemodynamically significant venous stenosis.

Retrochiasmal Vision Loss

Lesions affecting postchiasmal afferent nerve pathways generally produce homonymous visual field loss, referring to visual loss on the same side of the vertical meridian of the visual field of each eye. Unless there is concomitant involvement of the optic nerve or the field loss is bilateral, visual acuity is typically spared. The most common causes of homonymous visual field loss are stroke, followed by trauma and tumors.

Higher order visual areas are organized into a ventral visual stream involving the temporal lobe (the “what” pathway) that is concerned with object recognition, and a dorsal stream including the parietal lobe (the “where” pathway) involved with spatial processing and motion. Ventral pathway dysfunction may produce difficulty with object recognition (specifically face recognition), whereas dorsal pathway lesions are associated with impaired spatial attention. While a unilateral right parietal lesion causes a rightward bias of attention (i.e., left-sided neglect), bilateral parietal lesions cause profound spatial impairment referred to as Balint syndrome. Balint syndrome is characterized by simultanagnosia (difficulty recognizing multiple components of a visual stimulus or scene), optic ataxia (difficulty reaching under visual guidance), and ocular apraxia (difficulty making accurate saccadic eye movements to an intended target).

Neurodegenerative disorders that cause predominant visual deficits early in the clinical course include dementia with Lewy bodies and posterior cortical atrophy, which is typically characterized by Alzheimer disease pathology. The Heidenhain variant of Creutzfeldt–Jakob disease affects the occipital regions first and presents with progressive visual processing deficits quickly leading to profound dementia, myoclonus, and death.

Clinical Assessment

The history in patients with diplopia should concentrate on whether the disorder is binocular or monocular, the orientation of the images, and symptom modifiers. Monocular diplopia—diplopia that remains when one eye is closed—is generally related to ocular causes (e.g., corneal or lens opacity, refractive error), and is not neurologic in origin. It typically resolves with the pinhole test and should prompt ophthalmology referral. In contrast, binocular diplopia resolves with closure of either eye; it is related to misalignment of the eyes and is typically neurogenic in origin. The direction of misalignment and the pattern of misalignment in each position of gaze allow accurate localization. Other factors such as age, associated features (e.g., ptosis, pain), modifiers, and diurnal variation (e.g., fluctuations) guide the differential diagnosis as discussed below.

Ocular misalignment refers to any deviation of the visual axis of one eye compared to the other. Ocular alignment can be measured on examination in several ways. An imprecise method involves estimation of misalignment by displacement of the corneal light reflex (Hirschberg method). Light reflects from the same position on both corneas if the eyes are orthophoric, whereas the light is displaced from the center in one eye when misalignment exists; each millimeter of light reflex displacement equals approximately 7 to 10 degrees or 15 to 20 prism diopters.

The red Maddox rod is a simple method to quantify small amounts of ocular misalignment. The Maddox rod is composed of a series of parallel cylindrical grooves in a piece of red glass, mounted in a circular rim (the original consisted of a single cylindrical rod, hence the name). The device converts a light source into a red line perpendicular to the axis of the rod. The patient views a white light source with the left eye, while the Maddox rod is placed over the right eye. The position of the red line relative to the light source (seen by the left eye) indicates the presence and amount of misalignment. The red line can be made to appear vertically (to measure horizontal deviation from the light) or horizontally (to measure vertical deviation from the light), and prisms can be placed over the Maddox rod until the line intersects the light. If the red line appears to the left of the light, then an exotropia exists. If the line appears to the right of the light, an esotropia is present. If the line appears below the light, then a right hypertropia is present, and a red line perceived above the light indicates a left hypertropia. By convention, vertical misalignment is always quantified by the hypertropic eye.

To perform the alternate cover test, the patient fixates on a target such as a specific letter of the Snellen chart, while the examiner alternately covers one eye and then the other. This technique forces the patient to fixate with the uncovered eye, disrupting binocular fusion and unmasking an underlying misalignment of the two eyes. If the eyes are orthophoric (aligned with each other), then no corrective eye movement will be required to fixate on the target when the occluded eye is switched. If an eye moves down to fix the target immediately after it is uncovered, then a hypertropia exists on that side. An exotropia is identified by an eye that moves in toward the nose to fixate the target once it is uncovered. In contrast, an outward eye movement to fixate a target indicates an esotropia. Prisms of increasing strength can be placed over one eye to neutralize this shift and quantify the misalignment.

These alignment tests are repeated in the nine cardinal positions of gaze to discern the pattern of involvement. If the misalignment is roughly the same amount in different directions of gaze, it is considered comitant , and may be a congenital form of strabismus that is not due to an acquired neurologic lesion. In contrast, if the deviation varies in different directions of gaze, it is considered incomitant , and the pattern of misalignment can help localize the neurologic lesion responsible for the diplopia. An incomitant esodeviation greatest in horizontal gaze indicates lateral rectus weakness on that side, often due to a partial sixth nerve palsy. An incomitant exodeviation indicates medial rectus weakness, often due to partial third nerve palsy or internuclear ophthalmoplegia. An incomitant hyperdeviation that increases in contralateral gaze and with ipsilateral head tilt is the pattern of a fourth nerve palsy. A hyperdeviation in downgaze that switches to the opposite hyperdeviation in upgaze often suggests a partial third nerve palsy, owing to combined weakness of the inferior and superior rectus muscles of the same eye. A hyperdeviation that does not fit the pattern of a fourth nerve palsy or third nerve palsy often represents a skew deviation, which is a supranuclear disturbance of vertical alignment caused by a brainstem or cerebellar lesion. For any pattern of ocular misalignment, orbital processes and ocular myasthenia gravis may also need to be considered.

The motility examination also includes assessment of pursuit, saccades, ductions, and versions. Pursuit is tested with the patient following a target moving slowly (less than 20 degrees/sec). Saccades are rapid eye movements that bring fixation from one target immediately to another. Binocular movements in various directions are known as versions, while ductions refer to the movements of one eye while the other eye is covered.

It can be worthwhile to note a patient’s head position. Patients with diplopia may adopt a head posture to avoid the position of diplopia. For example, patients with impaired abduction of one eye may turn the head toward the side of the palsy. Patients with trochlear nerve palsy may present with a contralateral head tilt and chin-down position to avoid gaze into the diplopic field.

Examination of the eyelids, pupils, and position of the globe also provide important clues to the diagnosis. Ptosis should be quantified through measurement of the height of the palpebral fissure in millimeters. Pupil size should be measured in light, in dark, and with reactivity. Proptosis can be measured in millimeters of anterior displacement of each eye from the lateral canthus.

Anatomic localization is always the first task for a neurologist. The site of lesions causing binocular diplopia may be supranuclear (e.g., skew deviation or vergence dysfunction), or involve the ocular motor nerve nuclei or infranuclear segments of cranial nerves III, IV, and VI, the internuclear segment (i.e., medial longitudinal fasciculus [internuclear ophthalmoplegia]), neuromuscular junction (e.g., myasthenia gravis), or muscle (e.g., trauma, thyroid eye disease, neoplasm). A first step in localization is to consider the most specific patterns of ocular misalignment related to the ocular motor nerves or their nuclei as well as supranuclear and internuclear lesions ( Tables 24-7, 24-8, and 24-9 ). If the misalignment pattern does not conform to these specific patterns, attention should be directed toward neuromuscular junction disease, myopathy, or multiple cranial nerve palsies (e.g., Miller Fisher syndrome, Wernicke encephalopathy). One important caveat is that even if the pattern fits that of an ocular motor nerve, nucleus, or internuclear ophthalmoplegia, mimics such as myasthenia gravis must still be considered.

Supranuclear Causes of Ocular Dysmotility

The supranuclear ocular motor system is principally concerned with coordinating the movements of both eyes together, and when injured, produces gaze preferences or palsies. The set of inputs to the ocular motor nuclei in the brainstem arrive from the cerebral hemispheres, cerebellum, and portions of the brainstem, together governing distinct classes of eye movements including saccades, pursuit, the vestibular ocular reflex, gaze-holding, fixation, optokinetic nystagmus, and vergence. The hallmark of a supranuclear eye movement abnormality is that intact eye movements can be demonstrated when volitional pathways are bypassed, such as with the oculocephalic reflex.

The frontal eye fields of the cerebral hemispheres generate volitional contralateral saccades, and cerebral hemispheric lesions affecting these regions therefore produce a gaze deviation toward the side of the lesion. Occasionally, with deep lesions affecting the basal ganglia, the gaze deviation is toward the side of the lesion (so called wrong-way eyes ). Parietal lesions can interfere with smooth pursuit eye movements following a target moving toward the side of the lesion.

Supranuclear networks also control vergence eye movements. Convergence insufficiency is a relatively common example of vergence dysfunction, characterized by a larger exophoria (with diplopia) at near than far distance.

Within the pons, the paramedian pontine reticular formation just rostral to the abducens (VI) nucleus houses horizontal burst neurons. Lesions in this region produce slow or absent ipsilesional saccades. Burst neurons facilitating vertical saccades reside within the rostral interstitial medial longitudinal fasciculus, which is situated in the dorsal midbrain rostral to the oculomotor nucleus; dysfunction of this region produces slow or absent vertical saccades.

A dorsal midbrain syndrome, which is referred to by the eponym Parinaud syndrome, causes a supranuclear vertical gaze palsy. In its complete form, it is also accompanied by light-near dissociation of the pupils, eyelid retraction, and convergence retraction nystagmus.

The vestibulocerebellum, vermis, and fastigial nuclei perform critical coordination and calibration functions for the ocular motor system. The flocculus and paraflocculus are involved in smooth pursuit, gaze holding, and calibration of the vestibular ocular reflex. The vermis and fastigial nuclei are involved in saccadic and pursuit control. The nodulus and uvula participate in modulation of the vestibular system.

Skew deviation is a supranuclear cause of vertical diplopia, in which the nuclear and infranuclear third and fourth nerves are functioning normally but the supranuclear inputs that maintain normal vertical ocular alignment are perturbed. The vertical misalignment with skew is usually comitant (the same in all positions of gaze). Some cases of skew deviation may be incomitant, but usually not conforming to the pattern of misalignment of a third or fourth nerve palsy. The “high–high low–low rule” can be used to generally localize a lesion causing skew deviation; with lesions above the level of the pontine vestibular decussation, the ipsilesional eye is often hypertropic, and with lesions below this decussation, the ipsilesional eye is usually hypotropic. The ocular tilt reaction is a special circumstance of skew deviation with the additional features of involuntary head tilt and torsion of both eyes.