Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Section 5  Neuro-ophthalmology Chapter 37  Optic neuritis

Figure 37.9  A histogram of myelin fiber area illustrates the protective effect of SOD2 relative to control gene inoculation with AAV-GFP (P < 0.001), the uninoculated experimental autoimmune encephalomyelitis (EAE) nerve (P < 0.005), and the normal optic nerve (P < 0.05). Myelin fiber loss in EAE relative to normal is also shown (P < 0.05) (A). A histogram of retinal ganglion cell (RGC) counts shows the neuroprotective effect of SOD2 relative to control treatment with AAV-GFP (P < 0.005) and uninoculated EAE (P < 0.0001). No significant differences were detected between SOD2- treated and normal optic nerve (P > 0.05). A one-third loss of RGCs was seen in uninoculated EAE relative to the normal optic nerve (P < 0.0005). Treatment with AAV-GFP had a mild protective effect relative to EAE eyes that received no ocular injection (P < 0.05) (B). (Reproduced with permission from Qi X, Lewin AS, Sun L, et al. Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 2007;48:681–691.)

Whether neuroprotective treatments tested in the EAE animal model will suppress RGC and axonal injury that leads to permanent visual disability in optic neuritis and MS patients remains to be proven.

Conclusion

Axonal and neuronal degeneration rather than demyelination is now increasingly recognized as the primary cause of permanent visual and neurological disability in optic neuritis and MS. Currently, there is no effective treatment to suppress or repair this damage. Moreover, the mechanisms leading to neurodegeneration in optic neuritis and MS are poorly understood. Evidence demonstrates that peroxynitrite mediates nitration of key mitochondrial proteins. This commences during the earliest phase of the EAE animal model of MS, well before infiltration of ICs. Mitochondrial oxidative injury impaired mitochondrial bioenergetics and resulted in apoptosis of ganglion cells of the retina and oligodendrocytes in the optic nerve of animals with EAE. These novel findings implicate mitochondrial oxidative stress as a key event in the initiation of optic nerve degeneration and demyelination in EAE. Mitochondria play a key role in the pathogenesis of many neurological diseases, but the role of the organelle has only recently been recognized in MS. More importantly, modulation of mitochondrial gene expression effectively suppressed neurodegeneration in EAE, suggesting that antioxidant gene therapy targeted to mitochondria may be useful in patients with optic neuritis and MS.

1.Optic Neuritis Study Group. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial [see comments]. Arch Ophthalmol 1991;109: 1673–1678.

2.Guy J, Mao J, Bidgood WD Jr. et al. Enhancement and demyelination of the intraorbital optic nerve. Fat suppression magnetic resonance imaging. Ophthalmology 1992;99:713–719.

3.DeBroff BM, Donahue SP. Bilateral optic neuropathy as the initial manifestation of systemic sarcoidosis. Am J Ophthalmol 1993;116:108–111.

4.Galetta S, Schatz NJ, Glaser JS. Acute sarcoid optic neuropathy with spontaneous recovery. J Clin Neuroophthalmol 1989;9:27–32.

5.Dutton JJ, Burde RM, Klingele TG. Autoimmune retrobulbar optic neuritis. Am J Ophthalmol 1982;94:11–17.

6.Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic

neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003;54:38– 50.

7.Bar S, Segal M, Shapira R, et al. Neuroretinitis associated with cat scratch disease. Am J Ophthalmol 1990;110: 703–705.

8.Bhatti MT, Asif R, Bhatti LB. Macular star in neuroretinitis. Arch Neurol 2001;58: 1008–1009.

9.Burton BJ, Leff AP, Plant GT. Steroidresponsive HIV optic neuropathy. J Neuroophthalmol 1998;18:25–29.

10.Larsen M, Toft PB, Bernhard P, et al. Bilateral optic neuritis in acute human immunodeficiency virus infection. Acta Ophthalmol Scand 1998;76:737–738.

11.Rush JA, Ryan EJ. Syphilitic optic perineuritis. Am J Ophthalmol 1981;91: 404–406.

12.Benz MS, Glaser JS, Davis JL. Progressive outer retinal necrosis in immunocompetent patients treated

initially for optic neuropathy with systemic corticosteroids. Am J Ophthalmol 2003;135:551–553.

13.Francis PJ, Jackson H, Stanford MR, et al. Inflammatory optic neuropathy as the presenting feature of herpes simplex acute retinal necrosis. Br J Ophthalmol 2003;87:512–514.

14.Vital DD, Gerard A, Rousset H. [Neurological manifestations of Whipple disease.] Rev Neurol (Paris) 2002;158: 988–992.

15.Anninger WV, Lomeo MD, Dingle J, et al. West Nile virus-associated optic neuritis and chorioretinitis. Am J Ophthalmol 2003;136:1183–1185.

Clinical background

Five eye movement systems are utilized to achieve clear vision: (1) saccadic; (2) smooth pursuit; (3) optokinetic; (4) vestibulo-ocular; and (5) vergence. Four systems generate conjugate movements, called version, but vergence achieves binocular vision by generating disjunctive eye movements that align the two foveas on an object as it approaches the head. Saccades are fast eye movements that bring the fovea to a target, while pursuit, vestibular, optokinetic, and vergence smooth eye movements prevent slippage of retinal images.1,2 Gaze refers here to binocular movements achieved by saccades, smooth pursuit, or optokinetic tracking, and the vesitibulo-ocular reflex (VOR). This chapter reviews the pathophysiology of selected disorders of these movements caused by central nervous system lesions.

Familial paralysis of horizontal gaze is an autosomalrecessive disorder.5,6 Aplasia of the abducens nuclei or nondecussation of motor pathways may explain the gaze palsy. Congenital ocular motor apraxia can be inherited as an autosomal-dominant trait.7

Spinocerebellar ataxia types 1 or 2 (SCA1, SCA2) are autosomal dominant and associated with slow saccades.8 Progressive supranuclear palsy (PSP) with characteristic defective vertical gaze and extrapyramidal signs is associated with a mutation (S305S) in the tau gene on chromosome 17 that results in an increase in the splicing of exon 10, and the presence of tau containing four microtubulebinding repeats.9,10 Autosomal-dominant frontotemporal dementia and parkinsonism linked to chromosome 17, and its subset of families with pallido-ponto-nigral degeneration, are a group of four repeat tauopathies that often have vertical gaze palsy identical to that in PSP.11,12

Key symptoms and signs

Central disorders of gaze impair vision by causing retinal image slip, or inability to attain foveation. The cardinal sign of disordered gaze is limitation of version. Even with a normal range of version, the quality of version can be impaired for specific ocular motor systems, for example, by slow saccades or saccadic pursuit.

Epidemiology

The epidemiology is that of the many diseases that cause gaze disorders.

Genetics

Genetic predisposition is common among neurological disorders and direct inheritance is responsible for some. Gaze palsy may be a sign of lipid storage diseases. Vertical gaze paresis with foam cells or sea-blue histiocytes in the bone marrow is a neurovisceral storage disease with profiles of lipid analysis similar to Niemann–Pick disease type C (NPC).3 Paresis of horizontal saccades is a feature of Gaucher’s disease (GD).4 Saccade initiation failure is often the earliest neurological sign in GD type 3.

Diagnostic workup

Gaze deviations are manifestations of acute and often massive brain damage. Less severe disorders of gaze are apparent with subacute or chronic lesions and often signify discrete involvement of eye movement pathways. Systematic examination of saccades and smooth eye movements and brain imaging are often adequate for diagnosis. An operational classification of the direction of horizontal gaze paresis caused by lesions at different levels of the neuraxis is provided in Table 38.1.

Differential diagnosis

Gaze palsies carry the differential diagnosis of the myriad of disease processes that cause them.

Treatment

Therapy is first directed at the responsible neurological disease. Specific treatment of visual neglect resulting from nondominant parietal lobe damage and visual restoration therapy for homonymous hemianopia remain to be established by clinical trials and readers are referred to other sources.13

Prognosis and complications

The outcomes are determined by the disease causing the gaze disorder; readers may refer to reviews of those conditions.

Etiology

Infarction, hemorrhage, demyelination, neoplasia, and neurodegenerative diseases are common brain disorders affecting gaze.

Pathophysiology

Brainstem control of horizontal saccades

The innervational change in motoneurons during all types of eye movements consists of a phasic discharge (an eye velocity command) and a tonic discharge (an eye position command). During saccades, the phasic discharge consists of a high-frequency pulse of innervation that moves the eyes rapidly against orbital viscous forces. When a new eye position is attained, a position command, called a step change in innervation, is required to sustain position against elastic restoring forces of the eye muscles.1,2

Saccades are generated by excitatory burst neurons in the paramedian pontine reticular formation (PPRF) that project to the ipsilateral abducens nucleus.14 During fixation, the burst neurons are kept silent by omnipause neurons located in the midline of the caudal pons (Figure 38.1).15 Inhibitory burst neurons, located laterally in the rostral medulla, serve to turn antagonist motoneurons off, while the excitatory burst neurons drive the agonist motoneurons.16 Signals from the cerebral cortex and superior colliculus (SC) inhibit the pause neurons, thereby releasing the burst neurons to create the pulse. The step discharge (a position command) is generated from the pulse (a velocity command) by a neural integrator that “integrates” (in the mathematical sense) the pulse. The velocity-to-position neural integrator for horizontal saccades, smooth pursuit, and the VOR is located in the medial vestibular nucleus (MVN) and the nucleus prepositus hypoglossi, which lies just medial to it.17

The abducens nucleus contains both motoneurons to the lateral rectus muscle, and internuclear neurons that project in the contralateral medial longitudinal fasciculus to medial rectus motoneurons (Figure 38.1). These internuclear neurons transmit saccadic, pursuit, and vestibular signals to the medial rectus.

290

III

Figure 38.1  Schema of some brainstem projections for horizontal gaze. Saccades are dispatched when a trigger signal turns off pause neurons, which inhibit burst neurons. Reciprocal inhibition of antagonist muscles is achieved by excitation of inhibitory burst neurons. MR, medial rectus; LR, lateral rectus; III, oculomotor nucleus; MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation; PN, pause neurons; BN, excitatory burst neurons; IBN, inhibitory burst neurons; NPH, nucleus prepositus hypoglossi; MVN, medial vestibular nucleus; VI, abducens nucleus. (Modified from Sharpe JA, Morrow MJ, Newman NJ, et al. Neuroophthalmology: Continuum, American Academy of Neurology. Baltimore: Williams and Wilkins, 1995.)

Brainstem paralysis of horizontal saccades

Unilateral acute lesions of the caudal pontine tegmentum cause contraversive deviation of the eyes. Because the PPRF is damaged, ipsiversive saccades are paralyzed (Table 38.1). Disruption of projections from the vestibular nuclei to the abducens nucleus, or of the abducens nucleus itself, also paralyzes ipsiversive pursuit and the VOR. The eyes cannot be brought beyond the midline toward the side of damage. Contraversive jerk nystagmus is sometimes evident.18,19

Box 38.1  Pontine Horizontal Gaze Paresis

•Unilateral pontine tegmental lesions paralyze conjugate ipsiversive saccades

•Medial longitudinal fasciculus lesions cause pareses of adducting saccades (internuclear ophthalmoplegia) and reduce vertical vestibulo-ocular reflex speed

•Abducens nucleus lesions paralyze ipsiversive saccades, smooth pursuit and vestibular eye motion

•Combined paramedian pontine reticular formation (or abducens nucleus) and medial longitudinal fasciculus damage on one side causes the one-and-a-half syndrome

•The one-and-a-half syndrome consists of paralyzed adduction and abduction of the eye on the lesion side, and paralyzed adduction of the contralateral eye, which is exotropic in the acute stage

Pathophysiology

Figure 38.2  Cortical areas involved in generating voluntary and reflexive saccades to visual targets. The parietal eye field in posterior parietal cortex (PPC) governs the accuracy and latency of visually guided saccades. The frontal eye field (FEF), supplementary eye field (SEF; located in the mesial frontal cortex), and dorsolateral prefrontal cortex (DLPC) regulate voluntary and visually guided and memory-guided saccades (see text for description). VC, striate visual cortex (area V1).

Internuclear ophthalmoplegia (INO) consists of impaired adduction on the side of the lesion in the MLF and abducting jerk nystagmus of the opposite eye.20 In total INO, adduction is paralyzed to saccadic, pursuit, and vestibular stimulation (Box 38.1). A hypertropia on the side of MLF damage, a form of skew deviation, is often present. (Skew deviation is discussed elsewhere.) Slow adducting saccades are the only manifestation of incomplete or chronic MLF lesions.21 Convergence may be lost or spared. Lesions of the MLF disrupt the commands that ascend from the vestibular nuclei (Figure 38.1), resulting in slowed vertical pursuit and vertical VOR movements. Vertical saccades are normal. Gaze-evoked nystagmus occurs during upward, and sometimes downward, fixation.22

Damage to the PPRF or abducens nucleus and the MLF on one side causes paralysis of horizontal movements of the ipsilateral eye in both directions and paralysis of adduction in the opposite eye, a combination called the one-and-a-half syndrome.23 In the acute phase the opposite eye is exotropic (Box 38.1). This “paralytic pontine exotropia” is distinguished from other types of exotropia by slowed adducting saccades in the laterally deviated eye and the horizontal immobility of the eye on the side of pontine damage.24

Unilateral lesions of the midbrain reticular formation cause paresis of contraversive saccades and of ipsiversive or bidirectional smooth pursuit. Such lesions are usually associated with involvement of the ipsilateral oculomotor nucleus, or vertical gaze palsy.25

Box 38.2  Cerebral Saccade Control

•The cerebral hemispheres generate predominantly contraversive saccades

•Parietal eye field controls reflexive saccades to visual targets and other visually guided saccades

•Supplementary eye field governs voluntary sequences of saccades

•Dorsolateral prefrontal cortex contributes to programming saccades using memory of target location

•Acute frontal or parietal lobe lesions cause transient ipsiversive gaze deviation and paresis of contraversive saccades

•Normal horizontal vestibulo-ocular reflex motion to oculocephalic maneuvers is spared with cerebral lesions but often lost toward the side of pontine tegmental lesions

tion.27 The FEF, SEF, and SC dispatch contraversive saccades by delivering signals to the PPRF. In monkeys ablation of either the SC or the FEF produces only transient ipsiversive deviation of the eyes and reduced frequency of contraversive saccades. Bilateral ablation of the FEF and the SC produces enduring paralysis of saccades,28 indicating that redundant, parallel pathways subserve the generation of voluntary and visually guided saccades.

Cerebral cortical control of saccades

The cerebral hemispheres generate contraversive saccades. The frontal eye field (FEF) is reciprocally connected with the parietal eye field (PEF) in the posterior parietal cortex and the superior temporal sulcus. The FEF projects directly to the ipsilateral SC and the midbrain tegmentum, and the contralateral pontine tegmentum.26 The supplementary eye field (SEF) of the supplementary motor area plays a predominant role in directing voluntary sequences of saccades (Figure 38.2). The dorsolateral prefrontal cortex contributes to the advanced planning of environmental scanning using memory of target location (Box 38.2). Whereas the FEF is mainly involved in intentional saccade generation to visual targets, the PEF is more involved in reflexive visual explora-

Cerebral gaze paralysis

Massive acute cerebral lesions of the frontal or parietooccipital regions cause transient ipsiversive deviation of the eyes and inability to trigger contraversive voluntary or visually guided saccades (Table 38.1 and Box 38.2). Soon after, saccades can be initiated up to the midline of craniotopic space, but not beyond. Within hours or days, a full range of saccades recovers. Sparing of horizontal VOR motion to oculocephalic stimulation distinguishes this acute hemispheric gaze palsy from that caused by unilateral damage to caudal pontine tegmentum.18,29 Rehabilitation of contraversive saccades is nearly complete, but they are hypometric. Occasionally, thalamic hemorrhage causes transient contraversive, or “wrong-side,” deviation of the eyes.30

Pathophysiology

FEF

V5

Pontine nuclei

Paraflocculus

Vermis lobules

VI, VII FN

MVNVI

Figure 38.4  Putative pursuit pathway showing double decussation. The first decussation is from pontine nuclei (dorsolateral pontine nucleus (DLPN) and nucleus reticularis tegmenti pontis (NRTP)), the ocular motor vermis (lobules VI and VII) and to the cerebellar paraflocculus, which inhibits neurons in the medial vestibular nucleus (MVN). Excitatory projections from the MVN, the contralateral abducens nucleus (VI), constitute a second decussation. The caudal part of the fastigial nucleus (FN) processes pursuit signals from the vermis. (Modified from Sharpe JA. Neuroanatomy and neurophsiology of smooth pursuit: lesion studies. Brain Cognition 2008;68:241–254.)

nuclei (Figure 38.4). Direct connections from the vestibular nuclei to ocular motor nuclei complete the principal pursuit circuit in the brainstem. The vestibular nucleus activates the lateral rectus motoneurons and internuclear neurons in the contralateral abducens nucleus (and inhibits them in the ipsilateral abducens nucleus). The pontocerebellar projections, through the contralateral middle cerebellar peduncle, form a first decussation of the pursuit pathway, and the effect of MVN neurons on the contralateral abducens nucleus is a second decussation (Figure 38.3). The double decussation renders the pursuit pathway from the cerebral hemisphere to the abducens nucleus effectively ipsilateral.55

Smooth pursuit paresis

When smooth eye movements fail to match the speed of a slowly moving target, catch-up saccades compensate for the low velocity of smooth tracking, called saccadic pursuit. It is the sign of smooth pursuit paresis (Box 38.4).55

Unidirectional pursuit paresis

Saccadic pursuit occurs toward the side of posterior parietal and parietotemporal lobe lesions (Table 38.2), particularly

Box 38.4  Smooth Pursuit Paresis

•Saccadic tracking of a slowly moving object is the clinical sign of impaired, or paretic, smooth pursuit

•Ipsiversive pursuit defects consist of lowered smooth pursuit speed toward the side of unilateral cerebral lesions of area V5 or the frontal eye field, or their projections to the brainstem

•Ipsiversive pursuit defects are identified in response to a target moving anywhere in the visual field, either ipsilateral or contralateral to the side of the hemispheric lesion

•Retinotopic pursuit defects consist of lower smooth pursuit speed and inaccurate saccades in the area of the contralateral visual field subserved by damaged striate cortex, optic radiation, or area V5

•Craniotopic pursuit defects consist of reduced smooth pursuit speed and lowered saccade amplitudes in the hemirange of movement contralateral to unilateral acute frontal or parietal lobe lesions. They are identified in response to a pursuit target presented on the opposite side of the orbital midline

•Omnidirectional pursuit defects consist of low smooth pursuit speed in both horizontal and both vertical directions. They signify extensive unilateral or bilateral focal cerebral lesions, or diffuse cerebral cortical, basal ganglia, cerebellar, or brainstem disease

involving the angular gyrus and prestriate cortical Brodmann areas 19, 37, and 39 (area V5).51,52 Ipsiversive saccadic pursuit is usually associated with contralateral hemianopia but the smooth eye movement disorder is independent of the visual field defect. It does not accompany hemianopia from pregeniculate or striate cortical damage.56 Cerebral hemispheric control of smooth pursuit is not entirely ipsiversive, since unilateral lesions can cause some bidirectional impairment of horizontal smooth pursuit.51,52,55

Frontal lobe lesions may also cause ipsiversive pursuit paresis,57 attributed to FEF involvement.58 But saccadic pursuit after unilateral frontal lobe damage often appears to be bidirectional on clinical examination. Area V5 and dorsolateral frontal lobe provide two parallel routes through which cortical pursuit commands are conveyed to the brainstem. Impairment of ipsiversive pursuit accompanies posterior thalamic hemorrhage and may be explained by involvement of the posterior limb of the internal capsule which transmits pursuit commands.51

Optokinetic nystagmus asymmetry

Small hand-held striped tapes or drums, that are used in the clinic to test optokinetic nystagmus (OKN), activate both smooth pursuit and optokinetic smooth eye movements, but the slow phases of OKN stimulated by small targets are generated largely by the pursuit system. The pursuit system is concerned with foveal tracking of small objects, while the optokinetic system is responsible for panretinal tracking of large objects. Nonetheless small OKN stimuli are useful in the clinical setting since paretic pursuit typically accompanies impaired OKN, and asymmetry of OKN is more readily observed than is asymmetry of pursuit. Like smooth pursuit, OKN is defective when stimuli move toward the side of cerebral lesions.59 The amplitude and frequency of the nys-

tagmus response are reduced, but the primary deficit is reduction in the slow phase velocity. By convention nystagmus direction is named by the quick phase direction; therefore, defective slow phases of OKN (and smooth pursuit) toward the side of a posterior parietotemporal lobe lesion are identified at the bedside as defective OKN beating away from the side of the lesion.

Some patients with acute unilateral parietal or frontal lobe damage do not track targets past the orbital midline into the contralateral craniotopic field of gaze. This is a craniotopic paresis of pursuit.60 Cerebral hemispheric pursuit defects can be grouped into four categories55,61 (Table 38.2).

Ipsiversive saccadic pursuit also occurs toward the side of lesions that involve the cerebellar flocculus/paraflocculus (Figure 38.2). Unilateral tegmental damage in the caudal pons and rostral medulla can impair contraversive smooth pursuit.18,62 Greater paresis of contraversive pursuit after pontomedullary damage may signify disruption of excitatory projections from the vestibular nucleus to the contralateral abducens nucleus, or damage to connections with the cerebellum.

Omnidirectional pursuit paresis

Saccadic pursuit in all directions (Table 38.2) results from diffuse cerebral, cerebellar, or brainstem disease (Box 38.4); for example, multiple sclerosis,63 Parkinson’s disease,35 Alzheimer’s disease,64 and cerebellar degenerations,44 lower smooth pursuit speed. Similarly, advanced age, sedative drugs, fatigue, and inattention also cause saccadic tracking.65,66 When qualified by these influences, horizontal and vertical saccadic pursuit is the most sensitive ocular motor sign of brain dysfunction.

Vestibulo-ocular reflex disorders

Head rotation elicits the angular VOR. The ratio of the output of the angular VOR (smooth eye movement speed in one direction) to the input of the reflex (head speed in the opposite direction) is its gain. VOR gain must approximate 1.0 in order to prevent slippage of retinal images and maintain clear vision. The eyes and head must also be 180° out of phase; this normal phase difference is called zero, by convention. Abnormal gain or phase of the reflex causes visual blur and oscillopsia. Nystagmus quick phases correct for failures of smooth eye movement motion to match head speeds. Imbalance of the VOR is caused by damage to the vestibular labyrinthine or nerve on one side or by asymmetric damage to its central brainstem connections to the ocular motor nuclei. This imbalance creates jerk nystagmus beating toward the side of defective vestibular smooth eye motion (Box 38.5).

Low gain of the VOR signifies bilateral peripheral vestibular or brainstem disease. Acute unilateral labyrinthine or vestibular nerve damage lowers gain acutely but compensation occurs within days or weeks so that a gain asymmetry

of the reflex persists only during high frequency (>~2 Hz) head motion. High gain of the VOR (>1.0) is uncommon

and is a feature of cerebellar disease.67

Oculocephalic reflex

The oculocephalic reflex (OCR) elicited by passive head on body rotation (doll’s head reflex) tests the range of the VOR.

Box 38.5  VOR disorders

•The vestibulo-ocular reflex (VOR) achieves clear vision during head motion by moving the eye in the opposite direction at the same speed

•Abnormal VOR gain (ratio of eye velocity/head velocity) causes oscillopsia or blurring of vision

•Low VOR gain (head velocity > eye velocity) is a feature of peripheral vestibular or brainstem damage

•High VOR gain (eye velocity > head velocity) is an uncommon effect of cerebellar disease

•Abnormal gain can be detected by reduction in visual acuity during high-frequency head shaking

•Marked asymmetry of the VOR creates jerk nystagmus beating toward the direction of lowered smooth eye movement speed

•Asymmetry of the VOR can also be detected by the head impulse test and by the presence of nystagmus after head shaking

Limited range of the VOR indicates disruption of brainstem VOR pathways or damage to ocular motor nerves, nuclei, or muscles. Conversely, normal range of the OCR, in the presence of limited range of saccades or smooth pursuit, indicates that a lesion responsible for the gaze paresis is supranuclear. However the OCR does not assess the VOR alone. Passive movement of the head at low frequencies activates visual following responses, both smooth pursuit and optokinetic, as well as the VOR. If the VOR is absent, visual following reflexes can move the eyes at the same velocity as the head if the motion is below 1 Hz. Only in comatose patients do low-frequency passive OCR movements test the VOR alone.

Visual acuity during head shaking

When patients are instructed to shake their head from side to side at 2–3 Hz through an amplitude of about 20°, Snellen visual acuity should remain about the same as with the head immobile. If acuity falls by two or three lines the VOR gain is low or high, or its phase is abnormal (Box 38.5). If the VOR is hyperactive (gain > 1.0), the patient perceives movement of the image in the same direction as head movement. If the VOR is hypoactive (gain < 1.0), images appear to move opposite to the direction of head motion. One can also examine the eyes for nystagmus. If the VOR is normal while the patient fixates an object during high-frequency head oscillation, the eyes should remain stable in space. Vestibular nystagmus indicates abnormal VOR gain or phase.

Ophthalmoscopy during head shaking

Another technique for detecting VOR abnormalities is examination of one fundus while the patient shakes the head from side to side at 2–3 Hz.68 If the VOR is normal the optic disc (or other fundus landmark) remains stable. If the VOR is overactive (gain > 1.0) the disc moves in the same direction as the head whereas if the VOR is hypoactive (gain < 1.0) the disc moves opposite to the direction of head movement. Care must be taken that the head does not sway from side to side, since head translation causes the disc to move, even when the VOR is normal. This test can be difficult to perform and interpret. Patients must wear their regular glasses during the test, since the gain of the VOR is adapted

Pathophysiology

Box 38.6  Vertical Saccades Palsy

•Vertical gaze paresis indicates a bilateral or paramedian lesion, usually in the rostral midbrain tegmentum

•Upward saccadic palsy signifies damage to the posterior commissure or its adjacent fibers of passage

•Downward saccadic palsy signifies damage to neurons of the rostral intestinal nucleus of the medial longitudinal fasciculus (riMLF) and their projections to the interstitial nucleus of Cajal (INC)

•Combined upward and downward saccadic palsy indicates more extensive damage to the ventral midbrain tegmentum involving the riMLFs or their projections

according to the magnifying power of their lenses. Magnification can be predicted by the formula: magnification power = 40/(40 – D), where D is the lens power in diopters. For example, a –5 D myopic patient would have a VOR gain of 0.89 in darkness, instead of 1.0.

Head-shaking nystagmus

Patients with unilateral peripheral vestibular lesions have nystagmus directed away from the affected side after vigorous head shaking.69 The patient is instructed to shake the head through 40° of range at about 2 Hz for 20 seconds. Then, when the head is stopped, the observer examines the patient’s eyes under Frenzel glasses (plus 20 lenses which magnify the eyes and blur the patient’s fixation). Slow phases of head-shaking nystagmus (HSN) are directed toward the impaired ear. It lasts less than 20 seconds, and is sometimes followed by a low-amplitude reversed HSN with slow phases away from the impaired ear. After central vestibular lesions HSN may be directed in planes different from the direction of head shake or with slow phases away from the side of brainstem damage.70

Head impulse test

While the patient fixates a distant target the head is briskly moved to one side. The eyes should stay on target and the examiner should see only a smooth compensatory eye movement. Patients with unilateral vestibular loss make one or more saccades to bring the eyes on target when the head is moved toward the side of the impaired ear. As noted by Gauthier and Robinson, saccades in the same direction as the VOR signify inability of vestibular smooth eye movements to match head velocity.71 Thus a patient with right vestibular neuritis will make leftward saccades during rightward head movements. Compensatory, refixation saccades during rapid horizontal head rotations indicate a horizontal semicircular canal or vestibular nerve lesion on the side toward which the head is being rotated.72 The head must be moved at high velocity, because the VOR eventually becomes rebalanced for low-velocity head movements after unilateral peripheral vestibular damage.

Vertical gaze

As a general principle, vertical gaze is mediated by bilateral circuits and vertical gaze palsies signify bilateral or paramedian lesions (Box 38.6). Commands for vertical saccades

descend from the cerebral hemispheres, and ascend from the caudal PPRF, to the rostral interstitial nucleus of the MLF (riMLF), located rostral to the third nerve nucleus, and within the MLF. Excitatory short lead burst neurons for vertical and torsional saccades reside in the riMLF.73 Excitatory burst neurons with upward on-direction project bilaterally to oculomotor nucleus neurons (Figure 38.2), whereas neurons with downward on-directions project ipsilaterally to motoneurons of the oculomotor and trochlear nuclei74; this makes isolated lesions of the riMLF more likely to impair downward saccades selectively.75

Either a unilateral or bilateral pretectal lesion near the posterior commissure may destroy projections from both riMLF and the interstitial nucleus of Cajal (INC), selectively abolishing upward saccades. The nucleus of the posterior commissure (nPC) also contains upward short lead burst neurons that project across the commissure.76 The nPC projects to the contralateral nPC, riMLF, and INC and intra­ laminar nucleus of the thalamus. Lesions of the posterior commissure paralyze upward saccades in monkeys and humans73,77 as part of the pretectal syndrome.

The riMLF projects to the INC, which in concert with the vestibular nucleus and the paramedian tracts serves as the eye velocity-to-position integrator for vertical eye motion.78,79 The INC is located within the MLF just caudal to the riMLF in the rostral midbrain. The INC participates in vertical gaze holding, generation of the vertical and torsional VOR, and vertical smooth pursuit.80

Vertical smooth pursuit channels ascend from the vesti­ bular nuclei to the midbrain. They group of the vestibular nucleus, located at the junction of the brainstem and cerebellum, the MLF, and the superior cerebellar peduncle in monkeys carry signals for vertical pursuit. Pathways outside the MLF appear to carry much of the vertical smooth pursuit commands in humans.22 Lesions in the pretectum that affect the posterior commissure degrade upward pursuit.29,81 Both upward and downward smooth pursuit are limited by damage in the ventral tegmentum of the midbrain.82,83

Table 38.3  Pretectal syndrome

Paralysis of upward saccades

Paralysis of upward saccades and pursuit

Paralysis of upward gaze and the vestibulo-ocular reflex

Retraction and convergence oscillations

Eyelid retraction

Light-near dissociated enlarged pupils

eyelids (Table 38.3).84,85 Destruction of the posterior commissure is sufficient to cause the pretectal syndrome, but bilateral, or unilateral, extracommissural pretectal lesions that interrupt its fibers have the same effect. Limitation of upward gaze is also an effect of normal senescence.42 The pretectal syndrome has the eponyms sylvian aqueduct and dorsal midbrain syndromes.

Downward gaze palsy and ventral midbrain lesions

Lesions in the rostral midbrain tegmentum, ventral to the aqueduct of Sylvius, cause selective paralysis of downward saccades by disrupting projections from the riMLF to the INC and the oculomotor and trochlear nuclei. The responsible lesions are usually bilateral infarcts, but unilateral paramedian lesions can also paralyze downward gaze or both upward and downward gaze73,82; the pupils are usually of medium size and poorly reactive to light and during accommodation. We term these distinct ocular motor defects the ventral midbrain syndrome.

In both the dorsal and ventral syndromes, the vertical VOR and smooth pursuit often appear to be spared. However, reduced gain, limited amplitude, and abnormal phase lead of the vertical VOR, and slow, limited pursuit, occur with ventral infarcts involving the INC and riMLF.82,86

Upward gaze palsy in the pretectal syndrome

The pretectal syndrome consists of paralysis of upward saccades, light-near dissociation of the pupils, retraction, and convergent oscillations of the eyes which are evoked by attempted upward saccades, and retraction of the upper

Acknowledgment

This work was supported by Canadian Institutes of Health Research (CIHR) grants MT 15362, ME 5504, and MOP 57853.

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