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. 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.
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). Paresis of horizontal saccades is a feature of Gaucher’s disease (GD). Saccade initiation failure is often the earliest neurological sign in GD type 3.
Familial paralysis of horizontal gaze is an autosomal-recessive disorder. 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.
Spinocerebellar ataxia types 1 or 2 (SCA1, SCA2) are autosomal dominant and associated with slow saccades. 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 microtubule-binding repeats. 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.
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 .
| System involved | Frontal lobe | Parietotemporal lobes | Rostral midbrain | Pons | Cerebellum |
|---|---|---|---|---|---|
| Saccades | Contraversive | Contraversive | Contraversive | Ipsiversive | Contraversive, (acute) |
| Smooth pursuit | Ipsiversive or bidirectional * | Ipsiversive * | Ipsiversive or bidirectional | Ipsiversive | Ipsiversive or bidirectional |
| Vestibulo-ocular reflex | Spared | Spared | Usually spared | Ipsiversive | Spared |
* See Table 38.2 for additional types of pursuit paresis.
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.
Prognosis and complications
The outcomes are determined by the disease causing the gaze disorder; readers may refer to reviews of those conditions.
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.
Saccades are generated by excitatory burst neurons in the paramedian pontine reticular formation (PPRF) that project to the ipsilateral abducens nucleus. During fixation, the burst neurons are kept silent by omnipause neurons located in the midline of the caudal pons ( Figure 38.1 ). Inhibitory burst neurons, located laterally in the rostral medulla, serve to turn antagonist motoneurons off, while the excitatory burst neurons drive the agonist motoneurons. 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.
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.
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.
Internuclear ophthalmoplegia (INO) consists of impaired adduction on the side of the lesion in the MLF and abducting jerk nystagmus of the opposite eye. 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. 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.
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Unilateral pontine tegmental lesions paralyze conjugate ipsiversive saccades
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Medial longitudinal fasciculus lesions cause pareses of adducting saccades (internuclear ophthalmoplegia) and reduce vertical vestibulo-ocular reflex speed
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Abducens nucleus lesions paralyze ipsiversive saccades, smooth pursuit and vestibular eye motion
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Combined paramedian pontine reticular formation (or abducens nucleus) and medial longitudinal fasciculus damage on one side causes the one-and-a-half syndrome
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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
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. 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.
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.
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. 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 exploration. 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, indicating that redundant, parallel pathways subserve the generation of voluntary and visually guided saccades.
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The cerebral hemispheres generate predominantly contraversive saccades
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Parietal eye field controls reflexive saccades to visual targets and other visually guided saccades
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Supplementary eye field governs voluntary sequences of saccades
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Dorsolateral prefrontal cortex contributes to programming saccades using memory of target location
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Acute frontal or parietal lobe lesions cause transient ipsiversive gaze deviation and paresis of contraversive saccades
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Normal horizontal vestibulo-ocular reflex motion to oculocephalic maneuvers is spared with cerebral lesions but often lost toward the side of pontine tegmental lesions
Cerebral gaze paralysis
Massive acute cerebral lesions of the frontal or parieto-occipital 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. Rehabilitation of contraversive saccades is nearly complete, but they are hypometric. Occasionally, thalamic hemorrhage causes transient contraversive, or “wrong-side,” deviation of the eyes.
Basal ganglia
The basal ganglia participate in saccadic eye movements. The pars reticulata of the substantia nigra (SNr) and globus pallidus are major outflow pathways of the basal ganglia. In monkeys, neurons of the SNr decrease their tonic discharge rate before saccades to visual, auditory, or remembered targets. The FEF projects to the caudate nucleus which in turn projects to the SNr. The SNr projects to the SC and inhibits it. Saccades are triggered when SNr inhibition of the SC is removed by suppression of the tonic activity of SNr neurons.
Cerebellum
Cerebellar vermis lobules VI and VII, comprising the ocular motor vermis, and the caudal part of the fastigial nucleus and its outflow pathways control saccade accuracy. Saccadic dysmetria usually indicates a lesion of the ocular motor vermis or deep nuclei. Overshoot dysmetria (hypermetria) is apparent when the patient makes refixation saccades between two targets. Multiple-step hypometric saccades (discussed below) occur toward the side of lesions involving the cerebellar hemisphere.
Saccadic paresis
Paresis of saccades may be evident as delay in initiating them, undershooting the target (hypometria), or slowness of their trajectories ( Box 38.3 ).
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Saccade paresis consists of delayed or hypometric or slow saccades
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Saccade delay is usually a manifestation of cerebral cortical or basal ganglia disease
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Apraxia of saccades consists of severe delay of voluntary saccades with preservation of visual triggered reflexive saccades and nystagmus quick phases. Head saccades may be required to start eye saccades
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Dysmetric saccades may be hypermetric or hypometric. Hypometria is a sign of cerebral cortical, basal ganglia, or cerebellar damage. Hypermetria is a sign of cerebellar cortical or deep nuclear involvement
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Pulsion of saccades consists of unidirectional hypermetria of horizontal saccades, with hypometria in the opposite direction, and deviation of vertical saccades toward the side of hypermetria
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Pulsion toward the side of lateral medulla and inferior cerebellar peduncle damage is called ipsipulsion. Pulsion away from superior cerbellar peduncle damage is contrapulsion
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Slow saccades signify damage to paramedian pontine reticular formation burst neurons or omnipause neurons
Saccadic delay
Saccades are dispatched with latency about 200 ms after a visual stimulus. Saccadic delay in all directions can be an enduring sign of cerebral cortical and basal ganglia involvement, as in Alzheimer’s disease and Parkinson’s disease. Reflexive saccades to visual targets are delayed mainly contralateral to parietal lobe lesions. Prolonged saccadic latency is an obvious and fundamental defect in congenital ocular motor apraxia, and head motion is required to dispatch coincident saccades. Acquired ocular motor apraxia after frontal and parietal lobe damage consists of delayed and hypometric voluntary saccades with relative preservation of reflexive saccades to visual targets and intact nystagmus quick phases.
Hypometric saccades
Saccadic refixations normally consist of one or two steps. Refixations of three or more dysmetric steps to a target are called multiple-step hypometric saccades. They occur in some normal subjects after fatigue or in advanced age. They are conclusively abnormal if they predominate in one direction. Hypometric saccades occur contralateral to cerebral hemispheric damage and ipsilateral to cerebellar cortical lesions. Omnidirectional hypometric saccades accompany bilateral cerebral, basal ganglia, or cerebellar disease.
Lateropulsion of saccades is a form of dysmetria that occurs after lateral medullary infarcts, a phenomenon called ipsipulsion, in order to specify the direction of saccadic dysmetria relative to the side of the lesion. It consists of a triad of: (1) overshoot of ipsiversive saccades; (2) undershoot of contraversive saccades; and (3) ipsiversive deviation of vertical saccades ( Box 38.3 ). Lesions of the superior cerebellar peduncle and uncinate fasciculus cause contrapulsion, which is the triad of overshoot of contraversive saccades, undershoot of ipsiversive saccades, and contraversive deviation of vertical saccades.
Slow saccades
Damage to excitatory burst neurons in the PPRF or to inhibitory burst neurons or to omnipause neurons ( Figure 38.1 ) causes slow saccades. Lesions in the pontine tegmentum such as infarcts, tumors, degenerations such as PSP, Huntington’s disease, and variants of spinocerebellar degenerations, multiple sclerosis, lipid storage diseases, and infections (e.g., acquired immunodeficiency syndrome (AIDS), Whipple disease) cause slowing of voluntary and reflex saccades and of the fast phases of vestibular and optokinetic nystagmus.
Slow saccades are also caused by peripheral neuromuscular disease (ocular myopathy and nerve palsies). Involvement of cerebral projections to the brainstem by strokes, and degenerations such as Parkinson’s disease and Alzheimer’s disease, causes mild, but clinically imperceptible slowing. Mental fatigue, reduced vigilance, and ingestion of sedative drugs cause slight slowing of saccades.
Cerebral, cerebellar, and brainstem smooth pursuit circuits
Middle temporal (MT) visual area and middle superior temporal (MST) visual area of the superior temporal sulcus and inferior parietal lobe (IPL) or area 7a contain neurons that respond to image motion and generate smooth pursuit in monkeys. In humans the angular gyrus and prestriate cortical Brodmann areas 19, 37, and 39 at the temporal-occipital-parietal junction are the homologs of areas MT and MST (visual area V5) in the monkey brain. Area V5 and IPL project to the FEF and to pontine nuclei ( Figure 38.3 ).
Lesions of area MT cause retinotopic pursuit defects that are related to target position on the retina. Pursuit eye movements have subnormal speed when the target falls upon the region of the visual field represented by the damaged area. Retinotopic pursuit defects can be identified in the laboratory after parieto-temporo-occipital junction lesions in humans, but not by clinical examination ( Table 38.2 and Box 38.4 ). In contrast, lesions of area MST cause directional pursuit defects. Ipsiversive pursuit speed is reduced, regardless of target location on the retina.
