Saccadic Dyskinesia, Other Involuntary Eye Movements, and Gaze Deviations

■ A small saccade of 0.5–3° that takes the eye away from fixation, followed by a saccade that returns the eye back to fixation after about 200 msec (i.e., presence of intersaccadic interval during which visual feedback occurs) ■ So named because of its appearance in eye movement tracings ■ Normal subjects often have square wave jerks (SWJ), but the rate is only 4–6 per minute. ■ Pathologic SWJ occurs at a rate of >15 per minute. ■ Cerebellar diseases Square wave jerks result from damage of projections from the frontal eye field, rostral pole of the superior colliculus, and the central mesencephalic reticular formation to the omnipause cells in the pons. If symptomatic, SWJ may be treated with methylphenidate, diazepam, phenobarbital, or amphetamines. ■ Burst of saccades with defective steps of innervation (i.e., stepless saccades) ■ Conjugate or monocular Saccadic pulses are associated with multiple sclerosis. Saccadic pulses result from damage of omnipause cells or the neural integrator.

Introduction to the Six Eye Movement Systems and the Visual Fixation System

One main reason that we make eye movements is to solve a problem of information overload. A large field of vision allows an animal to survey the environment for food and to avoid predators, thus increasing its survival rate. Similarly, a high visual acuity also increases survival rates by allowing an animal to aim at a target more accurately, leading to higher killing rates and more food. However, there are simply not enough neurons in the brain to support a visual system that has high resolution over the entire field of vision. Faced with the competing evolutionary demands for high visual acuity and a large field of vision, an effective strategy is needed so that the brain will not be overwhelmed by a large amount of visual input. Some animals, such as rabbits, give up high resolution in favor of a larger field of vision (rabbits can see nearly 360°), whereas others, such as hawks, restrict their field of vision in return for a high visual acuity (hawks have vision as good as 20/2, about 10 times better than humans). In humans, rather than using one strategy over the other, the retina develops a very high spatial resolution in the center (i.e., the fovea), and a much lower resolution in the periphery. Although this “foveal compromise” strategy solves the problem of information overload, one result is that unless the image of an object of interest happens to fall on the fovea, the image is relegated to the low-resolution retinal periphery. The evolution of a mechanism to move the eyes is therefore necessary to complement this foveal compromise strategy by ensuring that an object of interest is maintained or brought to the fovea. To maintain the image of an object on the fovea, the vestibulo-ocular (VOR) and optokinetic systems generate eye movements to compensate for head motions. Likewise, the saccadic, smooth pursuit, and vergence systems generate eye movements to bring the image of an object of interest on the fovea. These different eye movements have different characteristics and involve different parts of the brain.

Ocular Motor Disorders Caused by Lesions in the Cerebrum

■ Receives inputs from the frontal eye field (FEF), supplementary eye field (SEF), dorsolateral prefrontal cortex (DLPC), internal medullary lamina of the thalamus, and substantia nigra pars compacta (SNpc, the dopaminergic portion) ■ Projects to substantia nigra pars reticulata (SNpr) and the globus pallidus ■ Receives inhibitory inputs from the caudate nucleus ■ Sends inhibitory signals to intermediate layers of the superior colliculus Parkinson’s disease is a progressive neurodegenerative disorder that affects about 1% of adults over 60 years of age. 1. Loss of pigmented dopaminergic neurons in the SNpc 2. Presence of Lewy bodies (not specific for Parkinson’s disease) 3. Decreased dopamine reaching the striatum causes increased inhibitory output from the globus pallidus internal segment and SNpr, thereby inhibiting movement 1. Standard therapy: levadopa and carbidopa (a peripheral decarboxylase inhibitor to reduce motor fluctuations and dyskinesia) e.g., such as Sinemet or Sinemet CR 2. Monoamine oxidase-β inhibitor (e.g., Selegiline); may have neuroprotective effect 3. Dopamine agonist (e.g., bromocriptine, a D2 agonist, and apomorphine, a D1 and D2 agonist) 4. Anticholinergics (e.g., Benzhexol) 5. Amantadine (seldom used) 6. Surgery ■ Thalamotomy or thalamic deep brain stimulation of the ventral lateral nucleus to reduce medically refractory tremor. The mechanism of action is unknown; these procedures may destroy autonomous neural activity (synchronous bursts) that has the same frequency as the limb tremor. ■ Pallidotomy or pallidal stimulation to reduce contralateral dyskinesia (e.g., bradykinesia, rigidity, and tremor).

Nystagmus

Nystagmus is involuntary eye oscillations initiated by slow eye movements that drive the eye away from the target. In contrast, saccadic dyskinesia consists of involuntary, fast eye movements that take the fovea off target. Nystagmus usually arises from lesions in the 1. Vestibulo-ocular system (VOR) 2. Gaze-holding system 3. Smooth pursuit and optokinetic system. 1. Pendular versus jerk ■ Pendular (see A in the figure below): both phases are slow eye movements. ■ Jerk (see B, C, and D in the figure below): one phase consists of fast eye movements (quick phase), and the other consists of slow eye movements. By convention, the direction of nystagmus is named after the direction of quick phases that return the eye to the target. 2. Plane: horizontal, vertical, torsional, or combined form (e.g., rotary, elliptical) 3. Conjugacy ■ Conjugate: Both eyes move in the same direction with similar amplitude and frequency. ■ Disconjugate: Both eyes move in the same direction with different amplitude and frequency (e.g., internuclear ophthalmoplegia). ■ Disjunctive: The eyes move in opposite directions (e.g., oculomasticatory myorhythmia seen in Whipple’s disease).

Disorders Affecting the Extraocular Muscles

Chronic progressive external ophthalmoplegia (CPEO) occurs in 90% of patients with mitochondrial myopathy. It is characterized by a slowly progressive ptosis and ophthalmoplegia. The ophthalmoplegia is usually preceded by ptosis for months to years, and downgaze is usually intact. Kearns-Sayre Syndrome is a subtype of chronic progressive external ophthalmoplegia. Most cases are sporadic and associated with single deletions of mitochondrial DNA. Ragged-red fibers are seen on light microscopy (using modified Gomori trichrome stain). ■ Due to accumulation of enlarged mitochondria under the sarcolemma of affected muscles ■ Found in skeletal muscles, orbicularis, and extraocular muscles ■ On electron microscopy, the mitochondria contain paracrystalline (“parking lot”) inclusions and disorganized cristae that are sometimes arranged concentrically. 1. Muscle biopsy (e.g., deltoid) 2. ERG 3. Electrocardiogram (EKG) 4. Genetic testing There is no effective treatment for CPEO. Maintaining a high-lipid, low-carbohydrate diet, taking co-enzyme Q10, biotin, or thiamine, and avoiding medications such as valproate and phenobarbital may be helpful. ■ MELAS stands for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. ■ Maternally inherited; caused by point mutations of mitochondrial DNA (A3243G mutation accounts for about 80% of all cases) ■ Clinical features 1. Strokelike episodes before age 40 (hallmark feature) 2. Encephalopathy characterized by developmental delay, seizures, or dementia 3. Mitochondrial dysfunction manifested as lactic acidosis or ragged-red fibers 4. Ophthalmoplegia 5. Optic atrophy and pigmentary retinopathy 6. Diabetes mellitus and hearing loss ■ MNGIE stands for mitochondrial neuro-gastrointestinal encephalomyopathy. ■ Autosomal recessive; caused by mutations in the nuclear gene ECGF1, resulting in thymidine phosphorylase deficiency, which in turn causes deletions, duplications, and depletion of mitochondrial DNA ■ Clinical features: ophthalmoplegia, peripheral neuropathy, leukoencephalopathy, and gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea) with intestinal dysmotility SANDO stands for sensory ataxic neuropathy, dysarthria, and ophthalmoplegia. It is sporadic and is caused by multiple deletions of mitochondrial DNA.

Disorders of Neuromuscular Transmission

Myasthenia gravis is the most common disorder affecting the neuromuscular junction (incidence: 5 per 100,000). Ocular involvement accounts for initial complaints in 75% of patients. Of patients presenting with ocular myasthenia, 50–80% eventually develop generalized myasthenia, usually within two years of onset. Myasthenia gravis is an autoimmune disease caused by the presence of antibodies against acetylcholine receptors, which leads to decreased number of available receptors (usually less than one-third that of normal). It is associated with other autoimmune diseases, including thymoma, dysthyroidism, sarcoidosis, pernicious anemia, aplastic anemia, and collagen vascular diseases (e.g., rheumatoid arthritis, lupus, ankylosing spondylitis, ulcerative colitis, Sjögren’s syndrome). ■ Side effects: cholinergic (e.g., bradycardia, angina, bronchospasm) ■ Steps for performing Tensilon test: 1. Prepare 10 mg/mL Tensilon in a tuberculin syringe, 0.6 mg atropine in a tuberculin syringe, and 10 mL normal saline. 2. Establish intravenous access using butterfly needle; flush with 1 mL normal saline. 3. Inject 0.2 mL Tensilon, flush with 1 ml normal saline, and wait 1 min for possible side effects. 4. Inject 0.6 mL Tensilon, flush with 1 mL normal saline, then attach atropine syringe. 5. Wait 3 min; improvement of ptosis or diplopia constitutes a positive test. Improvement of ptosis after application of ice for 2 min on the ptotic eyelid constitutes a positive test. The ice test is especially useful for very young, elderly, or ill patients. Improvement of ptosis or ocular alignment after 30–45 min of sleep constitutes a positive test. ■ Repetitive nerve stimulation with supramaximal stimuli delivered at 2–3 Hz: Rapid decrement of the amplitude of compound muscle action potentials (CMAPs) ≥10–15% confirms the diagnosis in 95% of cases. ■ Single-fiber electromyography (EMG; e.g., frontalis muscle) is highly sensitive (88–99% sensitivity). A positive test consists of increased jitter (increased latency between nerve stimulation and action potential of muscle fibers) and increased blockage (response failure). Acetylcholine receptor antibody is not detectable in about 15% of patients. Muscle-specific kinase is detected in 20% patients who have no acetylcholine receptor antibody and is usually detected in patients with generalized myasthenia gravis.

Nuclear and Infranuclear Ocular Motor Disorders

Binocular diplopia is usually caused by strabismus, whereas monocular diplopia is usually caused by ocular diseases. Incomitant diplopia is usually caused by an acquired strabismus resulting from abnormal innervation or mechanical restriction. The oculomotor (third) nerve: ■ Innervates the medial rectus, superior rectus, inferior rectus, inferior oblique, and levator palpebrae muscles ■ Carries parasympathetic fibers to the iris sphincter and the ciliary body. ■ Common causes of third nerve palsy: Adults: aneurysms, vascular disease (including ischemia, diabetes, hypertension, and inflammatory arteritis), trauma, migraine Children: birth trauma, accidental trauma, neonatal hypoxia, migraine The third nerve originates from the oculomotor nucleus complex, which lies at the ventral border of the periaqueductal gray matter in the midbrain. The nerve fascicle passes ventrally through the medial longitudinal fasciculus, the tegmentum, the red nucleus, and the substantia nigra, and finally emerges from the cerebral peduncle to form the oculomotor nerve trunk, which lies between the superior cerebellar and posterior cerebral arteries. The nerve then passes through the subarachnoid space, running beneath the free edge of the tentorium. It continues lateral to the posterior communicating artery and below the temporal lobe uncus, where it runs over the petroclinoid ligament. It pierces the dura mater at the top of the clivus to enter the cavernous sinus. Within the cavernous sinus, the nerve runs along the lateral wall of the sinus together with the trochlear nerve and the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve. As it leaves the cavernous sinus, it divides into the superior and inferior divisions, which pass through the superior orbital fissure, and enters the orbit within the annulus of Zinn. Within the orbit, the smaller superior division runs lateral to the optic nerve and ophthalmic artery and supplies the superior rectus and levator palpebrae muscles. The larger inferior division supplies the medial rectus, inferior rectus, and inferior oblique muscles, as well as the iris sphincter and ciliary body.

Ocular Motor Disorders Caused by Lesions in the Cerebellum

The vestibulocerebellum consists of the flocculus, ventral paraflocculus, nodulus, and uvula. ■ The flocculus receives inputs from the vestibular nucleus and nerve, nucleus prepositus hypoglossi (NPH), inferior olivary nucleus, cell groups of the paramedian tracts (PMT), nucleus reticularis tegmenti pontis (NRTP), and mesencephalic reticular formation. ■ The ventral paraflocculus receives inputs from contralateral pontine nuclei. ■ Project to ipsilateral superior and medial vestibular nuclei, and the y-group ■ Receive input from the medial and inferior vestibular nuclei, vestibular nerve, NPH, and inferior olivary nucleus ■ Project to the vestibular nuclei ■ The oculomotor vermis consists of parts of the declive, folium, tuber, and pyramis. ■ Receives inputs from the inferior olivary nucleus, vestibular nuclei, NPH, paramedian pontine reticular formation (PPRF), NRTP, and dorsolateral and dorsomedial pontine nuclei ■ Projects to the caudal fastigial nucleus ■ Stimulation of the Purkinje cells in the dorsal vermis elicits contralaterally directed saccades and smooth pursuit ■ Receives inputs from the dorsal vermis, inferior olivary nucleus, and NRTP ■ Decussates and projects via the uncinate fasciculus of the brachium conjunctivum to the contralateral PPRF, rostral interstitial nucleus of the medial longitudinal fasciculus, nucleus of the posterior commissure, omnipause neurons in nucleus raphe interpositus, the mesencephalic reticular formation, and superior colliculus ■ Neurons in the fastigial oculomotor region (FOR) fire during both ipsilateral and contralateral saccades. 1. The contralateral FOR neurons burst before the onset of saccade, and the onset of firing is not correlated with any property of the saccade. 2. Conversely, the time of onset for neurons in the ipsilateral FOR varies, with bursts occurring later for larger saccades. 3. Thus, the difference in time of onset between contralateral and ipsilateral FOR activity encodes the amplitude of saccades (i.e., the larger the difference in time of onset, the larger the saccade amplitude). Eye movement abnormalities in uncinate fasciculus lesion include hypometric ipsilesional saccades and hypermetric contralesional saccades (“contrapulsion”). Arnold-Chiari malformation is a malformation of the medullary–spinal junction with herniation of intracranial contents through the foramen magnum. The three types are illustrated in the figure below.

The Vergence System

Vergence eye movements shift the gaze point between near and far, such that the image of a target is maintained simultaneously on both foveae. Unlike other eye movement systems, vergence movements are disjunctive, meaning that the eyes move in opposite directions. To move from a far to a near target, the eyes converge (i.e., rotate toward the nose) so that the lines of sight of the two eyes intersect at the target. To aim at a target farther away, the eyes diverge (i.e., rotate toward the temples). When the target is located at optical infinity, the lines of sight are parallel. During deep sleep, deep anesthesia, and coma, the eyes diverge beyond parallel, indicating that eye alignment is normally actively maintained by the brain because the orbits, in which the eyeballs are located, are divergent. The vergence system is believed to be relatively new evolutionarily. Just as a new version of computer software tends to have bugs, perhaps it is for this reason that vergence is the last of the eye movement systems to reach full development in children, that it is often the first system to be affected by fatigue, alcohol, and other drugs, and that defective vergence is a common cause of strabismus and diplopia. Vergence eye movements are very slow, lasting 1 sec or longer. One reason for this may be that vergence, unlike saccades, is driven by visual feedback, which normally takes at least 80 msec. Another reason may be that the speed of vergence movements is limited by how fast the lenses change shape (accommodation) and how fast the pupils constrict. There may simply be no advantage for vergence to take place quickly and then wait for the lenses and pupils to catch up. The triad of convergence, accommodation, and pupillary constriction constitutes the near triad. The two most important stimuli for vergence are retinal image blur and retinal disparity. If the retinal image of an object is blurred, the target is either too near or too far away.

The Saccadic System

Saccades are fast conjugate eye movements that move both eyes quickly in the same direction, so that the image of an object of interest is brought on the foveae. Saccades can be made not only toward visual targets, but also toward auditory and tactile stimuli, as well as toward memorized targets. Saccades can be generated reflexively, and they are responsible for resetting the eyes back to the mid-orbital position during vestibulo-ocular or optokinetic stimulation. Saccades need to be fast to get the eyes on the target as soon as possible. They also need to be fast because our eyes act like cameras with slow shutters—vision is so blurred during saccades that the eyes have to move quickly to minimize the time during which no clear image is captured on the foveae. Indeed, saccades are the fastest type of eye movements, and they are among the fastest movements that the body can make. Saccade speed is not under voluntary control but depends on the size of the movement, with larger saccades attaining higher peak velocities. It has been estimated that we make more than 100,000 saccades per day. The burst neuron circuits in the brainstem provide the necessary motor signals to the extraocular muscles for the generation of saccades. There is a division of labor between the pons and the midbrain, with the pons primarily involved in generating horizontal saccades and the midbrain primarily involved in generating vertical and torsional saccades. However, because eye movements are a component of cognitive and purposeful behaviors in higher mammals, the process of deciding when and where to make a saccade occurs in the cerebral cortex. Not only does the cortex exert control over saccades through direct projections to the burst neuron circuits, it also acts via the superior colliculus. The superior colliculus is located in the midbrain and consists of seven layers: three superficial layers and four intermediate/ deep layers. The three superficial layers receive direct inputs from both the retina and striate cortex, and they contain a retinotopic representation of the contralateral visual hemifield.