Chapter 1: Relevant Anatomy and Physiology

Nystagmus in infancy and childhood outlines the understanding, evaluation, and treatments of nystagmus in infancy and childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians and scientists in the care of infants and children with nystagmus. The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus: algorithms for examination; descriptions of diagnostic techniques; medical, surgical, and alternative treatments of the visual system in infants and children; methodologies for investigation, including analysis software, models of the ocular motor system, and current hypotheses on the pathophysiology of ocular motor oscillations. Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them. The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for differential diagnosis and treatment options. Each chapter summarizes the results of ocular motor research in a narrative manner, identifying the important ideas and observations that point to underlying neurophysiological mechanisms. Based on insights from the authors' combined 75 years of clinical experience, Nystagmus in Infancy and Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the treatment of this condition.

OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 1 relevant anatomy and physiology 1.1 INFRA NUCLEAR OCULAR MOTOR ANATOMY 1 1.1.1 Extraocular Muscles 1 1.1.2 Extraocular Muscle Pulleys 4 1.1.3 Orbital Tissues 6 1.1.4 Extraocular Muscle/Orbit Nervous Anatomy 6 1.2 SUPRA NUCLEAR OCULAR MOTOR ANATOMY 8 1.2.1 Frontal Eye Fields 8 1.2.2 Superior Colliculus 9 1.2.3 Brainstem Control of Eye Movements 10 1.2.4 Vestibular Nuclei 10 1.2.5 Cerebellum 11 1.3 AFFERENT SYSTEM 12 1.3.1 Retina 12 1.3.2 Optic Nerve 13 1.3.3 Lateral Geniculate 14 1.3.4 Geniculostriate 14 1.3.5 Association Cortex 14 1.3.6 Ocular Motor Proprioception 14 1.4 EFFERENT SYSTEM 15 1.4.1 Smooth Pursuit System 15 1.4.2 Saccadic System 15 1.4.3 Vergence System 15 1.4.4 Vestibulo-Ocular System 16 The ocular motor system can make the eyes do anything it wants to. —Bert L. Zuber (circa 1972) EY E MOV EM ENTS bring visual stimuli to the fovea and also maintain foveal fi xation of stationary and moving targets during head movements. These movements are performed by the ocular motor system that consists of ocular motor nerves and nuclei in the brainstem originating in the cerebral cortex, cerebellum, vestibular structures, and the extraocular muscles. Anatomically, the ocular motor system may be divided according to location into infranuclear, nuclear, internuclear, and supranuclear components. It is important to distinguish between supranuclear, internuclear, nuclear, and infranuclear (orbital, cranial nerves) disorders because the disturbances have highly varied causes and present different clinical pictures. Eye-movement abnormalities of supranuclear origin are characterized by gaze palsies, tonic gaze deviation, saccadic and smooth pursuit disorders, vergence abnormalities, nystagmus, and saccadic oscillations. Supranuclear disorders such as nystagmus in infancy and childhood result from lesions above the level of the ocular motor nerve nuclei. 1.1 INFRANUCLEAR OCULAR MOTOR ANATOMY 1.1.1 Extraocular Muscles The insertions of the rectus muscles extend from the equator of the eye to the limbus early on in development. By processes of disparate differentiation between the sclera and the rectus • 01_Hertle_Ch01.indd 1 1 9/6/2012 9:46:32 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN tendon, posterior recession of the tendon from the limbus, and contemporaneous growth of the anterior segment of the eye, these tendons reach their adult location only between the ages of 18 months and 2 years.1,2 The tendons of origin and insertion of the extraocular muscles arise from mesenchymal tissue similar to that of their respective muscles. These tendon-muscle groups have developed from superior and inferior mesenchymal complexes. In humans there are three pairs of extraocular muscles in each orbit: a pair of horizontal rectus muscles, a pair of vertical rectus muscles, and a pair of oblique muscles. 3 The four rectus muscles are attached to the sclera anterior to the equator near the cornea (see Fig. 1.1). The two oblique muscles approach the globe from in front, at the medial side of the orbit, and continue obliquely and laterally to insert on the sclera posterior to the equator on the temporal part of the globe. The rectus muscles are almost flat narrow bands that attach themselves with broad, thin tendons to the globe. There are four of these muscles: the medial, lateral, superior, and inferior. The origins of the rectus muscles, the superior oblique muscle, and the levator muscle of the upper lid are arranged in an approximately circular fashion (the annulus of Zinn), surrounding the optic canal and in part the superior orbital fissure. Th rough this oval opening created by the origins of the muscles, the optic nerve, the ophthalmic artery, and parts of cranial nerves III and VI enter the muscle cone formed by the body of the rectus muscles. The interlocking of muscle and tendon fibers at the site of origin creates an extremely strong anchoring of the extraocular muscles. Attachments exist between the origins of the medial and superior recti and the dura of the optic nerve. The medial and lateral rectus muscles follow the corresponding walls of the orbit for a good part of their course, and the inferior rectus muscle remains in contact with the orbital floor for only about half its length. The superior rectus muscle is separated from the roof of the orbit by the levator muscle of the upper lid. If the rectus muscles were to continue their course in their original direction, they would not touch the globe; at about 10 mm posterior to the equator, the muscle paths curve toward the globe rather abruptly and eventually insert on the sclera at varying distances from the corneal limbus. The musculoorbital tissue connections (the muscle pulleys) are responsible for their changes in course. The insertions FIGURE 1.1 Orbital structures controlling eye movements. Parasagitt al section of the orbit showing bones, extraocular muscles, and cranial nerve III (CN III) of the orbit. CG, ciliary ganglion; ID CN III, inferior division of cranial nerve III; IO, inferior oblique; IR, inferior rectus; LP, levator palpebrae superioris; LR, cut ends of lateral rectus; MR, medial rectus; ON, optic nerve; SD CN III, superior division of cranial nerve III; SO, superior oblique; SR, superior rectus. 2 • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 2 9/6/2012 9:46:32 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN of the rectus muscles do not lie on a circle that is concentric with it but rather on a spiral (the spiral of Tillaux). The insertion of the medial rectus muscle is closest to the corneal limbus, followed by the inferior, lateral, and superior rectus insertions, with the superior rectus insertion being the most distant. The lines of insertion are generally not straight; they are curved and sometimes even wavy. The straightest ones are the insertions of the medial and lateral rectus muscles, but these too are often slightly convex toward the corneal limbus. The distance of the tendon from the limbus may be influenced by age and axial length of the eye. From its origin above and medial to the optic foramen, the superior oblique courses anteriorly in a line parallel with the upper part of the medial wall of the orbit, reaching the trochlea at the angle between the superior and medial wall. The trochlea is a tube 4 to 6 mm long formed in its medial aspect by bone (the trochlear fossa of the frontal bone). The rest of the circumference is composed of connective tissue that may contain cartilaginous or bony elements. After passing the trochlea, the superior oblique muscle turns in laterodorsally, forming an angle of about 54° with the pretrochlear or direct portion of the muscle. A fibrillar, vascular sheath surrounds the intratrochlear superior oblique tendon. Th is portion of the tendon consists of discrete fibers with few interfibrillar connections. Each fiber of FIGURE 1.2 the tendon moves through the trochlea in a sliding, telescoping fashion with the central fibers undergoing maximal excursion and the peripheral fibers the least excursion. The total travel of the central fibers appears to be 8 mm in either direction. A bursa-like structure lies between the trochlear “saddle” and the vascular sheath of the superior oblique tendon. At about the distal third of the direct portion (10 mm behind the trochlea), the muscle becomes tendinous and remains tendinous in its entire postt rochlear or reflected part. The tendon passes under the superior rectus muscle, fans out, and merges laterally with the sclera to the vertical meridian, forming a concave curved line toward the trochlea. The anterior end of the insertion lies 3.0 to 4.5 mm behind the lateral end of the insertion of the superior rectus muscle and 13.8 mm behind the corneal limbus (see Fig. 1.2). The posterior end of the insertion lies 13.6 mm behind the medial end of the insertion of the superior rectus muscle and 18.8 mm behind the corneal limbus. The width of the insertion of the superior oblique muscle varies greatly (from 7 to 18 mm) but is 11 mm on average. The medial end of the insertion lies about 8 mm from the posterior pole of the globe. Near its insertion the posterior border of the muscle is related to the superior vortex vein. The length of the direct part of the superior oblique muscle is about 40 mm and that of the reflected tendon is about 19.5 mm. Insertional anatomy of the extraocular muscles. All numbers are averages in millimeters. Nystagmus in Infancy and Childhood • 3 01_Hertle_Ch01.indd 3 9/6/2012 9:46:35 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN From a physiologic and kinematic standpoint, the trochlea is the origin of the muscle. The inferior oblique muscle is the shortest of all the eye muscles, being only 37 mm long. It arises in the anteroinferior angle of the bony orbit in a shallow depression in the orbital plate of the maxilla near the lateral edge of the entrance into the nasolacrimal canal. The origin is readily located by drawing a perpendicular line from the supraorbital notch to the lower orbital margin. The muscle continues from its origin backward, upward, and laterally, passing between the floor of the orbit and the inferior rectus muscle. It inserts by a short tendon (1 to 2 mm) in the posterior and external aspect of the sclera. The width of the insertion varies widely (5 to 14 mm) and may be around 9 mm on average. The insertion forms a curved concave line toward the origin of the muscle. Its anterior margin is about 10 mm behind the lower edge of the insertion of the lateral rectus muscle; its posterior end is 1 mm below and 1 to 2 mm in front of the macula. Near its insertion, the posterior border of the muscle is related to the inferior vortex vein. Unlike the other extraocular muscles, the inferior oblique is almost wholly muscular. It forms an angle of about 51° with the vertical plane of the globe. The medial and lateral rectus muscles have only horizontal actions. The medial rectus muscle is the primary adductor of the eye, and the lateral rectus muscle is the primary abductor of the eye. The superior and inferior rectus muscles are the primary vertical movers of the eye. The superior rectus acts as the primary elevator; the inferior rectus acts as the primary depressor of the eye. This vertical action is greatest with the eye in the abducted position. The direction of pull of the muscles forms a 23° angle relative to the visual axis in the primary position, giving rise to secondary and tertiary functions. The secondary action of vertical rectus muscles is torsion. The superior rectus is an incyclotorter, and the inferior rectus is an excyclotorter. The tertiary action of both muscles is adduction. The superior and inferior oblique muscles are the primary muscles of torsion. The superior oblique creates incyclotorsion, and the inferior oblique creates excyclotrosion (Table 1.1). 1.1.2 Extraocular Muscle Pulleys Modern imaging techniques such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) have revealed that the paths of the rectus muscles remain fi xed relative to the orbital wall during excursions of the globe and even after large surgical transpositions.4,5 There is no sideslip of the rectus muscles in relation to the orbital walls when the eye moves from primary into secondary gaze positions. Demer and coworkers suspected from these fi ndings that there must be musculo-orbital coupling through tissue connections that constrain the Table 1.1 Functions of the Extraocular Muscles M USCLE PR I M A RY AC T ION S E C ON DA R Y AC T ION TERTI A RY AC T ION Medial rectus Lateral rectus Superior rectus Inferior rectus Inferior oblique Superior oblique Levator palpebrae Adduction Abduction Elevation Depression Excyclotorsion Incyclotorsion Eyelid elevation ––– ––– Incyclotorsion Excyclotorsion Elevation Depression ––– ––– ––– Adduction Adduction Abduction Abduction ––– The superior muscles are incyloductors; the inferior muscles, excycloductors. The vertical muscles are adductors; the oblique muscles, adductors. 4 • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 4 9/6/2012 9:46:37 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN muscle paths during rotations of the globe.4–10 Subsequent studies with high-resolution MRI confi rmed this notion by demonstrating retroequatorial inflections of the rectus muscle paths. Gross dissection of orbits and histological and histochemical studies showed that these inflections are caused by musculo-orbital tissue connections in the form of fibroelastic sleeves that consist of smooth muscle, collagen, and elastin. During contraction the muscles travel through these sleeves, which act as pulleys by restraining the muscle paths. The orbital layer of the rectus muscle inserts directly on the pulley, whereas the global layer continues anteriorly to insert into the sclera.4–10 As Figure 1.3 shows, these pulleys are located in a coronal plane anterior to the muscle bellies and about 5 to 6 mm posterior to the equator. They are compliant rather than rigid, receive rich innervation involving numerous neurotransmitters in humans and nonhuman primates, and change their positions as a function of gaze direction.4–10 For instance, the pulleys of the horizontal rectus muscle move posteriorly during muscle contraction. Th is adjustability of pulley positions and the different insertion sites of the global and orbital layers of extraocular muscles may play a major but still undefi ned role in ocular kinematics. Several lines of evidence, MRI, CT, gross examinations, surgical exposures, and histological studies in humans and monkeys strongly suggest that the orbital layer of each rectus muscle inserts on its corresponding pulley, rather than on the globe.4–10 These anatomic differences in the two muscle layers suggest differences in their functions: the orbital layer probably acts against the continuous elastic load of the pulley suspension, whereas the global layer acts against the intermittent, viscous load of the antagonist extraocular muscle. Pulley Ring Glob Orbitaal Layer l Layer r l Laye Orbita al Layer b Glo Pulley Sling Smooth Muscle Collagen Elastin Trochlea LPS SO SR LR Pulley Sling IO Pulley Ring MR IR IO Orbital Layer FIGURE 1.3 Anatomy of the extraocular muscle “pulley” system around the recti muscles. IR, inferior oblique; IR, inferior rectus; LG, lacrimal gland; LPS, levator palpebrae superioris; LR, lateral rectus; LR-SR, lateral rectus-superior rectus; MR, medial rectus; MR-IR, medial rectus-inferior rectus; MR-SR, medial rectus-superior rectus; SR, superior rectus; SOT, superior oblique tendon. Nystagmus in Infancy and Childhood • 5 01_Hertle_Ch01.indd 5 9/6/2012 9:46:37 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 1.1.3 Orbital Tissues The eyeball is suspended within the orbit by a system of fasciae. The bulk of the system is made up of Tenon’s capsule, which is a condensation of fibrous tissue that covers the eyeball from the entrance of the optic nerve to near the corneal limbus, where it is fi rmly fused with the conjunctiva. Except for this area of fusion, the two structures are separated by the subconjunctival space. Tenon’s capsule is also separated from the sclera. Between the two is the episcleral space. On its outer aspect the capsule is intimately related to the orbital reticular tissue. Its posterior edge is not clearly delineated; it is thin and more or less continuous with the meshwork of the orbital fat. In their extracapsular portions, the extrinsic eye muscles are enveloped by the pulley system and muscle sheath.1,11 Th is sheath is a reflection of Tenon’s capsule and runs backward from the entrance of the muscles into the subcapsular space for a distance of 10 to 12 mm. At the lower aspect of the entrance, Tenon’s capsule is reduplicated. At the upper aspect, it continues forward as a single membrane. The muscle sheaths of the four rectus muscles are connected by a formation known as the intermuscular membrane, which closely relates these muscles to each other. In addition, there are numerous extensions from all the sheaths of the extraocular muscles, which form an intricate system of fibrous attachments interconnecting the muscles, attaching them to the orbit, supporting the globe, and contributing to the pulley system.12 1.1.4 Extraocular Muscle/Orbit Nervous Anatomy The oculomotor nerve (cranial nerve III) contains somatic motor fibers to the levator palpebrae, inferior rectus, medical rectus, superior rectus, inferior oblique, and sympathetic efferent fibers (preganglionic fibers) to the ciliary ganglion. The postganglionic fibers connected with these supply the ciliary muscle and the sphincter of the iris. The axons arise from the nucleus of the oculomotor nerve and pass in bundles through the posterior longitudinal bundle, the tegmentum, the red nucleus, and the 6 medial margin of the substantia nigra in a series of curves and fi nally emerge from the oculomotor sulcus on the medial side of the cerebral peduncle. The oculomotor nucleus lies in the gray substance of the floor of the cerebral aqueduct subjacent to the superior colliculus and extends in front of the aqueduct a short distance into the floor of the third ventricle. The inferior end is continuous with the trochlear nucleus. It is from 6 to 10 mm. The nucleus of the oculomotor nerve contains several distinct groups of cells that differ in size and appearance from each other and send their axons each to separate muscles. Much uncertainty still exists as to which group supplies which muscle. There are seven of these groups or nuclei on either side of the midline and one medial nucleus.13–16 The trochlear nerve (cranial nerve IV) contains somatic motor fibers only. It supplies the superior oblique muscle of the eye. Its nucleus of origin, trochlear nucleus, is a small, oval mass situated in the ventral part of the central gray matter of the cerebral aqueduct at the level of the upper part of the inferior colliculus. The axons from the nucleus pass downward in the tegmentum toward the pons, but they turn abruptly dorsalward before reaching it and pass into the superior medullary velum, in which they cross horizontally to decussate with the nerve of the opposite side; they emerge from the surface of the velum, immediately behind the inferior colliculus. The nuclei of the two sides are separated by the raphé, through which dendrites extend from one nucleus to the other.16–19 The trigeminal nerve (cranial nerve V) contains somatic motor and somatic sensory fibers. The motor fibers arise in the motor nucleus of the trigeminal and pass ventrolaterally through the pons to supply the muscles of mastication. The sensory fibers arise from the unipolar cells of the semilunar ganglion; the peripheral branches of the T-shaped fibers are distributed to the face and anterior two-thirds of the head; the central fibers pass into the pons with the motor root and bifurcate into ascending and descending branches that terminate in the sensory nuclei of the trigeminal ganglion. The motor nucleus of the trigeminal is situated in the upper part of the pons beneath the lateral angle of the fourth • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 6 9/6/2012 9:46:42 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN ventricle. It is serially homologous with the facial nucleus and the nucleus ambiguus (motor nucleus of the vagus and glossopharyngeal) that belong to the motor nuclei of the lateral somatic group.19–26 The axons arise from large pigmented multipolar cells. The motor nucleus receives reflex collaterals and terminals from (1) the terminal nucleus of the trigeminal of the same and a few from the opposite side, via the central sensory tract (trigeminothalamic tract); (2) the mesencephalic root of the trigeminal; (3) the posterior longitudinal bundle; (4) and probably fibers in the formatio reticularis. It also receives collaterals and terminals from the opposite pyramidal tract (corticopontine fibers) for voluntary movements.19–26 The terminal sensory nucleus consists of an enlarged upper end, the main sensory nucleus, and a long more slender descending portion that passes down through the pons and medulla to become continuous with the dorsal part of the posterior column of the gray matter, especially the substantia gelatinosa of the spinal cord. The main sensory nucleus lies lateral to the motor nucleus beneath the superior peduncle. It receives the short ascending branches of the sensory root. The cells of the sensory nucleus are of large and medium size and send their axons into the formatio reticularis, where they form a distinct bundle, the central path of the trigeminal (trigeminothalamic tract), which passes upward through the formatio reticularis and tegmentum to the ventrolateral part of the thalamus.19–26 Most of the fibers cross to the trigeminothalamic tract of the opposite side. Th is tract lies dorsal to the medial fi llet, approaches close to it in the tegmentum, and terminates in a distinct part of the thalamus. From the thalamus impulses are conveyed to the somatic sensory area of the cortex by axons of cells in the thalamus through the internal capsule and corona radiata. The abducens nerve (cranial nerve VI) contains somatic motor fibers only that supply the lateral rectus muscle of the eye.15,16,27,28 The fibers arise from the nucleus of the abducens nerve and pass ventrally through the formatio reticularis of the pons to emerge in the transverse groove between the caudal edge of the pons and the pyramid. The nucleus is serially homologous with the nuclei of the trochlear and oculomotor above and with the hypoglossal and medial part of the anterior column of the spinal cord below.15,16,27,28 It is situated close to the floor of the fourth ventricle, just above the level of the striæ medullares. Voluntary impulses from the cerebral cortex are conducted by the pyramidal tract fibers (corticopontine fibers). The abducens nucleus probably receives collaterals and terminals from the ventral longitudinal bundle (tectospinal fasciculus)—fibers that have their origin in the superior colliculus, the primary visual center, and are concerned with visual reflexes.15,16,27,28 The sensory innervation of the extraocular muscles is a contentious issue. Two distinct types of sensory receptors have been identified within human extraocular muscles, namely muscle spindles and palisade endings (myotendinous cylinders), but their precise function is not fully understood.19,22,23,25,29–35 The other main sensory receptors found within skeletal muscle, Golgi tendon organs, have as yet not been identified within human extraocular muscles, although they have been described in monkeys.24,33,34,36–38 Muscle spindles are found within the proximal and distal regions of human infant and adult extraocular muscles and are located at the junction of the orbital and global layers. Although they are found at a density similar to that of spindles in hand and neck muscles, suggesting a role in fi ne motor control, they also show features that hypothesize an ability to generate a proprioceptive signal. Palisade endings, a class of muscle receptor found exclusively within extraocular muscles, including those of humans, are located at the distal myotendinous junction of the multiply innervated non-twitch fibers of the global layer.24,33,34,36–38 They may be the principal source of proprioceptive feedback from extraocular muscles. Studies in the monkey suggest that proprioceptive signals ascend from the extraocular muscles to the central processing structures via the trigeminal nucleus. The precise pathway in humans has yet to be established. There is increasing scientific and clinical evidence that a nonvisual afferent signal, most likely to be derived from extraocular muscle proprioceptors, can under certain conditions influence visuomotor behavior. It may well be Nystagmus in Infancy and Childhood • 7 01_Hertle_Ch01.indd 7 9/6/2012 9:46:42 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN that for the majority of individuals with normal visual function and normal oculomotor systems that vision itself, combined with efference copy, is sufficient to determine eye position. In such individuals, extraocular muscle proprioception may have litt le to contribute to the control of eye movements and the representation of visual space. However, under certain circumstances of reduced or impaired vision or in those with ocular motility disorders, afferent feedback from the extraocular muscles might assume greater significance.24,33,34,36–38 1.2 SUPRANUCLEAR OCULAR MOTOR ANATOMY 1.2.1 Frontal Eye Fields The saccade-related activity of the superior colliculus neurons is shaped by inputs from the posterior parietal cortex, the frontal eye fields, and the substantia nigra pars reticulata (see Fig. 1.4). 39 The posterior parietal cortex is involved in the visual guidance of saccades by shaping the visual inputs to the superior colliculus.40 The posterior parietal cortex contains neurons that are modulated by visual attention, that is, by how behaviorally relevant are visual stimuli. They respond more effectively when the stimulus is the target for an eye movement. The frontal eye fields form an executive center that can selectively activate superior colliculus neurons, playing a role in the selection and production of voluntary saccades.40 The frontal eye fields are also involved in suppressing reflexive saccades and generating voluntary, nonvisual saccades. The complementary executive control exerted on saccade generation by the frontal eye fields and the superior colliculus is revealed by the effect of selective and combined ablation. 39,41–43 Lesions of the superior colliculus prevent the generation short-latency reflexive saccades, whereas the generation of voluntary saccades is disrupted by frontal-eye-field lesions. Although saccades can still be produced after FIGURE 1.4 Brainstem structures controlling eye movements. Parasagitt al section of the cerebrum and brainstem showing the areas of the ocular motor nuclei and brainstem structures involved with internuclear and supranuclear pathways. CN II, second cranial nerve (optic); CN III, third cranial nerve; MLF, medial longitudinal fasciculus; IC, inferior commissure; SC, superior colliculus. 8 • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 8 9/6/2012 9:46:42 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN the ablation of either the superior colliculus or the frontal eye fields, a combined ablation of these two structures results in the complete abolition of saccadic eye movements. The substantia nigra pars reticulata funnels inputs from the frontal cortex and acts as a gate for the voluntary control of saccades, keeping in check the superior colliculus activity. 39,41–43 The neural activity in the substantia nigra maintains the superior colliculus tonically inhibited to prevent unwanted saccades. Prior to a voluntary saccade, this tonic inhibition is reduced by inputs from the caudate, which is activated by signals form the cortex. Experimental and clinical studies specify the role of frontal eye fields in the volitional, inhibitory control of visually triggered saccades. The parietal lobe instead seems mainly concerned with privileged target selection. A parallel processing of saccade-related signals occurs in corticostriatal circuits. Evidence for peristriate and parietal cortical areas to encode the information relevant to smooth pursuit generation is provided by animal and clinical studies.40,43 1.2.2 Superior Colliculus The superior colliculus provides both the motor command to the PPRF’s burst neurons and the trigger command to the omnipause neurons.44–46 It is a laminated structure situated on the roof of the midbrain (see Fig. 1.5). It sends projections to both the horizontal (paramedian pontine reticular formation [PPRF]) and vertical gaze centers (rostral interstitial nucleus of the medial longitudinal fasciculus [riMLF]), providing the motor command to move the eye to an intended new position for the foveation of a visual stimulus.44–46 The superior colliculus contains a topographic motor map composed of neurons that discharge a high-frequency burst of action potentials immediately prior to saccades that have a specific vector, that is, a direction and amplitude, which is independent of the initial position of the eyes in the orbit.47 The integrity of the superior colliculus is crucial for the production of short-latency reflexive saccades, including the “express” saccades whose latency approaches the fastest time for visual FIGURE 1.5 The superior colliculus are a pair of oval masses composed of alternating layers of gray and white matter. They are centers for ocular movements. Some of the connections to the superior colliculus include the retina, visual and nonvisual cerebral cortex, inferior colliculus, paramedian pontine reticular formation, thalamus, basal ganglia, and spinal cord ventral gray horn. The fibers of the medial longitudinal fasciculus form a fringe on its ventrolateral side. 1-Superior colliculus, 2-Brachium of superior colliculus, 3-Medial geniculate nucleus, 4-Brachium of inferior colliculus, 5-Central gray substance, 6-Cerebralaqueduct, 7-Visceral nucleus of oculomotor nerve (Edinger-Westphal nucleus), 8-Nucleus of oculomotor nerve, 9-Medial lemniscus, 10-Central tegmental tract, 11-Medial longitudinal fasciculus, 12-Red nucleus, 13-Fibers of oculomotor nerve, 14-Substantia nigra, 15-Basis pedunculi. Nystagmus in Infancy and Childhood • 9 01_Hertle_Ch01.indd 9 9/6/2012 9:46:51 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN signals to reach the oculomotor system and trigger a saccade.45,46,48,49 Lesions of the superior colliculus permanently abolish the production of express saccades. 1.2.3 Brainstem Control of Eye Movements The problem of moving the eyes in the orbit entails two separate issues: controlling the amplitude of the movement (how far) and controlling the direction of the movement (which way).19,49,50 The amplitude of a saccade is determined by the activity in the lower motor neurons within the three oculomotor nuclei. The direction of a saccade is determined by which muscles are activated, as dictated by the activity in the premotor neurons within two separate gaze centers in the brainstem. The discharge frequency of extraocular motor neurons is directly proportional to the position and velocity of the eye. 51 The saccade signal of motor neurons has the form of a pulse-step. 51 The height of the step determines the amplitude of the saccade, while the height of the pulse determines the speed of the saccade. The duration of the pulse determines the duration of the saccade. The pulse is the phasic signal that commands the eyes to move. The step is the tonic signal that commands the eyes to hold in an eccentric position. The direction of saccades is dictated by premotor neurons in two gaze centers in the reticular formation: (1) the PPRF next to the abducens nucleus is the horizontal gaze center; and (2) the rostral iMLF in the midbrain reticular formation near the oculomotor nucleus is the vertical gaze center.45,47,51–53 To produce a rightward saccade, activation of premotor neurons in the right PPRF increases the activity of lower motor neurons in the right abducens nucleus, which innervate the lateral rectus muscle of the right eye. Activation in the right PPRF also increases the activity of internuclear neurons in the same (right) abducens nucleus, which send their axons along the medial longitudinal fasciculus to innervate the lower motor neurons in the left oculomotor nucleus, which in turn innervate the medial rectus muscle of the left eye. 32,49,54 Omnipause neurons (OPNs) discharge at a relatively constant rate during fi xation, but they stop 10 fi ring during saccades in all directions. The pause begins before the discharge of burst neurons and ends before the end of the saccade. 32,49,54 Longlead burst neurons (LLBNs) and excitatory burst neurons (EBNs) generate high-frequency bursts of activity before ipsilateral saccades. The burst of LLBNs are not as tightly coupled to saccade onset as the burst of EBNs.47 EBNs make excitatory, monosynaptic connections with neurons in the ipsilateral abducens and provide the main source of excitatory drive for the saccade-related pulse of motor neuron activity.47 The amplitude, duration, and velocity of saccades are coupled to the number of spikes generated, burst duration, and peak fi ring rate of the burst of activity, respectively.44,45,47,53 The tonic activity of many neurons in the nucleus prepositus hypoglossi and the medial vestibular nucleus is proportional to horizontal eye position, and these cells provide the excitation that is required for the step of motor neuron activity.44,45,47,53 Activity in the PPRF is specifically related to the control of horizontal saccades and the horizontal component of oblique saccades (see Fig. 1.6). Premotor neurons in the rostral midbrain produce the vertical pulse and step commands. Neurons in the riMLF generate a high-frequency burst before vertical saccades and convey this signal monosynaptically to the motor neurons (see Fig. 1.7).44,45,47,53 Vertical EBNs that discharge before upward saccades are intermingled with those that discharge before downward saccades in the riMLF. Neurons in the interstitial nucleus of Cajal (INC) and the vestibular nucleus discharge tonically at rates that are linearly related to vertical eye position, and provide the excitatory inputs that produce the step change in motor neuron activity.44,45,47,53 Many saccades have both horizontal and vertical components. Although the commands for the two components are generated in different regions of the brainstem, pontine OPNs inhibit both horizontal and vertical EBNs and tend to synchronize the onsets of the two components. 1.2.4 Vestibular Nuclei The vestibular neurons are bipolar with their cell bodies located in Scarpa’s ganglion in the internal auditory meatus. 55–58 The superior and • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 10 9/6/2012 9:46:52 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Left Lateral Rectus Right Medial Rectus Left Sixth Nerve III Right Third Nerve VI P P R F FIGURE 1.6 Schematic of brainstem pathways coordinating horizontal saccades. The PPRF, after receiving input from the ipsilateral cortical centers and superior colliculus, stimulates two sets of neurons in the abducens nucleus: (1) those that send axons to innervate the ipsilateral lateral rectus and (2) those whose axons join the medial longitudinal fasciculus and subsequently activate the medial rectus subnuclei of the contralateral third nerve. III, third cranial nerve nuclei; PPRF, paramedian pontine reticular formation; VI, sixth cranial nerve nuclei. inferior vestibular nerves join to form a common bundle that enters the brainstem. These fi rst-order neurons do not cross the midline. These afferent fibers terminate in the vestibular nuclei in the floor of the fourth ventricle. The nuclei are the superior vestibular nucleus, the lateral vestibular nucleus, the medial vestibular nucleus, and the descending vestibular nucleus. From the vestibular nuclei projections go to the cerebellum, extraocular muscle nuclei, antigravity muscles, and opposite vestibular nuclei. 55–58 The semicircular canals detect head rotation and drive the rotational vestibulo-ocular reflex (VOR), whereas the otoliths detect head translation and drive the translational VOR. The main “direct path” neural circuit for the horizontal rotational starts in the vestibular system, where semicircular canals are activated by head rotation and send their impulses via the vestibular nerve through Scarpa’s ganglion and end in the vestibular nuclei in the brainstem.46,59,60 From these nuclei, fibers cross to the contralateral cranial nerve VI nucleus. There they synapse with two additional pathways. One pathway projects directly to the lateral rectus of eye via the abducens nerve. Another nerve tract projects from the abducens nucleus by the abducens internuclear interneurons or abducens interneurons to the oculomotor nuclei, which contain motorneurons that drive eye muscle activity, specifically activating the medial rectus muscles of the eye through the oculomotor nerve.46,59,60 Another pathway directly projects from the vestibular nucleus through the ascending tract of Dieters to the ipsilateral medial rectus motoneurons.46,59,60 In addition, there are inhibitory vestibular pathways to the ipsilateral abducens nucleus. However, no direct vestibular neuron to medial rectus motoneuron pathway exists. Similar pathways exist for the vertical and torsional components of the VOR.61,62 1.2.5 Cerebellum The cerebellum plays an important role in eye movements.63 Together with several brainstem Nystagmus in Infancy and Childhood • 11 01_Hertle_Ch01.indd 11 9/6/2012 9:46:52 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Posterior Commissure Posterior Commissure Aqueduct riMLF P P R F Aqueduct riMLF INC INC III III IV IV riMLF riMLF INC P P R F INC III III IV IV P P R F P P R F FIGURE 1.7 Th is shows schematics of brainstem pathways coordinating downward (5A) and upward (5B) saccades. In 5A, the PPRF activates neurons in the riMLF that send fibers caudally to synapse upon the inferior rectus subnucleus of the ipsilateral third nerve and the contralateral superior oblique nucleus. Not shown in this diagram, fibers from the contralateral PPRF carry corresponding signals simultaneously. In 5B, the PPRF activates neurons in the riMLF that send fibers through the posterior commissure to the superior rectus subnucleus of the contralateral third nerve and fibers to the inferior oblique subnucleus of the ipsilateral third nerve. Not shown in this diagram, fibers from the contralateral PPRF carry corresponding signals simultaneously. III, third cranial nerve nucleus; INC, interstitial nucleus of Cajal; IV, fourth cranial nerve nucleus; PPRF, paramedian pontine reticular formation; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus. structures, including the nucleus prepositus hypoglossi and the medial vestibular nucleus, it appears to convert velocity signals to position signals for all conjugate eye movements through mathematical integration. Because of this, all of the structures involved in this process are often referred to as the neural integrator.64 Patients with faulty neural integration may show gazeevoked nystagmus, impaired smooth pursuit, inability to cancel the VOR during fi xation, saccadic dysmetria, defective optokinetic nystagmus response, and/or rebound nystagmus.65–67 Various types of image-stabilizing reflexes are also “cerebellar” functions. Pursuit, VOR cancellation, and holding the eye steady for fi xation, both immediately after saccades and in eccentric positions of gaze, are controlled by the flocculus (and probably paraflocculus).68 The nodulus (and ventral uvula) modulates “lowfrequency” aspects of vestibular responses and 12 • 01_Hertle_Ch01.indd 12 hence controls the duration (time constant) of the VOR.68 The dorsal vermis and underlying (posterior) fastigial nuclei participate in the control of the size of the saccadic pulse of innervation and hence saccadic accuracy.68 1.3 AFFERENT SYSTEM 1.3.1 Retina The retina is organized both vertically (in columns) and horizontally (in layers). The principal “vertically oriented” elements are receptors (rods and cones), the bipolar cells and the ganglion cells. The “horizontally oriented” elements are the horizontal, interplexiform and the Meuller cells. The human retina is approximately 0.2 mm thick and has an area of approximately 1100 mm 2 . Each retina possesses about 200 million neurons. The human retina is “inverted,” R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 9/6/2012 9:46:52 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN because the photoreceptor layer is located posteriorly and furthest from incident light. Rod and cone photoreceptors are easily distinguished by their outer segments.69–71 The outer segment contains photopigment in free-floating disks (rods) or folded layers (cones). Cone outer segments have a continuous outer membrane, whereas rods have discs, stacked like coins, in a sleeve.70 The rod and cone outer segment membranes are constantly being replenished. The capture of individual photons by the photopigment molecules in the disk membranes is what initiates neural signaling. Photoreceptors are actually specialized hair cells, and the inner and outer segments are connected by the cilium. The human retina contains approximately 120 million rod and 1 million cone photoreceptors. Cone density is highest at the fovea, where recent estimates place it at approximately 300,000/mm;2 rod density is highest at about 18° eccentric to the fovea (see Chapter 6 for electrophysiology).70 1.3.2 Optic Nerve The optic nerve (cranial nerve II) is considered to be part of the central nervous system as it is derived from an out-pouching of the diencephalon during embryonic development.71–73 Consequently, the fibers are covered with myelin produced by oligodendrocytes rather than the Schwann cells of the peripheral nervous system. Similarly, the optic nerve is ensheathed in all three meningeal layers (dura, arachnoid, and pia mater). The optic nerve is composed of retinal ganglion cell axons and support cells. It leaves the orbit via the optic canal, running posteromedially toward the optic chiasm, where there is a partial decussation (crossing) of fibers from the temporal visual fields of both eyes (see Fig. 1.8). Its diameter increases from about 1.6 mm within the eye, to 3.5 mm in the orbit, to 4.5 mm within the cranial space. The optic nerve component lengths are 1 mm in the globe, FIGURE 1.8 The retina consists of a large number of rod and cone photoreceptors. The photoreceptors synapse directly onto bipolar ganglion cells, which in turn synapse onto ganglion cells, which will then transmit signals through the optic nerve. The optic nerves from both eyes meet and cross at the optic chiasm, where information coming from both eyes is combined and then splits. Information from the right visual field (now on the left side of the brain) travels in the left optic tract. Information from the left visual field travels in the right optic tract. Each optic tract terminates in the lateral geniculate in the thalamus. The neurons of the lateral geniculate nucleus then relay the visual image via the optic radiations to the primary visual cortex. The visual cortex region that receives information directly from the lateral geniculate nucleus is called V1 or primary visual cortex. Visual information then flows through a cortical hierarchy that includes V2, V3, V4, and V5 medial temporal areas. After V1 is a further level of specialization of processing into two distinct pathways: the dorsal stream and the ventral stream occur. The dorsal stream, commonly referred to as the “where” stream, communicates with regions that control eye and hand movements. The ventral stream, commonly referred as the “what” stream, is involved in the recognition, identification, and categorization of visual stimuli. Nystagmus in Infancy and Childhood • 13 01_Hertle_Ch01.indd 13 9/6/2012 9:46:52 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 25 mm in the orbit, 9 mm in the optic canal, and 16 mm in the cranial space before joining the optic chiasm. There, partial decussation occurs and about 53% of the fibers cross to form the optic tracts. Most of these fibers terminate in the lateral geniculate body. 1.3.3 Lateral Geniculate The lateral geniculate nucleus (LGN) serves as a relay station in the projection of the visual pathway to the striate cortex.74–77 The microscopic structure of the LGN is characterized by a series of alternating gray matter and white matter layers.74–77 The LGN consists of six layers, with each alternating layer receiving inputs from a different eye, three layers for the left eye and three layers for the right. Layers 1, 4, and 6 correspond to information from the contralateral (crossed) fibers of the nasal visual field; layers 2, 3, and 5 correspond to information from the ipsilateral (uncrossed) fibers of the temporal visual field. The outer four layers are composed of small cells and, correspondingly, receive inputs from the small ganglion cells of the retina referred to as the parvocellular (P) ganglion cells; these cells dominate the fovea, are color sensitive, and are “fi ne-grained,” meaning their receptive fields are small enough that they can pick up a high level of detail. The two most ventral layers are referred to as the magnocellular layers and are composed of large cells, which receive their input from large ganglion cells referred to as the magnocellular (M) ganglion cells.76,78–80 These cells receive information from a wide radius of bipolar cells. They are mostly found in the peripheral retina, are insensitive to color, and are “coarse-grained,” meaning they are relatively insensitive to detail. Their main asset is that they are sensitive to motion. Therefore, it is evident that two types of information, motion versus color and form, are kept in separate layers in the LGN. of the magnocellular and parvocellular layers of the lateral geniculate body terminate in separate sublaminae of layer IV of striate cortex; a more superficial projection of the parvocellular layers to a narrow strip at the base of layer III (IVA in Brodmann’s terminology).73,78,81 Fibers carrying information from the contralateral superior visual field traverse Meyer’s loop to terminate in the lingual gyrus below the calcarine fissure in the occipital lobe, and fibers carrying information from the contralateral inferior visual field terminate more superiorly. 1.3.5 Association Cortex As visual information passes forward through the visual hierarchy, the complexity of the neural representations increases. Whereas a primary visual cortex (V1) neuron may respond selectively to a line segment of a particular orientation in a particular retinotopic location, neurons in the lateral occipital complex respond selectively to a complete object (e.g., a figure drawing), and neurons in visual association cortex may respond selectively to human faces or to a particular object.77,78,81–83 Along with this increasing complexity of neural representation may come a level of specialization of processing into two distinct pathways: the dorsal stream and the ventral stream fi rst proposed by Ungerleider and Mishkin. 84–86 The dorsal stream, commonly referred to as the “where” stream, is involved in spatial attention (covert and overt) and communicates with regions that control eye movements and hand movements. 84–86 More recently, this area has been called the “how” stream to emphasize its role in guiding behaviors to spatial locations. The ventral stream, commonly referred as the “what” stream, is involved in the recognition, identification, and categorization of visual stimuli.78 1.3.6 Ocular Motor Proprioception 1.3.4 Geniculostriate From the lateral geniculate body, fibers of the optic radiation pass to the visual cortex in the occipital lobe of the brain.73,78,81 The projections 14 Nonhuman primates have eye muscle proprioceptive signals that provide information used in normal sensorimotor functions; these include various aspects of perception and of the control • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 14 9/6/2012 9:46:54 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN of eye movement. It is possible that abnormalities of the eye muscle proprioceptors and their signals may play a part in the genesis of some types of ocular motor disorders. Studies of patients with these disorders in the course of their surgical or pharmacological treatment have yielded much interesting evidence about the central actions of the proprioceptive signals from the extraocular muscles. It is argued that such understanding of eye-muscle proprioception is a necessary part of the understanding of the physiology and pathophysiology of eye-movement control. The eye would seem to provide a unique system in which to study the way in which information derived within the brain about motor actions interacts with signals flowing in from peripheral receptors. 23 Muscle spindles are found within the proximal and distal regions of human infant and adult extraocular muscles and are located at the junction of the orbital and global layers.19,34,35 Palisade endings, a class of muscle receptor found exclusively within extraocular muscles, including those of humans, are located at the distal myotendinous junction of the multiply innervated non-twitch fibers of the global layer.19,34,35 They may be the principal source of proprioceptive feedback from extraocular muscles. Studies in the monkey suggest that proprioceptive signals ascend from the extraocular muscles to the central processing structures via the trigeminal nucleus.19,34,35 Based mainly on animal studies, Butt ner-Ennever et al. have suggested that each layer of the extraocular muscles has its own type of sensory receptor to generate afferent signals, with the orbital layer utilizing muscle spindles and the global layer relying on palisade endings.19 These investigators also suggest that sensory signals from palisade endings form part of a proprioceptive feedback network that modulates the non-twitch motor neurons that innervate the slow non-twitch extraocular muscle fibers. 1.4.1 Smooth Pursuit System Smooth pursuit permits us to maintain a steady image of a moving object on our foveas and to thereby track moving targets with clear vision. The pathways for smooth pursuit have not been fully elucidated, but extrastriate cortex transmits information about the motion of both the target and the eyes to the dorsolateral pontine nuclei (DLPN).87 Th is complex signal travels from the DLPN to the cerebellum, and from the cerebellum to the vestibular nuclei before reaching its fi nal destination—the ocular motor nerve nuclei III, IV, and VI. Unilateral lesions along the pathway result in an ipsilateral deficit of smooth pursuit.88 1.4.2 Saccadic System Several forms of saccades, the fastest eye movements, can be observed: voluntary saccades to objects of interest, reflex saccades to unexpected new stimuli, spontaneous saccades that occur in normal inactive subjects, and saccades that form the quick phases of vestibular and optokinetic nystagmus.47 Pathways descending from areas of cerebral cortex that govern saccades appear to decussate at the junction of the midbrain and pons.47 The superior colliculus acts as an important relay for some of these projections. In the brainstem, the riMLF and the PPRF provide the saccadic velocity commands to cranial nerves III, IV, and VI.47 Vertical and torsional components of saccades are generated in the riMLF, which is located at the mesencephalic-diencephalic junction, horizontal components are generated in the PPRF, which is found just ventral and lateral to the MLF in the pons. If an abnormality of saccadic eye movements is suspected, the quick phases of vestibular and optokinetic nystagmus can be easily evaluated in infants and young children.89 1.4.3 Vergence System 1.4 EFFERENT SYSTEM The functional classes of eye movements are listed in Table 1.2 with their functions, stimuli, clinical tests, and latencies/speed. Vergences are eye movements that turn the eyes in opposite directions (convergence, divergence, and cyclovergence) so that images of objects will fall on corresponding retinal points. Th ree Nystagmus in Infancy and Childhood • 15 01_Hertle_Ch01.indd 15 9/6/2012 9:46:55 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Table 1.2 Functional Classes of Human Eye Movements EYE M OV E M E N T Vestibular Saccades Vergence Optokinetic Pursuit F U N C T IO N STI M U LUS Maintains steady fi xation during head rotation Rapid refi xation to eccentric stimuli Dysconjugate slow movements to maintain binocular vision Steadies images of the world on the retina during sustained head rotation Conjugate continuous target tracking Head rotation, body, and head motion Eccentric retinal image Binasal or bitemporal disparity, retinal blur, motion Head rotation, body and world movement Retinal slip (motion) C L I N IC A L TEST L A T E N C Y/ SPE ED Fixate on object while moving head 15 msec Up to 800°/sec Voluntary movements, fast phases of OKN Fusional amplitudes, near point convergence Optokinetic drum, motion 200 msec 250–800°/sec Horizontal and vertical moving target 160 msec 30–150°/sec 60 msec Supplements VOR during lowfrequency movements 125 msec 0–30°/sec OKN, optokinetic nystagmus;VOR, vestibulo-ocular reflex. major stimuli are known to elicit vergences: (1) retinal disparity that leads to fusional vergences, (2) retinal blur that evokes accommodative vergences, and (3) motion induces both disparity and accommodative vergence. The full neuroanatomic substrate for vergence eye movements remains unknown.19,49,90,91 Neurons in the medial superior temporal visual area (MST), the supplementary eye field (SEF), the frontal eye field (FEF), and the cerebellar vermis are active during vergence eye movements. 39,49 MST and the caudal FEF neurons are likely to be involved in the initiation of vergence eye movements.46,49,91,92 Conjugate and vergence signals are generated independently and are combined at the extraocular motoneurons. Both convergence and divergence cells are found intermixed in the mesencephalic reticular formation outside the oculomotor nucleus, most within 1–2 mm of the nucleus.46,49,91,92 The vergence system has both a fast and a slow subsystem. Each subsystem has a different property. 16 The fast vergence system is best elicited by stimuli with large retinal disparity errors and/ or velocities larger than 4°/sec.93,94 The slow vergence system is elicited by small disparity errors and/or disparity velocities of less than 3°/sec. Tectal and pretectal midbrain areas contribute to the near triad, which is simultaneous convergence, accommodation of the lens, and miosis, occurring during shifts in fi xation between distance and near.93,94 1.4.4 Vestibulo-Ocular System The vestibular apparatus drives reflex eye movements, which allow us to keep images of the world steady on the retinas as we move our heads during various activities. The eyes move in the opposite direction to the movement of the head so that they remain in a steady position in space. The semicircular canals are the end organs that provide the innervation to the vestibular nuclei, which in turn drive cranial • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 16 9/6/2012 9:46:55 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN nerves III, IV, and VI to compensate for rotations of the head.95 In contrast, the otoliths respond to linear accelerations of the head and to gravity when the head is tilted. The principal brainstem areas of saccular nerve termination are the spinal vestibular nucleus, the lateral portion of the superior vestibular nucleus, ventral nucleus, and the external cuneate nucleus. The principal cerebellar projection is to the uvula. Principal brainstem areas of termination of the utricular nerve are the lateral/dorsal medial vestibular nucleus, ventral and lateral portions of the superior vestibular nucleus, and rostral portion of the spinal vestibular nucleus. In the cerebellum, a strong projection to the nodulus and weak projections to the flocculus, ventral paraflocculus, bilateral fastigial nuclei, and uvula are present. 50 REFERENCES 1. Abrahamian LM, Rothe MJ, Grant-Kels JM. Primary telangiectasia of childhood. Int J Dermatol 1992;31(5):307–313. 2. Baloh RW, Henn V, Jager J. Habituation of the human vestibulo-ocular reflex with low-frequency harmonic acceleration. Am J Otolaryngol 1982;3(4):235–241. 3. Hayek G, Mercier P, Fournier HD. Anatomy of the orbit and its surgical approach. Adv Tech Stand Neurosurg 2006;31:35–71. 4. Demer JL. The orbital pulley system: a revolution in concepts of orbital anatomy. Ann N Y Acad Sci 2002;956:17–32. 5. Demer JL, Miller JM, Poukens V, Vinters HV, Glasgow BJ. Evidence for fibromuscular pulleys of the recti extraocular muscles. Invest Ophthalmol Vis Sci 1995;36(6):1125–1136. 6. Demer JL, Kono R, Wright W. Magnetic resonance imaging of human extraocular muscles in convergence. J Neurophysiol 2003;89(4):2072–2085. 7. Kono R, Clark RA , Demer JL. Active pulleys: magnetic resonance imaging of rectus muscle paths in tertiary gazes. Invest Ophthalmol Vis Sci 2002;43(7):2179–2188. 8. Clark RA , Miller JM, Rosenbaum AL, Demer JL. Heterotopic muscle pulleys or oblique muscle dysfunction? J AAPOS 1998;2(1):17–25. 9. Demer JL, Poukens V, Miller JM, Micevych P. Innervation of extraocular pulley smooth 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. muscle in monkeys and humans. Invest Ophthalmol Vis Sci 1997;38(9):1774–1785. Porter JD, Poukens V, Baker RS, Demer JL. Structure-function correlations in the human medial rectus extraocular muscle pulleys. Invest Ophthalmol Vis Sci 1996;37(2):468–472. Roth A, Muhlendyck H, De Gott rau P. [The function of Tenon’s capsule revisited]. J Fr Ophtalmol 2002;25(9):968–976. Mourits MP, Koorneef L, van MourikNoordenbos AM, et al. Extraocular muscle surgery for Graves’ ophthalmopathy: does prior treatment influence surgical outcome? Br J Ophthalmol 1990;74(8):481–483. Lang W, Butt ner-Ennever JA, Butt ner U. Vestibular projections to the monkey thalamus: an autoradiographic study. Brain Res 1979;177(1):3–17. Butt ner-Ennever JA, Grob P, Akert K, Bizzini B. A transsynaptic autoradiographic study of the pathways controlling the extraocular eye muscles, using [125I]B-IIb tetanus toxin fragment. Ann NY Acad Sci 1981;374:157–170. Henn V, Butt ner-Ennever JA, Hepp K. The primate oculomotor system. I. Motoneurons. A synthesis of anatomical, physiological, and clinical data. Hum Neurobiol 1982;1(2):77–85. Butt ner-Ennever JA, Butt ner U. Neuroanatomy of the ocular motor pathways. Baillieres Clin Neurol 1992;1(2):263–287. Hepp K, Henn V, Jaeger J. Eye movement related neurons in the cerebellar nuclei of the alert monkey. Exp Brain Res 1982;45(1–2):253–264. Butt ner-Ennever JA. A review of otolith pathways to brainstem and cerebellum. Ann NY Acad Sci 1999;871:51–64. Butt ner-Ennever JA, Horn AK, Graf W, Ugolini G. Modern concepts of brainstem anatomy: from extraocular motoneurons to proprioceptive pathways. Ann NY Acad Sci 2002;956:75–84. Butt ner-Ennever JA, Butt ner U. Neuroanatomy of the oculomotor system. The reticular formation. Rev Oculomot Res 1988;2:119–176. Roll JP, Vedel JP, Roll R. Eye, head and skeletal muscle spindle feedback in the elaboration of body references. Prog Brain Res 1989;80: 113–123; discussion 157–160. Anderson CW, Nishikawa KC. The roles of visual and proprioceptive information during motor program choice in frogs. J Comp Physiol A 1996;179(6):753–762. Donaldson IM. The functions of the proprioceptors of the eye muscles. Nystagmus in Infancy and Childhood • 17 01_Hertle_Ch01.indd 17 9/6/2012 9:46:55 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 18 Philos Trans R Soc Lond B Biol Sci 2000;355(1404):1685–1754. Butt ner-Ennever JA, Konakci KZ, Blumer R. Sensory control of extraocular muscles. Prog Brain Res 2006;151:81–93. Weir CR. Proprioception in extraocular muscles. J Neuroophthalmol 2006;26(2):123–127. Ying HS, Fackelmann K, Messoudi A, Tang XF, Butt ner-Ennever JA, Horn AK. Neuronal signalling expression profi les of motoneurons supplying multiply or singly innervated extraocular muscle fibres in monkey. Prog Brain Res 2008;171:13–16. Steiger HJ, Butt ner-Ennever JA. Oculomotor nucleus afferents in the monkey demonstrated with horseradish peroxidase. Brain Res 1979;160(1):1–15. Butt ner-Ennever JA. The extraocular motor nuclei: organization and functional neuroanatomy. Prog Brain Res 2006;151:95–125. Gauthier GM, Nommay D, Vercher JL. The role of ocular muscle proprioception in visual localization of targets. Science 1990;249(4964):58–61. Crowell JA, Banks MS, Shenoy KV, Andersen RA . Visual self-motion perception during head turns. Nat Neurosci 1998;1(8):732–737. Dell’Osso LF, Hertle RW, Williams RW, Jacobs JB. A new surgery for congenital nystagmus: effects of tenotomy on an achiasmatic canine and the role of extraocular proprioception. J AAPOS 1999;3(3):166–182. Lewis RF, Zee DS, Hayman MR, Tamargo RJ. Oculomotor function in the rhesus monkey after deafferentation of the extraocular muscles. Exp Brain Res 2001;141(3):349–358. Butt ner-Ennever JA, Eberhorn A, Horn AK. Motor and sensory innervation of extraocular eye muscles. Ann NY Acad Sci 2003;1004:40–49. Eberhorn AC, Horn AK, Fischer P, Butt nerEnnever JA. Proprioception and palisade endings in extraocular eye muscles. Ann NY Acad Sci 2005;1039:1–8. Niechwiej-Szwedo E, Gonzalez E, Bega S, Verrier MC, Wong AM, Steinbach MJ. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vision Res 2006;46(14):2268–2279. Eberhorn AC, Horn AK, Eberhorn N, Fischer P, Boergen KP, Butt ner-Ennever JA. Palisade endings in extraocular eye muscles revealed 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. by SNAP-25 immunoreactivity. J Anat 2005;206(3):307–315. Butt ner-Ennever JA. Anatomy of the oculomotor system. Dev Ophthalmol 2007;40:1–14. Fackelmann K, Nouriani A, Horn AK, Butt nerEnnever JA. Histochemical characterisation of trigeminal neurons that innervate monkey extraocular muscles. Prog Brain Res 2008;171:17–20. Butt ner-Ennever JA, Horn AK. Anatomical substrates of oculomotor control. Curr Opin Neurobiol 1997;7(6):872–879. Bisley JW, Goldberg ME. The role of the parietal cortex in the neural processing of saccadic eye movements. Adv Neurol 2003;93:141–157. Ioannides AA, Fenwick PB, Pitri E, Liu L. A step towards non-invasive characterization of the human frontal eye fields of individual subjects. Nonlinear Biomed Phys 2010;4(Suppl. 1):S11. Fukushima K, Yamanobe T, Shinmei Y, Fukushima J, Kurkin S. Role of the frontal eye fields in smooth-gaze tracking. Prog Brain Res 2004;143:391–401. Avanzini G, Villani F. Ocular movements. Curr Opin Neurol 1994;7(1):74–80. Isa T, Hall WC. Exploring the superior colliculus in vitro. J Neurophysiol 2009;102(5):2581–2593. King AJ. The superior colliculus. Curr Biol 2004;14(9):R335–R338. Ron S, Gur S. Gaze and eye movement disorders. Curr Opin Neurol Neurosurg 1992;5(5):711–715. McDowell JE, Dyckman KA , Austin BP, Clementz BA. Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans. Brain Cogn 2008;68(3):255–270. May PJ. The mammalian superior colliculus: laminar structure and connections. Prog Brain Res 2006;151:321–378. Averbuch-Heller L, Leigh RJ. Eye movements. Curr Opin Neurol 1996;9(1):26–31. Newlands SD, Vrabec JT, Purcell IM, Stewart CM, Zimmerman BE, Perachio AA. Central projections of the saccular and utricular nerves in macaques. J Comp Neurol 2003;466(1):31–47. Ballanger B. Top-down control of saccades as part of a generalized model of proactive inhibitory control. J Neurophysiol 2009;102(5):2578–2580. • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 18 9/6/2012 9:46:55 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 52. Optican LM. Sensorimotor transformation for visually guided saccades. Ann NY Acad Sci 2005;1039:132–148. 53. Munoz DP. Commentary: saccadic eye movements: overview of neural circuitry. Prog Brain Res 2002;140:89–96. 54. Pierrot-Deseilligny C, Ploner CJ, Muri RM, Gaymard B, Rivaud-Pechoux S. Effects of cortical lesions on saccadic: eye movements in humans. Ann NY Acad Sci 2002;956:216–229. 55. Gitt is AH, du Lac S. Intrinsic and synaptic plasticity in the vestibular system. Curr Opin Neurobiol 2006;16(4):385–390. 56. Lackner JR, DiZio P. Vestibular, proprioceptive, and haptic contributions to spatial orientation. Annu Rev Psychol 2005;56:115–147. 57. Roy JE, Cullen KE. Brain stem pursuit pathways: dissociating visual, vestibular, and proprioceptive inputs during combined eye-head gaze tracking. J Neurophysiol 2003;90(1):271–290. 58. Balaban CD, Porter JD. Neuroanatomic substrates for vestibulo-autonomic interactions. J Vestib Res 1998;8(1):7–16. 59. Byl NN, Holland S, Jurek A, Hu SS. Postural imbalance and vibratory sensitivity in patients with idiopathic scoliosis: implications for treatment. J Orthop Sports Phys Ther 1997;26(2):60–68. 60. Wiener-Vacher SR, Toupet F, Narcy P. Canal and otolith vestibulo-ocular reflexes to vertical and off vertical axis rotations in children learning to walk. Acta Otolaryngol 1996;116(5):657–665. 61. Schubert MC, Migliaccio AA, Minor LB, Clendaniel RA . Retention of VOR gain following short-term VOR adaptation. Exp Brain Res 2008;187(1):117–127. 62. Jones MS, Ariel M. The effects of unilateral eighth nerve block on fictive VOR in the turtle. Brain Res 2006;1094(1):149–162. 63. Glickstein M, Sultan F, Voogd J. Functional localization in the cerebellum. Cortex 2009;47:59–80. 64. Glickstein M, Doron K. Cerebellum: connections and functions. Cerebellum 2008;7(4):589–594. 65. Th ier P, Dicke PW, Haas R, Th ielert CD, Catz N. The role of the oculomotor vermis in the control of saccadic eye movements. Ann NY Acad Sci 2002;978:50–62. 66. Robinson FR, Fuchs AF. The role of the cerebellum in voluntary eye movements. Annu Rev Neurosci 2001;24:981–1004. 67. Horn AK, Butt ner U, Butt ner-Ennever JA. Brainstem and cerebellar structures for eye movement generation. Adv Otorhinolaryngol 1999;55:1–25. 68. Lewis RF, Zee DS. Ocular motor disorders associated with cerebellar lesions: pathophysiology and topical localization. Rev Neurol (Paris) 1993;149(11): 665–677. 69. Westerfeld C, Mukai S. Retinal and choroidal biopsy. Int Ophthalmol Clin 2009;49(1):145–154. 70. Mustafi D, Engel AH, Palczewski K. Structure of cone photoreceptors. Prog Retin Eye Res 2009;28(4):289–302. 71. Gillig PM, Sanders RD. Cranial Nerve II: Vision. Psychiatry (Edgmont) 2009;6(9): 32–37. 72. Sanfi lippo PG, Cardini A, Hewitt AW, Crowston JG, Mackey DA. Optic disc morphology—rethinking shape. Prog Retin Eye Res 2009;28(4):227–248. 73. Balasubramanian V, Sterling P. Receptive fields and functional architecture in the retina. J Physiol 2009;587(Pt 12):2753–2767. 74. Guido W. Refi nement of the retinogeniculate pathway. J Physiol 2008;586(Pt 18): 4357–4362. 75. Sherman SM. Thalamic relays and cortical functioning. Prog Brain Res 2005;149: 107–126. 76. Shatz CJ. Emergence of order in visual system development. Proc Natl Acad Sci USA 1996;93(2):602–608. 77. Tieman SB. The anatomy of geniculocortical connections in monocularly deprived cats. Cell Mol Neurobiol 1985;5(1–2):35–45. 78. Sincich LC, Horton JC. The circuitry of V1 and V2: integration of color, form, and motion. Annu Rev Neurosci 2005;28:303–326. 79. Alitto HJ, Usrey WM. Dynamic properties of thalamic neurons for vision. Prog Brain Res 2005;149:83–90. 80. Crunelli V, Kelly JS, Leresche N, Pirchio M. The ventral and dorsal lateral geniculate nucleus of the rat: intracellular recordings in vitro. J Physiol 1987;384:587–601. 81. Hirsch HV. The role of visual experience in the development of cat striate cortex. Cell Mol Neurobiol 1985;5(1–2):103–121. 82. Callaway EM. Structure and function of parallel pathways in the primate early visual system. J Physiol 2005;566(Pt 1):13–19. 83. Tighilet B, Hashikawa T, Jones EG. Cell- and lamina-specific expression and Nystagmus in Infancy and Childhood • 19 01_Hertle_Ch01.indd 19 9/6/2012 9:46:56 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 84. 85. 86. 87. 88. 20 activity-dependent regulation of type II calcium/calmodulin-dependent protein kinase isoforms in monkey visual cortex. J Neurosci 1998;18(6):2129–2146. McCloskey M. Spatial representations and multiple-visual-systems hypotheses: evidence from a developmental deficit in visual location and orientation processing. Cortex 2004;40(4–5):677–694. Nascimento-Silva S, Gatt ass R, Fiorani M, Jr., Sousa AP. Th ree streams of visual information processing in V2 of Cebus monkey. J Comp Neurol 2003;466(1):104–118. Ungerleider LG, Galkin TW, Mishkin M. Visuotopic organization of projections from striate cortex to inferior and lateral pulvinar in rhesus monkey. J Comp Neurol 1983;217(2):137–157. Th ier P, Ilg UJ. The neural basis of smoothpursuit eye movements. Curr Opin Neurobiol 2005;15(6):645–652. Lencer R, Trillenberg P. Neurophysiology and neuroanatomy of smooth pursuit in humans. Brain Cogn 2008;68(3):219–228. 89. Gaymard B, Pierrot-Deseilligny C. Neurology of saccades and smooth pursuit. Curr Opin Neurol 1999;12(1):13–19. 90. Schor CM. Neuromuscular plasticity and rehabilitation of the ocular near response. Optom Vis Sci 2009;86(7):E788–E802. 91. Karatas M. Internuclear and supranuclear disorders of eye movements: clinical features and causes. Eur J Neurol 2009;16(12):1265–1277. 92. Tilikete C, Pelisson D. Ocular motor syndromes of the brainstem and cerebellum. Curr Opin Neurol 2008;21(1):22–28. 93. Bando T, Toda H. Cerebral cortical and brainstem areas related to the central control of lens accommodation in cat and monkey. Comp Biochem Physiol C 1991;98(1):229–237. 94. Hung GK, Ciuff reda KJ, Semmlow JL, Horng JL. Vergence eye movements under natural viewing conditions. Invest Ophthalmol Vis Sci 1994;35(9):3486–3492. 95. Nandi R, Luxon LM. Development and assessment of the vestibular system. Int J Audiol 2008;47(9):566–577. • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y 01_Hertle_Ch01.indd 20 9/6/2012 9:46:56 PM