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Within the inner ear are specialized sensory receptors responsible for the perception of the forces associated with head movement and gravity. Control centers within the brainstem integrate this information along with other biologic signals derived from vision and proprioceptive sensors in the final determination of an individual’s orientation in three-dimensional space.1 Although anatomically developed and responsive at birth, the vestibular system matures along with other senses in the first 7 to 10 years of life.2 Recognition of the head’s movement relative to the body is provided by the linear (otolithic macula) and angular (semicircular canals) acceleration receptors of the inner ear. Electrical activity generated within the inner ear travels along the vestibular nerve (primary afferent neuronal pathway) to the central vestibular nuclei of the brainstem, forming second-order neu- ronal pathways that become the vestibulo-ocular reflex (VOR), the vestibulospinal tracts, and the vestibulo- cerebellar tracts. Pathways derived from vestibular information also travel to the brainstem emetic centers, which serves to explain vegetative symptoms such as nausea, vomiting, and perspiration that a patient typi- cally experiences following an acute unilateral vestibu- lar loss (Figure 2-1). Disruption of peripheral (inner ear and the vestibu- lar nerve) or central vestibular pathways as a result of, for example , trauma, ototoxicity, or surgical deafferentation leads to the patient experiencing a distortion in orienta- tion. The patient often uses the term “dizziness,” which is an all-encompassing yet relatively nonspecific term that can include symptoms such as giddiness, light- headedness, and floating sensation. Clinically, the term “vertigo” is best suited to describe a precise type of dizziness—a hallucination of movement involving one- self (subjective vertigo) or the surrounding environment (objective vertigo) that is apt to occur when there is an acute interruption of vestibular pathways.1 Of all the human vestibular pathways, the VOR remains the most important and most studied. At its simplest level the VOR is required to maintain a stable retinal image with active head movement. When an active head movement is not accompanied by an equal but opposite conjugate movement of the eyes, retinal slip occurs. When the VOR is affected bilaterally (as could occur from systemic aminoglycoside poisoning) patients characteristically complain of visual blurring with head movement, better known as oscillopsia, in addition to having significant complaints of imbalance and ataxia.3 True vertigo is typically not a feature of a bilateral peripheral vestibular loss. CHAPTER 2 Physiology of the Vestibular System John A. Rutka, MD, FRCSC � Vestibulo-ocular Pathways Vestibulospinal Pathways Oculomotor nuclei S S LL D D MM Vestibular nucleus Reticular formation Utricle Medial longitudinal fasciculus Medial longitudinal fasciculus Other Pathways (not demonstrated) • To Emetic Centers • To Vestibulocerebellum Figure 2-1 Schematic representation of the vestibular system and its pathways. ANATOMY OF THE VESTIBULAR SYSTEM Peripheral Vestibular System The peripheral vestibular system includes the paired vestibular sensory end-organs of the semicircular canals (SCCs) and the otolithic organs. These receptors are found within the fluid-filled bony channels of the otic capsule (the dense endochondral-derived bone that surrounds the labyrinth and cochlea) and are responsible for perception of both the sense of position and motion. The vestibular nerve (both superior and inferior divisions of the VIIIth nerve) is the afferent connection to the brainstem nuclei for the peripheral vestibular system (Figure 2-2). Perception of angular accelerations is chiefly the responsibility of the three paired SCCs (superior, posterior, and lateral). Within the ampullated portion of the membranous labyrinth are the end-organs of the cristae, containing specialized hair cells that transduce mechanical shearing forces into neural impulses. Histologically the hair cells of the ampulla are located on its surface. Their cilia extend into a gelati- nous matrix better known as the cupula, which acts like a hinged gate between the vestibule and the canal itself (Figure 2-3). The otolithic organs of the utricle and the saccule are found within the vestibule. Chiefly responsible for the perception of linear accelerations (eg, gravity, deceleration in a car), their end-organs consist of a flat- tened, hair cell–rich macular area whose cilia project into a similar gelatinous matrix. The matrix, however, differs from the matrix associated with the SCCs in its support of a blanket of calcium carbonate crystals bet- ter known as otoliths, which have a mean thickness of approximately 50 µm (Figure 2-4).4 Information from the vestibular end-organs is transmitted along the superior (which receives infor- mation from the superior, horizontal SCCs and utricle) and inferior (which receives information from the pos- terior SCC and saccule) divisions of the vestibular nerve. Although its role is primarily afferent in the transmission of electrical activity to the central vestibu- lar nuclei of the brainstem, an efferent system does exist that probably serves to modify end-organ activ- ity.5 Each vestibular nerve consists of approximately 25,000 bipolar neurons whose cell bodies are located in a structure known as Scarpa’s ganglion, which is typi- cally found within the internal auditory canal (IAC).6 Type I neurons of the vestibular nerve derive informa- tion from corresponding type 1 hair cells, whereas type II neurons derive information from corresponding type 2 hair cells at its simplest. Physiology of the Vestibular System 21 Superior Posterior Lateral Utricle Saccule Superior Vestibular Nerve Inferior Vestibular Nerve Semicircular Canals Vestibule Figure 2-2 Anatomic organization of the peripheral vestibular system (vestibular end-organs and the vestibular nerve). Reproduced with permission from Solvay Pharma, Canada. Supporting Cells Ampullary Nerve Type 1 and 2 Hair Cells Cupula Figure 2-3 Stylized representation of the crista: angular acceleration receptor. Reproduced with permission from Solvay Pharma, Canada. Central Vestibular System Primary vestibular afferents enter the brainstem divid- ing into ascending and descending branches. Within the brainstem there appears to exist a nuclear region with four distinct anatomic types of second-order neurons that have been traditionally considered to con- stitute the vestibular nuclei. It appears, however, that not all these neurons receive input from the peripheral vestibular system.4,7 The main nuclei are generally recognized as the superior (Bechterew’s nucleus), lateral (Deiters’ nucleus), medial (Schwalbe’s nucleus ), and descending (spinal vestibular nucleus). Functionally, in primate models, the superior vestibular nucleus appears to be a major relay station for conjugate ocular reflexes mediated by the SCCs. The lateral vestibular nucleus appears to be important for control of ipsilateral vestibulospinal (the so-called “righting”) reflexes. The medial vestibular nucleus, because of its other connections with the medial longi- tudinal fasciculus, appears to be responsible for coordi- nating eye, head, and neck movements. The descending vestibular nucleus appears to have an integrative func- tion with respect to signals from both vestibular nuclei, the cerebellum, and an amorphous area in the reticular formation postulated to be a region of neural integra- tion. Commonly referred to as the “neural integrator” among neurophysiologists, it is responsible for the ultimate velocity and position command for the final common pathway for conjugate versional eye move- ments and position.8 The vestibular nerve in part also projects directly to the phylogenetically oldest parts of the cerebellum— namely, the flocculus, nodulus, ventral uvula, and the ventral paraflocculus—on its way directly through the vestibular nucleus. Better known as the vestibulocere- bellum, this area also receives input from other neuronal pathways in the central nervous system (CNS) responsible for conjugate eye movements, especially smooth-pursuit eye movements, which, in addition to the VOR, are responsible for holding the image of a moving target within a certain velocity range on the fovea of the retina. The Purkinje’s cells of the flocculus are the main recipients of this information, of which some appears to be directed back toward the ipsilateral vestibular nucleus for the purposes of modulating eye movements in relation to gaze (eye in space) velocity with the head still or during combined eye–head (vestibular signal-derived) tracking.9,10 Important for cancelling the effects of the VOR on eye movement when it is not in the best interest of the individual (think of twirling ballet dancers or figure skaters and how they can spin without getting dizzy), the vestibu- locerebellum is also important in the compensation process for a unilateral vestibular loss.7,9,10 The Hair Cells The fundamental unit for vestibular activity on a microscopic basis inside the inner ear consists of broadly classified type 1 and 2 hair cells (Figure 2-5). Type 1 hair cells are flask-shaped and surrounded by the afferent nerve terminal at its base in a chalice- like fashion. One unique characteristic of the afferent nerve fibers that envelop type 1 hair cells is that they are among the largest in the nervous system (up to 20 µm in diameter). The high amount of both tonic (sponta- neous) and dynamic (kinetic) electrical activity at any time arising from type 1 hair cells has probably neces- sitated this feature for the neurons that transfer this information to the CNS. Type 2 hair cells are more cylindrical and at their base are typically surrounded by multiple nerve terminals in contradistinction.11 22 Systemic Toxicity Blanket of Calcium Carbonate Crystals Gelatinous Matrix Afferent Neuron Type 1 and 2 Hair Cells Macula At Rest Figure 2-4 Stylized representation of macular end-organ: linear acceleration receptor. Reproduced with permission from Solvay Pharma, Canada. Each hair cell contains on its top a bundle of 50 to 100 stereocilia and one long kinocilium that project into the gelatinous matrix of the cupula or macula. It is thought that the location of the kinocilium relative to the stereocilia gives each hair cell an intrinsic polar- ity that can be influenced by angular or linear acceler- ations. It is important to realize that an individual is born with a maximum number of type 1 and 2 hair cells that cannot be replaced or regenerated if lost as a result of the effects of pathology (eg, ototoxicity or sur- gical trauma) or aging (the postulated presbyvestibular dropout from cellular apoptosis). Presumably the same process holds for the type I and II neurons that com- prise the vestibular nerve. APPLIED PHYSIOLOGY At the microscopic level, movements of the head or changes in linear accelerations deflect the cupula or shift the gelatinous matrix of the otolithic organs with its load of otolithic crystals that will either stimulate (depolarize) or inhibit (hyperpolarize) electrical activ- ity from type 1 and 2 hair cells. Displacement of the stereocilia either toward or away from the kinocilium influences calcium influx mechanisms at the apex of the cell that causes either the release or reduction of neurotransmitters from the cell to the surrounding afferent neurons (Figures 2-6 and 2-7 ).12 The electri- cal activity generated is then transferred along the vestibular nerve to the vestibular nuclei in the brain- stem. Information above the tonic (spontaneous) firing rate of the type 1 hair cells transmitted along type I neurons is largely thought to have a stimulatory effect in contrast to a more inhibitory effect attributable to type 2 hair cells and type II neurons. The SCCs largely appear to be responsible for the equal but opposite corresponding eye-to-head move- ments better known as the VOR. The otolithic organs are primarily responsible for ocular counter-rolling with tilts of the head and for vestibulospinal reflexes that help in the maintenance of body posture and muscle tone. In order to ultimately produce conjugate versional VOR-mediated movements of the eyes, each vestibular nucleus receives electrical information from both sides that is exchanged via the vestibular commissure in the brainstem. The organization is generally believed to be specific across the commissure. Neurons in the right vestibular nucleus, for example, that receive type I input from the right horizontal SCC project across the commissure to the neurons found in the left vestibular nucleus that are driven by the left horizontal SCC receiving contralateral type II input and vice versa.7 Physiology of the Vestibular System 23 Type 1 Type 2 KC KC H H N NC NE 1 NE 2NE 2 Nu NuM M Ct Ct Figure 2-5 Schematic representation of type 1 and type 2 hair cells. Ct = cuticular plate; H = hairs; KC = kinocillum; M = mitochondria; NC = nerve chalice; NE = nerve ending; Nu = nucleus. With Otolithic Displacement Figure 2-6 Physiology of macular stimulation and inhibition from otolithic shift and its shearing effect on stereocilia and kinocilium of the hair cells. Displacement of Sensory Hairs Resting Rate Toward Kinocilium Away from Kinocilium Discharge Rate Vestibular Nerve Tonic Resting Activity Stimulation (depolarization) Inhibition (hyperpolarization) Figure 2-7 The physiology of motion and position sense. Concept of hair cell signal (electrical activity generation) at rest (resting discharge rate) and with respect to effects of movement resulting in depolarization (stimulation) and hyperpolarization (inhibition). KEY CONCEPTS According to Leigh and Zee’s seminal text, the key con- cepts of vestibular physiology can be best appreciated in the context that “the push–pull pairings of the canals, the resting vestibular tone and exchange of neural input through the vestibular commissure maxi- mize vestibular sensitivity in health and provide a sub- strate for compensation and adaptation.”7 VOR Gain In order to maintain a stable retinal image during head movement, the eyes should move in an equal but oppo- site direction to head movement. Anything less than unity (corresponding eye movement/head movement) may result in the perception of visual blurring with head movement—oscillopsia being the classic sympto- matic complaint of an individual with a bilateral peripheral vestibular loss as might result from genta- micin vestibulotoxicity. Nystagmus Defined as a rhythmic to-and-fro, back-and-forth movement of the eyes, nystagmus represents the cardi- nal sign of unilateral peripheral vestibular or central vestibular dysfunction. In an acute unilateral loss of peripheral vestibular activity that might occur from topical aminoglycoside drops or certain disinfectant surgical preparation solu- tions used in the presence of a tympanic membrane defect, injury to the end-organ causes a difference in neural activity between the left and right vestibular nuclei. Should the push–pull pairings of the canals be affected as a result of pathology, the eyes are typically driven with a slow movement toward the affected side only to be corrected by a fast corrective saccade gen- erated within the CNS away from the side of the lesion in a repetitive fashion. Although somewhat misguided, the direction of the nystagmus by convention refers to the fast phase, typically away from the side of the lesion under circumstances of an acute unilateral peripheral vestibular loss. Habituation and Adaptation In humans the CNS may habituate (show a reduced response) the VOR depending on the environmental circumstances. This may happen in individuals who are blind or in those exposed to constant velocity rota- tions or continuous low-frequency oscillations (such as on a ship). The mechanisms for adaptation or the adap- tive plasticity of the VOR are usually visually driven and have been experimentally studied by subjects wearing reversing prisms.13 This phenomenon is frequently experienced by those wearing new prescriptive glasses with the explanation that “they take some time to get used to.” Eventually one adapts to the new lenses as the gain of the VOR changes accordingly. The same holds true to some extent for those with a unilateral periph- eral vestibular loss, where the gain can be somewhat influenced, though not perfectly. Compensation Clinical improvement following acute unilateral peripheral vestibular deafferentation requires the pres- ence of intact central vestibular connections primarily at the level of the vestibulocerebellum.4,7 The loss of tonic or spontaneous vestibular activity from the end- organ is ultimately replaced by the development of spontaneous electrical activity arising within the vestibular nuclei of the affected side.14 At rest the asym- metries that would be expected from the push–pull effects from the canals are kept in check, and as a result there is the gradual resolution of the once-present spon- taneous nystagmus. Quick head movements producing changes in the dynamic electrical activity, however, can never be completely compensated through this mecha- nism on the affected side, and a bilateral loss of inner ear function never does despite the insertion of midrota- tion corrective saccades. For a more detailed explana- tion of the phenomenon of compensation and why it often fails in the setting of a bilateral vestibular loss see Chapter 19, “Monitoring Vestibular Toxicity.” CLINICAL MANIFESTATIONS OF VESTIBULAR DYSFUNCTION Loss of vestibular function is associated with several signs and symptoms. Unilateral Peripheral Vestibular Loss With a loss of unilateral vestibular function the patient acutely experiences the sensation of true vertigo from interruptions of VOR pathways and tends to lie per- fectly still, as any movement aggravates vegetative symptoms such as nausea and vomiting that arise from the emetic centers. Nystagmus beating away from the side of lesion is the cardinal physical sign that obeys Alexander’s law (the quick phase of the nystagmus induced by the imbalance in activity at the level of the vestibular nuclei is greatest in amplitude and frequency when the eyes are turned away from the side of the lesion).15 Interruption in vestibulospinal tract pathways causes the patient to fall or list toward the affected side. Findings of ipsilateral hemispheric cerebellar dysfunc- tion presenting with behaviors such as past-pointing, an inability to perform rapid alternating movements (dysdiadochokinesis), and gait ataxia reflect acute vestibulocerebellar tract involvement. Features distin- guishing peripheral from central mediated nystagmus can be found in Table 2-1. With compensation (implying the existence of a normal functioning CNS and contralateral peripheral vestibular system) there may be minimal symptoma- 24 Systemic Toxicity tology that is only brought out by very rapid head movements. The spontaneous nystagmus disappears, vegetative symptoms resolve, gait improves, and in the case of a chronic condition the patient may experience only a slight imbalance when turning quickly. Bilateral Peripheral Vestibular Loss Vertigo is not a feature of a bilateral vestibular loss even when it occurs in an acute fashion. Injury to the end- organs as might occur in systemic aminoglycoside vestibulotoxicity causes a bilateral loss of function that tends to be electrically symmetric at the level of the vestibular nuclei in the brainstem. Instead the patient tends to complain of oscillopsia and imbalance. The gait is typically broad-based and ataxic, especially with eyes closed. Falls are not infrequent and in many instances the patient requires assistive devices for ambulation or is relegated to a w