Within the inner ear are specialized sensory receptorsresponsible for the perception of the forces associatedwith head movement and gravity. Control centerswithin the brainstem integrate this information alongwith other biologic signals derived from vision andproprioceptive sensors in the final determination of anindividual’s orientation in three-dimensional space.1

Although anatomically developed and responsive atbirth, the vestibular system matures along with othersenses in the first 7 to 10 years of life.2

Recognition of the head’s movement relative to thebody is provided by the linear (otolithic macula) andangular (semicircular canals) acceleration receptors ofthe inner ear. Electrical activity generated within theinner ear travels along the vestibular nerve (primaryafferent neuronal pathway) to the central vestibularnuclei 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 vestibularinformation also travel to the brainstem emetic centers,which serves to explain vegetative symptoms such asnausea, 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, forexample , trauma, ototoxicity, or surgical deafferentationleads to the patient experiencing a distortion in orienta-tion. The patient often uses the term “dizziness,” whichis an all-encompassing yet relatively nonspecific termthat can include symptoms such as giddiness, light-headedness, and floating sensation. Clinically, the term“vertigo” is best suited to describe a precise type ofdizziness—a hallucination of movement involving one-self (subjective vertigo) or the surrounding environment(objective vertigo) that is apt to occur when there is anacute interruption of vestibular pathways.1

Of all the human vestibular pathways, the VORremains the most important and most studied. At itssimplest level the VOR is required to maintain a stableretinal image with active head movement. When anactive head movement is not accompanied by an equalbut opposite conjugate movement of the eyes, retinalslip occurs. When the VOR is affected bilaterally (ascould occur from systemic aminoglycoside poisoning)patients characteristically complain of visual blurringwith head movement, better known as oscillopsia, inaddition to having significant complaints of imbalanceand ataxia.3 True vertigo is typically not a feature of abilateral peripheral vestibular loss.

CHAPTER 2

Physiology of the Vestibular SystemJohn A. Rutka, MD, FRCSC

�

Vestibulo-ocularPathways

VestibulospinalPathways

Oculomotornuclei

S S

LLD D

MM

Vestibularnucleus

Reticularformation

Utricle

Mediallongitudinalfasciculus

Mediallongitudinalfasciculus

Other Pathways(not demonstrated)

• To Emetic Centers• To Vestibulocerebellum

Figure 2-1 Schematic representation of the vestibular systemand its pathways.

ANATOMY OF THE VESTIBULAR SYSTEM

Peripheral Vestibular System

The peripheral vestibular system includes the pairedvestibular sensory end-organs of the semicircularcanals (SCCs) and the otolithic organs. These receptorsare found within the fluid-filled bony channels of theotic capsule (the dense endochondral-derived bonethat surrounds the labyrinth and cochlea) and areresponsible for perception of both the sense of positionand motion. The vestibular nerve (both superior andinferior divisions of the VIIIth nerve) is the afferentconnection to the brainstem nuclei for the peripheralvestibular system (Figure 2-2).

Perception of angular accelerations is chiefly theresponsibility of the three paired SCCs (superior,posterior, and lateral). Within the ampullated portionof the membranous labyrinth are the end-organs of thecristae, containing specialized hair cells that transducemechanical shearing forces into neural impulses.

Histologically the hair cells of the ampulla arelocated on its surface. Their cilia extend into a gelati-nous matrix better known as the cupula, which acts likea hinged gate between the vestibule and the canal itself(Figure 2-3).

The otolithic organs of the utricle and the sacculeare found within the vestibule. Chiefly responsible forthe 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 projectinto a similar gelatinous matrix. The matrix, however,differs from the matrix associated with the SCCs in itssupport of a blanket of calcium carbonate crystals bet-ter known as otoliths, which have a mean thickness ofapproximately 50 µm (Figure 2-4).4

Information from the vestibular end-organs istransmitted 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 vestibularnerve. Although its role is primarily afferent in thetransmission of electrical activity to the central vestibu-lar nuclei of the brainstem, an efferent system doesexist that probably serves to modify end-organ activ-ity.5 Each vestibular nerve consists of approximately25,000 bipolar neurons whose cell bodies are located ina 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, whereastype II neurons derive information from correspondingtype 2 hair cells at its simplest.

Physiology of the Vestibular System 21

Superior

Posterior

Lateral

Utricle

Saccule

Superior Vestibular

Nerve

Inferior Vestibular

Nerve

SemicircularCanals

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 2Hair Cells

Cupula

Figure 2-3 Stylized representation of the crista: angularacceleration receptor. Reproduced with permission fromSolvay Pharma, Canada.

Central Vestibular System

Primary vestibular afferents enter the brainstem divid-ing into ascending and descending branches. Withinthe brainstem there appears to exist a nuclear regionwith four distinct anatomic types of second-orderneurons that have been traditionally considered to con-stitute the vestibular nuclei. It appears, however, thatnot all these neurons receive input from the peripheralvestibular system.4,7 The main nuclei are generallyrecognized as the superior (Bechterew’s nucleus),lateral (Deiters’ nucleus), medial (Schwalbe’s nucleus ),and descending (spinal vestibular nucleus).

Functionally, in primate models, the superiorvestibular nucleus appears to be a major relay stationfor conjugate ocular reflexes mediated by the SCCs.The lateral vestibular nucleus appears to be importantfor 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 descendingvestibular nucleus appears to have an integrative func-tion with respect to signals from both vestibular nuclei,the cerebellum, and an amorphous area in the reticularformation postulated to be a region of neural integra-tion. Commonly referred to as the “neural integrator”among neurophysiologists, it is responsible for theultimate velocity and position command for the finalcommon pathway for conjugate versional eye move-ments and position.8

The vestibular nerve in part also projects directlyto the phylogenetically oldest parts of the cerebellum—namely, the flocculus, nodulus, ventral uvula, and theventral paraflocculus—on its way directly through thevestibular 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, especiallysmooth-pursuit eye movements, which, in addition tothe VOR, are responsible for holding the image of amoving target within a certain velocity range on thefovea of the retina. The Purkinje’s cells of the flocculusare the main recipients of this information, of whichsome appears to be directed back toward the ipsilateralvestibular nucleus for the purposes of modulating eyemovements in relation to gaze (eye in space) velocitywith the head still or during combined eye–head(vestibular signal-derived) tracking.9,10 Important forcancelling the effects of the VOR on eye movementwhen it is not in the best interest of the individual(think of twirling ballet dancers or figure skaters andhow they can spin without getting dizzy), the vestibu-locerebellum is also important in the compensationprocess for a unilateral vestibular loss.7,9,10

The Hair Cells

The fundamental unit for vestibular activity on amicroscopic basis inside the inner ear consists ofbroadly classified type 1 and 2 hair cells (Figure 2-5).

Type 1 hair cells are flask-shaped and surroundedby the afferent nerve terminal at its base in a chalice-like fashion. One unique characteristic of the afferentnerve fibers that envelop type 1 hair cells is that they areamong the largest in the nervous system (up to 20 µmin diameter). The high amount of both tonic (sponta-neous) and dynamic (kinetic) electrical activity at anytime arising from type 1 hair cells has probably neces-sitated this feature for the neurons that transfer thisinformation to the CNS. Type 2 hair cells are morecylindrical and at their base are typically surrounded bymultiple nerve terminals in contradistinction.11

22 Systemic Toxicity

Blanket of CalciumCarbonate 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 SolvayPharma, Canada.

Each hair cell contains on its top a bundle of 50 to100 stereocilia and one long kinocilium that projectinto the gelatinous matrix of the cupula or macula. Itis thought that the location of the kinocilium relativeto 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 isborn with a maximum number of type 1 and 2 haircells that cannot be replaced or regenerated if lost as aresult of the effects of pathology (eg, ototoxicity or sur-gical trauma) or aging (the postulated presbyvestibulardropout from cellular apoptosis). Presumably the sameprocess holds for the type I and II neurons that com-prise the vestibular nerve.

APPLIED PHYSIOLOGY

At the microscopic level, movements of the head orchanges in linear accelerations deflect the cupula orshift the gelatinous matrix of the otolithic organs withits load of otolithic crystals that will either stimulate(depolarize) or inhibit (hyperpolarize) electrical activ-ity from type 1 and 2 hair cells. Displacement of thestereocilia either toward or away from the kinociliuminfluences calcium influx mechanisms at the apex ofthe cell that causes either the release or reduction ofneurotransmitters from the cell to the surroundingafferent neurons (Figures 2-6 and 2-7 ).12 The electri-cal activity generated is then transferred along thevestibular nerve to the vestibular nuclei in the brain-stem. Information above the tonic (spontaneous) firingrate of the type 1 hair cells transmitted along type Ineurons is largely thought to have a stimulatory effectin contrast to a more inhibitory effect attributable totype 2 hair cells and type II neurons.

The SCCs largely appear to be responsible for theequal but opposite corresponding eye-to-head move-ments better known as the VOR. The otolithic organsare primarily responsible for ocular counter-rollingwith tilts of the head and for vestibulospinal reflexesthat help in the maintenance of body posture andmuscle tone.

In order to ultimately produce conjugate versionalVOR-mediated movements of the eyes, each vestibularnucleus receives electrical information from both sidesthat is exchanged via the vestibular commissure in thebrainstem. The organization is generally believed to bespecific across the commissure. Neurons in the rightvestibular nucleus, for example, that receive type Iinput from the right horizontal SCC project across thecommissure to the neurons found in the left vestibularnucleus that are driven by the left horizontal SCCreceiving contralateral type II input and vice versa.7

Physiology of the Vestibular System 23

Type 1 Type 2

KC KCH H

N

NC NE 1NE 2NE 2

NuNuM

M

Ct Ct

Figure 2-5 Schematic representation of type 1 and type 2 haircells. 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 inhibitionfrom otolithic shift and its shearing effect on stereocilia andkinocilium 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) atrest (resting discharge rate) and with respect to effects ofmovement resulting in depolarization (stimulation) andhyperpolarization (inhibition).

KEY CONCEPTS

According to Leigh and Zee’s seminal text, the key con-cepts of vestibular physiology can be best appreciatedin the context that “the push–pull pairings of thecanals, the resting vestibular tone and exchange ofneural 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 headmovement, the eyes should move in an equal but oppo-site direction to head movement. Anything less thanunity (corresponding eye movement/head movement)may result in the perception of visual blurring withhead movement—oscillopsia being the classic sympto-matic complaint of an individual with a bilateralperipheral vestibular loss as might result from genta-micin vestibulotoxicity.

Nystagmus

Defined as a rhythmic to-and-fro, back-and-forthmovement of the eyes, nystagmus represents the cardi-nal sign of unilateral peripheral vestibular or centralvestibular dysfunction.

In an acute unilateral loss of peripheral vestibularactivity that might occur from topical aminoglycosidedrops or certain disinfectant surgical preparation solu-tions used in the presence of a tympanic membranedefect, injury to the end-organ causes a difference inneural activity between the left and right vestibularnuclei. Should the push–pull pairings of the canals beaffected as a result of pathology, the eyes are typicallydriven with a slow movement toward the affected sideonly to be corrected by a fast corrective saccade gen-erated within the CNS away from the side of the lesionin a repetitive fashion. Although somewhat misguided,the direction of the nystagmus by convention refers tothe fast phase, typically away from the side of thelesion under circumstances of an acute unilateralperipheral vestibular loss.

Habituation and Adaptation

In humans the CNS may habituate (show a reducedresponse) the VOR depending on the environmentalcircumstances. This may happen in individuals whoare blind or in those exposed to constant velocity rota-tions or continuous low-frequency oscillations (such ason a ship). The mechanisms for adaptation or the adap-tive plasticity of the VOR are usually visually driven andhave been experimentally studied by subjects wearingreversing prisms.13 This phenomenon is frequentlyexperienced by those wearing new prescriptive glasseswith the explanation that “they take some time to getused to.” Eventually one adapts to the new lenses as the

gain of the VOR changes accordingly. The same holdstrue to some extent for those with a unilateral periph-eral vestibular loss, where the gain can be somewhatinfluenced, though not perfectly.

Compensation

Clinical improvement following acute unilateralperipheral vestibular deafferentation requires the pres-ence of intact central vestibular connections primarilyat the level of the vestibulocerebellum.4,7 The loss oftonic or spontaneous vestibular activity from the end-organ is ultimately replaced by the development ofspontaneous electrical activity arising within thevestibular nuclei of the affected side.14 At rest the asym-metries that would be expected from the push–pulleffects from the canals are kept in check, and as a resultthere is the gradual resolution of the once-present spon-taneous nystagmus. Quick head movements producingchanges in the dynamic electrical activity, however, cannever be completely compensated through this mecha-nism on the affected side, and a bilateral loss of inner earfunction never does despite the insertion of midrota-tion corrective saccades. For a more detailed explana-tion of the phenomenon of compensation and why itoften fails in the setting of a bilateral vestibular loss seeChapter 19, “Monitoring Vestibular Toxicity.”

CLINICAL MANIFESTATIONS OF VESTIBULARDYSFUNCTION

Loss of vestibular function is associated with severalsigns and symptoms.

Unilateral Peripheral Vestibular Loss

With a loss of unilateral vestibular function the patientacutely experiences the sensation of true vertigo frominterruptions of VOR pathways and tends to lie per-fectly still, as any movement aggravates vegetativesymptoms such as nausea and vomiting that arise fromthe emetic centers. Nystagmus beating away from theside of lesion is the cardinal physical sign that obeysAlexander’s law (the quick phase of the nystagmusinduced by the imbalance in activity at the level of thevestibular nuclei is greatest in amplitude and frequencywhen the eyes are turned away from the side of thelesion).15 Interruption in vestibulospinal tract pathwayscauses 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 acutevestibulocerebellar tract involvement. Features distin-guishing peripheral from central mediated nystagmuscan be found in Table 2-1.

With compensation (implying the existence of anormal functioning CNS and contralateral peripheralvestibular system) there may be minimal symptoma-

24 Systemic Toxicity

tology that is only brought out by very rapid headmovements. The spontaneous nystagmus disappears,vegetative symptoms resolve, gait improves, and in thecase of a chronic condition the patient may experienceonly a slight imbalance when turning quickly.

Bilateral Peripheral Vestibular Loss

Vertigo is not a feature of a bilateral vestibular loss evenwhen it occurs in an acute fashion. Injury to the end-organs as might occur in systemic aminoglycosidevestibulotoxicity causes a bilateral loss of function thattends to be electrically symmetric at the level of thevestibular nuclei in the brainstem. Instead the patienttends to complain of oscillopsia and imbalance. The gaitis typically broad-based and ataxic, especially with eyesclosed. Falls are not infrequent and in many instances

the patient requires assistive devices for ambulation oris relegated to a wheelchair. Compensation is generallyunlikely to occur despite the best efforts of vestibularrehabilitation therapy and a greater reliance on infor-mation from visual and proprioceptive receptors.

SPECIAL CLINICAL TESTS OFVESTIBULAR FUNCTION

The following clinical tests are used at the bedside inthe assessment of vestibular function and are specificfor the VOR. A summary can be found in Table 2-2.

High-Frequency Head Thrust or HalmagyiManeuver

Perhaps the most specific test for horizontal VORfunction, the high-frequency head thrust, shares the

Physiology of the Vestibular System 25

Table 2-1 Characteristics of Nystagmus/Oculomotor Abnormalities in Peripheral Vestibular vs Central Pathology

Feature Acute Unilateral Peripheral Loss Bilateral Peripheral Loss Central

Direction of nystagmus Mixed horizontal torsional None expected Mixed or pure torsional (arching) or vertical

Fixation/suppression Yes Yes No

Slow phase of nystagmus Constant No nystagmus Constant or increasing/expected decreasing exponentially

Smooth pursuit Normal Normal Usually saccadic

Saccades Normal Normal Often dysmetric

Caloric tests Unilateral loss Bilateral loss Intact/direction ofnystagmus often perverted (reverse direction)

CNS symptoms Absent Absent Often present

Symptoms Severe motion aggravated Oscillopsia/imbalance/gait Vertigo not as severe as in vertigo/vegetative symptoms ataxia, vertigo not a complaint acute unilateral loss

CNS = central nervous system.

Table 2-2 Special Clinical Tests of Vestibular Function

Clinical Vestibular Test Purpose

High-frequency head thrust (Halmagyi maneuver) High-frequency test of VOR function usually performed in the horizontalplane. Presence of refixation saccades to stabilize eyes on a target follow-ing fast head movement suggests a defect in the horizontal VOR

Head shake test for 15–20 seconds High-frequency vestibular test. Presence of post-headshake nystagmuscorrelates well with increasing right/left excitability difference on calorictesting. Fast phase of nystagmus usually directed away from side of lesion.

Oscillopsia test Visual loss of more than 5 lines with rapid horizontal head shaking whilelooking at a standard Snellen’s chart suggests a bilateral vestibular loss.

VOR suppression test Inability to visually suppress nystagmus during head rotations suggests adefect at the level of the vestibulocerebellum. Pursuit eye movements areinvariably saccadic

VOR = vestibulo-ocular reflex.

same physiologic basis as the “doll’s eye” maneuver inneurology. During a quick head movement to the nor-mal side with the patient focusing on a target, thereshould be almost perfect compensatory conjugate ver-sional movement of the eyes in an equal but oppositedirection to head movement. When a defect occurs inthe VOR, quick movements of the head are usuallyassociated with incomplete compensatory conjugateeye movements often requiring refixation saccades tostabilize gaze.16,17 Not surprisingly patients with a uni-lateral vestibular loss often volunteer subjective blur-ring of vision when they move their head to theaffected side.

Although a positive head thrust maneuver is alwaysindicative of pathology somewhere along the course ofVOR, false-negative findings can arise. This can occurwhen an individual throws in corrective midrotationsaccades that are imperceptible to the human eye. Iden-tification with advanced eye-movement recording sys-tems such as magnetic scleral coil search studies wouldtypically be required.18

Head Shake Test

Rapid horizontal head shaking for 15 to 20 secondsoccasionally results in horizontal post-headshakenystagmus usually (but not always) directed away fromthe side of a unilateral vestibular loss.19 Frenzel’s glassesare generally worn to prevent ocular fixation and sup-pression of nystagmus by vision. Headshake nystagmusis generally thought to occur when asymmetries in rest-ing vestibular tone are exaggerated at the level of thepostulated central velocity storage mechanism inthe brainstem.20

Dynamic Visual Acuity (Oscillopsia Testing)

Complaints of oscillopsia are best assessed by askingthe patient to read the lowest line possible on a stan-dard Snellen’s chart. While repetitively shaking thehead in the horizontal plane (at a frequency > 2 Hz) thepatient is asked to read the lowest line possible for com-parison purposes. A loss of more than five lines duringactive head-shaking is considered definitely clinicallysignificant for a bilateral vestibular loss.21 The test canalso be performed using an optotype such as the letter“E” (the so-called dynamic illegible “E,” or DIE, test)presented in random orientations and different sizes ona chart or monitor. Comparison between the static anddynamic optotypes correctly identified has been usedto determine if a bilateral vestibular loss exists.22,23

VOR Suppression Testing (Fixation of Vestibular-Induced Nystagmus)

This test assesses the ability of the CNS to suppress avestibular signal. It can be assessed by asking patientsto follow with the head in the same direction an objectthat rotates (eg, patients look at their outstretched

hands held together while seated in a chair that rotates).If the vestibulocerebellum is intact then the eyes shouldremain stable in the orbit from visual fixation and sup-pression of the VOR. In central vestibular pathology,oculomotor testing typically reveals pursuit eye move-ments that are saccadic associated with the presence ofa breakthrough nystagmus during head rotations asfixation is incomplete.24 VOR suppression testing issomewhat analogous to the parallel phenomenon offailure of fixation suppression during caloric testingwhen visual fixation does not suppress caloric-inducednystagmus.

SUMMARY

• The vestibular system is responsible for the per-ception of both the sense of position andmotion. Angular accelerations are perceived bythe SCCs, linear accelerations by the otolithicmacula of the utricle and saccule.

• Vestibular pathways include the VOR, vestibu-lospinal tracts, and vestibulocerebellar tracts.Overall the VOR remains the most importantand most clinically studied vestibular pathways,being responsible for the maintenance of a sta-ble retinal image with active head movement.Defects in these pathways arising from pathol-ogy demonstrate several well-recognized physi-cal signs, the cardinal sign of a unilateralperipheral vestibular loss being nystagmus.

• The concepts of VOR gain, nystagmus, habitua-tion or adaptive plasticity, and compensation allhave their substrates in the push–pull pairings ofthe canals, resting vestibular tone, and exchangeof neural input through the vestibular commis-sure from peripheral and central vestibular path-ways that maximize vestibular sensitivity inhealth and demonstrate pathologic featureswhen diseased. (For detailed informationregarding oculomotor and vestibular physiology,see Leigh and Zee7 and Baloh and Honrubia.4)

• True vertigo is usually present in an acute uni-lateral peripheral vestibular loss. A bilateralperipheral vestibular loss typically results inoscillopsia (visual blurring with head move-ment) and imbalance that worsens in theabsence of visual clues. True vertigo is rarely evera feature of bilateral peripheral vestibular loss.

• Clinical bedside tests apply the concepts ofvestibular physiology and are important in rec-ognizing disease pathology involving thevestibular system. The high-frequency headthrust (Halmagyi maneuver) is probably themost specific clinical test of vestibular function.Other tests include the headshake test, oscillop-sia testing, and VOR suppression and fixation.

26 Systemic Toxicity

Physiology of the Vestibular System 27

ACKNOWLEDGMENTS

The author thanks Mr David Mazierski (medical illus-trator), Ms Elise Walmsley (medical illustrator, TriFocalCommunications), and Solvay Pharma Canada (illus-trations and permissions).

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