Auris Nasus Larynx 35 (2008) 1–10 www.elsevier.com/locate/anl

A place principle for vertigo

Richard R. Gacek * Department of Otolaryngology, Head and Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA

Received 16 March 2007; accepted 13 April 2007 Available online 24 October 2007

Abstract

Objective: To provide a road map of the vestibular labyrinth and its innervation leading to a place principle for different forms of vertigo. Method: The literature describing the anatomy and physiology of the was reviewed. Results: Different forms of vertigo may be determined by the type of organ, type of cell and location in the vestibular . Conclusion: Partial lesions (viral) of the are manifested as various forms of vertigo. # 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Vertigo; ; Pathology

Contents

1. Introduction ...... 1 2. Sense organ...... 2 3. Ganglion cells ...... 4 4. Hair cells ...... 5 5. polarization ...... 5 6. Efferent vestibular system ...... 8 7. A place principle for vertigo ...... 9 8. Conclusion ...... 10 References ...... 10

1. Introduction membrane, , support cells in the ) determine the place for maximal displacement of this Sensory systems must be highly organized to function partition by a given traveling wave induced by an auditory effectively. The special are especially well developed. stimulus. This orderly transmission of frequencies is This organization exists at the periphery and is duplicated preserved over the primary auditory , and multiple with ascent of the system centrally. The central to the cortex for proper integration of provides an excellent example of a place principle for auditory messages. Vision and olfaction have a similar . The reception of frequencies in orderly fashion precise organization to their neural systems. from low at the apex of the to high at the base is Sufficient morphologic, physiologic and clinical evi- determined by the physical characteristics of the cochlear dence has accumulated in the past few decades to indicate an partition. Components in the (basilar organization in the vestibular system that may account for different forms of vertigo depending on the location of * Tel.: +1 508 856 4162; fax: +1 508 856 6703. pathology in the vestibular nerve. The evidence supporting E-mail address: [email protected]. such a ‘‘place principle for vertigo’’ will be reviewed in this

0385-8146/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2007.04.002 2 R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10

Fig. 2. Light microscope photomicrograph of the utricular macula demon- strates the otoconial blanket (arrow head) resting on the neurosensory epithelium (arrow). N: utricular nerve. Fig. 1. Section through the vestibular ganglion and nerve from a patient with vestibular neuronitis. Arrows point to the numerous bundles of degenerated resulting from degenerated groups of ganglion cells. in angular acceleration or deceleration of the fluid (endo- lymph) within the membranous canal. Such inertial changes report. Such a principle might aid our clinical approach to deform the cupular partition of the ampullary enlargement in the evaluation and treatment of vertigo in patients, with the canal resulting in deflection of the ciliary bundles of hair recurrent vertigo. The recurrent vestibulopathies are now cells in the sensory epithelium (Fig. 3) [6]. known to be caused by discrete vestibular ganglion cell lesions, likely viral induced. A significant body of histopathologic evidence has demonstrated that viral lesions are limited to discrete clusters of degenerating neurons in the vestibular ganglion in vestibular neuronitis, Meniere’s disease and benign paroxysmal positional vertigo (Fig. 1) [1–3]. This pattern of ganglion cell loss is typical of a viral neuropathy (4) caused by re-activation of a latent neurotropic virus (e.g. Zoster) [4]. Because the description of dizziness by patients may vary (i.e. vertigo, unsteadiness, positional vertigo), attempts have been made to classify vestibular disorders according to the nature of the imbalance symptom. An example of such a knowledge based system is that of Mira et al. [5]. This system used vertigo and dizziness to divide a long list of clinical pathologies encountered by the otologist or neurologist. The organization of the peripheral vestibular system is determined largely by two anatomical features. These are: (1) type of sense organ. (2) Type of ganglion cell.

2. Sense organ

Of the two types of vestibular sense organs, the organs are probably the most important in a gravity dependent environment. They are the oldest phylogenetically with the canal system making a presence as more mobility (swimming, walking, running) was acquired. Since the otolith organs feature a covering membrane containing high specific gravity (2.71) calcium carbonate particles (otoconia) resting on the ciliary bundles of the hair cells in the sensory epithelium, they are in a constant state of stimulation (Fig. 2). The canal Fig. 3. Photomicrograph of and its cupula. Note that the system, on the other hand, is activated by transitory increases cupula is attached to the ampullary roof. R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10 3

Fig. 5. Drawing summarizing the organization of vestibular ganglion and its peripheral and central axons (cat). The dark portion of the vestibular nerve signifies the location of type I ganglion cells that supply type I hair cells in the superior and lateral canal cristae. Cochlear and vestibular efferent axons are located at the interface of canal and otolith axons. SCA: superior canal ampulla; HCA: lateral canal ampulla; PCA: posterior Fig. 4. (A) Section through a human temporal bone where the utricular canal ampulla; UTR: ; SACC: ; Utric N: utricular nerve; PCN: macula is divided by a cleft (arrow) where there is an absence of neuro- posterior canal nerve; OCB: efferent bundle (cochlear and vestibular). epithelium (B).

The otolith organs are arranged horizontally (utricular rostral half of the nerve trunk and the otolith axons in the macula) and vertically (saccular macula) to record position caudal half. This differential location of otolith and canal and position change in these two planes. There is some neural input is necessary because of their different anatomical evidence which suggests each macula actually connections with second order neurons in the vestibular represents the merging of two smaller maculae with nuclei. The canal projections bifurcate on entering the oppositely polarized hair cells (Fig. 4). The interface of with the ascending branch terminating in the this merging is located at the striola line. The vestibular superior vestibular nucleus (SVN) and the descending nerve and ganglion supplying afferent innervation to the branch ending in the medial vestibular nucleus (MVN) vestibular sense organs has an arbitrary division into (rostral part) (Fig. 6). These two nuclei project bilaterally superior and inferior. The superior division supplies the into the medial longitudinal fasciculus (MLF). The SVN utricular macula, the cristae of the lateral and superior projects in the ipsilateral MLF to the IV and III nerve nuclei and a small portion of the saccular while the MVN sends a comparable projection in the macula macula while the inferior division innervates the contralateral MLF to terminate in the IV and III nuclei in a saccule and posterior canal crista (Fig. 5). reciprocal fashion [8]. These pathways serve the vestibule- The bipolar vestibular ganglion cells which supply ocular reflex (VOR) for vertical and oblique extraocular afferent input from the otolith organs are located ventrally in movements necessary for nystagmus. The MVN also the central portion of the ganglion (Fig. 5), while the canal projects bilaterally to the VI nerve nucleus and to the ganglion cells are located at the rostral and caudal ends [7]. ipsilateral medial rectus subnucleus in III n. over a tract As the axons from these ganglion cells form the vestibular called the ascending tract of Deiters. These projections are nerve trunk, those from the canals converge together in the responsible for the horizontal VOR. Some projections from 4 R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10

Fig. 6. Diagram of the central projections of afferents from the semicircular canals. MLF: medial longitudinal fasciculus; VS: vestibulo-spinal; VN: commissural; VO: vestibulo-ocular; INC: interstitial nucleus of Cajal; III: ; VI: ; IV: . the medial and descending vestibular (DVN) nuclei travel Fig. 7. Central projections of afferents from the utricular macula. LVST: down the MLF to the muscles of the neck region where they lateral ; MVST: medial vestibulospinal tract; III: ocu- are responsible for vestibulo-collic reflexes [8,9]. lomotor nucleus; VI: abducens nucleus. The bifurcating axons from the otolith organs terminate in the caudal —that is the lateral (LVN), medial 3. Ganglion cells and descending nuclei (Fig. 7). The ascending branches from utricular neurons terminate in the ventral portion of the LVN Since the inner and its sense organs with their nerve and in the rostral MVN [7]. The descending branches connect supply, develops from the same anlagen, it is not surprising with cells in the caudal MVN and DVN. The LVN is that two types of ganglion cells, as described in the spiral responsible for vestibulospinal tract activation of trunkal and ganglion of the cochlea, also exist in the vestibular nerve. limb muscle reflexes [9,10]. The MVN and DVN descend in The two types of ganglion cells in these two types of sense the MLF for cervical muscle reflexes. However, the utricle organs have similar features in morphology, physiology and also has connections with the VI and III nuclei for horizontal pathologic behavior. eye movements (compensatory). Type I ganglion cells have large caliber myelinated Input from the saccule is similar but much smaller. appendages () which innervate type I hair cells with Saccular neurons project to portions of the MVN and DVN for 1:1 or almost 1:1 ratio (Fig. 9). They possess an irregular neck muscle activation via the MLF. Projections to the spontaneous discharge pattern and degenerate following oculomotor nucleus over the group Y nucleus permit a VOR ablation of the sense organ (Fig. 10) [12–14]. In the cochlea response from the saccule involving the superior and inferior they provide 90% of the innervation of the organ of Corti rectus muscles as well as the oblique eye muscles (Fig. 8) [11]. where they supply inner hair cells (IHC) [15]. Type I In summary, the semicircular canal sense organs ganglion cells are sequestered from the type II cells in the primarily project to the nuclei for VOR activation vestibular ganglion forming the ampullary but have a (nystagmus) while the otolith organs are responsible for dispersed pattern in the nerves to otolith organs [7]. This activity in anti-gravity muscles of the neck, trunk and limbs distribution reflects their periphery termination on type I (ataxia). However, compensatory eye muscle activation also HC. The dendrites of type I ganglion cells travel in the center occurs from stimulation of the otolith organ pathway. of ampullary nerves because they terminate on the type I hair R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10 5

type I ganglion cells are concentrated at the most rostral end of the ganglion while type II cells occupy the caudal region of the superior division ganglion (Fig. 5). The dendrites of type II ganglion cells envelop those of type I ganglion cells as the ampullary nerves are formed. This separate location of type I and II ganglion cells in the superior vestibular division has been confirmed in the monkey and human vestibular nerve [20] and provides an opportunity for a differential functional response from injury to either of these two types of neurons.

4. Hair cells

The two types of hair cells (HC) in the vestibular organs are somewhat similar to the inner (HC) and outer hair (OHC) cells in the organ of corti. The type I HC in the vestibular organs (i.e. crista) are innervated by type I vestibular ganglion cells with the same irregular spontaneous electrical activity as the type I cells which innervate the IHC in the organ of corti [15,16]. In both systems they are responsible for the major afferent input to the brain for balance and hearing. The type II vestibular hair cells may play an enhancing role in the sensitivity of balance organs similar to the role Fig. 8. Central projections from the saccular macula. IFC: infracerebellar that OHC impose on the IHC and auditory sensitivity. The nucleus; Y: group Y nucleus; LVST: lateral vestibulospinal tract; MVST: contractile properties of OHC allow a change in the cochlear medial vestibulospinal tract; MLF: medial longitudinal fasciculus; III: amplifier effect in the organ of corti [21]. This contractile oculomotor nucleus. function of the OHC is under efferent neural control and cells which are concentrated at the crest of the crista serves to enhance the sensitivity of auditory neurons (type I). ampullaris [16,17]. These hair cells are positioned to be most sensitive to cupular displacement. The central projection of type I ganglion cells is to 5. Hair cell polarization vestibulo-ocular neurons in the SVN and MVN via axo- somatic (Fig. 11) [18]. Thus the type I hair cell – In addition to the different functionalities of two types of type I ganglion cell – vestibulo-ocular neuron in the HC (with their innervation) in the vestibular system, an vestibular nuclei (SVN, MVN) is responsible for the VOR important feature of vestibular hair cells is their alignment responses associated with stimulation or degeneration of the within an individual sense organ and the relationship of this cristae ampullaris. In the otolith system these type I ganglion orientation to that of other sense organs in the labyrinth cells project to large multipolar neurons of the vestibulosp- [16,17]. This is referred to as the ‘‘polarization of hair cells’’ inal tracts as well as to vestibulo-ocular neurons in the in the labyrinth. caudal vestibular nuclei. In contrast to cochlear hair cells vestibular HC have a Type II ganglion cells have small caliber myelinated ciliary bundle comprised of 70–100+ and one dendrites which, innervate type II hair cells in a diffuse longer [16,17]. This Kinocilium is located at the manner [16,17] (i.e. many HC supplied by a single fiber) end of the ciliary bundle where the longest sterocilia are (Fig. 9), and demonstrate a regular spontaneous discharge located. The significance of this arrangement is that when pattern [12,13,19]. They do not degenerate after end organ the cilia are deflected toward the kinocilium there is ablation (Fig. 10) [18]. The type II hair cells located along depolarization of the HC and an increase in the afferent the slopes of the crista ampullaris are not in a position to neural unit activity while deflection away from the optimally respond to cupular displacement but may have a kinocilium results in hyper-polarization and a decrease in supporting role in end organ sensitivity by virtue of their rich neural activity [16]. This has great functional significance efferent innervation. and accounts for the different responses obtained by testing Because the lateral canal sense organ is a recent individual canals by warm and cool caloric stimulation. phylogenetic development, making an appearance in An equally important consideration, however, is the amphibians (frog), the type I and II ganglion cell populations relationship of this polarity of HC between the five sense are separated in the superior division ganglion [7,20].The organs of the labyrinth. Any movement of the body and head 6 R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10

Fig. 9. Diagram of the innervation to the two types of vestibular hair cells. produces activation or deactivation in all sense organs of Normally a change in head position produces a force that both labyrinths. Figs. 12 and 13 summarize this polarity of causes excitation of the otolith and its corresponding canal. HC in the sense organs or parts of sense organs (maculae) However, if the otolith function is deficient, its correspond- [16,17]. It is obvious that the polarization of HC in coplanar ing canal will respond in an excitatory mode [22]. This could canals is opposite to each other. In this way, a given rotation be reflected in a position provoked vertigo and nystagmus. It produces excitation in one canal and decreased neural input has been suggested that this otolith–canal relationship is from the opposite coplanar canal, greatly enhancing the based on a velocity storage mechanism in the central differential response delivered to the brainstem for a VOR nervous system probably the vestibular nuclei [26]. The response. This difference in the input is also enhanced by polarization of HC in the otolith and corresponding canal commissural inhibition of the contralateral canal by activity sense organs play a role in this relationship. As seen in generated by the activated canal. Figs. 12 and 13 the maculae are each divided into halves by The relationship between the canals and otolith organs is the striola line with each half containing oppositely important but under recognized. Experiments conducted in polarized HC. Each half has HC that are aligned with a both zero gravity and one gravity environments have crista ampullaris. These would be activated by the same demonstrated a modulation of canal responses by stimula- vector during movement of the head. tion of the otolith organs [22–24]. Fluur and Siegborn have The number of neural units supplying the otolith and canal shown this in the cat [25]. They demonstrated that selective sense organs is important in understanding the vulnerability of denervation of an otolith (the utricle) produced a horizontal this otolith-canal interrelationship. In the mammalian ear nystagmus if the innervation to the lateral canal crista was where numerical data are available for the innervation of intact. However, if the lateral canal sense organ was individual vestibular sense organs (guinea pig, cat, monkey), denervated before selective denervation of the utricle, no the number of afferent neural units in the vestibular nerve nystagmus was observed. A similar relationship between the branches is approximately equal [27]. However, the otolith saccule and the posterior canal was observed. These innervation modulating each crista ampullaris is represented observations indicate that there is an inhibitory effect on by one half the total innervation of the macula, making the canal responsiveness by the otolith of the same vestibular effective otolith neural input one-half that supplying the crista nerve division. ampullaris. Quantitative assessment of thevestibular ganglion R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10 7

Fig. 12. View of the human vestibular nerve branches and sense organs demonstrating the polarization of hair cells in the cristae and utricular macula supplied by the superior division. F: ; V: vestibular nerve; S: saccular macula; U: utricular macula; PC: posterior canal crista; LC: lateral canal crista; SC: superior canal crista.

of TB from patients with BPPV have shown a greater than 50% loss of ganglion cells in both vestibular divisions [28].A loss of this magnitude in afferent units already a fraction of Fig. 10. Photomicrograph of the rostral part of the superior division axons those to the crista ampullaris is likely to cause a disruption in in the cat. (A) Normal vestibular nerve demonstrates the high concentration the otolith-canal relationship resulting in BPPV. of large diameter axons (type I ganglion cells). (B) Six months after This neuropathologic explanation may account for the labyrinthectomy the large axons have degenerated. various categories of BPPV. Posterior canal BPPV is by far the most common possibly because the saccular nerve is the smallest in all species studied [27]. Thus it represents the greatest mismatch between otolith and canal innervation and most likely to lose its inhibitory effect on posterior canal

Fig. 11. Diagram of the central projections of types I and II hair cells and Fig. 13. Posterior view of the specimen in Fig 12 shows the polarization of ganglion cells in the cristae. hair cells in the saccular macula and posterior canal crista (PC). 8 R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10 excitation. Lateral canal and anterior canal BPPV are less commonly recognized because of a smaller mismatch between otolith and canal innervation.

6. Efferent vestibular system

The final form of vestibular injury which may present as dysequilibrium relates to the efferent vestibular pathway. The vestibular efferent pathway originates bilaterally in the MVN just lateral to the abducens nucleus [29]. Axons of these neurons [30] merge with and travel with the efferent cochlear pathway (olivo-cochlear pathway) in the vestibular nerve as it exits the brainstem (Fig. 14) [31]. This common efferent bundle is clearly demonstrated by the high aceteyl cholinesterase activity which suggests acetycholine as its neurotransmitter agent (Fig. 15) [32]. This efferent bundle passes through the saccular portion of the vestibular Fig. 15. Transverse section of the vestibular (V) and cochlear (C) nerves in ganglion and, therefore, may be affected (loss of function) the cat shows the efferent labyrinthine pathway (arrow) in the center of the by inflammatory lesions in this area (Fig. 16). Individual vestibular nerve. Acetylcholinesterase preparation. F: facial nerve. efferent axons ramify as they travel in a dispersed arrangement to the sense organs (Fig. 17). This branching The role of the efferent cochlear pathway has been shown pattern permits a rich efferent termination on HC in the sense to be one of modifying the physical characteristics of the organ neuroepithelium. sense organ to enhance sensitivity for stimulation of the Although an inhibitory effect is associated with stimula- primary auditory unit. By activating the contractile potential tion of the vestibular efferent pathway [33–35], the function of the OHC to lengthen or shorten thus adjusting the reticular of this neural system in balance has not been demonstrated. lamina and the to sharpen the tuning However, certain established facts on efferent systems curves for the primary auditory units (IHC and type I spiral permit speculation on the role that the efferent system may ganglion cells) [21]. Otoacoustic emissions (OAE) gener- play in balance. ated by this ‘‘cochlear amplifier’’ [36] have been shown to be

Fig. 14. Diagram of the efferent vestibular pathway (solid lines); stippled area = efferent cochlear pathway. LVN: lateral vestibular nucleus; MVN: medial vestibular nucleus; DCN: dorsal ventral cochlear nuclei; VCN: ventral cochlear nuclei; VII: genu of facial nerve; VI: abducens nucleus; ASO: accessory superior olivary nucleus; LSO: lateral superior olivary nucleus. R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10 9

organs by altering the covering membrane (cupula, otoconial blanket) during vigorous physical activity. The clinical syndrome that could result from dysfunction of the efferent vestibular system might be motion sickness. A particularly efficient efferent system would be a requirement for a gymnast or figure skater.

7. A place principle for vertigo

This anatomical organization (supported by physiologi- cal correlates) provides a basis for attributing various forms of vertigo to pathology in discrete part of the vestibular ganglion. There is increasing pathologic evidence that the recurrent vestibulopathies (ventricular neuronitis, Meniere’s disease, benign paroxysmal positional vertigo) are caused by Fig. 16. This section through the same specimen as Fig. 15 shows the discrete ganglion injury (degeneration) from reactivation of efferent cochlear pathway (OC) leaves the saccular nerve while vestibular neurotropic viruses (herpes virinae family) [1–3]. The efferents have entered the vestibular nerve branches. severity and form of dysequilibrium described by such patients will depend on the location and number of inhibited by the activity of the crossed (efferent) olivo- vestibular ganglion cells injured by virus [40]. The location cochlear pathway. of sites in the vestibular ganglion responsible for different Efferent vestibular activity in lower forms (fish) has been forms of vertigo are represented by the numbers 1–5 in shown to be increased before vigorous movement (swim- Fig. 5. ming) which would over stimulate the organ of balance (lateral line) [37–39]. Presumably this efferent activation is 1. Lesions in the most rostral part of the vestibular ganglion intended to reduce (prevent) self-stimulation by the animals (type I GC) are responsible for episodes of rotatory activity. vertigo. A strong VOR disturbance (nystagmus) signals This a role is compatible with the numerous demonstra- this form of vertigo. tions of inhibition of afferent neural transmission following 2. If the ganglion cell lesion is located immediately caudal stimulation of the vestibular efferent system [33,34]. Such a to this rostral pole of the superior division type II GC are system may play a role in preventing auto stimulation of affected. Unsteadiness, especially on head movement, vestibular sense organs during physical activity. will be experienced because these type II GC project to A suggested corollary in the vestibular system would be commissural pathways. for the efferent pathway to prevent auto-stimulation of sense 3. Degeneration of ganglion cells in ventral parts of both organs by mechanically changing the sensitivity of the sense the superior (utricle) and inferior (saccule) divisions of the vestibular ganglion, causes loss of function in the vestibulospinal tract to neck, trunk and limb muscles. Frequently these are described by patients as ‘‘drop’’ attacks. Ataxia may be a lingering form of this form of dysequilibrium. 4. The most common form of vertigo encountered in practice is position induced. Short duration episodes of a rotatory vertigo which is fatiquable have been described since Barany [41]. Both Barany [41] and Citron and Hallpike [42] felt this was an otolith disorder but the nystagmus response observed in this syndrome prevented acceptance of an otolith cause. Hallpike’s description of utricular degeneration [42] in the TB of BPPV was not enough to neutralize the predominant support of a canal etiology. Although the clinical response is a rotatory form of vertigo, the uninhibited response is caused by loss of the inhibitory role of the otolith organs. 5. Lesions in the saccular portion of the vestibular ganglion Fig. 17. The vestibular efferent axons (arrows) are spread throughout the (inferior vestibular) may secondarily interrupt the afferent fibers before reaching the sense organ epithelium. efferent pathways to the cochlear and vestibular sense 10 R.R. Gacek / Auris Nasus Larynx 35 (2008) 1–10

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