Disorders of cochlear blood flow

Brain Research Reviews 43 (2003) 17–28www.elsevier.com/ locate/brainresrev

Review

D isorders of cochlear blood flowa , b a a*Tsutomu Nakashima , Shinji Naganawa , Michihiko Sone , Mitsuo Tominaga ,a a a,c d,eHideo Hayashi , Hiroshi Yamamoto , Xiuli Liu , Alfred L. Nuttall

aDepartment of Otorhinolaryngology, Nagoya University School of Medicine, Nagoya, JapanbDepartment of Radiology, Nagoya University School of Medicine, Nagoya, Japan

cDepartment of Otolaryngology, First Affiliated Hospital of Dalian Medical University, Dalian, ChinadOregon Hearing Research Center, Oregon Health and Science University, Portland OR, USA

eKresge Hearing Research Institute, The University of Michigan, Ann Arbor, MI, USA

Accepted 18 April 2003

Abstract

The cochlea is principally supplied from the inner ear artery (labyrinthine artery), which is usually a branch of the anterior inferiorcerebellar artery. Cochlear blood flow is a function of cochlear perfusion pressure, which is calculated as the difference between meanarterial blood pressure and inner ear fluid pressure. Many otologic disorders such as noise-induced hearing loss, endolymphatic hydropsand presbycusis are suspected of being related to alterations in cochlear blood flow. However, the human cochlea is not easily accessiblefor investigation because this delicate sensory organ is hidden deep in the temporal bone. In patients with sensorineural hearing loss,magnetic resonance imaging, laser-Doppler flowmetry and ultrasonography have been used to investigate the status of cochlear bloodflow. There have been many reports of hearing loss that were considered to be caused by blood flow disturbance in the cochlea. However,direct evidence of blood flow disturbance in the cochlea is still lacking in most of the cases. 2003 Elsevier B.V. All rights reserved.

Theme: Sensory systems

Topic: Auditory systems; ischemia

Keywords: Cochlea; Blood flow; Hearing loss; Magnetic resonance imaging; Laser-Doppler flowmetry; Ultrasonography

Contents

1 . Introduction ............................................................................................................................................................................................ 182 . Anatomy of cochlear blood vessels ........................................................................................................................................................... 183 . Volume and distribution of cochlear blood flow ......................................................................................................................................... 194 . Autoregulation of cochlear blood flow....................................................................................................................................................... 19

4 .1. Association with systemic changes ................................................................................................................................................... 194 .2. Occlusion of anterior inferior cerebellar artery (AICA)....................................................................................................................... 204 .3. Occlusion of venous drainage........................................................................................................................................................... 204 .4. Elevation of inner ear pressure ......................................................................................................................................................... 20

5 . Morbidity associated with impaired cochlear blood flow............................................................................................................................. 205 .1. Noise-induced hearing loss .............................................................................................................................................................. 205 .2. Endolymphatic hydrops ................................................................................................................................................................... 215 .3. Presbycusis ..................................................................................................................................................................................... 21

6 . Role of nitric oxide.................................................................................................................................................................................. 217 . Methods of evaluation of cochlear blood flow or endolymphatic space in humans and guinea pigs ................................................................ 22

*Corresponding author. Tel.:181-52-744-2320; fax:181-52-744-2325.

E-mail address: [email protected](T. Nakashima).

0165-0173/03/$ – see front matter 2003 Elsevier B.V. All rights reserved.doi:10.1016/S0165-0173(03)00189-9

mailto:[email protected]

18 T. Nakashima et al. / Brain Research Reviews 43 (2003) 17–28

7 .1. Magnetic resonance imaging ............................................................................................................................................................ 227 .2. Laser-Doppler flowmetry ................................................................................................................................................................. 227 .3. Ultrasonography.............................................................................................................................................................................. 23

8 . Sensorineural hearing loss caused by disturbance of cochlear blood flow ..................................................................................................... 238 .1. Effect of cerebrospinal or cochlear fluid............................................................................................................................................ 238 .2. Disorders of blood vessels ............................................................................................................................................................... 238 .3. Blood disorders ............................................................................................................................................................................... 24

9 . Management of sensorineural hearing loss caused by disturbance of cochlear blood flow.............................................................................. 241 0. Conclusion ............................................................................................................................................................................................ 24Acknowledgements ...................................................................................................................................................................................... 24References................................................................................................................................................................................................... 24

The purpose of this report is to review investigations1 . Introductionabout blood flow disturbances in the human cochlea tohelp direct further studies in the future.Impairment of cochlear blood flow has been considered

to be one of the factors implicated in the pathophysiologyof various kinds of sensorineural hearing loss[49,82].However, it has been difficult to find direct evidence of 2 . Anatomy of cochlear blood vesselsimpairment of cochlear blood flow in each case. This isbecause the cochlea is surrounded by bone and prevents The inner ear artery (labyrinthine artery), which isdirect observation of blood vessels, unlike the ocular usually a branch of the AICA, nourishes the inner ear,fundus. The cochlea is not large enough to use angiog-which is composed of the cochlea and the vestibularraphy as can be used in the brain. Recently, magneticapparatus. The middle ear is usually supplied by theresonance imaging made it possible[6] to reveal the region carotid arterial system. There is no functional anastomosisof blood flow disturbance in patients with auditory of blood vessels between the middle ear and the inner ear,dysfunction in stroke[46]. in spite of their close anatomical relationship[93].Vascular

The inner ear is supplied principally from the inner ear anatomy of mammalian cochleas has been studied inartery (labyrinthine artery), which is usually a branch of guinea pigs[9,14,161], rats [11], cats [12], gerbils [13],the anterior inferior cerebellar artery, (AICA) (Fig. 1). chinchillas[161], rabbits[4], mice [56], monkeys[10] andWhen blood flow disturbance occurs in the AICA region, humans [9,15,101]. The arterial blood supply to themagnetic resonance imaging can demonstrate it. Even incochlea is maintained by an artery running spirally withincases in which a blood flow disturbance was recognized in the modiolus, which is the direct continuation of the innerthe AICA region, cochlear function is probably maintained ear artery, and from its terminal branch (Fig. 1).in some cases. This is due to collateral circulation to the As shown inFig. 2, arterioles leave the artery runningcochlea. Accordingly, it is necessary to obtain a suitable centrifugally and radiate both over the scala vestibuli andmethod to evaluate cochlear blood flow itself. across the spiral lamina. The capillary system in the

external wall and in the spiral lamina are drained centripet-

ally by radiating collecting venules. In the lateral wall ofthe cochlea, blood flows from the scala vestibuli towardsthe scala tympani, and through capillary networks in thestria vascularis at the scala media (Figs. 1 and 2). Thecapillaries of the stria vascularis appear to be composed ofendothelial cells without smooth muscle cells[142]. Thespiral ligament, which is located at the outer layer of thestria vascularis, contains blood vessels morphologicallysimilar to arteriovenous anastomoses.Fig. 2 also showsthat there are arterioles coming out from the spiralmodiolar artery and running across the spiral lamina. Theblood vessels supplying the spiral lamina are similar inappearance to those of the spiral ligament[142]. However,adrenergic fibers were found in the vicinity of bloodvessels in the spiral lamina, not in the spiral ligament

Fig. 1. Schematic view of major arteries from the labyrinthine artery.[153,154]. In the lateral wall, perivascular adrenergicAnterior inferior cerebellar artery (AICA). Labyrinthine artery (Innerinnervation extends beyond the immediate branches of theear artery). Common cochlear artery. Anterior vestibular artery.

Cochlear artery (Spiral modiolar artery). Vestibulo-cochlear artery; modiolar artery and reaches into the radiating arterioles,Cochlear branch. Vestibular branch. Capillaries of the stria but not into the area of the scala media[110].

vascularis. Arrows indicate the blood flow direction. The terminal vessels of the arterioles of the spiral lamina

T. Nakashima et al. / Brain Research Reviews 43 (2003) 17–28 19

3 . Volume and distribution of cochlear blood flow

The absolute and relative distribution of cochlear bloodflow has been investigated using microspheres in variousanimals. Cochlear blood flow volume was 1.460.9ml /min[5], 1.8060.8 ml /min [94] in guinea pigs, 1.6460.49ml /min [5], 1.6460.70 mg/min[141] in rats, 3.1061.19mg/min in cats[5], 2.3460.71 mg/min [5], 2.4860.56ml /min [67], 3.861.1ml /min [145] in rabbits, 1.2ml /minin gerbils [113], 2.5861.2 mg/min[5] in chinchillas, and0.75ml /min in chickens[176].

In rodents such as guinea pigs or rats, cochlear bloodflow was on the order of 1/10 000 of total cardiac output,and in rabbits it was on the order of 1/100 000 of totalcardiac output. In humans, it is estimated that cochlearblood flow is on the order of 1/1 000 000 of total cardiacoutput. Thus, the volume of cochlear blood flow isextremely small compared to the total cardiac output.However, its volume is about four times larger than that inthe vestibular apparatus[94].

Cochlear vascular areas can be divided into three parts:lateral, spiral and central portions (Fig. 2). The striaFig. 2. Schematic view of blood vessels in one cochlear turn. SV, scala

vestibuli; SM, scala media; ST, scala tympani. Vessel of the basilar vascularis and the spiral ligament are included in themembrane (VSBM). Vessel of the tympanic lip (VSTL). These vessels lateral portion, and the osseous spiral lamina and the organare belonging to the spiral portion. Capillaries of the stria vascularis.

of Corti are included in the spiral portion. The modiolus,Vessel of the spiral ligament. These vessels are belonging to the lateralwhich contains the cochlear nerve, is the central portion.portion. Arrows indicate the blood flow direction.The arterial blood supply to the cochlea is maintainedthrough the central portion. Because terminal blood vesselsin the spiral portion (VSBM and VSTL) have no com-municating blood vessels with the lateral portion except inare the vessel of the basilar membrane (VSBM) or thethe developing period of the cochlea, the lateral and spiralvessel of the tympanic lip (VSTL). The VSBM is locatedportions are clearly divided. The central portion is sobeneath the tunnel of Corti and the VSTL is located closedesignated because part of the arterial blood that entersto the VSBM (Fig. 2). These two capillary vessels areinto the central portion returns without going to the lateralspiral and parallel. Regarding the VSBM beneath the organor spiral portion.of Corti, there are relatively large inter-species differences.

In animal studies regarding blood flow distribution, theIn contrast, the blood vessels in the lateral wall have verypercentage of microspheres is the largest in the lateralsimilar distribution among species[143]. In guinea pigs,portion [94,113,123,141].In rabbits, more than 80% ofthe VSBM and VSTL are nearly continuously connectedmicrospheres were found in the lateral portion, 9% in thethroughout the cochlea. In humans, the VSBM is relativelyspiral portion and 9% in the central portion[4]. In rats, thecontinuous but the VSTL is not as continuous as it is indistribution of microspheres in the lateral, spiral, andguinea pigs[9]. Interestingly, in rabbits and mice, thecentral portions was 5769%, 1966%, and 2467%, re-VSBM is almost lacking in adults[4,56].spectively[93].A great similarity has been observed in the vascular

anatomy among mammalian cochleas, and the vascularanatomy of the human cochlea has been described[8]. The

4 . Autoregulation of cochlear blood flowvenous system of the human cochlea is relatively morecomplex than other mammals. There are separate venous

4 .1. Association with systemic changessystems running spirally within the modiolus in closeproximity to the scala tympani and the scala vestibuli. This

Yamamoto et al.[171] measured inner ear and brainstemis in contrast to the venous system in guinea pigs in whichblood circulation while systemic blood pressure wasthere is only a spiral vein at the scala tympani. Themodulated by norepinephrine infusion or exsanguination incochlear venous system is also more complicated than theguinea pigs. They stated that autoregulation was signifi-arterial system. The labyrinthine artery supplies the coch-cantly stronger in the brain than in the cochlea. Kawakamilea, whereas the venous system is divided into threeet al. [59] also stated that cochlear blood flow wasvessels; the vein of the cochlear aqueduct (VCAQ), theautoregulated, but this autoregulation was less than brainvein of the vestibular aqueduct and the vein passingblood flow in guinea pigs.through the inner acoustic meatus.


Some studies in the guinea pig, however, have shown flow was reduced to various degrees but recovery wasstrong intrinsic autoregulation in the cochlea[24]. Suzuki observed.et al. [146] investigated the effect of increased cerebrospi-nal fluid pressure on cochlear and cerebral blood flow in 4 .4. Elevation of inner ear pressureguinea pigs where cerebrospinal fluid pressure was trans-mitted directly to the inner ear through the patent cochlear Elevation of perilymphatic pressure reduced cochlearaqueduct. They reported that cochlear blood flow was not blood flow just as increased cerebrospinal fluid pressuredecreased by the fluid pressure elevation as much as was lowers cerebral blood flow[90,96]. Since endolymphaticcerebral blood flow. These differences in results regarding pressure varies to match perilymphatic pressure[164],the strength of autoregulation in comparison to cochlear perilymphatic and endolymphatic pressures can be consid-and cerebral blood flow may depend on the differences ered as the inner ear pressure. Because of the elevation ofbetween the experimental conditions. the inner ear pressure, cochlear blood flow, except to the

Autoregulation of cochlear blood flow was obviously modiolus, decreased significantly. Above all, the bloodstronger than that of middle ear blood flow in the external flow in the capillaries or microcirculation in the cochleacarotid artery system[170]. was most easily impaired by the elevation of inner ear

pressure[96]. Since the modiolus is surrounded by bone, it4 .2. Occlusion of anterior inferior cerebellar artery was proposed that the increased inner ear pressure did not(AICA) transmit directly to the blood vessels in the modiolus.

Cochlear perfusion pressure can be calculated as theVarious experiments to observe the effect of AICA (or difference between arterial blood pressure and inner ear

labyrinthine artery) occlusion on cochlear blood flow have pressure[96].been done in guinea pigs[73,103,120,151],mice [147], When inner ear pressure was raised to a relatively highgerbils [121], rats [93,98,130] and cats [54]. In these level, endocochlear potential decreased to a negative value,experiments, the closer the occlusion point is to the as in the response to anoxia, because of the cessation ofinternal auditory meatus, the more severe the reduction in blood flow in the lateral wall of the cochlea[90]. Thecochlear blood flow. Anastomoses between AICA and phenomenon whereby the lowest inner ear pressure thatcollateral blood vessels to the cochlea would be the basis could reduce endocochlear potential to a negative valuefor the finding that if the occlusion point is very close to increased gradually during pressure alterations may bethe internal auditory meatus, more blood flow reduction is associated with autoregulation of cochlear blood flow[87].produced [87]. Many anastomoses between AICA and The autoregulation phenomenon of gradual recovery ofbasilar artery pontine branches were also reported in blood flow during a certain level of inner ear pressure, orhumans[43,99]. rebound phenomenon of increased blood flow over initial

In the experiments above in which the AICA was levels after releasing the increased inner ear pressure, wasoccluded, recovery of cochlear blood flow occurred even also observed[96], as in the response to AICA occlusion.during the occlusion. This fact and the observed hyperemiaafter occlusion release are indicative of autoregulation.

Stria vascularis, spiral ligament, the organ of Corti and 5 . Morbidity associated with impaired cochlear bloodspiral ganglion were strikingly vulnerable to occlusion of flowthe AICA [61]. Bone surrounding the cochlea was notfundamentally damaged by the occlusion, which suggested5 .1. Noise-induced hearing lossthat the bone was not perfused from the AICA. Interesting-ly, the inner hair cells were more vulnerable to ischemia The cause of noise-induced hearing loss remains un-than the outer hair cells in the organ of Corti[42,61]. clear, despite years of investigations. Among the many

possible pathophysiologic mechanisms that may contribute4 .3. Occlusion of venous drainage to noise-induced temporary or permanent threshold shifts

are insufficiencies in cochlear blood flow. Although theCompared to the number of experiments investigating literature is inconsistent, several histologic and physiologic

the effect of occluding arteries to the cochlea, there are far studies demonstrate signs of reduced circulation in thefewer experiments involving occlusions of the draining cochlea after noise exposure[36,65,116,131].Vasoconstric-veins [87]. The vein of the cochlear aqueduct (VCAQ) is tion of the capillaries of the basilar membrane, spiralone of the main draining veins from the cochlea. The ligament and stria vascularis in response to noise has beenVCAQ runs linear and parallel to the cochlear aqueduct by reported[47,57,115].The capillaries of the basilar mem-the side of the middle ear[9]. Watanabe et al.[166,167] brane, which are the terminal vessels of the spiral laminaoccluded the point where the VCAQ joined the dural sinus (VSBM), have been considered to supply oxygen to theand observed the change in cochlear blood flow in guinea organ of Corti[70].pigs. Following occlusion of the VCAQ, cochlear blood It has been demonstrated that audiogenic stress can


induce elevation of arterial blood pressure in animals and 5 .3. Presbycusishumans and that noise-induced hearing loss may beassociated with alterations in magnesium metabolism[2]. Some of the mechanisms responsible for hypoperfusion,Haupt and Scheibe[44] examined noise-induced changes and possibly ischemia, within the cochlea are associatedof cochlear blood flow using laser-Doppler flowmetry in with age-related hearing loss[131]. Prazma et al.[112]the guinea pig with and without dietary magnesium reported that cochlear blood flow in old gerbils was lesssupplement. They found that magnesium prevented noise- than in young animals and used these findings to support ainduced decreases in cochlear blood flow. Free radical vascular theory of presbycusis. However, Hillerdal et al.production may also be associated with noise-induced [48] reported that cochlear blood flow does not varyhearing loss[172]. between young and aged normotensive rats. These conflict-

The typical audiogram pattern of noise-induced hearing ing results may reflect a difference in the species studied orloss is a dip around 4 or 6 kHz. It has been suggested that the ages at which animals were selected for investigation.the origin of the frequency dip is vasoconstriction of blood The mouse is a suitable animal for aged-related studiesvessels at the tonotopic location in the cochlea corre- because of its short life span and its previous use insponding to maximum basilar membrane activitation[155]. investigations of aged-related hearing loss. Brown et al.It has also been noted that the tonotopic location of the dip [23] investigated changes in cochlear blood flow followingfrequency has an anatomical correspondence to the anas- topical application of nitroprusside, a vasodilating agent,tomosing region between the main cochlear artery and the onto the round window membrane in young and old micecochlear branch of the vestibulo-cochlear artery[137] (Fig. (from 2 to 21 months old). They observed that cochlear1). vascular reactivity was less in old mice than in young

mice. Suzuki et al.[147] also observed changes in cochlear5 .2. Endolymphatic hydrops blood flow during and after AICA occlusion in 6- and

21-month-old mice, and reported that autoregulation wasEndolymphatic hydrops is a condition in which too significantly reduced in the aged group.

much endolymph is present. Even in endolymphatic hy- In a human temporal bone study, loss of hair cells anddrops, the difference between endolymphatic and neurons and atrophy of the stria vascularis have beenperilymphatic pressure is non-existent or extremely small revealed in patients with presbycusis[129]. The associa-[20,164]. In Meniere’s disease, the degree of hydrops tion of these pathological changes with disturbance offluctuates with the severity of hearing loss. cochlear blood flow is not clear at present. However,

Larsen et al.[68] measured cochlear blood flow in atrophy or disappearance of the capillary networks wasguinea pigs with endolymphatic hydrops using the micro- shown in the strial area. In the stria vascularis, thesphere technique and reported that there was no significant marginal cells that face the endolymph surround thedifference in blood flow between normal and hydropic capillary networks, with their basal surfaces exhibitingears. Baldwin et al.[16] investigated the effect of hy- numerous extensions and infoldings in the basal plasmaperosmotic agents on cochlear blood flow in guinea pigs membrane that interdigitate with other cells, including thewith normal and hydropic ears. They did not observe a capillary endothelial cells[144].difference in response to the agents between normal andhydropic cochleas.

Autoregulation of cochlear blood flow may be abnormal 6 . Role of nitric oxidein hydropic ears[22,81,171,174].Yamamoto et al.[171]measured cochlear blood flow in guinea pigs with unilater- Nitric oxide (NO) has been implicated as a mediator ofal endolymphatic hydrops while systemic blood pressure vasodilation and neurotransmission in the mammalianwas lowered by removal of whole blood. The decrease in cochlea[124,150].This is demonstrated by the presence ofcochlear blood flow was larger on the hydropic ear side nitric oxide synthase (NOS) and nitric oxide (NO) inthan on the intact side. Brechtelsbauer et al.[22] occluded various parts of the cochlea. Staining for endothelial eNOSthe AICA and reported reduced autoregulation of cochlear was found in the spiral ligament, in the stria vascularis, inblood flow in guinea pigs with endolymphatic hydrops. cells of the organ of Corti, in nerve fibers and in some

Human temporal bone studies have revealed that the perikaryia of the spiral ganglion[77]. Staining for eNOSendolymphatic duct and sac were degenerated in most of was also found in blood vessels of the lateral wall and inthe patients with Meniere’s disease with endolymphatic the cochlear glomeruli vessels[35].hydrops. Along the endolymphatic duct, venous drainage Neuronal bNOS was found in the endosteum of thethrough the vein of the vestibular aqueduct may be modiolus and cochlea, in the spiral ganglion and in thedisturbed in those patients. Gussen described that venous spiral ligament[77]. Inducible iNOS was faint or notdrainage is crucial to inner ear fluid mechanics and present in the ordinary cochlea but the expression of iNOSproposed vascular mechanisms as one of the causes of was increased in pathological conditions such as endo-Meniere’s disease[39,40]. lymphatic hydrops[78], ischemia[157], ototoxicity [165]


and aging[52]. A potent NO donar, sodium nitroprusside cause sudden deafness, cochlear hemorrhage may alsoelevated cochlear blood flow but it deteriorated hearing cause sudden hearing loss[138,159]. One study tried toability [62]. NO has been detected in endothelial cells and visualize inner ear perfusion by dynamic contrast enhancedvarious cells of the organ of Corti (including hair cells) by MR imaging, however, they showed that it was impossiblea fluorescent dye method[136]. It has also been detected to visualize the small amounts of blood flow in an innerelectrochemically in perilymph[135]. Inhibition of NOS in ear using current MR techniques[85].the cochlea leads to a reduction of cochlear blood flow Contrast enhancement to visualize the endolymphaticthus, there is a vasodilative tone produced by endogenous sac is still a controversial issue. The sac had been believedrelease of NO in the cochlea[21]. to show no enhancement in normal subjects; however, one

The second messenger system of NO has been investi- study recently showed that endolymphatic sac enhance-gated by immunoreactivity to soluble cyclase (sGC) and ment is very frequently found in normal subjects[60]. Acyclic guanosine-menophosphate (GMP). It was suggested high frequency of endolymphatic sac enhancement hasthat the NO/cyclic GMP pathway may be involved in been reported in patients with Meniere’s disease[34].neurotransmission, cochlear blood flow, and regulation of Recent rapid developments in high-resolution MR tech-the cochlear amplifier[32,33,77]. The NO/cyclic GMP niques provide a variety of techniques that may havepathway attenuated ATP-evoked intracellular calcium in- played a role in the discrepancy in the results.crease of inner hair cells[134] and supporting cells[75] in Contrast-enhancement in the inner ear has been widelythe organ of Corti. reported in cases of tumor[84] and inflammation[6,30]. In

NO is involved in many drug-induced elevations in patients with sudden hearing loss, contrast enhancement ofcochlear blood flow, including ATP and capsaicin cochlear turns is also reported[74,133]. The position of[122,160]. Haupt et al. [45] produced local vascular segmental enhancement of cochlear turns is reported toimpairment of cochlear blood vessels by ferromagnetic correlate to the sound frequency of hearing loss[74].thrombosis, and observed improvement in the blood flow Sometimes inner ear enhancement is seen in patients withassociated with NO in guinea pigs. Nagura et al.[86] facial palsy[126,177].produced focal microcirculation disorders by a photo- To exclude inner ear hemorrhage[168], pre-contrast T1chemical reaction at the lateral wall of the cochlea, and weighted images should definitely be obtained[138]. Eveninvestigated cochlear blood flow with and without pre- with the highest spatial resolution techniques, MR imagingadministration ofN omega-nitro-L-arginine methyl ester cannot evaluate the organ of Corti directly. Contrast-(L-NAME) in guinea pigs. They reported that blood flow enhanced images may prove helpful to detect the presencewas significantly decreased around the disorder zone in the of pathological changes in vascular permeability in theL-NAME pretreatment group compared to the control inner ear[55].group. They reported that formation of endogenous NOplays a key role in the maintenance of cochlear blood flow 7 .2. Laser-Doppler flowmetryin acute focal cochlear microcirculation disorder.

Laser-Doppler flowmetry has been used to evaluatecochlear blood flow in humans. Cochlear blood flow was

7 . Methods of evaluation of cochlear blood flow or measured in patients undergoing tympanoplasty[1,29] orendolymphatic space in humans and guinea pigs middle ear surgery[80,115,156], in patients undergoing

operations for perilymphatic fistulas[95,97], in patients7 .1. Magnetic resonance imaging undergoing acoustic tumor surgery[114], and in patients

receiving cochlear implants[89]. Selmani et al. [132]Direct visualization of inner ear perfusion by MR measured cochlear blood flow through a myringotomy

imaging is rarely reported. In normal guinea pigs, adminis- perforation in patients with Meniere’s disease, progressivetration of extremely high doses of intravenous gadolinium- sensorineural hearing loss and sudden deafness.based contrast material causes contrast enhancement of the Autoregulation of cochlear blood flow was investigatedperilymph and allows visualization of the perilymphatic by changing systemic blood pressure[1,29,115,156].Al-space[100]. To visualize the endolymphatic space, this bera et al.[1] observed a slight increase in cochlear bloodstudy took advantage of the timing difference of enhance- flow in spite of a significant reduction of systemic bloodment between endolymph and perilymph, the contrast pressure under general anesthesia with isoflurane. On theenhancement of the perilymphatic space occurring first in contrary, Preckel et al.[115] found that inner ear bloodtime. In the future, this method may allow us to separately flow is autoregulated under propofol but not isofluranevisualize the endolymphatic and perilymphatic spaces in during controlled hypotension in humans. Degoute et al.humans. [29] reported that sympathetic nerve regulation via its

One study suggested that slow blood flow detected on vasomotor tone at the level of cochlear microcirculationMR imaging may be one of the causes of sudden hearing occurred markedly when blood pressure was above 160loss [173]. As various types of hematological diseases mmHg and that the autonomic nervous system appeared to


control cochlear blood flow against large variations in non-invasive, clinical application to more cases is ex-blood flow in response to hypertensive phenomena. Tono pected.et al. [156] observed the reaction of cochlear blood flow totrimetaphan-induced hypotension in seven patients duringmiddle ear surgery. Blood flow in the cochlea generally 8 . Sensorineural hearing loss caused by disturbancefollowed blood pressure changes with the same pattern butof cochlear blood flowblood flow changes were smaller in magnitude than themaximum change in blood pressure in four of the seven 8 .1. Effect of cerebrospinal or cochlear fluidpatients, suggesting an autoregulatory mechanism. Thus,autoregulation of cochlear blood flow in humans has been As the relationship between cochlear blood flow andreported, but its degree or strength needs to be studied fluid pressure of the inner ear is similar to that betweenfurther. cerebral blood flow and cerebrospinal fluid pressure,

Topical administration of epinephrine to the round increased fluid pressure in the inner ear elicits hearing losswindow lowered cochlear blood flow but inhalation of that is considered to be associated with reduced cochlearcarbon dioxide (carbogen) did not change cochlear blood blood flow. Deafness associated with subarachnoid hemor-flow in most cases[80,97]. rhage has also been reported[38,107]. In patients with

Although it is possible to detect minute changes in large vestibular aqueducts that transmit cerebrospinal fluidcapillary blood flow through the intact human promontory pressure to the inner ear very easily, sudden increases in[41,128], the contribution of bone blood flow surrounding cerebrospinal fluid pressure can cause further deteriorationthe cochlea to the laser-Doppler output should not be of hearing.neglected, especially in humans having thick promontory Conversely, acute reduction of cerebrospinal fluid pres-bones. It was found that 30–40% of laser-Doppler output sure sometimes causes hearing loss. Reduction in cere-came from the bone blood flow in rats[93]. In humans, brospinal and perilymphatic fluid with a compensatorywho have thicker bone than rats, the contribution of the endolymphatic hydrops may be responsible for hearingbone blood flow may be larger than in rats. Accordingly, loss[162].insertion of the laser-Doppler probe into the perilymphaticspace may be effective in removing the component of bone 8 .2. Disorders of blood vesselsblood flow[89]. This idea is important because bone bloodflow, which is considered to belong to the carotid artery It has been reported that sensorineural hearing losssystem, is completely different from cochlear blood flow, appears in some diseases with angiopathy. Susac syndromewhich belongs to the vertebral /basilar artery system[170]. is an occlusive arteriolar disease that provokes infarcts inIn analysis of cochlear blood flow in humans, the position the cochlea, retina, and brain of young subjects, mostlyof the probe tip and the effect of bone blood flow must be women[72,76,83,109,127].Its cause is unknown. Au-sufficiently evaluated. diograms usually reveal bilateral hearing loss predominat-

ing in the low frequencies. Fundoscopy and fluorescein7 .3. Ultrasonography retinal angiography demonstrate retinal arterial occlusions,

and brain MRI T2-weighted images disclose small mul-Doppler ultrasonographic measurements have revealed tifocal hyperintensities in white and gray matter of the

that blood flow disturbance in the vertebral artery is brain. Although direct evidence of blood flow disturbanceassociated with vertigo due to inner ear diseases such as could not be obtained in the cochlea, blood flow dis-Meniere’s disease[37,149]. turbance due to cochlear angiopathy is considered to be the

Association between blood flow disturbance in the circle cause of sensorineural hearing loss in Susac syndrome. Aof Willis and idiopathic sudden deafness has been revealed case of fluctuating hearing loss with Susac syndrome hasby ultrasonography. De Felice et al.[28] investigated the been reported[17].effect of compression of the common carotid artery on In contrast to microangiopathy in Susac syndrome, largeblood flow in extracranial and intracranial blood vessels by blood vessels are disturbed in Takayasu’s disease, knownultrasonographic measurement. They also evaluated the as ‘pulseless disease’ or ‘aortic arch syndrome’. Althoughfunction of the communicating artery of the circle of Willis the etiology is unknown, it is suspected to be an au-according to the method described by Yoneda et al.[175]. toimmune disorder. Cases of sensorineural hearing lossTheir findings suggested a strong association between a with Takayasu’s disease have also been reported[140].non-functioning posterior communicating artery of the Systemic vasculitis such as polyarteritis nodosa, which hascircle of Willis and sudden deafness. also been reported to cause sensorineural hearing loss

Thus, ultrasonography has suggested that blood flow [64,158], is strongly suspected to disturb cochlear blooddisturbance is associated with various inner ear diseases, flow.though it was not possible to measure directly in the inner Norrie disease, which is an X-linked recessive disorderear [37,105]. Because ultrasonographic measurement is of blood vessels, results in hearing loss, blindness and


mental retardation[118]. In Norrie disease, hearing loss is should be investigated for treatment of sensorineuralprogressive and more severe in the high frequencies. hearing loss with impaired blood flow in the cochlea.Recently, a knock-out mouse model of Norrie disease wasestablished. Histology of the cochlea from the knock-outmouse revealed that the earliest primary site of cellular 1 0. Conclusionpathology occurs in the stria vascularis[119].

We reviewed the literature regarding human cochlearblood flow and its disturbance. Many cases of sensorineur-8 .3. Blood disordersal hearing loss, which were considered to be associatedwith blood flow disturbance, have been treated withBlood disorders, like leukemia[3], sickle cell anemiavarious kinds of drugs such as vasodilators and anti-[111], cryoglobulinemia[102], macroglobulinemia[148]coagulants. Precise diagnosis of blood flow disturbance inand polycythemia[49] may also present their primarythe cochlea is necessary in order to establish effectivesymptoms in the cochlea. Intracochlear hemorrhage due tomethods of the treatment. However, technical advances areleukemia causes sudden hearing loss. Fibrosis and newneeded for the measurement of human cochlear blood flow.bone formation in the perilymphatic spaces as a late

consequence of hemorrhage has been reported[125]. It isgenerally believed that cochlear ossification suggests avascular etiology of hearing loss[19]. Microembolism has A cknowledgementsalso been listed as a cause of blood flow disturbance in thecochlea by Wasted et al.[163], who reported four cases This study was supported by the Program for thewith sudden deafness after cardiopulmonary bypass Invitation of Foreign Scientists to Japanese Institutessurgery. provided by Japan Foundation for Aging and Health. This

study was also supported by United States NIH researchgrant DC00105 and Japanese Grant-in-Aid for ScientificResearch B-11470355,15390515.9 . Management of sensorineural hearing loss caused

by disturbance of cochlear blood flow

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Disorders of cochlear blood flow