Considerations on Anatomy and Pathophysiological Notions Concerning the Inner Ear

REVIEW

CONSIDERATIONS ON ANATOMY AND PATHOPHYSIOLOGICAL NOTIONS CONCERNING THE INNER EAR

Iulia M. Burghiu-Hobeanu1, Viorel Zainea2,3 1 Clinical Emergency Hospital „St. Pantelimon”, Bucharest, Romania 2 University of Medicine and Pharmacy „Carol Davila”, Bucharest, Romania 3 Institute of Phonoaudiology and Functional ENT Surgery „Prof. Dr. D. Hociota”, Bucharest, Romania

ABSTRACT RÉSUMÉ

Sudden hearing loss is a medical emergency requiring Considérations sur l’anatomie et notions pathophy- immediate clinical and laboratory tests, as well as an siologiques concernant l’oreille interne adequate and quickly established treatment. Sudden hearing loss is disabling for the patient and its perma- La surdité brusquement installée est une urgence mé- nence has implications on the patient’s quality of life. dicale nécessitant des investigations cliniques et para- According to literature data, the earliness of treatment cliniques immédiates, ainsi qu’un traitement approprié initiation is directly correlated to therapeutic results. et rapidement installé. L’hypoacousie brusque est inva- An individual response to therapy exists, which is due lidante pour le patient et sa permanence a des implica- to anatomical particularities: individual vascular pat- tions sur la qualité de vie de celui-ci. Conformément tern, poor vascularity and fragility of cochlear vascular- aux données de la littérature, la précocité du début du ization, as well as the existence of some malformations. traitement est directement corrélée aux résultats théra- The knowledge of the pathophysiological mechanisms peutiques. La réponse à la thérapie est individuelle en of brain ischemia led to a new paradigm in the modern raison des particularités anatomiques: le terrain vascu- therapeutic protocols for acute and aggravated stroke: laire individuel, la vascularité pauci-immune et la fra- the neural growth factors. Nerve growth factors are a gilité de la vascularité cochléaire, ainsi que l’existence modern and advanced therapeutic approach through des malformations. La connaissance des mécanismes multimodal effects: neuroprotector, neurotrophic and physiopathologiques de l’ischémie cérébrale a conduit neuroregenerative effects. à un nouveau paradigme dans les protocoles thérapeu- tiques modernes pour les micro-accidents vasculaires Key words: cochlear vasculature, nerve growth factor, cérébraux ischémiques aigus et aggravés : les facteurs cochlear ischemia, sudden hearing loss treatment. de croissance nerveuse. Les facteurs de croissance nerveux représentent une approche thérapeutique Abbreviations: NGF – Nerve growth factor, moderne et prometteuse, par ses effets multimodaux, SHL – Sudden hearing loss, BDNF – Brain-derived

Correspondence address: Iulia-Mihaela Burghiu-Hobeanu, M.D. e-mail: [email protected] ENT Compartment, Clinical Emergency Hospital „St. Pantelimon“ Archives of the Balkan Medical Union neurotrophic factor, AICA – anterior-inferior cerebel- parmi lesquels on mentionne: l’effet neuroprotecteur, lar artery, LTP/LDP – long-term potentiation/depres- neurotrophique et neurorégénérateur. sion, Ang 1 – Angiopoietin 1, tPA – tissue plasminogen activator, Shh – Sonic Hedgehog, miRs – microRNAs. Mots-clefs: vascularité cochléaire, facteur de croissance nerveuse, ischémie cochléaire , traitement d’hypoacousie.

INTRODUCTION one irrigating the middle ear and the bony labyrinth. However, in several cases, it was observed at the level Sudden hearing loss is a medical emergency of the inner ear canal the presence of a cerebellar requiring immediate clinical and laboratory tests, anse disposed between nerves VII-VIII and called ar- as well as an adequate and quickly established treat- cuate artery (Characon)5. It is the only anastomosis be- ment1. Sudden hearing loss is disabling for the pa- tween the inner and middle ear vascularization and tient and its permanence has implications on the pa- explains the relationship between the tubo-tympanic tient’s quality of life. According to literature data, the diseases and the cochlear-vestibular system. This ar- earliness of treatment initiation is directly correlated cuate artery arises from the middle cerebellar artery, to therapeutic results2. after exceeds the posterior edge of the acoustic-facial Sudden hearing loss treatment is one of the package, at several millimeters distance from the most controversial issue in otology literature in the labyrinthine artery, and which penetrates into the past years3. Regarding etiology, sudden hearing loss petro-mastoid canal where it branches on the internal is a cochlear vasculopathy with multiple pathological wall of the mastoid antrum5. mechanisms: spasm, thrombosis, embolism, hemor- rhage. This theory is sustained by the anatomy of ARTERIAL VASCULATURE OF INNER EAR the cochlea, as well as the frequent association with different cardiovascular diseases (arterial hyperten- Arterial vasculature of the membranous sion, atrial fibrillation, carotid atheromatosis). The labyrinth originates from the vessels situated within changes of cerebral vasculature and the default of the cranial cavity, being ensured through the laby- the cochlear vasculature can be highlighted through rinthine artery (internal auditory artery), which imaging studies like Doppler carotid and vertebral often is a branch of the anterior-inferior cerebellar ar- ultrasound and angio-MRI. The correct diagnosis tery (AICA). The anterior-inferior cerebellar artery of the etiology is very important to establish an ade- is a branch of the basilar artery (basilar trunk), issued quate treatment4. from the union of the two vertebral arteries, which Treatment of sudden hearing loss must be cho- are branches of the subclavian artery5. sen from a variety of therapeutic solutions and should According to Guerrier, in 17.5 % of cases, the be individualized depending on the pathogenic con- labyrinthine artery may be detached from the basi- ditions of each patient4. The therapeutic results de- lar artery or more rarely, from the vertebral artery. pend on many factors such as the time until presen- The anterior-inferior cerebellar artery may have the tation to medical exam, the degree of hearing loss, following relationships with the acoustic-facial pedi- the presence of other comorbidities. An individual cle, as mentioned by Guerrier: response to therapy exists, which is due to anatomical  anterior – the most frequently – the common particularities. There is mild hearing loss rebellious trunk of the middle cerebellar artery and labyrin- to treatment and severe hearing loss that answers thine artery is divided at large distance from the spectacular to medical treatment. The evolution of inner ear canal, the recurrent branches arising each case depends on individual vascular pattern, from the common trunk or from the middle cere- poor vascularity and fragility of cochlear vasculariza- bellar artery itself; tion, as well as the existence of some malformations.  median – less frequently – the common trunk The fundamental and comparative studies regarding is divided in the vicinity of the facial nerve, into embryology, anatomy and physiology of the cochlea two branches: the middle cerebellar artery and the and cochlear vestibular nerve still remain full of un- cerebellar-labyrinthine artery; known aspects.  posterior – the common trunk is very short and The anatomical studies showed that inner ear’s immediately bifurcates, after crossing the external vascularity is composed of arteries and veins, while oculomotor nerve, in the middle cerebellar artery, the lymphatic vascularity is still unknown. The in- which slides back, and the cerebellar-labyrinthine ner ear’s vascularity is generally separated from the artery; the cerebellar-labyrinthine artery will divide

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in the internal auditory artery and two recurrent vessels, which makes them very fragile, so that they cerebellar branches, which will form two storeyed can be damaged at the smallest injury6. anses advance-back, passing one over and the oth- The complete model of cochlea vascularization er beneath the nerve VIII. From the anterior re- incited numerous discussions, some of the schemes current branch arises the internal auditory artery. widely accepted in the scientific literature is the one The origin of the auditory artery can be variable, presented by Hawkins (1968) as follows6,7: according to Mazzoni (1969)6:  the main cochlear artery vascularizes ¾ of the co-  In 80% of cases it is a main branch of the anteri- chlea, including the modiolus; or-inferior cerebellar artery.  the cochlear branch irrigates ¼ from the basal  In 17% of cases it is a branch of the basilar artery. trunk of the cochlea and adjacent modiolus;  in 3% of cases it is a branch of the vertebral artery.  the anterior vestibular artery irrigates the utricle’s Localization of the labyrinthine artery in the re- macula, a small part of the saccule’s macula, the gion of inner ear canal also presents a high individual crista and membranous portions of the superior variability, as demonstrated by Mazzoni in a study and lateral semi-circular canals, the upper face of made on 100 human specimens, as follows6: utricle and saccule;  40% of cases within inner ear canal;  the posterior vestibular artery irrigates the macula  27% of cases at the level of the internal acoustic of saccule, the crista and membranous portion of meatus; semi-circular posterior canal, the lower face of utri-  33% of cases in the cerebellopontine angle. cle and saccule. The arterial irrigation of the membranous laby- The vascularization of cochlea is ensured by the rinth is ensured by one or two vessels not exceeding main cochlear artery and by the cochlear branch of 200 μ in diameter, as follows6: the vestibular cochlear artery. At the cochlea level,  mono-arterial system, where a unique labyrinthine the vessels and nerves present a special distribution, artery exists, and which divides into common co- of spiral type, proved by a radial section, performed chlear artery and anterior vestibular artery; parallel to the middle of modiolus axis7,8.  bi-arterial system, where an inferior labyrinthine artery exists, situated on the inferior face of the SPIRAL MODIOLUS VASCULARIZATION OF COCHLEA cochlear nerve and which will be the vestibulo-co- (ACCORDING TO ANSON AND DONALDSON) chlear artery and a superior labyrinthine artery, with a path similar to the one from the mono-arte- The main cochlear artery or the spiral modio- rial systems. In the mono-arterial system a supple- lar artery, penetrates within the central canal of the mentary artery exists, which irrigates the inner ear modiolus, where it anastomoses with the cochlear canal elements, without penetrating the labyrinth branch of the vestibule-cochlear artery on the inner and which is situated beneath the cochlear nerve, edge of the spiral lamina and then is distributed from having a path similar to the one of the inferior bottom to top, being located before the spiral gangli- labyrinthine artery from the bi-arterial system. on and having a spiral trajectory. Several primary and This mono- and bi-arterial arrangement is almost secondary arteries emerge from it and they immedi- the same as frequency, and in some subjects the ately twist away. arterial system type may vary from one ear to the The vascularization of cochlea is of parietal type, other. According to Fish, the arteries for the vesti- as following8: bule are bigger than the ones directed towards the  within the (inner) modiolar wall, towards the spiral cochlea, which explains the more frequent patho- lamina, is situated the modiolar spiral artery from logical damage of the cochlea. which are detached the inner radial arterioles, The labyrinthine artery from the mono-arterial which vascularize the spiral ganglion, the limbus, system, is divided into6: the tympanic edge of the osseous spiral lamina and  Anterior vestibular artery; the basilar membranes;  Common cochlear artery that branches into:  within the external wall of the cochlear canal are – Main Cochlear artery (which may be replaced by situated the external radial arterioles, which form the cochlear branch of the vestibular-cochlear two independent vascular networks: artery) – stria vascularis, a network rich in capillaries, – Vestibular-cochlear artery divides in: forming a closed polygonal circle;  Posterior vestibular artery – vessels of spiral prominence, located parallel  Cochlear branch. to and below the stria vascularis. A characteristic of these arteries is the reduced The vessels of the external wall and those of thickness of the muscular wall as compared to others the inner wall do not present between them any

52 / vol. 52, no. 1 Archives of the Balkan Medical Union anastomoses, and neither between the stria vascularis  Cochlea is a neo-structure appearing in terrestrial and the spiral prominence8. life, and presenting a pauci-vasculature as compared The radial arterioles are tertiary or quaterna- to the posterior labyrinth, which is a paleo-struc- ry branches forming arcades near the edge of each ture and has bulkier vessels. tour, on the tympanic lip, before the basilar mem-  Cochlea’s vascularization is of parietal type (does brane where they are situated, beneath the Corti ca- not penetrate into the labyrinth) either of terminal nal. When the radial arterioles reach the marginal type (non-existence of anastomoses between stria vessels, they return at right angle forming a „T“ or vascularis and the spiral prominence and neither building arcades. The radial arterioles are forming between the internal and external wall vessels of two arcades: one that irrigates the external wall struc- cochlea). tures – the external radial arterioles, and one irrigating  Cochlea presents multiple vascularization variants; the internal wall structures of the cochlea – the inner the most common are the mono- or bi-arterial radial arterioles9. types. The external radial arterioles form an arcade above  There is a variability of individual vascularization the scala vestibuli until the interscalar septum and, of the inner ear, as well as the variability between after supplying the vessels of the scala vestibuli’s the two ears at the same patient, which may ex- walls, enter into the anterior region of the spiral lig- plain impaired unilateral sudden hearing loss. ament. These vessels divide in order to form the fol-  From phylogenetic point of view, the cochlear lowing capillary networks9: nerve is also new and therefore presents a poorer  The spiral vessels up to the spiral ligament, in the vascularization than the one for vestibular or facial area where the ligament face of vestibular scale nerves from inner ear canal. That’s why it is the approaches the extension of Reissner membrane most susceptible to hypoxia, in case of extrinsic (the vessels of the vestibular scale, the vessels of compression of the acoustic-facial package. Reissner membrane).  Cochlea’s vessels are very fragile, due to the re-  The capillary network of stria vascularis, the ves- duced thickness of muscular wall. sels of spiral prominence.  The apical part of the cochlea is characterized by a  The vessels located up to the spiral ligament, on marked simplification of vascularization. the tympanic scale face at the level of basilar crest,  Vestibular membrane, tectorial membrane and which serve for collecting the venules and are mor- pectinate zone of basilar membrane are avascular. phologically identic to capillaries vessels. The capillaries vessels of stria vascularis contin- INNER EAR PATHOPHYSIOLOGY ue the spiral direction, are interconnected and located perpendicular to the radial arterioles and collector The progresses of the molecular biology field venules, giving the appearance of a border network. continue to be extremely fast. Usually, for a normal These vessels are quite straight and parallel9. mature nervous system, the neural circuits suffer Within vestibular scale, where the vasculariza- adaptation modifications. In the case of a neural tion is poorer, one or two thin spiral capillary vessels cell, the old synapses may regress (until their com- have been highlighted, located at the origin of vestib- plete disappearance), with simultaneous forming of ular membrane. In the medium scale, however, a net- new branches (new neuritis) which will establish new work exists, as well as the vessels of spiral prominence. synapses. These modifications of neuronal and synap- Both are irrigated by the external radial arterioles, tic architecture prove the high adaptation plasticity of but no anastomoses exist between them. the nervous system to the environmental conditions. The inner radial arterioles pass very close to the Nowadays, it is considered that two major classes of basis up to the modiolus, enter within the vestibular intracellular factors (signals) exist, which adjust the lamina of the osseous spiral lamina, supplying the neural development and adaptation: the growth fac- vessels of limbus and marginal vessels and give rise to tors (neural growth factor, fibroblast growth factor, branches for the spiral ganglion9. ciliary neurotrophic factor etc.) and neurotransmit- The marginal vessels form two groups of inde- ter factors (dopamine, serotonin, acetylcholine, glu- pendent arcades which function together as arterial tamate)10. and venous canals; a group forms the vessels of basi- The equilibrium loss between the two systems lar membrane and the other the vessels of tympanic of factors triggers pathological conditions. Amongst edge of the spiral lamina. them, an important place is occupied by the degener- There is a series of embryogenetic and anatomi- ative disorders of the nervous system, being charac- cal aspects explaining the cochlea’s increased suscep- terized by neuronal degeneration (neuronal death) in tibility to ischemia: certain cerebral territories11.

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Generally, it can be considered that all auditory far from being discovered. In the conditions of ho- pathologies are a result of cellular homeostasis alter- meostasis, the cochlear blood flow is controlled by a ation. Under the impact of genetic mutations, but also multitude of factors13: systemic variations, influence of environmental aggressions, the cells must adapt to of sympathetic nervous system on the cochlear vascu- new changes. Sometimes, they are „overwhelmed“ by larization, local self-regulation. Long time ago it was these changes and cannot maintain their functions believed that the cochlear blood flow is in accordance and anatomic integrity. The importance of maintain- with systemic blood flow13. In the past years it was ing the internal environment constant was observed proved that, although obviously the cochlear blood and described many years before by Claude Bernard flow is influenced by the total blood flow, cochlea (1878), but since 1929 Walter Cannon proposed the has its own mechanisms for regulating the blood term of „homeostasis“ which is used also nowadays to quantity reaching to it14. The influence of somatic define the cellular equilibrium condition11. Each cell nervous system on the cochlear blood flow is due to a has a multitude of mechanisms by which it tries to strong intervention starting at the level of the stellate maintain its homeostasis: barrier membranes, trans- ganglion15, but also at the level of ipsilateral innerva- porting systems and paths of cellular adjustment. If tions from the superior cervical ganglion16. these mechanisms of cellular protection are defeated, The cochlear blood supply is very sensitive to then the cell begins to die. Even by its death, the cell intrinsic factors, like carbon dioxide content of the tries to protect the other cells, preferring the cellular blood flow reaching the cochlear level, but a larger se- apoptosis. Cellular apoptosis is a programmed death, ries of factors are considered being implied in the co- an ordered disassembly of the cell, when cell wastes chlear self-regulation among which also nitric oxide, are internalized, and not externally eliminated, an ac- prostaglandins or tropomyosin17. tive process requiring energy. Necrosis is the cellular The biochemical mechanisms of cerebral is- death that had no time for being programmed11. The chemia are extremely complex and include: necrosis same phenomenon occurs also in the case of cochlear (cellular death), post-reperfusion oxidative stress, sensorial cells. At the moment, when their internal „sludge“ phenomenon, „no reflow“ phenomenon18. environment is imbalanced either by normal physio- (Figure 1A). logical imbalances occurring due to aging, either by The ischemic loss of the brain tissue is a direct the aggressions that we bring, either by the working consequence of the impossibility of normal me tabolic conditions implying exposure to noise, either by the changes (in particular oxygen and glucose supply rhythm of life one lives and the environment where from the vessels to the brain parenchyma), due to one chooses to live, the sensorial cells from Corti the loss of the integrity of brain microcirculation19. organ die by cellular apoptosis or necrosis. The disruption of the microcirculation depends on The studies in this field showed that when hear- the endothelial dysfunction stage, the presence of ing losses are of 40 dB and more, then the injuries previous vascular risk factors, the development of occur to both cell types (external and internal senso- collateral circulation, the time duration since the ini- rial cells)12. tial occlusion of the artery19. These events at the level The role of cochlear vascular system in local de- of the microcirculation are the key-elements which gradation due to ischemia is still widely studied and allow or not the reperfusion of the brain tissue in

Figure 1A. No reflow is a process that starts during the Figure 1B. Various mechanisms are implicated in the ischemic period and then increases during reperfusion. genesis of the no-reflow phenomenon.

54 / vol. 52, no. 1 Archives of the Balkan Medical Union the ischemic area, even if the treatment is initiated CONCLUSIONS quickly. Understanding the role of the brain microcirculation during the acute ischemia is essential to un- Sudden hearing loss remains an important issue derstand the ‘no-reflow’ phenomenon18,19 (Figure 1B): in the otology literature, from the point of view of Brain-derived neurotrophic factor (BDNF) is etiology and treatment. An individual response to the most abundant neurotrophin within the brain. It therapy exists, which is due to anatomical particulari- regulates neurovascular functions such as neural and ties: individual vascular pattern, poor vascularity and vascular plasticity, angiogenesis, neurogenesis and fragility of cochlear vascularization. The knowledge neuroinflammation. Low circulating BDNF levels of pathophysiological mechanisms of brain ischemia were found to be associated with poorer memory led to a new paradigm in the modern therapeutic performance, as well as with the occurrence of de- protocols for acute and aggravated stroke: the neural pression and stress disorder in patients with sudden growth factors. Nerve growth factors are a modern hearing loss20. and advanced therapeutic approach through mul- In addition, BDNF gene polymorphisms were timodal effects: neuroprotector, neurotrophic and shown to influence plasticity in the prefrontal cor- neuroregenerative effect. The increase of endogenous tex, preservation of general cognitive functioning, BDNF levels induced by exogenous nerve growth fac- delayed alteration of memory processing, memory tor might account for improving cochlear ischemic and processing speed, long-term potentiation/depres- effects (tinnitus, vertigo, dizziness) and probably au- sion (LTP, LDP), recovery of executive functioning, ditory recovery. However, large short-term controlled and the response of depression to treatment after trials and long-term efficacy and prevention studies is chemic events20. Therefore, strategies aimed at en- with peptidergic drugs are still needed. hancing endogenous BDNF seem to represent an effective option for improving neurocognitive deficits 21 and probably auditory recovery after SHL . REFERENCES Exogenous nerve growth factor has potent re- storative therapeutic effects for the treatments of 1. Bittar RSM, Oticia J, Zerati FE, Sudden hearing loss: a ten nervous ischemia. 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