**3. Physiopathology**

Among the mechanisms causing SHL, in particular, intracochlear hypoxia and/or inflammation in the inner ear play a major role. Several causes, which were suggested regarding the pathogenesis of SHL, can be classified into four main groups. Vascular factors, viral infections, autoimmune processes, and intracochlear membrane rupture.

#### **3.1. Vascular factors**

The physician, first of all, should calm the patient and then examine his/her medical condition, proceed immediately with the diagnostic procedures, identify—if possible—the etiology

**Figure 1.** A: Sudden hearing loss sample audiogram. B: After treatment normal hearing level.

Although SHL constitutes approx. 1% of all sensorineural hearing losses, its incidence changes between 5 and 20/100,000 in different sources [2]. However, high rates such as 160/100,000 had also been reported in the literature and 40,000 new cases were diagnosed every year in the USA [3]. The incidence and prevalence of SHL are probably slightly higher than the calculated values, because of the rapid development of SHL and the high rate of spontaneous regression. Many studies reported that SHL had no correlation with gender and that the female/male ratio was equal or insignificantly different. In this regard, it seems safe to say that gender is not a risk factor. Similarly, no significant left/right ear distinction was detected. Although SHL is usually unilateral, bilateral involvement is emerging in a small percentage of patients (1–2%) [4]. Nevertheless, bilateral SHL is a more serious condition compared to the unilateral form and is often related to systemic disorders and has a relatively worse prognosis [5, 6].

Among the mechanisms causing SHL, in particular, intracochlear hypoxia and/or inflammation in the inner ear play a major role. Several causes, which were suggested regarding the

and initiate without delay the proper treatment.

**2. Epidemiology**

72 An Excursus into Hearing Loss

**3. Physiopathology**

As it is well known, the cochlea is an end-organ perfused by the labyrinthine artery, which is a branch of the basilar artery and does not have collateral circulation [7]. The labyrinthine artery divides into two branches (vestibular and cochlear arteries) after entering through the internal acoustic meatus. The cochlear artery enters the cochlea after the division of its branch the vestibulocochlear artery [8]. Therefore, factors such as thrombi, emboli, atherosclerosis, vasospasm, and decreased blood flow may end up with vascular insufficiency and consequently a loss of function in the cochlea. A sudden interruption of the blood flow to the cochlea may induce the development of SHL, which will cause a complete restriction of the oxygen supply.

The obstructions in the vertebrobasilar system may also cause SHL. Here, it should be noticed that a bilateral SHL emerges, in these cases, as the basilar artery, which is the only artery supplying that region. Kim et al. [9] detected a thrombus in the bilateral distal vertebral artery in a patient with bilateral SHL and observed improvement after the restoration of the circulation with a stent. In his experimental study, Perlman [10] stated that the occlusion of the internal auditory artery caused changes in the cochlea secondary to the ischemia and some of these changes were irreversible. The difference of this study from SHL patients is that the findings in SHL are reversible. In a recent study similar to these studies, Chung [11] found out a relation between increased arterial stiffness and SHL development and the response to the treatment and drew attention to the development of SHL with vascular causes. Subclinical atherosclerosis has also been reported in the literature, as a cause of SHL [12].

It is understandable that the temporary and permanent problems in the cochlear microcirculation may cause SHL depending on the damage in the cochlear hair cells [13]. Also, in cases of hypercoagulopathy, a possible intravascular obstruction may cause damage to the inner ear in the same way. Bernhard [14] investigated the effects of experimental hyperfibrinogenemia on the development of SHL and stated that although they did not respond to corticosteroids, intravenous defibrinogenation (ancrod) improved the process markedly. He suggested that defibrinogenation therapy should be considered in non-responding SHL patients. Similarly, the relation of SHL to the factors capable of intravenous obstruction such as sickle cell anemia, Waldenström's macroglobulinemia or contraceptive drugs have been reported in the literature [15]. Although, some studies have suggested that there is a relationship between Factor V Leiden mutation and SHL, it was shown with a meta-analysis that there is no clear relationship between these two pathologies [16]. It is clear that these diseases will not respond to corticosteroids and the main treatment should be targeted to the underlying cause. Cochlear damage may emerge due to the acute emboli after the cardiopulmonary bypass or non-otological, non-coronary operations and may result consequently in SHL [17]. Any obstruction due to any reason in the cochlear microcirculation will manifest itself with the symptoms corresponding to the level of the obstructed artery. For example, although hearing loss is the only finding in the presence of the cochlear artery obstructions, vestibular symptoms like vertigo and tinnitus will also emerge in the labyrinthine artery obstructions along with hearing loss.

Cappacio [18] suggested that dyslipidemia may be associated with SHL pathogenesis and that impaired serum lipid profile might be an important factor in the development of SHL. There are also other studies in the literature linking serum lipid levels with SHL [19]. However, Chang [20] reported in his meta-analysis that serum lipid profile did not have any correlation with the SHL development and its prognosis.

the spread of the virus. The second hypothesis is that the latent virus infection in the inner ear may reactivate due to several reasons and cause SHL. Especially, it is a fact that *Varicella zoster* and other neurotropic viruses may cause latent virus infections, which strengthens this hypothesis. The next hypothesis is more complicated than the first two hypotheses and is indirectly related to viruses as well. As follows: the antibodies found in the systemic circulation and secreted against the viral antigens outside the inner ear may cause the development of a cross-reaction against the structural antigens in the inner ear, which may damage the inner ear and consequently cause hearing loss. In one respect, this last theory is an example of

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These findings, clinical, and histopathological studies eventually give the impression that viral etiology is one of the main etiologies in SHL. Nevertheless, it is also believed that the corticosteroids, which constitute the main therapeutic approach to SHL, have an anti-inflammatory effect in the inner ear, cures the emerged cochleitis, and enable healing through these

Autoimmunity theory is based on the main principle of the cross-reaction of the circulating antibodies or activated-cytotoxic T cells with the inner ear antigens [33]. The antibodies in the systemic circulation may be formed not only against a virus or bacterium, but also against several allergens. Eventually, these antibodies may become sensitive to the target antigens in the inner ear such as Type 2 collagen, tectorin, and beta-actin. The best documented among these antigens is the choline transporters like protein 2 (CTL-2) an inner ear glycoprotein [34– 38]. In a study, antibodies formed against CLK-2 were detected in the systemic circulation in 9 of 20 patients [39]. In an experimental study on mice with Cogan syndrome, it was shown that the antibodies, which were formed against some supportive cells called CD148 and against

In some SHL patients, antibodies against some cochlear proteins (p30, p80) and against some antigens such as Type 2 collagen and cardiolipin in the membranous labyrinth [41–43]. In some studies, it was also found out that the levels of some T-lymphocyte substances like C3b were increased in SHL [44]. Anti-endothelial antibodies (AECA) present another example. These antibodies are a group of heterogeneous autoantibodies that develop against endothelial cells and cause damage to the vessel walls. These antibodies may cause inflammation in the vascular endothelial cells in many different regions of the body via the immune system. They were also associated with many connective tissue disorders and systemic vasculitis; therewith, they got specific terminological naming [45]. The relationship between AECA and SHL was demonstrated with several studies [46, 47]. Harris reported that the relationship between circulating antibodies and bilateral, progressive, and fluctuating SHL was sufficiently evident [48]. In this study, although he detected antibodies against an antigen, which he thought was specific to the inner ear. He concluded that his further analyses revealed that this antigen was heat-shock protein 70 (Hsp-70) and that it existed not only in the inner ear, but also in different regions of the body. The relationship between the anti-Hsp70 antibodies

connexin 26 (a well-known gap-junction protein), caused hearing loss [40].

and SHL were tried to be confirmed by further studies [49, 50].

the relation between SHL and autoimmunity.

mechanisms.

**3.3. Autoimmunity**

### **3.2. Viral infections**

Viral infections are the most common factor worldwide in the etiology of SHL in the world [21]. In 1954, Lindsay and Hemenway [22] detected degeneration in the tectorial membrane, corti organ, and stria vascularis during their cochlear histopathological examination and determined findings of measles virus in the cochlea in the same study. Shortly thereafter, Lindsay [23] found that the mumps virus could also do similar damage to the inner ear. So, the relationship between hearing loss and viral infections is well known. In a meta-analysis, it has been reported that 40% of the congenital hearing loss is associated with viruses and the most common responsible agent is cytomegalovirus (CMV) along with some other viral in utero infections [24]. Similarly, Van Dishoeck [25] suggested that there might be a link between upper airway infections and SHL and those upper airway viruses, which might penetrate the inner ear through neighborhood or blood circulation, might cause an immune response and an eventual damage in the inner ear. Especially, the herpes family of viruses, influenza, and enteroviruses are frequently blamed viral agents in the SHL etiology [26]. In a study conducted by Wilson [27], he found out that viral serology titration in SHL patients was two times higher than in the control group. It is believed that the penetration of the virus itself or the viral antigens to the membranous labyrinth cause an immune response and the resulting inflammation the formation of SHL. As the emerged cochleitis causes hearing loss, it is believed that the presence of vertigo, which is considered as a sign of bad prognosis for SHL, depends on the labyrinthitis emerging concomitantly.

In addition to the viral infections, bacteria can also cause the formation of SHL. In the USA, the two most common bacterial diseases causing SHL are Lyme disease and syphilis [28]. Lyme disease is caused by Borrelia burgdorferi and in long-term it may involve neurologic structures, especially the seventh nerve, which may cause facial paralysis. It may also cause hearing loss due to the involvement of the eighth nerve [28]. Although some studies showed that the incidence of Lyme disease is relatively high in SHL (up to 20%), some other reported very low rates [29, 30]. Syphilis is a systemic infection caused by *Treponema pallidum* and may present diverse clinical manifestations. Especially at the stage of neurosyphilis, if the neuritis of eighth nerve and cochleitis are added to the picture, it is called as otosyphilis. Otosyphilis may be encountered in different forms such as SHL, progressive hearing loss, fluctuating hearing loss or Meniere's syndrome [31].

In fact, viral infection hypothesis depends on three possible mechanisms considering its relation to the hearing loss [32]. The first of them, as mentioned above, is that the virus itself or its antigens, which may induce an immune response, penetrate the inner ear, and may cause cochleitis and neuritis in the cochlear nerve. The path may be hematogenous, but it may also spread directly through the neighborhood. The cerebrospinal fluid may be also a vehicle for the spread of the virus. The second hypothesis is that the latent virus infection in the inner ear may reactivate due to several reasons and cause SHL. Especially, it is a fact that *Varicella zoster* and other neurotropic viruses may cause latent virus infections, which strengthens this hypothesis. The next hypothesis is more complicated than the first two hypotheses and is indirectly related to viruses as well. As follows: the antibodies found in the systemic circulation and secreted against the viral antigens outside the inner ear may cause the development of a cross-reaction against the structural antigens in the inner ear, which may damage the inner ear and consequently cause hearing loss. In one respect, this last theory is an example of the relation between SHL and autoimmunity.

These findings, clinical, and histopathological studies eventually give the impression that viral etiology is one of the main etiologies in SHL. Nevertheless, it is also believed that the corticosteroids, which constitute the main therapeutic approach to SHL, have an anti-inflammatory effect in the inner ear, cures the emerged cochleitis, and enable healing through these mechanisms.

#### **3.3. Autoimmunity**

Cappacio [18] suggested that dyslipidemia may be associated with SHL pathogenesis and that impaired serum lipid profile might be an important factor in the development of SHL. There are also other studies in the literature linking serum lipid levels with SHL [19]. However, Chang [20] reported in his meta-analysis that serum lipid profile did not have any correlation

Viral infections are the most common factor worldwide in the etiology of SHL in the world [21]. In 1954, Lindsay and Hemenway [22] detected degeneration in the tectorial membrane, corti organ, and stria vascularis during their cochlear histopathological examination and determined findings of measles virus in the cochlea in the same study. Shortly thereafter, Lindsay [23] found that the mumps virus could also do similar damage to the inner ear. So, the relationship between hearing loss and viral infections is well known. In a meta-analysis, it has been reported that 40% of the congenital hearing loss is associated with viruses and the most common responsible agent is cytomegalovirus (CMV) along with some other viral in utero infections [24]. Similarly, Van Dishoeck [25] suggested that there might be a link between upper airway infections and SHL and those upper airway viruses, which might penetrate the inner ear through neighborhood or blood circulation, might cause an immune response and an eventual damage in the inner ear. Especially, the herpes family of viruses, influenza, and enteroviruses are frequently blamed viral agents in the SHL etiology [26]. In a study conducted by Wilson [27], he found out that viral serology titration in SHL patients was two times higher than in the control group. It is believed that the penetration of the virus itself or the viral antigens to the membranous labyrinth cause an immune response and the resulting inflammation the formation of SHL. As the emerged cochleitis causes hearing loss, it is believed that the presence of vertigo, which is considered as a sign of bad prognosis for SHL, depends on the

In addition to the viral infections, bacteria can also cause the formation of SHL. In the USA, the two most common bacterial diseases causing SHL are Lyme disease and syphilis [28]. Lyme disease is caused by Borrelia burgdorferi and in long-term it may involve neurologic structures, especially the seventh nerve, which may cause facial paralysis. It may also cause hearing loss due to the involvement of the eighth nerve [28]. Although some studies showed that the incidence of Lyme disease is relatively high in SHL (up to 20%), some other reported very low rates [29, 30]. Syphilis is a systemic infection caused by *Treponema pallidum* and may present diverse clinical manifestations. Especially at the stage of neurosyphilis, if the neuritis of eighth nerve and cochleitis are added to the picture, it is called as otosyphilis. Otosyphilis may be encountered in different forms such as SHL, progressive hearing loss, fluctuating

In fact, viral infection hypothesis depends on three possible mechanisms considering its relation to the hearing loss [32]. The first of them, as mentioned above, is that the virus itself or its antigens, which may induce an immune response, penetrate the inner ear, and may cause cochleitis and neuritis in the cochlear nerve. The path may be hematogenous, but it may also spread directly through the neighborhood. The cerebrospinal fluid may be also a vehicle for

with the SHL development and its prognosis.

labyrinthitis emerging concomitantly.

hearing loss or Meniere's syndrome [31].

**3.2. Viral infections**

74 An Excursus into Hearing Loss

Autoimmunity theory is based on the main principle of the cross-reaction of the circulating antibodies or activated-cytotoxic T cells with the inner ear antigens [33]. The antibodies in the systemic circulation may be formed not only against a virus or bacterium, but also against several allergens. Eventually, these antibodies may become sensitive to the target antigens in the inner ear such as Type 2 collagen, tectorin, and beta-actin. The best documented among these antigens is the choline transporters like protein 2 (CTL-2) an inner ear glycoprotein [34– 38]. In a study, antibodies formed against CLK-2 were detected in the systemic circulation in 9 of 20 patients [39]. In an experimental study on mice with Cogan syndrome, it was shown that the antibodies, which were formed against some supportive cells called CD148 and against connexin 26 (a well-known gap-junction protein), caused hearing loss [40].

In some SHL patients, antibodies against some cochlear proteins (p30, p80) and against some antigens such as Type 2 collagen and cardiolipin in the membranous labyrinth [41–43]. In some studies, it was also found out that the levels of some T-lymphocyte substances like C3b were increased in SHL [44]. Anti-endothelial antibodies (AECA) present another example. These antibodies are a group of heterogeneous autoantibodies that develop against endothelial cells and cause damage to the vessel walls. These antibodies may cause inflammation in the vascular endothelial cells in many different regions of the body via the immune system. They were also associated with many connective tissue disorders and systemic vasculitis; therewith, they got specific terminological naming [45]. The relationship between AECA and SHL was demonstrated with several studies [46, 47]. Harris reported that the relationship between circulating antibodies and bilateral, progressive, and fluctuating SHL was sufficiently evident [48]. In this study, although he detected antibodies against an antigen, which he thought was specific to the inner ear. He concluded that his further analyses revealed that this antigen was heat-shock protein 70 (Hsp-70) and that it existed not only in the inner ear, but also in different regions of the body. The relationship between the anti-Hsp70 antibodies and SHL were tried to be confirmed by further studies [49, 50].

It has also been reported in the literature that there is a relation between systemic lupus erythematosus (SLE) and SHL. It was reported that circulating autoantibodies might enter into the reaction directly with the inner ear antigens in SLE patients and the activated T cells might increase the levels of intracellular interferon gamma and some other cytokines and thus cause cellular damage [51]. Additionally, it is well known that in SLE, circulation antibodies such as anticardiolipin antibody, lupus anticoagulant, and anti-β2 GP1, antiphospholipid antibodies cause emboli and microinfarcts in the systemic circulation. As these antibodies may cause the same problems in the cochlear microcirculation, they may also cause SHL with the mechanism explained in the vascular hypothesis of SHL. Meanwhile, it was also stated in the literature that the SHL, which is believed to be developed due to SLE, might improve with a proper anticoagulant treatment [52, 53].

or conservative procedures. But, the main thing that should be known about these patients is that they will not respond to standard SHL treatment protocols. However, if we look at the

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The histopathology of SHL is quite diverse because of the several factors blamed regarding its etiology. In the temporal bone studies, as mentioned above, along with the membrane ruptures, degenerative findings such as atrophy in the corti organ, loss of cochlear neurons, and neuron fibrils might be encountered in the viral etiology. On the other hand, histopathological findings such as labyrinthine fibrosis and new bone formation are the predominant histopathological findings in vascular events. Yood [61] observed certain changes in 7 of 11 temporal bones in his histopathological study. These changes include especially damage to the corti organ or loss of total corti organ; even it may differ according to the etiology. On the other hand, Vasama [62] determined in his study on 12 temporal bones degeneration and loss in the spiral ligament and stria vascularis. He also observed cochlear ossification in one patient. Since SHL's etiology is multifactorial, multiple histopathological findings are expected and it can be suggested that majority of these findings might be reversible regarding the spontane-

Although an etiological factor could be determined only in a small number of SHL patients, a wide spectrum of etiologic factors and diseases were blamed. Among these, infectious cause being in the first place, vascular causes, endothelial dysfunctions, hyperlipidemia, hypercoagulopathy, increased oxidative stress, autoimmunity, trauma, neurological disorders, endocrinopathies, iron deficiency anemia, neoplastic causes, paraneoplastic causes, and toxic causes are the most important factors. The most blamed causes in the SHL etiology are shown in **Table 1**. But it should be emphasized that none of these factors has been confirmed as a cause of SHL and idiosyncrasy is still the most common category in SHL

classic definition of SHL, they also conform to the SHL definition.

**Vascular Causes Trauma**

Hypercoagulopathy Perilymph fistula Vertebrobasilar Insufficiency Round window rupture Thrombo-embolism Rupture of the oval window Sickle Cell Anemia Intralabyrinthine hemorrhage Moyamoya disease Temporal bone fractures Polycythemia vera Previous otological surgeries

**4. Histopathology**

ous healing rates of SHL.

**5. Etiology**

(**Table 1**).

Hearing losses, which are believed that they develop in relationship with autoimmunity and manifest themselves with progressive, recurrent, and fluctuating clinical picture, are also called autoimmune hearing loss or autoimmune inner ear disease [54]. Yoo [41] created hearing loss in rats with Type 2 collagen immunization and showed the monoclonal antibodies, which were formed against the antigen related to the otic capsule, with radioimmunoassay. Harris [55] identified five antibodies formed against the inner ear antigens and suggested that the inner ear might have its own immunoreactive mechanism apart from the systemic immune response, but this was not supported by studies conducted after this hypothesis was introduced. Lymphocyte transformation and Western-blot tests are recommended for the diagnosis of the autoimmune hearing loss. Heywood [56] used infliximab in the treatment of fluctuating and progressive high-frequency recurrent hearing loss and reported that the patients benefited from this anti-TNF-alpha agent. Although all these findings might show the place of the autoimmunity in the etiology of SHL, there is still a need for further studies with larger samples size, as the sample sizes in the available studies are relatively small.

#### **3.4. Intracochlear membrane rupture**

Round- and oval-window membranes are two anatomical structures that separate the inner and middle ear from each other. These structures are responsible for restricting the endolymph to the inner ear and for preventing its penetration to the middle ear. There are other additional membranes in the inner ear that prevent the endolymph from interfering with the perilymph, and it is well known that their rupture will cause hearing loss. Goodhill [57] detected a perilymph fistula in three patients with SHL. Simmons [58] was one of the earliest authors, who suggested that the labyrinthine membrane damages might play a role in the etiology of SHL. Gussen [59] has identified healed Reissner membrane in the temporal bone dissections and succeeded to reveal membrane ruptures in the SHL etiology. Similarly, Kamerer [60] demonstrated microfissures between the posterior canal ampulla and the roundwindow niche during his temporal bone studies. Although there are other studies with small patient sizes, the main question is whether the hearing losses depending on membrane ruptures should be classified as SHL. Because, in that case, we have to assume that SHL arises from a mechanical problem and the treatment procedure should be based mainly on surgical or conservative procedures. But, the main thing that should be known about these patients is that they will not respond to standard SHL treatment protocols. However, if we look at the classic definition of SHL, they also conform to the SHL definition.
