1. Introduction

The active development of ear microsurgery since the middle of the 20th century, based on the introduction of high-resolution optical equipment and microsurgical instruments into everyday practice, has by now made it possible to achieve significant success in the treatment of otiatric patients [1,6,12]. Along with new approaches to performing sanitizing interventions, methods of surgical restoration began to be developed, which, according to rumors, made it possible to rehabilitate thousands of patients who were previously doomed to disability [2,5,10,15]. Despite the high level of performance of reconstructive hearing-improving operations, hearing restoration in patients with tympanosclerosis is still associated with significant difficulties [6,9,13].

Tympanosclerosis is a non-purulent disease of the middle ear, characterized by the formation in the mucous membrane of peculiar foci of tympanosclerotic plaques that limit the mobility of the tympanic membrane; and/or auditory ossicles [3,12]. The proportion of patients with tympanosclerosis in the structure of patients with hearing pathology caused by chronic; inflammatory processes in the middle ear is very significant and amounts to 33% [4,11,14].

Despite many studies, including morphological, immunological, histochemical and electron microscopic studies, the issues of pathogenesis, treatment and prevention of tympanosclerosis have not been fully studied [5,7,12].

Currently, surgical treatment is considered the only effective way to restore hearing in patients with tympanosclerosis [7,8], however, the long-term results of the operation often do not suit either the patient or the doctor. This is due to the fact that the removal of characteristic tympanosclerotic plaques, performed in order to mobilize the intact elements of the sound-conducting circuit, is inevitably accompanied by the formation of a wound surface, which subsequently leads to the formation of scars and bone refixation [5]. Subsequent interventions, including dissection of scars and re-mobilization, are usually ineffective due to the development of even more pronounced cicatricial changes and aggravation of the sensorineural component of hearing loss [9].

The presence of a large number of patients suffering from tympanosclerosis and the relatively low efficiency of traditional surgical treatment of these patients determine the relevance of the topic and the study.

Purpose: To study the development of tympanosclerosis in children with chronic suppurative otitis media.

2. Material and Methods of Research

Scientific publications on this subject, published over the past 10 years in the E-library and PubMed databases, were studied.

3. Results of the Study and Their Discussion

Despite many studies, not only clinical and morphological, but also immunological, histochemical, and electron microscopy, the pathogenesis of this disease has not been fully studied [11].

Inflammation is considered as an etiological factor in the development of tympanosclerosis, and ectopic calcification is considered the main mechanism for the formation of tympanosclerotic changes [4].

A number of researchers consider tympanosclerosis to be the final and static outcome of various inflammatory processes in the middle ear, while others consider it to be a slowly progressive destructive process [10].

Most authors agree that tympanosclerosis, as a rule, begins to form in childhood or adolescence, and any inflammatory disease in the middle ear is the initiating moment. It has been established that tympanosclerotic changes occur as a result of various acute and chronic diseases of the middle ear, and are a manifestation of a degenerative lesion of the mucoperiost [8].

It is noteworthy that in some patients tympanosclerosis is actively formed after a single otitis media, in others, despite frequent otitis media, signs of tympanosclerosis never appear [13].

It has already been proven that some factors are likely to influence the development of the tympanosclerotic process.

So, a significant role is assigned to genetic predisposition. Based on the results obtained, it was found that the serum levels of HLA-B35 and -DR3 in patients with diagnosed tympanosclerosis are significantly higher than in healthy people, and attention was focused on a possible immunogenetic predisposition to the development of tympanosclerosis [15]. Similar results have been obtained in other studies examining the expression levels of genes encoding type I, II, III, and IV collagen (COL1A1, COL2A1, COL3A1, COL4A1), as well as osteopontin. The revealed correlation between the expression of type I, II, IV collagen, as well as osteopontin, and the severity of clinical manifestations of tympanosclerosis indicates the participation of these proteins in excessive fibrosis and pathological sclerotic remodeling of the tympanic membrane [10].

It has been proven that an important role in the occurrence of tympanosclerosis is played by free radicals, which are formed, in particular, during hyperoxia associated with long-term perforation of the tympanic membrane [6]. A relationship was found between a decrease in the levels of cellular antioxidants - superoxide dismutase and catalase, and the development of tympanosclerosis [2]. In an experiment on rats, it was found that the local application of acetylcysteine, a mucolytic drug with antioxidant and antitoxic properties, prevents the development of tympanosclerosis after myringotomy [14]. In other experiments on laboratory animals, a similar effect was observed with the systemic use of a number of antioxidants, including caffeic acid phenyl ester contained in propolis, L-carnitine, and selenium [7].

There is information about the development of the tympanosclerotic process as a result of an injury to the tympanic membrane [11]. According to many authors, myringotomy with the installation of a tympanoventilation tube in the treatment of exudative otitis media in children contributes to the formation of myringosclerosis [7]. The results of clinical studies indicate an increase in the occurrence of tympanosclerotic lesions in the thickness of the tympanic membrane after bypass tympanic cavity [3]. The effectiveness of the use of vitamin E for the prevention of the development of tympanosclerosis after the installation of tympanoventilation tubes has been proven [2].

The activity of inducible nitric oxide synthetase, which is involved in various processes, including the body's defense responses against pathogens, was studied, and its effect on the severity of tympanosclerosis was shown [9]. When studying the level of serum fibronectin in patients with tympanosclerosis, an inverse correlation was established between the severity of tympanosclerotic manifestations and the level of serum fibronectin [12].

Currently, one of the promising areas for studying the pathogenesis of tympanosclerosis is the study of the features of calcium metabolism in patients with tympanosclerosis [14]. Studies have proven the effectiveness of the use of calcium channel blockers to prevent the development of tympanosclerosis [7]. Data have been published on a significant increase in the levels of parathyroid hormone and bone resorption marker β-CrossLaps in the blood of patients with tympanosclerosis, while reducing the concentration of vitamin D, which regulates osteogenesis. It has been established that an increased content of parathyroid hormone in the blood serum in patients with tympanosclerosis enhances bone resorption and stimulates the flow of calcium and phosphates into the blood, while the first stage of bone formation, the synthesis of collagen and osteocalcin precursor proteins are insufficient. This imbalance leads to episodic hypercalcemia and hyperphosphatemia, which contributes to the deposition of phosphorus-calcium compounds in tissues (ectopic calcification) and, in particular, in the mucous membrane of the middle ear [12].

It was shown that the concentration of parathyroid hormone in the middle ear in patients with CGSO with tympanosclerosis compared with patients with CGSO without tympanosclerosis, as well as healthy people, is higher by 21.5%. When tympanosclerosis is combined with other pathological processes in the middle ear (cholesteatoma, caries), the concentration of parathyroid hormone is increased by 38.3% [15].

The role of matrix metalloproteinases involved in the degradation of extracellular matrix structures has been studied [4].

The results of washings from the mucous membrane of the middle ear in patients with tympanosclerosis indicate an increase in titers of interleukin-8, a pro-inflammatory cytokine that regulates cellular calcium metabolism [7]. And the concentration of another cytokine - interleukin-6, according to some data, on the contrary, is lowered [1]. Information related to the immunological aspects of the pathogenesis of tympanosclerosis can be found in the works of both domestic and foreign authors [10].

To date, it has been established that in patients with severe atherosclerotic changes, tympanosclerosis occurs significantly more often than in patients without manifestations of atherosclerosis, and therefore, studies are ongoing aimed at identifying the general mechanisms of the development of these diseases [8].

The role of infectious agents penetrating the middle ear cavity through perforation of the tympanic membrane is considered [11]. An attempt has already been made to identify the relationship between the development of tympanosclerosis foci and the bacteria Chlamydia pneumoniae and Helicobacter pylori [6].

There is evidence of the involvement of the autonomic nervous system in the pathogenesis of tympanosclerosis [8].

A characteristic morphological manifestation of tympanosclerosis is a tympanosclerotic focus (plaque), which is a whitish, dense, often bumpy formation delimited from the surrounding tissues, located in the mucous membrane of the middle ear or in the thickness of the tympanic membrane [15].

While otoscopy gives the impression of superficial localization of tympanosclerosis foci, it has long been proven that they are located exclusively in the connective tissue layer of the mucous membrane of the middle ear or tympanic membrane. Even foreign scientists described tympanosclerosis as a hyaline degeneration of the connective tissue with the deposition of lime salts and the formation of a new bone [4].

Numerous histological studies have shown that tympanosclerosis is a kind of lesion of the mucoperiost, a deep connective tissue layer of the mucous membrane lining the bony walls of the middle ear cavities and covering the auditory ossicles [7].

Sclerosis of the mucous membrane is uneven. In some cases, it is possible to distinguish a zone of subepithelial sclerosis and a zone of sclerosis in the area of mucoperiost [5]. The mucoperiost retains the potency of the embryonic connective tissue, including the ability to form bone and cartilage, and can respond to inflammation with fibro- and osteoplastic reactions [15]. This allows a number of researchers to consider tympanosclerosis as a process of heterotopic formation of bone tissue, the source of which is progenitor cells, apparently located in the connective tissue and capable of differentiating into osteoblasts under the influence of inducing factors, which synthesize and secrete non-mineralized intercellular bone substance (osteoid), participate in its calcification, regulate the flow of calcium and phosphorus into and out of bone tissue [10]. According to other scientists, bone neoformation with subsequent dystrophy of the type of avascular necrosis is the morphological basis for the recurrence of tympanosclerosis [6].

Many researchers believe that histopathological changes in the mucosa in tympanosclerosis are always homogeneous and begin with the transformation of young granulation tissue into scar tissue [12]. In the future, hyalinosis of the scar tissue occurs, its calcification and, possibly, ossification [11]. Others believe that tympanosclerosis should not be considered as a direct result of purulent inflammation, and tympanosclerotic plaque as a derivative of granulation tissue. It is believed that the development of tympanosclerosis begins with tissue hypoxia, which occurs in the acute stage of inflammation under conditions of insufficient blood circulation, which leads to the death of some parenchymal elements and the development of sclerotic changes in the mucoperiost [3]. First, there is a change in the number and structure of the collagen fibers of the mucoperiost. Further, hyaline degeneration develops with focal accumulation of remnants of cell decay, calcification due to precipitation of calcium salts in dead structures, and, finally, the formation of a tympanosclerotic focus [9].

There are several histological variants of tympanosclerotic plaque, including: dystrophic, sclerotic (fibrous), hyaline, petrified (calcareous) and mixed [6].

In the literature, two types of sclerotic conglomerates were distinguished depending on their structure: 1 - creamy, rubbery, soft, cartilaginous density, exfoliating like bulbous scales; 2 - white, hard, tightly adjacent to the surrounding tissues and breaking when trying to remove [11].

From a histological point of view, there are: early tympanosclerosis, characterized only by a violation of the normal arrangement of connective tissue fibers; intermediate - with well-defined areas of hyalinization; late, characterized by the presence of characteristic foci of tympanosclerosis with or without signs of calcification and/or ossification [12].

Initial, preclinical, detected only histologically focal manifestations of tympanosclerosis in the stage of fibrinoid swelling and hyalinosis, not detected by otomicroscopy, fall under the definition of "histological tympanosclerosis" [15].

In general, histological data indicate a metabolic disorder in the connective tissue of the tympanic membrane and the mucous membrane of the middle ear, which manifests itself in the form of protein dystrophy - extracellular dysproteinoses (fibrinoid, hyalinosis) and mineral dystrophy (calcification). It has been proven that tympanosclerotic changes resulting from inflammation are staging [6]. Stage I is characterized by damage to collagen fibers and is reversible. Stage II is accompanied by fibroblast invasion leading to excessive collagen formation. There is a thinning and melting of collagen fibers, hyalinization, resulting in the formation of a homogeneous mass with indistinguishable fibers, which looks like a soft white cartilaginous tissue or a compacted tissue of a rubber-like structure. III - stage of tympanosclerosis is characterized by calcification and is irreversible.

Most authors attribute tympanosclerosis to the completed forms of fibrosing otitis media, describing it as the final stage of catarrhal inflammation of the mucous membrane of the tympanic cavity. At the same time, the results of some recent studies indicate the incompleteness of the productive phase of the inflammatory process, as evidenced by the levels of cytokines and the histological features of the surgical material [7].

Depending on the nature of the inflammation (purulent or serous), morphologically, the fibrous process proceeds according to the principle of epimorphosis (compensation of a tissue defect with granulation tissue with its maturation and transformation into a scar) or endomorphosis (development of connective tissue in the mucosa itself). Tympanosclerosis is a typical manifestation of endomorphosis after serous inflammation in the middle ear, in which degenerative processes occur in the mucous membrane of the middle ear and the tympanic membrane with the formation of dense conglomerates (foci of tympanosclerosis). The appearance of the mucous structure of tympanosclerotic foci is associated with the process of many cycles of calcification of hyaline masses, which, forming plates, undergo degeneration [5].

One of the little-studied aspects of the morphology of tympanosclerosis remains the so-called “ossification” of the tympanosclerotic focus and the addition by some authors of the option “plaque with signs of ossification” [7]. The presence of signs of ossification in tympanosclerotic plaques is explained by two theories: the realization of osteogenic potencies of the mucoperiost and the formation of part of the plaques from dystrophically altered areas of the auditory ossicles and bone walls of the tympanic cavity, that is, the formation of bone sequesters [12]. Macroscopically, an ossified focus looks like a fragment of pathological bone density tissue, which is detected and relatively easily separated from the underlying bone tissue in the process of removing typical petrified or hyaline foci of tympanosclerosis, mainly in the medial wall of the tympanic cavity.

It is known from special literature that bone tissue consists of cellular elements and a mineralized bone matrix - an intercellular (organic) substance impregnated with mineral compounds. The bulk of the organic component is represented by type I collagen, and the mineral component is represented by hydroxyapatite and amorphous calcium phosphate. From hexagonal crystals of hydroxyapatite enclosed in systems of collagen fibers, bone plates are formed, which in turn form osteons - the structural units of bone tissue. The gaps between the osteons are filled with intercalated plates representing the remnants of osteons lysed during bone development. These formations are interconnected by hypermineralized cementation lines. The cellular structure of bone is formed by three types of cells: osteoblasts, osteoclasts, and osteocytes. Osteoblasts are large cells with basophilic cytoplasm that develop from bone marrow stromal cells, the main function of which is the synthesis of bone tissue proteins (collagen and protein glycans) and the implementation of the process of osteogenesis. Osteoclasts are giant multinucleated cells, analogues of macrophages, developing from precursor cells of mononuclear leukocytes, the main function of which is bone resorption (resorption). Osteocytes are metabolically inactive bone cells that originate from osteoblasts immured in their own bone matrix. They carry out the transport of nutrients and minerals in the bone tissue.

The vital activity of the skeletal system is based on two interrelated and mutually replacing processes: the process of creation - the formation of a new bone and the process of destruction - resorption of the old one (bone remodeling). In bone remodeling, the order of events is clearly programmed. Under the influence of certain stimuli, a group of osteoclasts resorb bone tissue to a depth of about 50 microns. The space of the resorbed bone is covered with osteoblasts, which form the newly formed bone tissue with osteocytes embedded in the mature bone [7].

The destruction of the bone structures of the middle ear, observed in patients with chronic otitis media, is due to a number of pathological processes, most often - cholesteatoma and carious-granulation process, less often - tympanosclerosis. While in cholesteatoma the process is clear and pronounced, and often leads to the destruction of not only the auditory ossicles, but also a significant part of the temporal bone, in tympanosclerosis, bone tissue destruction is limited and is more often observed in the zone of maximum sclerotic manifestations. It is known that the resorption of bone structures during the development of cholesteatoma is due to its passive growth and the enzymatic activity of the perimatrix [9].

Destruction of bone tissue in tympanosclerosis, apparently, is due to other mechanisms and is a consequence of dystrophic and necrotic processes arising from damage to the mucoperiost and malnutrition of the underlying bone area [2].

Taking into account the already proven facts about the degenerative-dystrophic nature of tympanosclerosis and the staging of the disease, the assumption of dystrophy and destruction of bone tissue in the area of massive sclerotic lesions of the mucoperiost with the formation of bone sequesters looks more plausible compared to the assumption of neoosteogenesis in the focus of dystrophy. But for a reasonable answer to this question, it is necessary to conduct a morphological study of ossified foci.

4. Conclusions

Thus, it follows that all of the above indicates the need for in-depth studies of the mechanisms of development of tympanosclerosis in children with CSOM in order to develop effective methods for diagnosing, treating and preventing the disease.