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Otosclerosis: etiopathogenesis and histopathology
American Journal of Otolaryngology–Head and Neck Medicine and Surgery 27 (2006) 334 – 340 www.elsevier.com/locate/amjoto
Review
Otosclerosis: etiopathogenesis and histopathologyB Sebahattin Cureoglu, MDa, Patricia A. Schachern, BSb, Alfio Ferlito, MD, DLO, DPath, FRSM, FRCSEd, FRCS, FASCP, FRCSGlasg, FRCSI, MCAP, FACS, FRCPath, FHKCORL, FDSRCSb,*, Alessandra Rinaldo, MDb, Vladimir Tsuprun, MDa, Michael M. Paparella, MDa a
Department of Otolaryngology, University of Minnesota, Minneapolis, MN, USA Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy
b
Abstract
Otosclerosis is a disease of the bony labyrinth manifesting clinically as a progressive conductive hearing loss, a mixed-type hearing loss, or a sensorineural hearing loss. The age of onset of the hearing loss caused by otosclerosis is principally between 15 and 40 years. Although histopathological inner ear changes due to otosclerosis have been very well documented, the true etiopathogenesis of the disease has yet to be described despite intensive research. Both genetic and environmental factors have been implicated, however. D 2006 Elsevier Inc. All rights reserved.
1. Introduction Otosclerosis is a primary disorder of the bony labyrinth and stapes known to affect only humans, leading to progressive conductive and sensorineural hearing loss [1,2]. In 1735, the Italian anatomist and surgeon Antonio Maria Valsalva of Bologna was the first to report on the lesion [3]. In 1912, Siebenmann [4] demonstrated the bone spongification and called the condition otospongiosis. Wang et al [5] obtained biopsies from other skeletal sites and showed that otosclerosis is unlikely to occur outside the temporal bone. Otosclerosis is a disease particularly widespread among Caucasian populations, whereas it is very rare among blacks, Asians, and Native Americans [6]. The incidence of clinical otosclerosis among family members of otosclerotic patients is approximately 20% to 25% as opposed to 0.3% in the overall population [7,8]. Hueb et al [9] found the incidence of histological otosclerosis to be 12.7%, however, and Guild [1] recorded rates of 12% in women and 6.5% in men, after excluding B
This study was supported by Hubbard Broadcasting Foundation, Saint Paul, MN, and The Starkey Hearing Foundation Eden Prairie, MN. 4 Corresponding reviewer. Department of Surgical Sciences, ENT Clinic, University of Udine, Policlinico Universitario, Piazzale S. Maria della Misericordia, I-33100 Udine, Italy. Tel.: +39 0432 559302; fax: +39 0432 559339. E-mail address: [email protected] (A. Ferlito). 0196-0709/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjoto.2005.11.001
infants and non-Caucasians. Many studies have established that the period of onset is mainly between 15 and 40 years of age, with a higher prevalence in women than in men [10]. The disease is bilateral in about 75% of patients [9]. The most common site is anterior to the oval window, followed by the round window niche, and the apical and medial cochlear wall, respectively [1,9,11]. Other sites of involvement are posterior to the oval window, the posterior wall of the internal auditory canal, the anterior wall of the internal auditory canal, around the cochlear aqueduct, around the semicircular canals, and within the footplate [11]. The incidence of extensive oval window and footplate involvement in otosclerosis ranges from 7% to 11% [12,13]. The incidence of round window obliteration is approximately 1% [12,14]. Schuknecht and Barber [11] classified otosclerosis as clinical and histological. Whereas clinical otosclerosis is defined as a lesion that fixes the stapes footplate, histological otosclerosis refers to cases without footplate fixation. Cochlear otosclerosis refers to cases of histological otosclerosis extensive enough to involve the endosteum of the cochlea without stapes fixation [15]. Otosclerotic bone undergoes a remodeling process in which normal bone is replaced by otosclerotic bone (Figs. 1-8). Osteoclasts and osteoblasts can be seen within active foci of otosclerosis. The otosclerotic focus may include a number of components, such as bone formation by
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Fig. 1. Otosclerosis is located anterior to the oval window. There is no fixation at the stapes footplate (F). C indicates cochlea (hematoxylin and eosin staining, original magnification 25).
osteoblasts, bone destruction by osteoclasts, vascular proliferation, fibroblasts, and histiocytes. Schuknecht and Barber [11] used the following criteria as indicative of histological activity in an otosclerotic focus: (1) areas of non-osseous tissue showing increased cellularity; (2) evidence of osteoclastic bone resorption and/or osteoblastic new bone formation; (3) increased vascularity and fibrous thickening of overlying mucosa; and (4) affinity of the osseous tissue for acidophilic stains. In addition, Lim et al [16] identified three types of otosclerotic lesions: cellular (spongiotic), fibrotic, and sclerotic. The cellular type is characterized by monocyte, macrophage, osteoblast, and osteoclast recruitment and activation; the fibrotic type typically shows extensive bone fibrosis; and the sclerotic type features a paucity of bone cells. Parahy and Linthicum [17] observed that otosclerotic and otospongiotic lesions can occur simultaneously, and one does not necessarily precede the other.
Fig. 2. Atrophy of the stria vascularis (arrowhead) and atrophy and hyalinization (*) of the spiral ligament can be seen in this temporal bone with cochlear otosclerosis. RM indicates Reissner membrane; BM, basilar membrane (hematoxylin and eosin staining, original magnification 100).
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Fig. 3. There is an otosclerotic focus (O) located anterior to the oval window in this temporal bone with chronic otitis media. F indicates stapedial footplate; GT, granulation tissue; C, cochlea (hematoxylin and eosin staining, original magnification 25).
As the lesion expands through preexisting vascular channels, the tissue shows an affinity for hematoxylin, making the bone appear darker in this area [18]. Chole and McKenna [19] reported that more active lesions in otosclerotic tissue frequently show osteoclast disruption and less active lesions display new, woven bone formation with hypercellularity. Chevance et al [20] observed that osteoclasts were located in the center but not at the margins of otosclerotic foci. They said that osteoclasts play a less significant part in bone resorption, refuting a previously accepted theory. Causse et al [21] found histiocytes that contain lysosomes in the advancing edge of the otosclerotic lesion. These cells were undergoing a lytic process with characteristic zones of hydrolytic enzymes. In addition, osteolytic enzymes were found in the perilymph of patients undergoing stapedectomy [22]: it has been suggested that these enzymes have a major role in the progressive inner ear disease in otosclerosis [22].
Fig. 4. Osteoclasts (arrowheads) can be seen in this active otosclerotic lesion (hematoxylin and eosin staining, original magnification 125).
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Fig. 5. There is fixation of the stapes footplate by direct extension of the otosclerotic lesion. Note profound saccular hydrops (arrowheads) (hematoxylin and eosin staining, original magnification 25).
Stapes fixation begins with calcification of the annular ligament joining the oval window otosclerotic lesion with the stapedial footplate. The stapes subsequently becomes fixed by the lesion [18]. Guild [1] indicated that hearing impairment began with bony fixation. Some lesions involve the whole inner ear, including the labyrinth. Active spongiotic lesions are frequently surrounded by a less active sclerotic lesion with an indistinct advancing edge [18]. This peripheral portion of the lesion is what Manasse [23] calls the pre-otosclerotic lesion. In the healing phase, the disease has been noted to possess no absorptive activity, although some disorganized, dense bones, partially small vascular vessels exist [18]. Gussen [24] reported loss of capillaries and pericapillary spaces in the spiral ligament and erosion of the cochlear capsular bone with a greater width of soft tissue endosteum separating the spiral ligament from the bony surface. Spiral ligament changes have been referred to as atrophy, fibrosis,
Fig. 6. Hyaline degeneration of the spiral ligament and profound endolymphatic hydrops (arrows) of the cochlea can be seen in this temporal bone with cochlear otosclerosis. IAC indicates internal auditory canal (hematoxylin and eosin staining, original magnification 20).
Fig. 7. There is obliteration of the round window membrane by otosclerosis (O). SV indicates scala vestibuli; ST, scala tympani (hematoxylin and eosin staining, original magnification 25).
and thickening, especially when they are found adjacent to the endosteal bone surface [2]. There is also a loss of cellularity of the ligament adjacent to the endosteum of the portion of cochlea affected by the destructive lesion. Lindsay and Beal [25] described the pink-stained thickening of the spiral ligament as hyaline. Although spiral ligament hyalinization is not observed in the areas closer to the preotosclerotic lesion, it is apparent in areas closer to active spongiotic lesions or healed otosclerotic lesions [18]. Moreover, Parahy and Linthicum [26] showed a relationship between the degree of cochlear endosteal involvement with spiral ligament hyalinization and sensorineural hearing loss. This hyalinization has thus been thought to support the theory that a substance leaks from the active otospongiotic lesion into the ligament and interacts with the peripheral auditory neural elements, thereby causing sensorineural hearing loss [26]. Bone conduction thresholds and air-bone gaps were worse in cases with sclerotic lesions [11]. The airbone gap seemed to be determined by narrowing and loss of the annular ligament [27]. Sensorineural hearing loss has only been found in temporal bones with extensive and multifocal otosclerosis [25], and an associated increase in bone conduction levels is only reported in ears with two or more sites of endosteal involvement [28]. On the other hand, Schuknecht and Barber [11] found no correlation between the magnitude of sensorineural hearing loss and endosteal involvement or the size, activity, or location of the otosclerotic lesion. Otosclerotic lesions large enough to cause sensorineural hearing loss invariably also fix the stapes [15]. Hinojosa and Marion [29] observed, however, that the pattern of degeneration of the peripheral sensory and neural elements in cases of otosclerosis with sensorineural hearing loss was similar to the situation observed in cases with presbycusis. Some researchers have identified blue mantles as preotosclerotic manifestations [30,31]. Lindsay [32] observed that blue mantles usually manifested around blood vessels
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Fig. 8. (A) This temporal bone has multiple otosclerotic foci with fibrotic and sclerotic lesions. SV indicates scala vestibuli; ST, scala tympani; arrows show endolymphatic hydrops of the cochlea (hematoxylin and eosin staining, original magnification 20). (B) Higher magnification of a sclerotic lesion involving the area anterior to the oval window and the cochleariform process (hematoxylin and eosin staining, original magnification 45). (C) Higher magnification of a fibrotic lesion involving the internal auditory canal (hematoxylin and eosin staining, original magnification 45).
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in the region of otosclerotic foci. Sorensen [33], on the other hand, described blue mantles as incomplete perivascular secondary osteons, detectable in every capsular layer of a normal temporal bone, including the bnoremodelingQ zone, so they should not be regarded as pre-otosclerotic lesions. Blue mantles were found in 59% of bones with clinical otosclerosis and in 45% of cases with histological otosclerosis; they were also more common in multifocal (60%) than in unifocal lesions (42%) [9]. Histopathological studies suggest that certain combinations of otological diseases, such as otosclerosis and Meniere’s disease, can occur and may have causative links [34,35], although other associations (eg, otitis media or tumors of the temporal bone) are commonly only coincidental, not causative [36]. Otosclerosis may cause endolymphatic hydrops by abutting the spiral ligament, resulting in a chemical disruption of ion-fluid recycling [37], obstruction of the endolymphatic duct and sac [38], and biochemical changes [39,40]. Tinnitus is a common symptom in patients with otosclerosis [41] and tinnitus and vestibular disorders occur more frequently in patients with the sclerotic type of lesion [42]. Otosclerotic lesions can also involve facial, utricular, or cochlear nerve regions and cause neural degeneration [43]. Saim and Nadol [44] stated that vestibular symptoms in patients with otosclerosis are more common in cases with elevated bone-conduction thresholds, correlating with vestibular nerve degeneration, which appears to be independent of the severity of the otosclerotic involvement of the vestibular end organs. Their findings also suggested that Scarpa’s ganglion cell degeneration is an important histological correlation of the vestibular symptoms in patients with otosclerosis [44]. In addition, Sando et al [45] observed vestibular nerve degeneration distal to the otosclerotic foci. The incidence of malleus fixation in association with otosclerosis is reportedly between 1% and 10% [46-49]. Malleus fixation may stem from ossification of the superior and anterior suspensory ligaments, leading to attachment of the head to the anterior wall of the epitympanum [50]. It may follow a congenital anomaly [51] or chronic infection of the ear [52]. It has also been suggested that otosclerotic bones have a high incidence of anterior mallear ligament hyalinization [53,54]. The differential diagnosis from Paget disease (osteitis deformans) should be considered. Otosclerosis differs from Paget disease in that it affects only the osseous labyrinth and no other bones in the body and occurs in a younger population [55,56]. The cause of otosclerosis is unknown, although a variety of factors involved in the development of the disease have been postulated. Arnold and Plester [57,58] suggested that pathological changes of the vessels caused pathological reactions of the mucosa and submucosa of the middle ear and finally bone resorption. Causse et al [21] observed a disturbed trypsin-antitrypsin enzyme balance
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within the otosclerotic focus, with a spread of enzymes into the otic capsule. A gene for otosclerosis has been reported in several loci, that is, OTSC1 on chromosome 15q25-q26 [59], OTSC2 on chromosome 7q34-36 [60], and OTSC3 on chromosome 6p21.3-22.3 [61]. In addition, a fourth locus, OTSC4, has been reserved by the Human Genome Organization nomenclature committee, but this has not been published; while recently, a fifth locus, OTSC5, was localized on chromosome 3q22-24 [62]. The role of measles in the pathogenesis of otosclerosis has been extensively studied [63-66]. The presence of measles virus has been shown in patients with otosclerosis by using immunohistochemistry for the detection of the virus proteins [67,68] and reverse transcriptase polymerase chain reaction for the amplification of the viral RNA [69]. Arnold et al [64] also showed the presence of measles virus–specific antibodies in perilymph samples from patients with otosclerosis. These studies support the idea that the etiologic role of the measles virus in the pathogenesis of otosclerosis should be considered, at least in some cases. A number of studies have tried to establish an association between HLA antigens and otosclerosis. Miyazawa et al [70] reported a higher frequency of HLA-Aw33 in Japanese patients with otosclerosis and Gregoriadis et al [71] found a higher frequency of HLAA11 Bw35 and B14 in Greek patients with otosclerosis. However, others found no association between HLA antigens and otosclerosis [72-74]. Mutations of the collagen gene COL1A1 and a consequently reduced collagen type I synthesis have been observed in patients with otosclerosis [75]. A more recent investigation suggests that only a small percentage of cases of clinical otosclerosis are caused by mutations in the COL1A1 gene. They believe that most cases of clinical otosclerosis are related to other genetic abnormalities that have yet to be identified [76]. Rodriguez et al [77] found no evidence supporting the putative link of COL1A1 and COL1A2 genes with otosclerosis. Some studies have supported the hypothesis of an autoimmune process, such as antibodies against collagen II [78] and collagen IX [79], in the pathogenesis of otosclerosis. Immunofluorescence studies demonstrated deposition of immunoglobulin and complement on the bone matrix and wall within the area of spongiosis. Levels of antibodies to type II collagen were significantly higher in patients with otosclerosis than in control subjects, whereas no differences were found among levels of antibodies to collagen type I or type IV. These observations suggest a possible role for type II collagen autoimmunity in the etiology of otosclerosis and Meniere’s disease [80]. Bujia et al [79] demonstrated that the levels of antibodies to collagens type II and IX were significantly higher in patients with otosclerosis, whereas no differences were found between the levels of antibodies to collagens type I, III, VI, and XI.
Otosclerotic bone undergoes a remodeling process in which normal bone is replaced by otosclerotic bone and some preliminary studies point to an error in the connective tissue remodeling system involving collagenases [81,82]. Collagen remodeling includes many interacting components in the connective tissue including proteinases, which are associated with collagen degradation. Gordon et al [81] indicated that there were significantly lower levels of messenger RNA production for stromelysin in patients with otosclerosis as compared with all others tested. Thalmann et al [83] found significantly increased collagenase levels in the tissue fluid of the media from human skin fibroblast cultures taken from patients with otosclerosis. Although otosclerosis is one of the most common causes of hearing loss in the general population, its etiology and etiopathogenesis, and even the pathology of the disease, are still mainly unexplained. To gain a better understanding of the etiopathogenesis of otosclerosis in relation to its pathology, it is important to use human temporal bones with otosclerosis, applying modern biologic methods. References [1] Guild SR. Histologic otosclerosis. Ann Otol 1944;53:246 - 67. [2] Schuknecht HF. Disorders of bone. In: Schuknecht HF, editor. Pathology of the ear. 2nd ed. Philadelphia7 Lea & Febiger; 1993. p. 365 - 414. [3] Valsalva AM. Valsalvae opera et Morgagni epistolae. Venetiis (Italy)7 Francescus Pitteri; 1741. p. 2. [4] Siebenmann F. Demonstration mikroskopischer Pr7parate von Otospongiosis. Proc Int Otol Congr 1912;9:207. [5] Wang PC, Merchant SN, McKenna MJ, et al. Does otosclerosis occur only in the temporal bone? Am J Otol 1999;20:162 - 5. [6] Altmann F, Glasgold A, Macduff JP. The incidence of otosclerosis as related to race and sex. Ann Otol 1967;76:377 - 92. [7] Morrison AW. Genetic factors in otosclerosis. Ann R Coll Surg Engl 1967;41:202 - 37. [8] Hall JG. Otosclerosis in Norway, a geographical and genetical study. Acta Otolaryngol Suppl 1974;324:1 - 20. [9] Hueb MM, Goycoolea MV, Paparella MM, et al. Otosclerosis: the University of Minnesota temporal bone collection. Otolaryngol Head Neck Surg 1991;105:396 - 405. [10] Gordon MA. The genetics of otosclerosis: a review. Am J Otol 1989;10:426 - 38. [11] Schuknecht HF, Barber W. Histologic variants in otosclerosis. Laryngoscope 1985;95:1307 - 17. [12] Gristwood RE, Venables WN. Otosclerosis of oval window niche: an analysis of the results of surgery. J Laryngol Otol 1975;89:1185 - 217. [13] Farrior B. Contraindications to the small hole stapedectomy. Ann Otol 1981;90:636 - 9. [14] Shea JJ, Farrior JB. Stapedectomy and round window closure. Laryngoscope 1987;97:10 - 2. [15] Schuknecht HF, Kirchner JC. Cochlear otosclerosis: fact or fantasy? Laryngoscope 1974;84:766 - 82. [16] Lim DJ, Robinson M, Saunders WH. Morphologic and immunohistochemical observation of otosclerotic stapes: a preliminary study. Am J Otolaryngol 1987;8:282 - 95. [17] Parahy C, Linthicum FH Jr. Otosclerosis and otospongiosis: clinical and histological comparisons. Laryngoscope 1984;94:508 - 12. [18] Linthicum FH Jr. Histopathology of otosclerosis. Otolaryngol Clin North Am 1993;26:335 - 52.
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Review
Otosclerosis: etiopathogenesis and histopathologyB Sebahattin Cureoglu, MDa, Patricia A. Schachern, BSb, Alfio Ferlito, MD, DLO, DPath, FRSM, FRCSEd, FRCS, FASCP, FRCSGlasg, FRCSI, MCAP, FACS, FRCPath, FHKCORL, FDSRCSb,*, Alessandra Rinaldo, MDb, Vladimir Tsuprun, MDa, Michael M. Paparella, MDa a
Department of Otolaryngology, University of Minnesota, Minneapolis, MN, USA Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy
b
Abstract
Otosclerosis is a disease of the bony labyrinth manifesting clinically as a progressive conductive hearing loss, a mixed-type hearing loss, or a sensorineural hearing loss. The age of onset of the hearing loss caused by otosclerosis is principally between 15 and 40 years. Although histopathological inner ear changes due to otosclerosis have been very well documented, the true etiopathogenesis of the disease has yet to be described despite intensive research. Both genetic and environmental factors have been implicated, however. D 2006 Elsevier Inc. All rights reserved.
1. Introduction Otosclerosis is a primary disorder of the bony labyrinth and stapes known to affect only humans, leading to progressive conductive and sensorineural hearing loss [1,2]. In 1735, the Italian anatomist and surgeon Antonio Maria Valsalva of Bologna was the first to report on the lesion [3]. In 1912, Siebenmann [4] demonstrated the bone spongification and called the condition otospongiosis. Wang et al [5] obtained biopsies from other skeletal sites and showed that otosclerosis is unlikely to occur outside the temporal bone. Otosclerosis is a disease particularly widespread among Caucasian populations, whereas it is very rare among blacks, Asians, and Native Americans [6]. The incidence of clinical otosclerosis among family members of otosclerotic patients is approximately 20% to 25% as opposed to 0.3% in the overall population [7,8]. Hueb et al [9] found the incidence of histological otosclerosis to be 12.7%, however, and Guild [1] recorded rates of 12% in women and 6.5% in men, after excluding B
This study was supported by Hubbard Broadcasting Foundation, Saint Paul, MN, and The Starkey Hearing Foundation Eden Prairie, MN. 4 Corresponding reviewer. Department of Surgical Sciences, ENT Clinic, University of Udine, Policlinico Universitario, Piazzale S. Maria della Misericordia, I-33100 Udine, Italy. Tel.: +39 0432 559302; fax: +39 0432 559339. E-mail address: [email protected] (A. Ferlito). 0196-0709/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjoto.2005.11.001
infants and non-Caucasians. Many studies have established that the period of onset is mainly between 15 and 40 years of age, with a higher prevalence in women than in men [10]. The disease is bilateral in about 75% of patients [9]. The most common site is anterior to the oval window, followed by the round window niche, and the apical and medial cochlear wall, respectively [1,9,11]. Other sites of involvement are posterior to the oval window, the posterior wall of the internal auditory canal, the anterior wall of the internal auditory canal, around the cochlear aqueduct, around the semicircular canals, and within the footplate [11]. The incidence of extensive oval window and footplate involvement in otosclerosis ranges from 7% to 11% [12,13]. The incidence of round window obliteration is approximately 1% [12,14]. Schuknecht and Barber [11] classified otosclerosis as clinical and histological. Whereas clinical otosclerosis is defined as a lesion that fixes the stapes footplate, histological otosclerosis refers to cases without footplate fixation. Cochlear otosclerosis refers to cases of histological otosclerosis extensive enough to involve the endosteum of the cochlea without stapes fixation [15]. Otosclerotic bone undergoes a remodeling process in which normal bone is replaced by otosclerotic bone (Figs. 1-8). Osteoclasts and osteoblasts can be seen within active foci of otosclerosis. The otosclerotic focus may include a number of components, such as bone formation by
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Fig. 1. Otosclerosis is located anterior to the oval window. There is no fixation at the stapes footplate (F). C indicates cochlea (hematoxylin and eosin staining, original magnification 25).
osteoblasts, bone destruction by osteoclasts, vascular proliferation, fibroblasts, and histiocytes. Schuknecht and Barber [11] used the following criteria as indicative of histological activity in an otosclerotic focus: (1) areas of non-osseous tissue showing increased cellularity; (2) evidence of osteoclastic bone resorption and/or osteoblastic new bone formation; (3) increased vascularity and fibrous thickening of overlying mucosa; and (4) affinity of the osseous tissue for acidophilic stains. In addition, Lim et al [16] identified three types of otosclerotic lesions: cellular (spongiotic), fibrotic, and sclerotic. The cellular type is characterized by monocyte, macrophage, osteoblast, and osteoclast recruitment and activation; the fibrotic type typically shows extensive bone fibrosis; and the sclerotic type features a paucity of bone cells. Parahy and Linthicum [17] observed that otosclerotic and otospongiotic lesions can occur simultaneously, and one does not necessarily precede the other.
Fig. 2. Atrophy of the stria vascularis (arrowhead) and atrophy and hyalinization (*) of the spiral ligament can be seen in this temporal bone with cochlear otosclerosis. RM indicates Reissner membrane; BM, basilar membrane (hematoxylin and eosin staining, original magnification 100).
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Fig. 3. There is an otosclerotic focus (O) located anterior to the oval window in this temporal bone with chronic otitis media. F indicates stapedial footplate; GT, granulation tissue; C, cochlea (hematoxylin and eosin staining, original magnification 25).
As the lesion expands through preexisting vascular channels, the tissue shows an affinity for hematoxylin, making the bone appear darker in this area [18]. Chole and McKenna [19] reported that more active lesions in otosclerotic tissue frequently show osteoclast disruption and less active lesions display new, woven bone formation with hypercellularity. Chevance et al [20] observed that osteoclasts were located in the center but not at the margins of otosclerotic foci. They said that osteoclasts play a less significant part in bone resorption, refuting a previously accepted theory. Causse et al [21] found histiocytes that contain lysosomes in the advancing edge of the otosclerotic lesion. These cells were undergoing a lytic process with characteristic zones of hydrolytic enzymes. In addition, osteolytic enzymes were found in the perilymph of patients undergoing stapedectomy [22]: it has been suggested that these enzymes have a major role in the progressive inner ear disease in otosclerosis [22].
Fig. 4. Osteoclasts (arrowheads) can be seen in this active otosclerotic lesion (hematoxylin and eosin staining, original magnification 125).
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Fig. 5. There is fixation of the stapes footplate by direct extension of the otosclerotic lesion. Note profound saccular hydrops (arrowheads) (hematoxylin and eosin staining, original magnification 25).
Stapes fixation begins with calcification of the annular ligament joining the oval window otosclerotic lesion with the stapedial footplate. The stapes subsequently becomes fixed by the lesion [18]. Guild [1] indicated that hearing impairment began with bony fixation. Some lesions involve the whole inner ear, including the labyrinth. Active spongiotic lesions are frequently surrounded by a less active sclerotic lesion with an indistinct advancing edge [18]. This peripheral portion of the lesion is what Manasse [23] calls the pre-otosclerotic lesion. In the healing phase, the disease has been noted to possess no absorptive activity, although some disorganized, dense bones, partially small vascular vessels exist [18]. Gussen [24] reported loss of capillaries and pericapillary spaces in the spiral ligament and erosion of the cochlear capsular bone with a greater width of soft tissue endosteum separating the spiral ligament from the bony surface. Spiral ligament changes have been referred to as atrophy, fibrosis,
Fig. 6. Hyaline degeneration of the spiral ligament and profound endolymphatic hydrops (arrows) of the cochlea can be seen in this temporal bone with cochlear otosclerosis. IAC indicates internal auditory canal (hematoxylin and eosin staining, original magnification 20).
Fig. 7. There is obliteration of the round window membrane by otosclerosis (O). SV indicates scala vestibuli; ST, scala tympani (hematoxylin and eosin staining, original magnification 25).
and thickening, especially when they are found adjacent to the endosteal bone surface [2]. There is also a loss of cellularity of the ligament adjacent to the endosteum of the portion of cochlea affected by the destructive lesion. Lindsay and Beal [25] described the pink-stained thickening of the spiral ligament as hyaline. Although spiral ligament hyalinization is not observed in the areas closer to the preotosclerotic lesion, it is apparent in areas closer to active spongiotic lesions or healed otosclerotic lesions [18]. Moreover, Parahy and Linthicum [26] showed a relationship between the degree of cochlear endosteal involvement with spiral ligament hyalinization and sensorineural hearing loss. This hyalinization has thus been thought to support the theory that a substance leaks from the active otospongiotic lesion into the ligament and interacts with the peripheral auditory neural elements, thereby causing sensorineural hearing loss [26]. Bone conduction thresholds and air-bone gaps were worse in cases with sclerotic lesions [11]. The airbone gap seemed to be determined by narrowing and loss of the annular ligament [27]. Sensorineural hearing loss has only been found in temporal bones with extensive and multifocal otosclerosis [25], and an associated increase in bone conduction levels is only reported in ears with two or more sites of endosteal involvement [28]. On the other hand, Schuknecht and Barber [11] found no correlation between the magnitude of sensorineural hearing loss and endosteal involvement or the size, activity, or location of the otosclerotic lesion. Otosclerotic lesions large enough to cause sensorineural hearing loss invariably also fix the stapes [15]. Hinojosa and Marion [29] observed, however, that the pattern of degeneration of the peripheral sensory and neural elements in cases of otosclerosis with sensorineural hearing loss was similar to the situation observed in cases with presbycusis. Some researchers have identified blue mantles as preotosclerotic manifestations [30,31]. Lindsay [32] observed that blue mantles usually manifested around blood vessels
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Fig. 8. (A) This temporal bone has multiple otosclerotic foci with fibrotic and sclerotic lesions. SV indicates scala vestibuli; ST, scala tympani; arrows show endolymphatic hydrops of the cochlea (hematoxylin and eosin staining, original magnification 20). (B) Higher magnification of a sclerotic lesion involving the area anterior to the oval window and the cochleariform process (hematoxylin and eosin staining, original magnification 45). (C) Higher magnification of a fibrotic lesion involving the internal auditory canal (hematoxylin and eosin staining, original magnification 45).
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in the region of otosclerotic foci. Sorensen [33], on the other hand, described blue mantles as incomplete perivascular secondary osteons, detectable in every capsular layer of a normal temporal bone, including the bnoremodelingQ zone, so they should not be regarded as pre-otosclerotic lesions. Blue mantles were found in 59% of bones with clinical otosclerosis and in 45% of cases with histological otosclerosis; they were also more common in multifocal (60%) than in unifocal lesions (42%) [9]. Histopathological studies suggest that certain combinations of otological diseases, such as otosclerosis and Meniere’s disease, can occur and may have causative links [34,35], although other associations (eg, otitis media or tumors of the temporal bone) are commonly only coincidental, not causative [36]. Otosclerosis may cause endolymphatic hydrops by abutting the spiral ligament, resulting in a chemical disruption of ion-fluid recycling [37], obstruction of the endolymphatic duct and sac [38], and biochemical changes [39,40]. Tinnitus is a common symptom in patients with otosclerosis [41] and tinnitus and vestibular disorders occur more frequently in patients with the sclerotic type of lesion [42]. Otosclerotic lesions can also involve facial, utricular, or cochlear nerve regions and cause neural degeneration [43]. Saim and Nadol [44] stated that vestibular symptoms in patients with otosclerosis are more common in cases with elevated bone-conduction thresholds, correlating with vestibular nerve degeneration, which appears to be independent of the severity of the otosclerotic involvement of the vestibular end organs. Their findings also suggested that Scarpa’s ganglion cell degeneration is an important histological correlation of the vestibular symptoms in patients with otosclerosis [44]. In addition, Sando et al [45] observed vestibular nerve degeneration distal to the otosclerotic foci. The incidence of malleus fixation in association with otosclerosis is reportedly between 1% and 10% [46-49]. Malleus fixation may stem from ossification of the superior and anterior suspensory ligaments, leading to attachment of the head to the anterior wall of the epitympanum [50]. It may follow a congenital anomaly [51] or chronic infection of the ear [52]. It has also been suggested that otosclerotic bones have a high incidence of anterior mallear ligament hyalinization [53,54]. The differential diagnosis from Paget disease (osteitis deformans) should be considered. Otosclerosis differs from Paget disease in that it affects only the osseous labyrinth and no other bones in the body and occurs in a younger population [55,56]. The cause of otosclerosis is unknown, although a variety of factors involved in the development of the disease have been postulated. Arnold and Plester [57,58] suggested that pathological changes of the vessels caused pathological reactions of the mucosa and submucosa of the middle ear and finally bone resorption. Causse et al [21] observed a disturbed trypsin-antitrypsin enzyme balance
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within the otosclerotic focus, with a spread of enzymes into the otic capsule. A gene for otosclerosis has been reported in several loci, that is, OTSC1 on chromosome 15q25-q26 [59], OTSC2 on chromosome 7q34-36 [60], and OTSC3 on chromosome 6p21.3-22.3 [61]. In addition, a fourth locus, OTSC4, has been reserved by the Human Genome Organization nomenclature committee, but this has not been published; while recently, a fifth locus, OTSC5, was localized on chromosome 3q22-24 [62]. The role of measles in the pathogenesis of otosclerosis has been extensively studied [63-66]. The presence of measles virus has been shown in patients with otosclerosis by using immunohistochemistry for the detection of the virus proteins [67,68] and reverse transcriptase polymerase chain reaction for the amplification of the viral RNA [69]. Arnold et al [64] also showed the presence of measles virus–specific antibodies in perilymph samples from patients with otosclerosis. These studies support the idea that the etiologic role of the measles virus in the pathogenesis of otosclerosis should be considered, at least in some cases. A number of studies have tried to establish an association between HLA antigens and otosclerosis. Miyazawa et al [70] reported a higher frequency of HLA-Aw33 in Japanese patients with otosclerosis and Gregoriadis et al [71] found a higher frequency of HLAA11 Bw35 and B14 in Greek patients with otosclerosis. However, others found no association between HLA antigens and otosclerosis [72-74]. Mutations of the collagen gene COL1A1 and a consequently reduced collagen type I synthesis have been observed in patients with otosclerosis [75]. A more recent investigation suggests that only a small percentage of cases of clinical otosclerosis are caused by mutations in the COL1A1 gene. They believe that most cases of clinical otosclerosis are related to other genetic abnormalities that have yet to be identified [76]. Rodriguez et al [77] found no evidence supporting the putative link of COL1A1 and COL1A2 genes with otosclerosis. Some studies have supported the hypothesis of an autoimmune process, such as antibodies against collagen II [78] and collagen IX [79], in the pathogenesis of otosclerosis. Immunofluorescence studies demonstrated deposition of immunoglobulin and complement on the bone matrix and wall within the area of spongiosis. Levels of antibodies to type II collagen were significantly higher in patients with otosclerosis than in control subjects, whereas no differences were found among levels of antibodies to collagen type I or type IV. These observations suggest a possible role for type II collagen autoimmunity in the etiology of otosclerosis and Meniere’s disease [80]. Bujia et al [79] demonstrated that the levels of antibodies to collagens type II and IX were significantly higher in patients with otosclerosis, whereas no differences were found between the levels of antibodies to collagens type I, III, VI, and XI.
Otosclerotic bone undergoes a remodeling process in which normal bone is replaced by otosclerotic bone and some preliminary studies point to an error in the connective tissue remodeling system involving collagenases [81,82]. Collagen remodeling includes many interacting components in the connective tissue including proteinases, which are associated with collagen degradation. Gordon et al [81] indicated that there were significantly lower levels of messenger RNA production for stromelysin in patients with otosclerosis as compared with all others tested. Thalmann et al [83] found significantly increased collagenase levels in the tissue fluid of the media from human skin fibroblast cultures taken from patients with otosclerosis. Although otosclerosis is one of the most common causes of hearing loss in the general population, its etiology and etiopathogenesis, and even the pathology of the disease, are still mainly unexplained. To gain a better understanding of the etiopathogenesis of otosclerosis in relation to its pathology, it is important to use human temporal bones with otosclerosis, applying modern biologic methods. References [1] Guild SR. Histologic otosclerosis. Ann Otol 1944;53:246 - 67. [2] Schuknecht HF. Disorders of bone. In: Schuknecht HF, editor. Pathology of the ear. 2nd ed. Philadelphia7 Lea & Febiger; 1993. p. 365 - 414. [3] Valsalva AM. Valsalvae opera et Morgagni epistolae. Venetiis (Italy)7 Francescus Pitteri; 1741. p. 2. [4] Siebenmann F. Demonstration mikroskopischer Pr7parate von Otospongiosis. Proc Int Otol Congr 1912;9:207. [5] Wang PC, Merchant SN, McKenna MJ, et al. Does otosclerosis occur only in the temporal bone? Am J Otol 1999;20:162 - 5. [6] Altmann F, Glasgold A, Macduff JP. The incidence of otosclerosis as related to race and sex. Ann Otol 1967;76:377 - 92. [7] Morrison AW. Genetic factors in otosclerosis. Ann R Coll Surg Engl 1967;41:202 - 37. [8] Hall JG. Otosclerosis in Norway, a geographical and genetical study. Acta Otolaryngol Suppl 1974;324:1 - 20. [9] Hueb MM, Goycoolea MV, Paparella MM, et al. Otosclerosis: the University of Minnesota temporal bone collection. Otolaryngol Head Neck Surg 1991;105:396 - 405. [10] Gordon MA. The genetics of otosclerosis: a review. Am J Otol 1989;10:426 - 38. [11] Schuknecht HF, Barber W. Histologic variants in otosclerosis. Laryngoscope 1985;95:1307 - 17. [12] Gristwood RE, Venables WN. Otosclerosis of oval window niche: an analysis of the results of surgery. J Laryngol Otol 1975;89:1185 - 217. [13] Farrior B. Contraindications to the small hole stapedectomy. Ann Otol 1981;90:636 - 9. [14] Shea JJ, Farrior JB. Stapedectomy and round window closure. Laryngoscope 1987;97:10 - 2. [15] Schuknecht HF, Kirchner JC. Cochlear otosclerosis: fact or fantasy? Laryngoscope 1974;84:766 - 82. [16] Lim DJ, Robinson M, Saunders WH. Morphologic and immunohistochemical observation of otosclerotic stapes: a preliminary study. Am J Otolaryngol 1987;8:282 - 95. [17] Parahy C, Linthicum FH Jr. Otosclerosis and otospongiosis: clinical and histological comparisons. Laryngoscope 1984;94:508 - 12. [18] Linthicum FH Jr. Histopathology of otosclerosis. Otolaryngol Clin North Am 1993;26:335 - 52.
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