[Otosclerosis. 1st part: pathogenesis]. / Otosclerosis. 1. rész: patogenezis.

Otosclerosis can be found exclusively in the human otic capsule of the temporal bone. Its etiology is still unknown. In the past decades, several potential etiopathogenetic factors have been revealed, however, most studies were based on otosclerotic patients diagnosed by clinical symptoms only. The current experience indicates that one third of this group suffer from non-otosclerotic stapes fixation. In our experimental series, we have diagnosed and classified otosclerotic patients based on histologic examination, and analyzed also the pathogenetic factors. Recent data demonstrate that measles virus and rs1800472 SNP of transforming growth factor beta 1 (TGFß1) gene are marked obvious etiologic factors, which have no therapeutic consequences so far. Furthermore, we summarize the genetic and environmental factors to be found in the literature, which may play a fundamental role in the pathogenesis of otosclerosis. Orv Hetil. 2018; 159(30): 1215-1220.

Absence of Measles Virus Detection from Stapes of Patients with Otosclerosis.

Objective To determine molecularly the presence of measles virus genetic material in the stapes of patients with otosclerosis. Study Design A cross-sectional study. Setting A tertiary referral hospital. Subjects and Methods Genetic material was extracted from the stapes of patients with otosclerosis (n = 93) during the period from March 2011 to April 2012. The presence of viral measles sequences was evaluated by the real-time reverse transcriptase polymerase chain reaction (RT-PCR). The expression of the CD46 gene was determined. Results Ninety-three patients were included in the study. No sample was positive for any of 3 measles virus genes (H, N, and F). Measles virus RNA was not detected in any sample by real-time RT-PCR. CD46 levels were positive in 3.3% (n = 3) and negative in 96.7% (n = 90). Conclusion This study does not support the theory of measles virus as the cause of otosclerosis. It is necessary to do more research about other causal theories to clarify its etiology and prevention.

Expression of TNF-α, OPG, IL-1ß and the presence of the measles virus RNA in the stapes of the patients with otosclerosis.

Persistent measles virus infections play a crucial role in the pathomechanism of otosclerosis. The study was undertaken to investigate the role of tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß) and osteoprotegerin (OPG) in otosclerotic bone remodeling and to assess the relation of TNF-α, OPG and IL-1ß expression levels in otosclerotic stape footplates to the occurrence of measles virus infection. 61 patients with otosclerosis were treated surgically. Thirty-one stapes obtained from cadavers of people, who had died from a sudden cause were used as a control group. The presence of measles virus RNA and the expression levels of TNF-α, IL-1ß and OPG in otosclerotic foci were assessed using one-step RT-PCR. The presence of measles virus RNA was noted in 80.3 % of otosclerotic stapes (49 out of 61) and 9.7 % of normal tissues (3 out of 31). Transcript of TNF-α, IL-1ß and OPG was detected in 40, 46 and 18 virus-positive stapes, respectively. The transcript level of TNF-α and IL-1ß was significantly higher in otosclerotic tissues comparing to normal tissue. The OPG expression level was significantly lower in otosclerotic tissues comparing to controls. The presence of measles virus RNA in the stapes may indicate its role in the pathogenesis of otosclerosis. The presence of TNF-α and IL-1ß mRNA in the virus-positive stapes could be the result of viral antigen stimulation and may be a marker of inflammation the otosclerotic focus. The lack of OPG mRNA and the presence of TNF-α and IL-1ß mRNA in the majority of otosclerotic tissues reflect the bone remodeling process occurring in the stapes.

Perspectives of pharmacological treatment in otosclerosis.

To review our current knowledge of the pathologic bone metabolism in otosclerosis and to discuss the possibilities of non-surgical, pharmacological intervention. Otosclerosis has been suspected to be associated with defective measles virus infection, local inflammation and consecutive bone deterioration in the human otic capsule. In the early stages of otosclerosis, different pharmacological agents may delay the progression or prevent further deterioration of the disease and consecutive hearing loss. Although effective anti-osteoporotic drugs have become available, the use of sodium fluoride and bisphosphonates in otosclerosis has not yet been successful. Bioflavonoids may relieve tinnitus due to otosclerosis, but there is no data available on long-term application and effects on sensorineural hearing loss. In the initial inflammatory phase, corticosteroids or non-steroidal anti-inflammatory drugs may be effective; however, extended systemic application may lead to serious side effects. Vitamin D administration may have effects on the pathological bone loss, as well as on inflammation. No information has been reported on the use of immunosuppressive drugs. Anti-cytokine targeted biological therapy, however, may be feasible. Indeed, one study on the local administration of infliximab has been reported. Potential targets of future therapy may include osteoprotegerin, RANK ligand, cathepsins and also the Wnt-ß-catenin pathway. Finally, anti-measles vaccination may delay the progression of the disease and potentially decrease the number of new cases. In conclusion, stapes surgery remains to be widely accepted treatment of conductive hearing loss due to otosclerosis. Due to lack of solid evidence, the place of pharmacological treatment targeting inflammation and bone metabolism needs to be determined by future studies.

No evidence for an association between persistent measles virus infection and otosclerosis among patients with otosclerosis in Japan.

Otosclerosis, which is characterized by disordered bone remodeling, occurs exclusively in the human temporal bone. The etiology of the disease is unknown, but a popular hypothesis is that it is caused by persistent measles virus (MV) infection. Paramyxovirus-like filamentous structures were found in otosclerotic lesions of stapes footplates from patients with otosclerosis. Although MV RNAs have been detected in otosclerotic samples by using reverse transcription-PCR, no complete MV mRNA sequence has been reported, nor has infectious virus been isolated from clinical samples. Furthermore, one study failed to obtain evidence of MV infection in otosclerotic bone samples. In this study, we tested, by three different protocols, for the presence of MV in clinical samples from patients with otosclerosis in Japan. We used a highly sensitive reverse transcription-quantitative PCR method which is able to detect viral mRNA in cells infected with MV at around one infectious unit per well. We obtained no evidence of MV infection in bone samples, primary cell cultures derived from stapes bones, or MV-susceptible cell lines (Vero/hSLAM and II-18 cells) cocultured with bone samples or primary cell cultures derived from them. Thus, our results do not support the hypothesis that persistent MV infection is involved in the pathoetiology of otosclerosis.

The etiology of otosclerosis: a combination of genes and environment.

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is a complex genetic disease, caused by a combination of genetic and environmental factors. During the past decade, several attempts have been made to identify factors for otosclerosis. This review provides an overview of the current understanding of the etiology of otosclerosis and describes the genetic and environmental factors that have been implicated in the disease. Environmental factors include fluoride and viral factors, particularly measles. Genetic association studies for otosclerosis have reported several associations of genetic variants that influence the risk of disease, mainly involving bone remodeling pathways, although their individual risk contributions are small. Rare monogenic forms of otosclerosis also exist, which are caused by a mutation in a single gene leading to a clear familial segregation of the disease. Linkage analysis of large otosclerosis families has led to the identification of seven loci, and recently evidence was found that T cell receptor beta is a gene responsible for familial otosclerosis, suggesting an underlying immunological pathway. However, this might also represent an autoimmune process, a hypothesis that is supported by other data as well. In conclusion, a variety of pathways have been identified to be involved in the development of otosclerosis, showing that distinct mechanisms involving both genetic and environmental risk factors can influence and contribute to a similar disease outcome.

An overview of the etiology of otosclerosis.

Otosclerosis is the primary disease affecting the homeostasis of otic capsule and is among the most common causes of acquired hearing loss. Otosclerosis is considered as a multifactor disease, caused by both genetic and environmental factors. The aim of the present review is to summarize and analyze the bibliographic data, associated with the etiology of the disease. In some cases, the otosclerosis has an autosomal dominant mode of inheritance with incomplete penetrance. Genetic studies reveal the occurrence of at least nine chromosomal loci as candidate genes of the disease. The localized measles virus infection of the otic capsule has been postulated as a possible etiological theory. The role of hormonal factors, immune and bone-remodeling system in the etiopathogenesis of otosclerosis and the association of the disease with the disorders of the connective tissue are the issues of the present study. Despite the extensive research, many etiological factors and theories have been suggested and the process of development of the otosclerosis remains unclear.

Disease-associated novel CD46 splicing variants and pathologic bone remodeling in otosclerosis.

OBJECTIVE/HYPOTHESIS: Otosclerotic bone is supposed to show unique CD46 expression pattern because otosclerosis is an organ-specific disease with viral etiology. STUDY DESIGN: Otosclerosis is a complex bone remodeling disorder of the human otic capsule, which is associated with persisting measles virus infection. The general cellular receptor of measles virus is the CD46, which has 14-known splicing isoforms. METHODS: Nucleic acid was extracted from ankylotic stapes footplates (N = 99) removed during stapedectomies. Consecutive histological, CD46 specific immunohistologic analysis, and multiple polymerase chain reaction (PCR) amplifications were performed. Measles virus was detected by seminested reverse transcriptase-PCR. Splicing variants of CD46 were identified by nested reverse transcriptase-PCR and finally determined by mass sequencing of complementary DNA. RESULTS: Measles virus RNA was detectable only in histologically otosclerotic stapes footplates. Virus negative-fixed stapes represent degenerative disorders of variable histopathology. Otosclerosis is featured by an increased number of osteoclasts showing strong CD46 immunoreaction in contrast to nonotosclerotic stapes fixations. Normal and nonotosclerotic stapes footplates show consistent expression of "c," "d," "e," "f," and "l" CD46 splicing isoforms. In contrast, four novel CD46 splicing variants were additionally detected in otosclerosis: os1, os2, os3, and os4. CONCLUSIONS: Newly described CD46 isoforms have shorter or missing transmembrane domain and a rare cytoplasmic tail with pathological or uncommon signal transduction; however, virus binding ability remains equal and invariable. These changes may be responsible for the smooth virus replication. A special expression pattern and altered functions of CD46 could explain the organ-specific and virus-associated pathogenesis of otosclerosis.

Otosclerosis and measles virus - association or causation?

Otosclerosis is a frequent condition which occurs exclusively in the human temporal bone. This peculiar disease affects mainly Caucasians and Indians and may cause conductive, mixed conductive-sensorineural or occasionally merely sensorineural hearing loss. Morphological investigations of the otosclerotic focus show all three phases of a chronic inflammation with bone resorption, formation of new bone and finally eburnation. Various hypotheses about the cause of inflammation were proposed in the past. Immunological reactivity to collagen, the existence of otosclerosis genes (OTSC 1-5) including mutations of the collagen gene 1A1 and 1A2 or a measles virus (MV) infection were suggested. The existence of the MV proteins and RNA within the otosclerotic tissue has been shown by several authors. However, due to mainly technical problems, no further progress to elucidate the role of the virus could be made. Epidemiological studies revealed a dramatic decrease of measles and related diseases such as the subacute sclerosing panencephalitis since the introduction of MV vaccination programs in USA and Europe. Indeed, some surgeons reported decreasing numbers of stapes surgery and a shift towards elder patients. Our epidemiological survey of all patients hospitalized with otosclerosis in Germany between 1993 and 2004 demonstrates a highly significant decrease in otosclerosis among the population vaccinated against the MV. The strong correlation makes it most plausible that the MV is at least one triggering factor for the development of otosclerosis.

Expression of measles virus receptors in otosclerotic, non-otosclerotic and in normal stapes footplates.

Otosclerosis is a bone remodeling disorder of complex etiology. Persistent measles virus infection of the otic capsule could increase the expression level of measles virus receptors (CD46) on the osteoclasts and endothelial cells of the otosclerotic foci. Presence of measles virus RNA was demonstrated in the footplates of histologically diagnosed otosclerotic patients by RT-PCR; however, no reports were available about the CD46 expression pattern and level in otosclerosis. Nucleic acid was extracted from stapes footplates of clinically otosclerotic patients (N = 116). Genomic RNA of measles virus was amplified by RT-PCR. Amplification results were correlated with postoperative histologic and CD46 specific immunhistologic findings. Among 116 stapes fixation cases, 87 otosclerotic stapes contained measles virus RNA. Histology for virus negative stapes (N = 29) represented degenerative disorders with heterogeneous histopathology. Active otosclerosis was featured by increased numbers of osteoclasts showing strong CD46 expression. In virus negative, non-otosclerotic stapes fixation and in normal stapes footplates weak CD46 immunoreaction was demonstrated on the osteocytes and fibroblasts. In otosclerosis, it is reasonable to assume that measles virus increases the expression level of its own cellular receptor. Furthermore, intensive CD46 reaction could relate to active virus replication and continuous receptor internalisation. Otosclerosis is a disease of disturbed osteoid turnover due to persistent measles virus infection and special CD46 receptor pattern of the otic capsule.

Measles virus and otosclerosis.

Measles virus (MeV) might play an important role as an environmental stimulus in the etiopathogenesis of otosclerosis. Chronic inflammation was shown in morphologic investigations of otosclerotic foci and MeV N, P, and F proteins were detected within cells of the otosclerotic focus by immunohistochemical investigations. MeV RNA was extracted from fresh-frozen otosclerotic tissue by the use of in vitro RT-PCR. This result was validated through amplification of MeV genome sequences by RT-PCR from celloidin-embedded sections with morphologically ascertained otosclerotic foci. In searching for an immune response of the inner ear immune system against MeV proteins, elevated anti-MeV IgG levels were detected in the perilymph of patients with otosclerosis in comparison with the serum levels. In situ RT-PCR allowed the localization of MeV sequences in osteoclasts, osteoblasts, chondrocytes, macrophages, and epithelial cells in middle ear mucosa of otosclerotic tissue. Further evidence for MeV persistence has recently been given. Genotyping of MeV in otosclerotic foci demonstrated the presence of MeV genotype A, which circulated in Europe around 1960. All the above results confirm a strong association between MeV and otosclerosis.

Measles virus prevalence in otosclerotic foci.

The etiology of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. The presence of measles virus was shown in otosclerotic patients by RT-PCR amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and antimeasles immunoglobulin G in the perilymph samples. Nucleic acid (mRNA, vRNA, DNA) was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by RT-PCR: reverse transcription and the first-round PCR amplification were performed by heat-stable recombinant Thermus thermophilus polymerase, while in the nested round PCR Taq polymerase was employed. Oligonucleotide primers specific to measles virus nucleoprotein and matrix protein RNA were used in these reactions. Edmonston- and Schwartze-type measles viruses served as positive controls and cortical bone fragments, stapes superstructures, cadaver stapes, incus and malleolar samples served as negative controls. Among 102 otosclerotic patients, 62 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients. The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 40 negative samples may be genetically determined otosclerotic cases or stapes fixations due to other causes.

Antimeasles immunoglobulin G and virus-neutralizing activity in sera of patients with otosclerosis.

Otosclerosis is considered as an organ-specific measles virus (MV)-induced disease. The majority of people are infected with MV during childhood, and the immune activation is characterized by a lifelong persistence. Any kind of depressed systemic antimeasles reaction can lead to induction of a local immune response in the inner ear. MV proteins were resolved by conventional polyacrylamide gel electrophoresis in the presence of a denaturing detergent. In subsequent Western blot, healthy blood donors demonstrated a stronger reaction against most proteins than age- and sex-matched otosclerotic patients. Different serum dilutions were tested for neutralizing activity against constant MV concentration. Nearly complete viral neutralization was achieved with samples containing inactivated complement and in immunoglobulin-G-containing fractions, and activity in sera from patients with confirmed otosclerosis was significantly weaker than in healthy individuals. Our observations are consistent with viral participation in otosclerotic pathogenesis, but it is difficult to say if the diminished antimeasles humoral response is a consequence of or the cause for a local measles infection.

Molecular detection of measles virus in primary cell cultures of otosclerotic tissue.

CONCLUSION: Primary cell cultures were established from otosclerotic/otospongiotic footplate bone particles. Although this procedure is time-consuming, the quality and quantity of RNA isolated from these cells were much higher in comparison with the direct isolation of RNA from footplate bone samples and the preparation was more suitable for the detection of measles virus (MeV) RNA. OBJECTIVE: Morphological and biochemical investigations suggest that persistent MeV infection participates in the development of otosclerotic foci. However, this hypothesis is controversial because the detection of MeV in otosclerotic foci is inconsistent since the results are dependent on the presence and stage of foci in the investigated bone particles. Unfortunately, this cannot be confirmed before investigation. To study the presence of the MeV by different techniques in otosclerotic foci, stapes footplate fragments were collected during stapedectomy from patients suffering from clinical otosclerosis. MATERIALS AND METHODS: MeV-specific RT-PCR was performed on total RNA isolated directly from four fresh frozen footplate bone fragments and from the cells of 16 primary cultures of otosclerotic tissue samples. In order to rescue persisting MeV, the primary footplate cells were cocultured with MeV permissive B95a cells. RESULTS: MeV was not detected in RNA from fresh frozen otosclerotic materials, but analysis of the RNA from 5 of the 16 primary cell cultures showed MeV-positive results. Nucleotide sequencing of a 317 bp MeV-specific RT-PCR fragment confirmed the presence of the MeV RNA genome. Here, we report the first determination of MeV sequences in total RNA isolated from primary cells cultured from otosclerotic tissue. Persisting MeV in primary footplate cells could not be recovered by coculturing with B95a cells.

Antimeasles immunoglobulin g for serologic diagnosis of otosclerotic hearing loss.

HYPOTHESIS: Persistent measles virus infection of the otic capsule is suggested to be an etiologic factor in otosclerosis. Otosclerosis is a disease of complex unknown etiology causing progressive conductive and/or sensorineural hearing loss (HL). BACKGROUND: Diagnostic methods of otosclerosis are sensitive to ossicular chain fixation with low specificity for otosclerotic stapes ankylosis. METHODS: Nucleic acid was extracted from stapes foot plates of clinically stapes fixation patients (N = 213). Measles virus nucleoprotein RNA was amplified by reverse-transcriptase polymerase chain reaction. Amplification results were correlated to histologic findings in 49 cases. Antimeasles IgG levels of all clinically stapes fixation as well as control sera specimens were measured by enzyme-linked immunosorbent assay. RESULTS: Among clinically stapes fixation patients, 141 stapes foot plates contained measles virus RNA. Among 49 histologic specimens, viral RNA was detectable only in histologically otosclerotic stapes foot plates (n = 35). Histology for virus-negative foot plates (n = 14) excluded otosclerosis. Antimeasles IgG levels were significantly lower in the sera of patients with virus-positive stapes than in control sera. CONCLUSIONS: Combination of decreased antimeasles IgG serum level and conductive HL has a great specificity and sensitivity as a diagnostic method in the preoperative evaluation of ossicular chain fixations otosclerosis. Low antimeasles IgG level indicates otosclerosis, whereas high level suggests non-otosclerotic ossicular chain fixations. Preoperative elucidation of the cause of a conductive HL may suggest optional medical treatment in preference to surgical methods.

Histologic otosclerosis is associated with the presence of measles virus in the stapes footplate.

HYPOTHESIS: Persistent measles virus infection of the otic capsule is presumed to be one of the etiologic factors in otosclerosis. The viral pathogenesis of otosclerosis could be established only by correlative analysis: histologic examination of the stapes footplates and reverse-transcriptase polymerase chain reaction amplification of the viral RNA. At present, histologic analysis of the removed stapes footplates is the only appropriate method of distinguishing otosclerotic and nonotosclerotic stapes fixations. BACKGROUND: The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA and detecting the viral proteins by immunohistochemistry. METHODS: Nucleic acids (mRNA, vRNA, and DNA) were extracted from ankylotic stapes footplates of stapes fixation patients (n = 44). Measles virus genomic nucleoprotein RNA was amplified by seminested reverse-transcriptase polymerase chain reaction. Amplification results were correlated to postoperative histologic findings. RESULTS: Measles virus RNA was detectable only in histologically otosclerotic stapes footplates (n = 32). Histology for virus-negative footplates (n = 12) excluded otosclerosis. Virus-negative stapes footplates showed annular calcification (n = 8), bone resorption with increased numbers of hemosiderophages (n = 2), and mononuclear cell infiltration with osteolysis (n = 2). CONCLUSION: Stapes ankylosis is a heterogenous disease causing conductive hearing loss with different causes. Nonotosclerotic stapes fixations may belong to degenerative disorders with variable histopathology. Otosclerosis is an inflammatory disease resulting from persisting measles virus infection of the otic capsule.

Codetection of measles virus and tumor necrosis factor-alpha mRNA in otosclerotic stapes footplates.

HYPOTHESIS: Otosclerosis is a disease of unknown etiology causing conductive or sensorineural hearing loss. Persistent measles virus infection of the otic capsule is considered to be one of the etiologic factors in otosclerosis. BACKGROUND: Determinants of measles virus infection and reactive inflammation were studied in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcription polymerase chain reaction (RT-PCR) amplification of the viral RNA. No report is available, however, on the types and features of paracrine cytokines in otosclerosis. METHODS: Nucleic acid was extracted from stapes footplate samples of clinically otosclerotic patients. Measles virus nucleoprotein RNA was amplified by seminested RT-PCR. Tumor necrosis factor (TNF)-alpha mRNA expression was detected by RT-PCR in otosclerotic bone and was correlated with preoperative audiologic findings and measles virus positivity. RESULTS: Among 154 clinically otosclerotic patients, 99 stapes footplate specimens contained measles virus RNA. TNF-alpha mRNA was detectable in 88 virus-positive and in 6 virus-negative stapes footplates. There was no detectable TNF-alpha mRNA expression in virus negative cases. CONCLUSION: The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. Detection of TNF-alpha mRNA demonstrates activated osteoclast functions and inflammatory pathways in otosclerotic stapes footplates associated with measles virus presence. Virus-associated and virus-negative pathomechanisms of otosclerosis should be distinguished.

Otosclerosis--do we have a viral aetiology?

The etiology of otosclerosis remains an enigma though there are evidences suggesting a viral involvement. This study aimed to find out the relationship between viral infections and otosclerosis. Twenty two patients with otosclerosis and 10 healthy controls were included in the study. IgM antibodies to varicella zoster virus (VZV), measles, rubella, human cytomegalovirus (HCMV) and herpes simplex virus (HSV) were detected using micro ELISA. Paul Bunnel Davidsohn test was performed to rule out Ebstein Barr virus (EBV) infection. Overall, 5(22.7%) patients showed antibodies to one or more viruses. IgM antibodies against measles and VZV could be demonstrated in 4(18.1%) and 1(4.5%) patients respectively. None of the samples were found to be positive for HSV, HCMV, rubella and EBV antibodies. Controls were negative for all the viruses tested. The difference in seropositivity between the patient and control group was not statistically significant (p>0.05). Thus, this study suggests that otosclerosis is not commonly associated with a systemic viral infection.

Measles virus prevalence in otosclerotic stapes footplate samples.

HYPOTHESIS: The cause of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. Chronic viral antigen expression on the surface of infected cells can induce a secondary autoimmune reaction against the otic capsule. BACKGROUND: In the past 15 years, some reports proposed the possible etiologic role of measles virus in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and detecting antimeasles immunoglobulin G in the perilymph samples. Many concerns were elicited by these results. METHODS: Nucleic acid was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by reverse-transcriptase polymerase chain reaction: reverse transcription and the first round polymerase chain reaction amplification was performed by heat stable recombinant Thermus thermophilus polymerase, whereas in the nested round, polymerase chain reaction Taq-polymerase was used. Measles virus nucleoprotein RNA-specific oligonucleotide primers were used in these reactions. An Edmonston-type measles virus served as a positive control and cortical bone fragments or stapes superstructures served as negative controls. RESULTS: Among 34 otosclerotic patients, 20 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients. CONCLUSION: The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 14 negative samples may be genetically determined otosclerotic cases.