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Persistent measles virus infection as a possible cause of otosclerosis: State of the art.


The etiopathogenesis of otosclerosis is still largely unexplained and remains controversial. Morphologic examinations have shown the presence of a chronic inflammation in otosclerotic tissue. Among the proposed explanations for this inflammation are an immunologic reaction against collagen, mutations of collagen gene 1A1, and a viral infection.

In this paper, we focus on the role of measles virus in otosclerosis, and we review the current literature, devoting particular attention to a suspected paramyxoviral etiopathogenesis in Paget's disease. Our examination of footplate fragments by reverse transcription polymerase chain reaction testing in 95 patients with otosclerosis revealed the presence of measles virus RNA in 83% of cases. Quantification of measles virus immunoglobulin G (IgG) in otosclerosis patients indicated that the ratio of antimeasles virus IgG in total IgG was higher in perilymph than in serum. Furthermore, an almost identical incidence of otosclerosis and measles virus-caused mortality in women suggests that women are more susceptible to measles virus infection. Finally, since the introduction of the measles virus vaccination program in Europe, there has been a decline in the incidence of otosclerosis. Moreover, the average age of patients at diagnosis and surgery at our hospital has increased to 54 years.

Our findings, when they are considered along with findings regarding the presence of paramyxoviral RNA in Paget's disease, support the hypothesis that measles virus is involved in the etiopathogenesis of otosclerosis.


Otosclerosis was first described by Valsalva (1666-1723). In 1841, Toynbee recognized that otosclerosis can cause hearing loss. [1] Morphologically, the otosclerotic focus arises in the ontogenically "weak" border region between bone and cartilage.

We distinguish between two forms of otosclerosis: histologic and clinical. In 90% of patients, otosclerotic foci are observed only histologically, and inner ear hearing loss can develop. In the remaining 10%, the otosclerotic focus encroaches the oval window and causes a conductive or combined hearing loss (figure 1). [2] In the United States, approximately 15 million persons have otosclerosis, and it is considered to be among the most common causes of acquired deafness. [3]

Otosclerosis affects only the human temporal bone, although very similar lesions that led to conductive or combined hearing loss have been detected in the crura of LP/J mice. [4] Hueb et al analyzed more than 1,400 temporal bones and found otosclerotic foci in 12.8% of them. [5] Similar findings were reported by Engstrom and Muller. [6,7] Studies show that otosclerosis is more common in women than in men; for example, Guild examined 518 temporal bones and found histologic otosclerosis in 12.3% of the specimens of females, compared with only 6.5% of the specimens from males. [8] Clinical observations have suggested that pregnancy might somehow promote or induce the growth of otosclerotic foci. On the other hand, there is no evidence that estrogen or progesterone influences the development of clinical otosclerosis. [9]

Morphologic investigations of patients with otosclerosis have shown that an inflammatory process occurs in the temporal bone, and that it has three distinct stages: bone resorption, new bone formation, and final eburnation of the affected bone. The inflammatory nature of this process has been observed in immunohistochemical examinations of specimens, which revealed the presence of a variety of immunocompetent cells, including macrophages, HLA-DR-positive cells, cells expressing beta-2 microglobulin, suppressor T cells, and complement C3. [10,11] Deposits of immunoglobulins (Ig) G, M, and A and complement C3 can be found along the resorption lacunae and in osteocytes and chondrocytes surrounding the affected areas (table). [11,12] The origin of this chronic inflammation has still not been elucidated. Among the possible etiopathogenic factors that have been discussed are metabolic disorders such as an imbalance between trypsin and antitrypsin, [13,14] vascular disturbances leading to necrosis of the bone, [15] and mechanical distress. [16]

Yoo et al immunized rats against collagen type II and found lesions very similar to otosclerosis in the temporal bone. [17] Extended serologic investigations have shown the presence of autoantibodies to collagen type II and type IX in patients with otosclerosis, which supports the hypothesis that a collagen immune etiopathogenesis is involved. [18,19] However, it is not clear whether the antibodies are the consequence or the cause of the inflammatory process. If the latter is true, inflammatory reactions should also be observed in various other locations in the skeleton.

Hereditary and genetic factors in the development of otosclerosis have been widely considered in the literature, and the occurrence of multiple cases in certain families supports this hypothesis. [20] A genetic predisposition influenced by one or more unidentified factors could lead to the development of the characteristic otospongiotic process in the border region between bone and cartilage in the otic capsule. Genetic factors might account for an enhanced susceptibility to infection by certain viruses with specific tropism in cells in particular regions such as the globuli ossei. [21] Recently, a mutation in the collagen 1A1 gene has been identified in one familial case of otosclerosis; this is the same mutation that is seen in osteogenesis imperfecta. [22] In another family with 16 affected members, an otosclerosis locus has been mapped to chromosome 15q25-q26. [23] However, in our clinical practice, familial otosclerosis is very rare.

The morphologic characteristics of Paget's disease--a remodeling bone disease of the ileosacral joint, pelvis, skull, and long bones--are similar to those of otosclerosis. In their examination of specimens obtained from patients with Paget's disease, Mills and Singer found on electron microscopy herringbone-like structures very similar to paramyxoviral nucleocapsids. [24] In a subsequent immunohistochemical analysis, Mills et al confirmed the presence of measles virus in affected tissue. [25] In two other cases of otosclerosis, McKenna et al also observed on electron microscopy filamentous structures that were morphologically very similar to paramyxoviral nucleocapsids in osteoblasts. [26] Immunohistochemical studies have demonstrated the expression of measles virus nucleocapsid [11] and fusion [27] proteins in chondrocytes, osteocytes, osteoblasts, and the connective tissue, especially in otospongiotic (resorptive) areas. Thus far, attempts to detect measles virus in otosclerotic bone by tissue culturing or localizing the virus by in situ hybridization have failed. Because the isolation of the infectious virus has been unsuccessful, a coupled reverse transcription polymerase chain reaction (RT-PCR) assay has been used both by our group and by McKenna's to detect measles virus RNA.

Because the otosclerotic focus usually is in close contact with inner ear fluids, an immunologic reaction of the inner ear immune system, presumably in the endolymphatic sac, should be observed. [28] A measles virus infection and measles virus protein expression in the otosclerotic focus should lead to a measurable humoral and cellular immune response in the inner ear immune system (figure 2).

Detection of measles virus RNA in otosclerotic bone

We studied 176 patients--123 females (70%) and 53 males, aged 16 to 79 years (mean: 54)--who had been treated for the spontaneous type of otosclerosis at our ENT department from 1994 to 1999. We assembled a control group (n = 45) that consisted of five patients with a malignant tumor (squamous cell carcinoma) of the temporal bone, 20 patients with exostosis of the outer ear canal, and 20 patients who had a cholesteatoma. Some 74% of the patients with otosclerosis remembered that they had had a measles virus infection in the past, and only 18% said that they had received a measles virus vaccination. Among the controls, a childhood measles virus infection was reported by four of the five patients who had a malignant tumor, 14 of the 20 who had exostosis, and 12 of the 20 who had a cholesteatoma. Measles virus antibody titers in serum were determined for all patients and controls by enzyme-linked immunosorbent assay (ELISA). Antimeasles virus IgG titers in patients and controls ranged from 1:2,000 to 1:10,000, a nd antimeasles virus IgM testing was negative in all individuals.

Specimens were obtained from 95 of the 176 otosclerosis patients and from all 45 controls in an attempt to detect measles virus RNA by RT-PCR. These specimens included stapes footplates, crura, and bone chips from the outer ear canal of the otosclerosis patients and the five controls with a malignancy of the temporal bone; bone chips from the outer ear canal of the 20 controls with exostosis; and bone chips from the mastoid and outer ear canal of the 20 controls with cholesteatoma. They were snap-frozen immediately after surgery and stored in liquid nitrogen. The bone specimens were pulverized mechanically under liquid nitrogen, and total RNA was isolated with a modified guanidinium thiocyanate-phenol-chloroform method. RT-PCR testing to detect measles virus RNA was performed as previously described. [29] The successful extraction of RNA was controlled by the detection of actin mRNA, and the specificity of the amplification product was confirmed by Southern blot hybridization or sequencing. RNA from measles virus-infected and -uninfected Vero cells was used as positive and negative controls, respectively.

In the otosclerosis patients, measles virus-specific amplification products were obtained from 79 of the 95 footplate specimens (83%), and crura and bone chips from the outer ear canal were consistently negative (figure 3). Tissue specimens from the control groups were all negative for measles virus RNA. Actin mRNA was successfully amplified in all patient and control specimens, which confirmed a successful RNA extraction.

These data are in good agreement with observations by McKenna et al, who analyzed fixed and celloidin-embedded specimens from temporal bone by RT-PCR. [30] McKenna's technique offers the advantage that the specimen can be morphologically examined for otosclerotic foci in the sample. However, the sensitivity of the subsequent RT-PCR is lower because the efficiency of the RNA extraction procedure is diminished.

In our investigations, we were unable to detect any measles virus-related sequences in 16 of the 95 footplates (17%) of patients with clinical otosclerosis. There are several possible reasons that might account for this. One reason might be that the tissue was never infected by measles virus. Another might be that the infected cells were lost during the final stages of otosclerotic eburnation. The latter explanation is supported by the well-known morphologic pattern seen in late-stage otosclerosis, in which only a very small number of osteoblasts, blood vessels, and connective tissue cells can be found. [31] Furthermore, we cannot rule out the possibility that some of our samples did not contain otosclerotic tissue. Our experimental settings were designed for efficient RNA extraction and highly sensitive RT-PCR amplification. Unlike McKenna et al, who used embedded material, [30] we did not fixate and decalcify the bone specimens, which is necessary for histologic examinations. Decalcification and celloidin embedding can seriously damage RNA, which might account for the negative results in McKenna et al's examinations. Finally, the size of the sample was usually very small ([sim]1 [mm.sup.3]), and it is known that the level of viral replication and transcription in persistent infections is very low. Therefore, the number of measles virus templates in the RNA preparations might have been below the detection limit of RT-PCR. Even so, when they are considered in total, our findings demonstrate conclusively that measles virus RNA is present in the vast majority of cases of clinical otosclerosis.

Immune reaction of the inner ear

Various morphologic and experimental studies have provided evidence for an inner ear immune system localized in the endolymphatic sac. [28,32] These observations have been confirmed in experiments of immunologic challenge with keyhole-limpet hemocyanin in guinea pigs. [33] In contrast, Fukuda et al found that scala tympani inoculation with cytomegalovirus following systemic cytomegalovirus infection of guinea pigs did not lead to a humoral immune response in either serum or perilymph. These authors argued that the immunologic reaction might be delayed and therefore might need more time to develop. [34]

In clinical otosclerosis, the otosclerotic focus is in close contact with the inner ear fluids. It is reasonable to suppose that antigens from the otosclerotic focus are shed into perilymph. These antigens might reach the endolymphatic sac and stimulate its immune system by eliciting a humoral immune response. To test this theory, we analyzed the perilymph of otosclerosis patients for the presence of measles virus-specific antibodies. We collected 1 to 2.5 [micro]1 of perilymph from 30 of the patients with otosclerosis and from all five controls who had squamous cell carcinoma of the temporal bone. As an additional control measure, we also obtained perilymph from an additional control group of 20 patients with Meniere's disease who were subjected to vestibulotomy. All 30 of the otosclerosis patients were positive for measles virus on RT-PCR of footplate material, whereas the five controls with temporal bone carcinoma were all negative (no tissue samples could be obtained from the controls with Meniere's dise ase). ELISA revealed positive antimeasles virus IgG titers (1:2,000-1:10,000) in the sera of all 30 otosclerosis patients, all five patients with carcinoma, and all 20 patients with Meniere's disease. Antimeasles virus 1gM was not detected in any of these subjects.

Because blood contamination during perilymph sampling cannot be completely avoided, total IgG and albumin were measured with a nephelometer. We calculated the blood contamination of the perilymph based on a serum-to-perilymph gradient of 35-to-1. [35] The results showed that in patients with otosclerosis, the ratio of antimeasles virus IgG to total IgG was 52 times higher in the perilymph than in the serum (figure 4). [36] The absolute amounts of antimeasles virus IgG were about 28 times higher in the serum than in the perilymph. In the five controls with malignant tumors and in the 20 controls with Meniere's s disease, we found no difference between the IgG ratios in serum and perilymph. These results support the hypothesis that there is a local production of antibodies in the inner ear immune system. Unfortunately, the immune status of perilymph has been poorly examined, and no other reports of antimeasles virus IgG in perilymph are available in the current literature.

Involvement of herpes simplex virus has been suggested in Meniere's disease. Morphologic examinations by in situ hybridization have provided evidence that latent herpes simplex virus exists in the endothelium of the endolymphatic sac. Serum analysis has demonstrated that patients with Meniere's disease have a higher titer of antiherpes simplex virus IgG and higher levels of antiherpes simplex virus IgE. [37,38] Patients with Meniere's s disease have also been found to have a higher ratio of antiherpes simplex virus IgG to total IgG in perilymph than in serum. These results are in good agreement with other morphologic and serologic findings in patients with Meniere's disease. [39]

Investigations of antimeasles virus antibodies in the cerebrospinal fluid and serum of patients with subacute sclerosing panencephalitis--a lethal brain disease that is caused by a persistent measles virus infection--have provided evidence that antimeasles virus antibodies are produced in the intrathecal space. [40] The production of these antibodies is believed to be one of the basic events in the development of measles virus persistence in the brain. The immunologic pressure is thought to select for measles virus mutants that have an attenuated replication and transcription and a diminished expression of the viral surface proteins. [41]

Measles virus infection of bone tissue

As mentioned, measles virus is known to cause persistent infections in the brain that can lead to subacute sclerosing panencephalitis and "measles virus inclusion body encephalitis." [41] A correlation between Paget's disease and measles virus infection is controversial. Early investigations with electron microscopy revealed the presence of paramyxoviral structures in the affected bone. [24] Measles virus RNA was found by Basle et al by in situ hybridization, [42] but other investigators were not able to detect it, even with more sensitive techniques such as RT-PCR [43] or in situ RT. [44] Finally, in 1995, Reddy et al detected measles virus RNA in bone specimens of patients with Paget's disease. [45] RNA from other members of the morbillivirus group has also been detected in patients with Paget's disease. For example, Gordon et al described the presence of canine distemper virus RNA in pagetic bone lesions. [46] This observation was supported by Mee et al, who detected canine distemper virus RNA in 15 of 15 bone specimens from patients with Paget's disease. [47] On the other hand, Hamill et al were not able to detect antibodies against canine distemper virus in a serologic study of patients with Paget's disease, [48] and there are no published serologic studies describing the occurrence of a humoral immune reaction against measles virus in patients with Paget's disease. These findings indicate that morbilliviruses seem to be involved in the onset of Paget's disease, but their exact contribution to the viral infection is still not clear.

Because otosclerosis and Paget's disease have very similar morphologies, some authors believe that otosclerosis is a pagetic focus localized in the temporal bone and that a morbillivirus infection might be involved in the onset of both diseases. Morphologic and molecular investigations of measles virus in otosclerosis have revealed its presence in the affected tissue and its absence in control tissues from the same patient and in tissues from other control patients. However, the importance and etiopathogenic role of measles virus in otosclerosis is still unclear. Future epidemiologic investigations might help determine whether measles virus infection is a cause of otosclerosis or just an epiphenomenon of the disease.

Epidemiologic considerations

Epidemiologic data strongly support the hypothesis that there is a measles virus etiology in otosclerosis. According to World Health Organization data on mortality from measles virus infection between 1950 and 1994, females are at higher risk. [49] The female-to-male ratio among children aged 4 years and younger was 1.04-to-1. In children aged 5 through 14 years, the ratio widened to 1.1-to-1, and from age 15 through 44, it increased again to 1.4-to-1. Likewise, otosclerosis is 1.4 times more common in females than in males. Garenne concluded that the immune defense against measles virus infection is signifi-cantly lower in adolescent girls. [49] Periods of high estrogen production appear to interfere with the elimination of the virus, which could favor the establishment of persistent infection.

In the 1970s, the measles virus vaccination program was introduced in Europe. Since then, the average age of patients at the onset of otosclerosis as well as at diagnosis and stapes surgery in our department increased to 54 years. The female-to-male ratio has remained about 1.4-to-l. The increase in age might be the result of the introduction of the vaccination program, but we need a longer observation period and a larger population before we can be certain.

In conclusion, measles virus should be considered as a possible cause of the spontaneous form of otosclerosis. However, the question still remains as to whether measles virus infection is a factor that initiates the proliferation and aggressive infiltration of connective tissue and blood vessels into the bone of the otic capsule, or whether it is merely an epiphenomenon in otosclerosis.

From the Department of Otorhinolaryngology--Head and Neck Surgery, Klinikum r. d. Isar, Technische Universitat, Munich (Dr. Niedermeyer, Dr. Arnold, and Dr. Sedlmeier), and the Department of Virology, Institute of Biochemistry, Max-Planck Institut, Martinsried/Munich (Dr. Neubert and Dr. Sedlmeier).


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Author:Sedlmeier, Reinhard
Publication:Ear, Nose and Throat Journal
Geographic Code:4EUGE
Date:Aug 1, 2000
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