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C L I N I C A L A N D L A B O R A T O R Y I N V E S TI G A T I O N S

BJD

British Journal of Dermatology

Most individuals with either segmental or non-segmental vitiligo display evidence of bilateral cochlear dysfunction* T.S. Anbar,1 M.M. El-Badry,2 J.A. McGrath3 and E.S. Abdel-Azim1 1 3

Dermatology Department and 2Audiology Unit, ENT Department, Al-Minya University, 129 El-Hosany street, Al-Minya 61111, Egypt St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, U.K.

Summary Correspondence Tag S. Anbar.

E-mail: taganbar@yahoo.com

Accepted for publication 7 July 2014

Funding sources No external funding.

Conflicts of interest None declared. *Plain language summary available online.

DOI 10.1111/bjd.13276

Background Vitiligo has been classified clinically into segmental vitiligo (SV) and nonsegmental vitiligo (NSV) and may also be associated with audiological abnormalities.

Objectives We examined cochlear function in ears of individuals with SV and NSV, including subjects with facial and nonfacial lesions, and in patients who have SV with unilateral facial involvement.

Methods This study included 25 patients with SV and 28 patients with NSV. Fifteen age- and sex-matched healthy individuals served as controls. Cochlear function was studied using the distortion product otoacoustic emissions (DPOAEs).

Data were analysed using SPSS. Results Sixty-four ears (60%) of patients with vitiligo had cochlear dysfunction while the control group exhibited no abnormalities. On comparing the cochlear dysfunction of patients with SV with patients with NSV, no statistically significant difference was found. The ears on both sides, affected and unaffected by vitiligo, in patients with SV showed cochlear dysfunction with no statistically significant difference in DPOAE. To determine the effect of the lesion side on cochlear function, we compared DPOAE amplitude using Student’s t-test. The comparisons included NSV of the face vs. NSV on other areas, NSV of the face vs. SV of the face and SV of the face vs. SV of other areas. No statistically significant difference was found in these comparisons.

Conclusions Bilateral cochlear dysfunction is common in both NSV and SV and does not reflect the appearance of vitiligo in the skin. Our results underscore the important role of melanocytes and melanin in cochlear function, and suggest that the cochlear abnormalities in SV point to the presence of additional nonsegmental pathophysiological events underlying all forms of vitiligo.

What’s already known about this topic?

• • •

Melanocytes, the targeted cells in vitiligo skin, are also present in the inner ear and are critical for normal cochlear function.

Clinical studies revealed that 12 5–18 9% of patients with vitiligo had sensorineural hearing loss.

No studies have correlated the cochlear function and vitiligo subtype.

What does this study add?

• •

406

We compared cochlear function, measured by distortion product otoacoustic emissions, in patients with segmental vitiligo and nonsegmental vitiligo.

Bilateral cochlear dysfunction is common in both types.

British Journal of Dermatology (2015) 172, pp406–411

© 2014 British Association of Dermatologists

Vitiligo and cochlear function, T.S. Anbar et al. 407

Vitiligo has been classified based on clinical grounds into two major forms, namely, segmental vitiligo (SV) and nonsegmental vitiligo (NSV).1 Separating SV from other types of vitiligo is important principally because of its prognostic implications.

The term ‘nonsegmental vitiligo’ has been used as an umbrella term to include all other multifocal, usually symmetrical forms of vitiligo not occurring in a segmental pattern.2 The difference in the age of onset, course of the disease, onset of poliosis, incidence of association with autoimmune disorders and treatment outcome has indicated different pathophysiological aetiologies for SV and NSV.2,3 Melanocytes (MCs), the targeted cells in vitiligo skin, are also present in the inner ear. In particular, MCs are located in the stria vascularis of the cochlea, cochlear hair cells, modiolus, osseous spiral lamina, Reissner membrane and endolymphatic sac.4 MCs and melanin in the inner ear are required for maintenance of normal function of the stria vascularis, for the development of the endolymphatic potentials, and for preserving the ion and fluid gradient between the endolymph and perilymph, all of which are critical for normal cochlear function and sensory hair-cell survival.5 There are two types of sensory cells in the cochlea: inner hair cells (IHCs) and outer hair cells (OHCs). Inner hair cells are the transducing cells that convert sounds coming from the middle ear to electrical signals and send them to the auditory nerve. Outer hair cells act as the cochlear amplifier that gives the cochlea its sharp frequency selectivity. Otoacoustic emissions (OAEs) are sounds generated from the OHCs as a by-product of their cochlear amplifier function. The presence of OAEs indicates normal OHC function and that other structures critical for maintaining normal functions of the OHCs, such as the stria vascularis, are intact. The absence of OAEs or abnormal OAEs indicates cochlear dysfunction due to OHC impairment.6 Recording distortion product otoacoustic emissions (DPOAEs), which are a category of OAEs, is a reliable and sensitive method used to detect subtle cochlear dysfunction.

This technique has been used to monitor cochlear function in patients taking ototoxic drug medications and subjects affected by noise exposure. An advantage of this method is that it can uncover cochlear dysfunction, in its subclinical state, before such dysfunction is manifested in the traditional audiogram.7,8 It has been hypothesized that the loss of MCs and the subsequent decrease in melanin production, which occurs in vitiligo, could lead to cochlear dysfunction and subsequently to sensorineural hearing loss.5 Although some investigators could not find a significant association between vitiligo and sensorineural hearing loss,9 several clinical studies using conventional pure tone audiograms revealed that 12 5–18 9% of patients with vitiligo had sensorineural hearing loss.10–12 Studies also revealed that patients with vitiligo, who were asymptomatic for hearing loss and had normal hearing sensitivity, had subclinical cochlear pathology.12–14 This subclinical cochlear dysfunction in patients with vitiligo was revealed by absent or abnormal OAEs. © 2014 British Association of Dermatologists

Nevertheless, one issue that has not been addressed in the literature is whether there is a correlation between cochlear function and vitiligo subtype (SV or NSV). In the current study, we compared cochlear function, as measured by the DPOAEs, in patients with either SV or NSV. In addition, in patients with SV affecting one side of the face, we compared the cochlear function of both ears. Our findings provide new insight into the extent of vitiligo pathology in SV and NSV and have implications for disease pathophysiology and optimal patient management.

Patients and methods The study group consisted of 53 patients with vitiligo (30 female patients and 23 male patients). In the group of patients with SV, 20 had SV affecting the face and five had SV at other sites (two had SV on the abdomen, one had SV on the arm, and two had SV on the thigh). The NSV group consisted of 28 patients (19 had NSV involving the face and nine had NSV not involving the face). The age of the patients with vitiligo ranged from 9 to 45 years with a mean age of 22 3 11 years. Fifteen age- and sex-matched healthy individuals (nine female patients and six male patients) served as the control group. The age of the control group ranged between 11 and 44 years with a mean age of 23 2 10 8 years. Patients were recruited from the Dermatology Department, Al-Minya University Hospital, AlMinya, Egypt. Patients’ relatives were selected as control subjects. Both patients and control subjects agreed to be enrolled in the current study following a thorough explanation of the purpose of the current study and methodology used. Only patients and control subjects considered to have normal hearing sensitivity were selected (i.e. 20 dB hearing level or lower air conduction thresholds in the frequencies 250, 500, 1000, 2000, 4000 and 8000 Hz according to the American Speech Language Hearing Association).15 Exclusion criteria included history or evidence of otological disorders, history or evidence of middle-ear pathologies, family history of hearing loss, chronic noise exposure, history of ototoxic drug intake, and current or history of a systemic disorder known to affect hearing such as diabetes mellitus or hypertension. Patients over 50 years of age were also excluded from the study. Participants were subjected to otological examination and audiological evaluation, carried out at the Audiology Unit, ENT Department, Al-Minya University Hospital, Al-Minya, Egypt. This study was approved by the local ethics committee and each patient or guardian signed a written consent form for inclusion in the study.

Statistical analysis Data were analysed using the Statistical Package for the Social Sciences (SPSS for Windows version 11.0; IBM, Armonk, NY, U.S.A.). Descriptive statistics in the form of the frequency, percentage, range, mean and SD were calculated.

British Journal of Dermatology (2015) 172, pp406–411

408 Vitiligo and cochlear function, T.S. Anbar et al.

The comparison between patients and control subjects was carried out using the Student’s t-test for paired observations.

Audiological evaluation Immittancemetry was conducted using a Zodiac 401 immittance meter (GN Otometrics A/S, Taastrup, Denmark) to measure middle-ear pressure and stapedial muscle reflex at frequencies of 500, 1000, 2000 and 4000 Hz and to exclude middle-ear pathologies.

Pure tone audiometry was done using an Amplaid 309 audiometer (Amplus Corp., Boulder, CO, U.S.A.) to assess hearing sensitivity. Air conduction threshold was obtained for the frequency range 250–8000 Hz at single octave intervals using a TDH 49 ear phone (Telephonics Corporation, Farmingdale, NY, U.S.A.), while bone conduction threshold was obtained for the frequency range 500–4000 Hz at single octave intervals using a B71 bone vibrator (Radioear, New Eagle, PA, U.S.A.).

DPOAE was used to test cochlear function. DPOAE was recorded using the Intelligent Hearingâ system with Smart OAE 4 5 software (Intelligent Hearing Systems, Miami, FL, U.S.A.). Two tones were used: L1 = 65 dB sound pressure level (SPL) and L2 = 55 dB SPL, while f2/f1 was 1 22.

Both the amplitude of response of the distortion product (DP) at 2f1–f2 and background noise (Ns) were obtained at nine points corresponding to f2 frequencies of 553, 783, 1105, 1560, 2211, 3125, 4416, 6250 and 8837 Hz. These measurements were used to build a DP-gram by displaying the DP against the f2 frequency. The signal-to-noise ratio (SNR) was measured (SNR = DP – Ns) at each of these nine points. DPOAE was considered normal, thereby reflecting normal cochlear function, if the SNR was ≥ 3 dB SPL on at least 70% of the tested frequencies.16 For statistical analysis, the average amplitude of the tested frequency was calculated so that one single average was used for the right ear and one single average was used for the left ear.

Results Cochlear function in patients with vitiligo and control subjects Qualitatively, 64 ears (60%) of patients with vitiligo had cochlear dysfunction, while the examined control group had no abnormality. Quantitatively, Student’s t-test revealed a statistically significant difference between the two groups in both ears (t-value = 6 3; P < 0 001 for the right ear and t-value = 6 4; P = 0 000 for the left ear) (Fig. 1).

Cochlear function in patients with segmental vitiligo and patients with nonsegmental vitiligo On comparing the cochlear function of patients with SV with patients with NSV, 35 (62%) of the ears in patients with SV had cochlear dysfunction compared with 29 (58%) ears in patients with NSV. The v2-test revealed no statistically significant difference (v2-value = 3 21; P = 0 3). Quantitatively, although the mean DPOAE scores were lower in the individuals with SV compared with those who had NSV, the differences were not significant using the Student’s t-test (tvalue = 1 5; P = 0 13 for the right ear and t-value = 1 46; P = 0 15 for the left ear) (Fig. 2).

Cochlear function in the ears on affected and unaffected sides of patients with segmental vitiligo We compared the DPOAE amplitude of ears on the affected side of patients who had SV with facial involvement and ears on the other, unaffected side (Fig. 3). Paired sample t-test revealed no statistically significant difference between both sides (t-value = 1; P = 0 3). In 13 of the 20 patients, the DPOAE amplitude was larger in the unaffected side (range of the difference between both sides was between 1 dB SPL and 7 8 dB SPL), and was larger in the affected side in seven patients (range of the difference was between 1 2 dB SPL and 8 8 dB SPL). These data are shown in Figure 4.

Fig 1. Cochlear function in patients with vitiligo and control subjects. The mean and SD of distortion product otoacoustic emission amplitude for the patients with vitiligo were 14 25 5 88 dB sound pressure level (SPL) and 14 55 4 6 dB SPL for the right and left ears, respectively, compared with 22 8 4 6 dB SPL and 21 3 3 1 dB SPL for the control subjects.

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© 2014 British Association of Dermatologists

Vitiligo and cochlear function, T.S. Anbar et al. 409

Fig 2. Cochlear function in patients with segmental vitiligo (SV) and nonsegmental vitiligo (NSV). The mean and SD of distortion product otoacoustic emission (DPOAE) amplitude was 15 6 5 9 dB sound pressure level (SPL) and 15 9 5 7 in the right and left ears, respectively, in patients with NSV. The mean and SD of DPOAE amplitude were 12 9 6 5 dB SPL and 13 2 6 7 in the right and left ear, respectively, in patients with SV.

Fig 3. Cochlear function on affected and unaffected sides of patients with segmental vitiligo. The mean and SD amplitudes were 12 4 5 8 and 13 5 6 0, respectively.

Fig 5. Distortion product otoacoustic emission amplitude in the unaffected and affected sides of patients with segmental vitiligo compared with control subjects.

(t-value = 4 1, P = 0 001 for the affected side and tvalue = 3 4, P = 0 002 for the unaffected side).

Effect of lesion site on cochlear function

Fig 4. Distortion product otoacoustic emission amplitude difference between the unaffected and affected side in the patients with segmental vitiligo (i.e. unaffected side minus the affected side).

Figure 5 shows DPOAE amplitudes for the affected and unaffected sides of patients in comparison with control subjects. For both sides, DPOAE amplitudes were significantly lower in patients with vitiligo compared with control subjects © 2014 British Association of Dermatologists

To determine whether the lesion site (face vs. nonface) has an effect on cochlear function, three comparisons were made with regard to the DPOAE amplitude using Student’s t-tests. These comparisons included NSV involving the face vs. patients with NSV of other areas, patients with NSV on the face vs. SV on the face, and SV on the face vs. SV involving sites other than the face. For the NSV group, the amplitudes of DPOAE of the right and left ears, respectively, were averaged for each patient to calculate a single mean for the group. For the SV group, the amplitude of DPOAE of the ear on the same side as the lesion was used in statistical analysis. Table 1 shows the mean, SD, number of patients, t-value and P-value of these comparisons. There were no statistically significant differences for any of these comparisons.

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410 Vitiligo and cochlear function, T.S. Anbar et al.

Table 1 Effect of lesion site (face vs. nonface) on cochlear function in patients with vitiligo

NSV of the face (n = 19) vs. NSV not of the face (n = 9) NSV of the face (n = 19) vs. SV involving only the face (n = 20) SV involving only the face (n = 20) vs. SV not of the face (n = 5)

dB SPL, mean SD

t-value

P-value

13 1 6 5 vs. 12 8 6 4 13 1 6 5 vs. 12 42 5 77 12 42 5 77 vs. 13 5 6 4

0 02 0 12 0 32

0 984 0 74 0 45

NSV, nonsegmental vitiligo; SV, segmental vitiligo; SPL, sound pressure level.

Effect of disease duration on cochlear function The disease duration for all the patients with vitiligo (SV and NSV) showed no statistically significant correlation with cochlear function as measured by DPOAE (r = 0 025; P = 0 89).

Moreover, no statistically significant correlation was found between cochlear function and disease duration in either the affected side or unaffected side of patients with SV (r = 0 035; P = 0 79 for the affected side and r = 0 045; P = 0 68 for the unaffected side).

Discussion In this study, we tested cochlear function in patients with NSV and patients with SV using DPOAE. This is a very sensitive test for detecting cochlear dysfunction given that it can detect abnormalities even before cochlear dysfunction manifests itself in the traditional audiogram.7,8 In the current study, only patients with vitiligo who had normal hearing sensitivity were included. Patients with any degree of hearing loss were excluded to prevent any bias in the DPOAE test.

Moreover, patients with diseases or history known to affect cochlear function (e.g. diabetes mellitus, hypertension, chronic noise exposure or history of ototoxic drug intake) were all excluded to maximize the likelihood that any cochlear dysfunction found in the patients with vitiligo could be attributed to the vitiligo itself and not to any other cause.

On comparing the cochlear function of both ears in patients with vitiligo with the cochlear function of the control group, cochlear dysfunction was evident in patients with vitiligo, as shown from the smaller amplitude and higher percentage of abnormal DPOAE findings. This supports previous studies that demonstrated subclinical abnormalities of melanin-containing cellular elements of the auditory system in patients with vitiligo.10,11 However, those previous studies did not test the relationship between cochlear function and vitiligo subtype (i.e. NSV vs. SV). In the current study, we compared the cochlear function of the ears on the affected side of patients with SV with the cochlear function of the ears of patients with NSV and found no statistically significant difference in the amplitude of DPOAE between the two conditions, which suggests that there is no significant effect of vitiligo subtype on cochlear function: it is impaired in both.

Another matter that was not assessed in previous studies10,11 is the cochlear function of the ear on the same side as the SV compared with the ear on the unaffected side in the British Journal of Dermatology (2015) 172, pp406–411

same patients. In the current study, when DPOAE amplitudes of ears on the same side as SV lesions were compared with the DPOAE amplitudes of ears on the unaffected side, there was no statistically significant difference. Meanwhile, the DPOAE amplitudes were lower on both the affected and unaffected sides of patients with SV compared with control subjects. Therefore, as in the case of NSV, both ears in SV display cochlear dysfunction despite the presence of unilateral vitiligo.

Our audiological findings might be expected in NSV because it is potentially a generalized disorder from its start.

Conversely, bilateral cochlear dysfunction might not be expected in SV because of its localized nature and previous suggestions of postzygotic mosaicism contributing to its aetiology.17 In type I mosaicism, when SV affects one site of the body away from the face, the expectation is that the ears should be clinically normal. In contrast, our study showed abnormalities of cochlear function in both ears of patients with SV, even in cases with no SV on the face. This was evidenced by lower DPOAE amplitude in patients with SV compared with control subjects. In terms of the mosaicism paradigm, these findings may be consistent with type 2 mosaicism – with a heterozygous germline abnormality and second event such as loss of heterozygosity in the SV – although whether a heterozygous event is sufficient to trigger cochlear dysfunction or whether a second pathology (genetic, autoimmune, endocrine etc.) is needed to create the cochlear pathology is not known.

In conclusion, we demonstrate that bilateral cochlear dysfunction is common in both NSV and SV, including SV with a nonfacial pattern. These observations underscore the important role of MCs and melanin in cochlear function, and suggest that there are additional nonsegmental pathophysiological events underlying all forms of vitiligo.

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