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Evaluation of cochlear functions in children with Familial Mediterranean Fever
International Journal of Pediatric Otorhinolaryngology 87 (2016) 139e142
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Evaluation of cochlear functions in children with Familial Mediterranean Fever Begüm Lordoglu a, Baran Acar b, Fatma Yazilitas c, Sare Gulfem Ozlu c, Saliha Senel a, d, * a
Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training Hospital, Ankara, Turkey Department of ENT, Kecioren Training and Research Hospital, Ankara, Turkey c Department of Pediatric Nephrology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training Hospital, Ankara, Turkey d Yildirim Beyazit University School of Medicine, Ankara, Turkey b
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 14 June 2016
Objectives: To evaluate cochlear functions in patients with Familial Mediterranean Fever in relation to the disease severity score and treatment duration. Methods: 50 patients (4e18 years) who had been followed-up with the diagnosis of FMF and regularly receiving appropriate colchicine treatment and 39 healthy controls were included in the study. All the patients and controls were evaluated by audiologic evaluation, including high-frequency pure-tone audiometry and distortion product otoacoustic emission tests (DPOAE). The disease severity was determined by scoring system developed by Pras et al. Results: Fifty patients (52% female, 48% male; mean age12.2 ± 4.1 years) and 39 controls (58.9% female, 41.1% male, mean age 11.1 ± 3.4 years) were enrolled the study. The pure tone average of FMF patients was significantly higher than that of the control group at 500, 4000, and 8000 Hz frequencies. The patients' DPOAE signal values at 6 kHz, 8 kHz frequencies and SNR values at 8 kHz were significantly higher than control group. The patients' audiometry and DPOAE results were compared with the disease severity scores. Pure tone average was significantly higher in severe and moderate patient groups compared to the mild patient group at 2000 Hz frequency. DPOAE signal values showed statistically significant differences between the patient severity scores at 1.4 and 2.8 kHz frequencies. The mean colchicine treatment duration was found to be 5.1 ± 3.7 years. There were significant differences at 250 and 500 Hz frequencies when patients' audiometry results were compared with the treatment periods. Conclusions: FMF affects cochlear functions particularly at high frequencies. © 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Familial Mediterranean Fever FMF Cochlear function Colchicine Severity score Children
1. Introduction Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent episodes, usually manifested with fever and pain due to peritoneal, pleural or synovial inflammation and/or skin rashes [1]. The incidence rate of the disease was reported to be 1/1075 in Turkey [2]. The disease is diagnosed according to the Tell-Hashomer criteria which were defined in 1967 [3,4]. Pras et al. developed severity scoring system which divides
* Corresponding author. Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Telsizler, 06080, Ankara, Turkey. E-mail addresses: [email protected] (B. Lordoglu), dremrah2000@ yahoo.com (B. Acar), [email protected] (F. Yazilitas), drsare_ozlu@yahoo. com (S.G. Ozlu), [email protected] (S. Senel). http://dx.doi.org/10.1016/j.ijporl.2016.06.015 0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.
the disease into three groups; mild, moderate and severe, based on clinical findings [5]. Familial Mediterranean Fever is categorized within the systemic auto-inflammatory group of diseases [6]. This group has been described as causing visual and hearing impairment [7]. There are a limited number of studies about the effects of Familial Mediterranean Fever on auditory functions. The majority of these studies were conducted in adults. Familial Mediterranean Fever is thought to affect cochlear function due to increased inflammatory cytokines [7]. Loss of hearing adversely affects the development of language skills such as verbal communication and reading and as a result academic and professional success. This study aims to evaluate auditory function in children with FMF in relation to the disease severity score and the duration of treatment.
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2. Materials and methods
3. Results
This study is a case control study performed in two medical centers; Pediatric Nephrology Department of Dr. Sami Ulus Obstetrics, Child Health and Diseases Training and Research Hospital and Ear Nose Throat Department of Kecioren Training and Research Hospital. A total of 50 patients between the ages of 4e18 years who had been followed-up with the diagnosis of FMF and who had been regularly receiving appropriate colchicine treatment. without signs and symptoms of ear infection were enrolled the study. The diagnosis of FMF was made according to Tell-Hashomer criteria [4]. 39 healthy volunteers were enrolled the study as a control group. The study was approved by Institutional Ethics Board. Informed consent was obtained from parents. Exclusion criterias were to have another chronic illness besides FMF, during attack period, those who had developed amyloidosis, those who had outer and middle-ear related diseases, those with a history of exposure to high levels of noise, head trauma, usage of ototoxic drugs or had undergone ear surgery. Patients below 4 years of age were also excluded from the study due to their inability to cooperate with audiometry. Patients were grouped according to the severity of Familial Mediterranean Fever using the severity scoring system developed by Pras et al. [5]. Taking into consideration the starting time of the symptoms, frequency of attacks, colchicine doses, arthritis, the presence of erysipelas-like erythema and amyloidosis. The severity scores 3e5, 6e8 and 9 were evaluated as mild, moderate and severe scores of the disease, respectively. The study group were evaluated by a detailed ear, nose and throat (ENT) examination with audiologic evaluation including audiometry and Distortion product otoacoustic emission (DPOAE) tests separately for the right and the left ear. The tests were done once at attack free period. Madsen Orbiter 922-2 Clinical audiometry (Denmark) device was used for pure tone and speech audiometry. TDH-39 standard headphones were used for airway thresholds, speaking tests and radio ear B-71 vibrators were used for bone conduction thresholds. Airway thresholds were examined at 250, 500, 1000, 2000, 4000 and 8000 Hz. The pure tone average (PTA) air conduction thresholds were calculated separately for each ear. Conductive hearing loss patients were excluded from the study due to its effects on the OAE result. DPOAE test was performed in a soundproof room. A hand held Echocheck brand instrument, which uses ILO 88 system based recording, was used for testing. The instrument's probe portion which comprises of two speakers and a microphone was placed in the clean external ear canal. Then two stimuli were created in the cochlea at 60 dB and higher intensity resulting in two different progressive waves. The DPOAE (signal and SNR) results of the patients were recorded by measuring the overlapping parts of these waves in the cochlea. All of the patients' age, gender, age at onset of FMF, follow-up records, colchicine treatment period, genetic mutation analysis results, disease severity scores and hearing tests results (audiometry, DPOAE separately for the right and the left ear) were recorded. The data of averages of both ears were compared with control group. “Statistical Package for Social Sciences- SPSS 17” (Chicago, USA) program was used for the evaluation of results. Student's t-test was used for normally distributed quantitative variables whereas Mann-Whitney U test was used for numerical variables. Chi-square test was used for the comparison of categorical variables. Results were evaluated within the 95% confidence interval at p < 0.05 significance level, and reevaluated at p < 0.01 and p < 0.001 significance level.
Fifty patients (52% female, 48% male) with FMF and 39 healthy controls (58.9% female, 41.1% male) were enrolled the study. The mean age was 12.2 ± 4.1 years in patient group and 11.1 ± 3.4 years in control group. There were no significant differences between the patient and the control group in respect to age and gender distribution (p > 0.05). According to disease severity score developed by Pras et al.; 16% (n ¼ 8) patients were placed in the mild group, 72% (n ¼ 36) were placed in moderate group, and 12%(n ¼ 6) were placed in severe group. Patients had a median disease severity score of 7 [4e10]. The audiogram data were analyzed separately for the right and the left ear in both groups. The mean pure tone average (PTA) values of patient group were significantly higher than control group at 500, 4000 and 8000 Hz frequencies (p < 0.05) (Table 1). DPOAE and SNR values were evaluated at different frequencies in both groups. The signal values of FMF patients at 6 kHz and 8 kHz frequencies were significantly higher than control group (p < 0.05) (Table 1). SNR values were evaluated in the DPOAE test. The FMF patients had significantly lower SNR values than the control group at 1 and 1.4 kHz (p < 0.05). The SNR values of FMF patients were detected to be significantly higher than the control group at 8 kHz (p < 0.05). (Table 1). The patients' audiometry results were compared with the disease severity scores. Pure tone average was significantly higher in severe and moderate patient groups compared to the mild patient group at 2000 Hz frequency (p < 0.05) (Table 2). The patients' DPOAE test results at different frequencies were compared with the disease severity scores. There were statistically significant differences between the patient severity scores at 1.4 and 2.8 kHz frequency (p < 0.05) (Table 2). The patients' SNR ratio results at different frequencies were compared with the disease severity scores. There were no statistically significant differences between the SNR results and the patient severity scores (p > 0.05) (Table 2). All the patients were taking colchicine treatment. Durations were <5 years in 52% (n ¼ 26) and, 5 in 48% (n ¼ 24). The mean
Table 1 Comparison of the audiometry, DPOAE and SNR results between the patient and the control group. Tests PTA 250 500 1000 2000 4000 8000 DPOAE 1 khzsignal 1.4 khzsignal 2 khzsignal 2.8 khzsignal 4 khzsignal 6 khzsignal 8 khzsignal SNR 1 khzsnr 1.4 khzsnr 2 khzsnr 2.8 khzsnr 4 khzsnr 6 khzsnr 8 khzsnr
Patient group
Control group
P Value
12.5(10e15) 10(6.25e15) 10(5e15) 10(5e10) 10(5e15) 15(10e20)
10(5e15) 10(5e11,25) 10(5e15) 10(5e15) 10(5e10) 10(5e15)
0.097 0,008 0.799 0.749 0.009 0.001
6.5(-1.75e11.75) 7.35(3.8-15.175) 9.35(1.2-15.6) 7.8(0.25-12.35) 11.8(4.925e15.325) 12.65(4.45e15.75) 5.9(22.65e0.45)
6.75(-1.075-11.075) 12.35(4.05-16.85) 8.35(0.275-14,55) 5.95(1.75e10,125) 9.85(3.675e13.1) 6.45(-0.1e11.3) 21.65(-30e6275)
0.799 0.108 0.721 0.156 0.084 <0.001 <0.001
7.95(-2e15.725) 14.55(5.4e23.175) 17.05(8.95e23.6) 19,6(8125e24.875) 24.05(17.45e28.3) 23.75(16.4e29.55) 9,7(-8.725e15.975)
12.35(2875e20.825) 18.1(11.325e27.2) 16.75(9.6e25.6) 18.2(11.75e22.625) 22.25(17.3e27.125) 21.05(14,85e26.325) 4.05(-10.45e11.2)
0.011 0.020 0.618 0.616 0.312 0.063 0.022
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Table 2 Comparison of the patients' audiometry, DPOAE and SNR results with disease severity scores. FMF severity scores
PTA 250 500 1000 2000 4000 8000 DPOAE 1 khzsignal 1.4 khzsignal 2 khzsignal 2.8 khzsignal 4 khzsignal 6 khzsignal 8 khzsignal SNR 1 khzsnr 1.4 khzsnr 2 khzsnr 2.8 khzsnr 4 khzsnr 6 khzsnr 8 khzsnr a b c
Mild
Moderate
Severe
P value
10(5e15) 10(5e13.75) 10(5e15) 5(0e10) 5(0e13.75) 10(5e18.75)
10(10e15) 10(10e15) 10(10e10) 10(5e10) 10(6.25e15) 15(10e20)
15(10e18.75) 15(10e15) 10(5e15) 10(6.25e10) 10(5e15) 12.5(10e15)
0.700 0.313 0.998 0.015 0.087 0.126
4.05(-4.5e10.525) 6.15(-1.425e13.85) 9(4.225e15.125) 7.4(1.7e13.8) 12.5(2,45e17.175) 14(4.9e18.525) 8.9(-25.25e-1.725)
8,2(0.175e13.725) 8,05(4.625e16.425) 11.2(1.325e16.225) 9(1.1e12.7) 11.95(6.775e16.175) 12.4(4e15.75) 5.75(-21.175e0)
3,3(-3.625e6.425) 4.75(-5.4e8.8) 3.7(-0.625e8.85) 2.65(-11.05e5.325) 5.7(-1.95e14.8) 7.25(4.125e13.875) 5.3(-24.375e0.125)
0.113 0.046 0.071 0.015 0.269 0.382 0.559
4.85(-2.825e13.1) 9.85(1.8e18.975) 17.05(9.475e23.3) 15.75(10.625e23.55) 24.85(14.5e28.6) 27.45(17.15e30.775) 7.35(-8.725e13.075)
9.1(-1.85e16.8) 15.7(5.65e24.6) 18.55(8.725e25.35) 21.25(8.05e26.8) 24.4(17.875e28.725) 23.95(15.65e29.55) 9.75(-9.3e16.4)
6.7(-0.35e11.925) 11.05(-1.85e16.55) 12.4(5.425e20.125) 13.75(-1.15e18.225) 20.65(7.775e26.45) 20.25(11.475e27.675) 11.95(-10,95e14.375)
0.421 0.094 0.349 0.083 0.279 0.335 0.786
P1a
P2b
P3c
0.695
0.006
0.024
0.024
0.181
0.296
0.005
0.875
0.019
P1 (mild - severe). P2 (mild - moderate). P3 (mild - severe).
treatment duration was found to be 5.1 ± 3.7 years. The PTA values of patient group with 5 year treatment period were significantly higher at 250 and 500 Hz frequencies (p < 0.05) (Table 3). There were no significant differences when patients' DPOAE and SNR results were compared with the treatment periods (p > 0.05) (Table 3). 4. Discussion Familial Mediterranean Fever is observed at similar frequency in both males and females. In our study, male/female ratio was found Table 3 Comparison of the patients' audiometry, DPOAE and SNR results with treatment durations. Tests
PTA 250 Hz 500 Hz 1000 Hz 2000 Hz 4000 Hz 8000 Hz DPOAE 1 khz 1.4 khz 2 khz 2.8 khz 4 khz 6 khzl 8 khz 1 khz SNR 1.4 khz 2 khz 2.8 khz 4 khz 6 khz 8 khz
FMF course
p
<5 year
5 year
10(5e15)X 10(5e15) 10(5e10) 10(5e10) 10(5e15) 10(10e15)
15(10e20) 15(10e15) 10(10e15) 10(5e10) 10(5e15) 15(10e20)
0,008 0,034 0.160 0.695 0.951 0.171
7.2(1,05e11,525) 6.95(3.95e14.45) 5,9(1,2e15,6) 6.35(-3.475e12.775) 10.75(4.575e15.05) 13.25(3.275e15.2) 4.2(23.45e0.675) 6.85(2.225e17.65)
6(-2e11.75) 8.05(2.975e15.525) 9,85(1575e15,575) 8.35(1.325e11.7) 12.35(5.675e16.025) 12.4(5.25e16.075) 7.9(21.3e0.125) 8.05(1.6e15.425)
0.586 0.980 0.816 0.773 0.466 0.712 0.717 0.997
13.65(5.4e21.9) 17.45(6.6e23.6) 18.05(5.825e23.55) 23.95(15.95e27.3) 25.65(10.9e28.825) 11.7(8.325e16.775)
15.4(4.725e23.55) 16.65(9.55e24.225) 20(10.625e25.75) 24.5(17.625e28.725) 23.65(16.8e30,575) 8.7(9.975e15.325)
0.660 0.768 0.335 0.488 0.588 0.479
to be 1.08/1. The ratio is similar to the 2005 study conducted by Turkish FMF study group [8]. Additionally, our study has a similar ratio to the 1999 study carried out by Majeed et al. [9] in Arab society. Despite the differences in ethnic origins, FMF is observed at a similar frequency in both males and females. Cochlear function plays a particularly important role in the development of language skills in children. FMF, which is categorized in the systemic auto-inflammatory disease group is thought to affect the cochlea due to vasculitis and thrombophilia complications. In our study, pure tone averages of participants were studied with audiometric testing separately for the right and the left ear at different frequencies. FMF patients had significantly higher pure tone averages at 500, 4000 and 8000 Hz frequencies when compared with the control group. This data suggests that particularly at high frequencies the disease affects cochlear function. DPOAE signal values of FMF patients at 6 kHz and 8 kHz and the SNR values of FMF patients at 8 kHz were high. These results shows that the hearing function of FMF patients is unaffected. However, the audiometry test is more objective and it is considered to be more sensitive than the DPOAE test in demonstrating cochlear influences. It is thought that FMF patients may have cochlear involvement especially at high frequencies if audiometry test results are considered. There are few studies in literature which have evaluated the cochlear function in FMF patients at pediatric age. The study performed with 34 pediatric FMF patients was the first study on the pediatric age group [10]. In this study it has shown that FMF disease affects cochlear function as in our study. In 2011 Uysal et al. [11] examined the hearing function of 56 FMF patients between 5 and 17 years of age and 30 healthy individuals using only the TEOAE method but did not find a significant difference between the two groups. Similarly, in 2012 Polat et al. [12] did not find significant effects on cochlea in adult FMF patients with TEOAE and audiometry testing. In 2006 Hornigold et al. [13] published a case report in which they demonstrated an adult patient who developed amyloidosis also had bilateral hearing loss. Another hypothesis
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trying to explain the observed effects on cochlea emphasizes the development of hypercoagulability [14]. In this hypothesis, it is thought that increased fibrinogen levels during FMF episodes play a role in the coagulation cascade and affect the blood flow of the cochlea [15]. Recently, Keskindemirci et al. [7]. compared cochlear functions according to severity scores and no significant differences were shown between the groups and controls. In our study, the audiometry and DPOAE test results of mild, moderate and severe FMF patients, based on the disease severity scoring system developed by Pras et al. [5], were compared with each other. Pure tone averages of moderate and severe patients were found to be high in the right ear at 2000 Hz frequency. High pure tone average results especially at high frequencies suggested that as the clinical severity of the disease increases cochlear function deteriorates relatively. Yalçinkaya et al. [16] showed that early onset disease has a more severe course than late onset disease. In our study, comparison of the patients' audiometry results with treatment durations revealed significant increase at 250 and 500 Hz frequencies showing that a prolonged treatment periods increase the possibility of ear complications.
References [1] C. Fonnesu, C. Cerquaglia, M. Giovinale, et al., Familial Mediterranean Fever: a review for clinical management, Jt. Bone Spine 76 (2009) 227e233. € [2] E. Yılmaz, S. Ozen, B. Balcı, et al., Mutation frequency of familial mediterranean
[3]
[4] [5] [6] [7]
[8] [9] [10]
[11]
5. Conclusion Our study contributes to scientific literature with the evaluation of cochlear functions in respect to the severity scores of the disease and treatment durations. Our study shows that FMF affects cochlear function especially at higher frequencies and prolonged course of illness. Disclosure There is no financial disclosure. There is no conflict of interest.
[12] [13]
[14] [15] [16]
fever and evidence for high carrier rate in the Turkish population, Eur. J. Hum. Genet. 9 (2001) 553e555. € ı ve AmiE. Orün, F. Yalçınkaya, Türk Tıbbında Ailevi Akdeniz Ates¸i Hastalıg loidoz. Familial Mediterranean Fever and amyloidosis in Turkish medical literature, Turk. Neph. Dial. Transpl. 12 (2003) 1e7. A. Livneh, P. Langevitz, D. Zemer, et al., Criteria for the diagnosis of familial mediterranean fever, Arthritis-Rheumatism 40 (1997) 1879e1885. M. Pras, J. Gafhi, E. Jacop, et al., Recent advances in familial mediterranean fever, Adv. Nephrol. 13 (1984) 261e271. E. Ben-Chetrit, M. Levy, Familial mediterranean fever, Lancet 351 (1998) 659e664. lu-Karaaltın, et al., Cochlear functions in G. Keskindemirci, N.A. Ayaz, A. Batıog children with familial Mediterranean fever: any role of the severity of the disease? Int. J. Pediatr. Otorhinolaryngol. 79 (2015) 1566e1570. Turkish FMF Study Group, Familial mediterranean fever in Turkey. results of a nationwide multicenter study, Medicine 84 (2005) 1e11. H.A. Majeed, M. Rawashdeh, H. El-Shanti, et al., Familial Mediterranean Fever in children: the expanded clinical profile, Q. J. Med. 92 (1999) 309e318. S. Koybası, H.I. Atasoy, Y.O. Bicer, E. Tug, Cochlear involvement in familial mediterranean fever: a new feature of an old disease, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 244e247. I. Uysal, L. Gürbüzler, A. Kaya, et al., Evaluation of cochlear function using transient evoked otoacoustic emission in children with Familial Mediterranean Fever, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 379e381. _ Uysal, S. S¸enel, et al., Evaluation of hearing in patients with familal K. Polat, I. mediterranean fever, Eur. Arch. Otorhinolaryngol. 270 (2013) 2871e2874. R. Hornigold, A.V. Patel, V.M. Ward, A.F. O'Connor, Familial systemic amyloidosis associated with bilateral sensorineural hearing loss and bilateral facial palsies, J. Laryngol. Otol. 120 (2006) 778e780. O.E. Tayer-Shifman, E. Ben-Chetrit, Familial mediterranean fever and hypercoagulability, Mediterr. J. Hematol. Infect. Dis. 3 (2011) e2011017. A. Demirel, T. Celkan, O. Kasapcopur, et al., Is familial mediterranean fever a thrombotic disease or not? Eur. J. Pediatr. 167 (2008) 279e285. F. Yalçinkaya, Z.B. Ozcakar, M. Tanyıldız, A.H. Elhan, Familial mediterranean fever in small children in Turkey, Clin. Exp. Rheumatol. 29 (2011) 87e90.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: http://www.ijporlonline.com/
Evaluation of cochlear functions in children with Familial Mediterranean Fever Begüm Lordoglu a, Baran Acar b, Fatma Yazilitas c, Sare Gulfem Ozlu c, Saliha Senel a, d, * a
Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training Hospital, Ankara, Turkey Department of ENT, Kecioren Training and Research Hospital, Ankara, Turkey c Department of Pediatric Nephrology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training Hospital, Ankara, Turkey d Yildirim Beyazit University School of Medicine, Ankara, Turkey b
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 14 June 2016
Objectives: To evaluate cochlear functions in patients with Familial Mediterranean Fever in relation to the disease severity score and treatment duration. Methods: 50 patients (4e18 years) who had been followed-up with the diagnosis of FMF and regularly receiving appropriate colchicine treatment and 39 healthy controls were included in the study. All the patients and controls were evaluated by audiologic evaluation, including high-frequency pure-tone audiometry and distortion product otoacoustic emission tests (DPOAE). The disease severity was determined by scoring system developed by Pras et al. Results: Fifty patients (52% female, 48% male; mean age12.2 ± 4.1 years) and 39 controls (58.9% female, 41.1% male, mean age 11.1 ± 3.4 years) were enrolled the study. The pure tone average of FMF patients was significantly higher than that of the control group at 500, 4000, and 8000 Hz frequencies. The patients' DPOAE signal values at 6 kHz, 8 kHz frequencies and SNR values at 8 kHz were significantly higher than control group. The patients' audiometry and DPOAE results were compared with the disease severity scores. Pure tone average was significantly higher in severe and moderate patient groups compared to the mild patient group at 2000 Hz frequency. DPOAE signal values showed statistically significant differences between the patient severity scores at 1.4 and 2.8 kHz frequencies. The mean colchicine treatment duration was found to be 5.1 ± 3.7 years. There were significant differences at 250 and 500 Hz frequencies when patients' audiometry results were compared with the treatment periods. Conclusions: FMF affects cochlear functions particularly at high frequencies. © 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Familial Mediterranean Fever FMF Cochlear function Colchicine Severity score Children
1. Introduction Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent episodes, usually manifested with fever and pain due to peritoneal, pleural or synovial inflammation and/or skin rashes [1]. The incidence rate of the disease was reported to be 1/1075 in Turkey [2]. The disease is diagnosed according to the Tell-Hashomer criteria which were defined in 1967 [3,4]. Pras et al. developed severity scoring system which divides
* Corresponding author. Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Telsizler, 06080, Ankara, Turkey. E-mail addresses: [email protected] (B. Lordoglu), dremrah2000@ yahoo.com (B. Acar), [email protected] (F. Yazilitas), drsare_ozlu@yahoo. com (S.G. Ozlu), [email protected] (S. Senel). http://dx.doi.org/10.1016/j.ijporl.2016.06.015 0165-5876/© 2016 Elsevier Ireland Ltd. All rights reserved.
the disease into three groups; mild, moderate and severe, based on clinical findings [5]. Familial Mediterranean Fever is categorized within the systemic auto-inflammatory group of diseases [6]. This group has been described as causing visual and hearing impairment [7]. There are a limited number of studies about the effects of Familial Mediterranean Fever on auditory functions. The majority of these studies were conducted in adults. Familial Mediterranean Fever is thought to affect cochlear function due to increased inflammatory cytokines [7]. Loss of hearing adversely affects the development of language skills such as verbal communication and reading and as a result academic and professional success. This study aims to evaluate auditory function in children with FMF in relation to the disease severity score and the duration of treatment.
140
B. Lordoglu et al. / International Journal of Pediatric Otorhinolaryngology 87 (2016) 139e142
2. Materials and methods
3. Results
This study is a case control study performed in two medical centers; Pediatric Nephrology Department of Dr. Sami Ulus Obstetrics, Child Health and Diseases Training and Research Hospital and Ear Nose Throat Department of Kecioren Training and Research Hospital. A total of 50 patients between the ages of 4e18 years who had been followed-up with the diagnosis of FMF and who had been regularly receiving appropriate colchicine treatment. without signs and symptoms of ear infection were enrolled the study. The diagnosis of FMF was made according to Tell-Hashomer criteria [4]. 39 healthy volunteers were enrolled the study as a control group. The study was approved by Institutional Ethics Board. Informed consent was obtained from parents. Exclusion criterias were to have another chronic illness besides FMF, during attack period, those who had developed amyloidosis, those who had outer and middle-ear related diseases, those with a history of exposure to high levels of noise, head trauma, usage of ototoxic drugs or had undergone ear surgery. Patients below 4 years of age were also excluded from the study due to their inability to cooperate with audiometry. Patients were grouped according to the severity of Familial Mediterranean Fever using the severity scoring system developed by Pras et al. [5]. Taking into consideration the starting time of the symptoms, frequency of attacks, colchicine doses, arthritis, the presence of erysipelas-like erythema and amyloidosis. The severity scores 3e5, 6e8 and 9 were evaluated as mild, moderate and severe scores of the disease, respectively. The study group were evaluated by a detailed ear, nose and throat (ENT) examination with audiologic evaluation including audiometry and Distortion product otoacoustic emission (DPOAE) tests separately for the right and the left ear. The tests were done once at attack free period. Madsen Orbiter 922-2 Clinical audiometry (Denmark) device was used for pure tone and speech audiometry. TDH-39 standard headphones were used for airway thresholds, speaking tests and radio ear B-71 vibrators were used for bone conduction thresholds. Airway thresholds were examined at 250, 500, 1000, 2000, 4000 and 8000 Hz. The pure tone average (PTA) air conduction thresholds were calculated separately for each ear. Conductive hearing loss patients were excluded from the study due to its effects on the OAE result. DPOAE test was performed in a soundproof room. A hand held Echocheck brand instrument, which uses ILO 88 system based recording, was used for testing. The instrument's probe portion which comprises of two speakers and a microphone was placed in the clean external ear canal. Then two stimuli were created in the cochlea at 60 dB and higher intensity resulting in two different progressive waves. The DPOAE (signal and SNR) results of the patients were recorded by measuring the overlapping parts of these waves in the cochlea. All of the patients' age, gender, age at onset of FMF, follow-up records, colchicine treatment period, genetic mutation analysis results, disease severity scores and hearing tests results (audiometry, DPOAE separately for the right and the left ear) were recorded. The data of averages of both ears were compared with control group. “Statistical Package for Social Sciences- SPSS 17” (Chicago, USA) program was used for the evaluation of results. Student's t-test was used for normally distributed quantitative variables whereas Mann-Whitney U test was used for numerical variables. Chi-square test was used for the comparison of categorical variables. Results were evaluated within the 95% confidence interval at p < 0.05 significance level, and reevaluated at p < 0.01 and p < 0.001 significance level.
Fifty patients (52% female, 48% male) with FMF and 39 healthy controls (58.9% female, 41.1% male) were enrolled the study. The mean age was 12.2 ± 4.1 years in patient group and 11.1 ± 3.4 years in control group. There were no significant differences between the patient and the control group in respect to age and gender distribution (p > 0.05). According to disease severity score developed by Pras et al.; 16% (n ¼ 8) patients were placed in the mild group, 72% (n ¼ 36) were placed in moderate group, and 12%(n ¼ 6) were placed in severe group. Patients had a median disease severity score of 7 [4e10]. The audiogram data were analyzed separately for the right and the left ear in both groups. The mean pure tone average (PTA) values of patient group were significantly higher than control group at 500, 4000 and 8000 Hz frequencies (p < 0.05) (Table 1). DPOAE and SNR values were evaluated at different frequencies in both groups. The signal values of FMF patients at 6 kHz and 8 kHz frequencies were significantly higher than control group (p < 0.05) (Table 1). SNR values were evaluated in the DPOAE test. The FMF patients had significantly lower SNR values than the control group at 1 and 1.4 kHz (p < 0.05). The SNR values of FMF patients were detected to be significantly higher than the control group at 8 kHz (p < 0.05). (Table 1). The patients' audiometry results were compared with the disease severity scores. Pure tone average was significantly higher in severe and moderate patient groups compared to the mild patient group at 2000 Hz frequency (p < 0.05) (Table 2). The patients' DPOAE test results at different frequencies were compared with the disease severity scores. There were statistically significant differences between the patient severity scores at 1.4 and 2.8 kHz frequency (p < 0.05) (Table 2). The patients' SNR ratio results at different frequencies were compared with the disease severity scores. There were no statistically significant differences between the SNR results and the patient severity scores (p > 0.05) (Table 2). All the patients were taking colchicine treatment. Durations were <5 years in 52% (n ¼ 26) and, 5 in 48% (n ¼ 24). The mean
Table 1 Comparison of the audiometry, DPOAE and SNR results between the patient and the control group. Tests PTA 250 500 1000 2000 4000 8000 DPOAE 1 khzsignal 1.4 khzsignal 2 khzsignal 2.8 khzsignal 4 khzsignal 6 khzsignal 8 khzsignal SNR 1 khzsnr 1.4 khzsnr 2 khzsnr 2.8 khzsnr 4 khzsnr 6 khzsnr 8 khzsnr
Patient group
Control group
P Value
12.5(10e15) 10(6.25e15) 10(5e15) 10(5e10) 10(5e15) 15(10e20)
10(5e15) 10(5e11,25) 10(5e15) 10(5e15) 10(5e10) 10(5e15)
0.097 0,008 0.799 0.749 0.009 0.001
6.5(-1.75e11.75) 7.35(3.8-15.175) 9.35(1.2-15.6) 7.8(0.25-12.35) 11.8(4.925e15.325) 12.65(4.45e15.75) 5.9(22.65e0.45)
6.75(-1.075-11.075) 12.35(4.05-16.85) 8.35(0.275-14,55) 5.95(1.75e10,125) 9.85(3.675e13.1) 6.45(-0.1e11.3) 21.65(-30e6275)
0.799 0.108 0.721 0.156 0.084 <0.001 <0.001
7.95(-2e15.725) 14.55(5.4e23.175) 17.05(8.95e23.6) 19,6(8125e24.875) 24.05(17.45e28.3) 23.75(16.4e29.55) 9,7(-8.725e15.975)
12.35(2875e20.825) 18.1(11.325e27.2) 16.75(9.6e25.6) 18.2(11.75e22.625) 22.25(17.3e27.125) 21.05(14,85e26.325) 4.05(-10.45e11.2)
0.011 0.020 0.618 0.616 0.312 0.063 0.022
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Table 2 Comparison of the patients' audiometry, DPOAE and SNR results with disease severity scores. FMF severity scores
PTA 250 500 1000 2000 4000 8000 DPOAE 1 khzsignal 1.4 khzsignal 2 khzsignal 2.8 khzsignal 4 khzsignal 6 khzsignal 8 khzsignal SNR 1 khzsnr 1.4 khzsnr 2 khzsnr 2.8 khzsnr 4 khzsnr 6 khzsnr 8 khzsnr a b c
Mild
Moderate
Severe
P value
10(5e15) 10(5e13.75) 10(5e15) 5(0e10) 5(0e13.75) 10(5e18.75)
10(10e15) 10(10e15) 10(10e10) 10(5e10) 10(6.25e15) 15(10e20)
15(10e18.75) 15(10e15) 10(5e15) 10(6.25e10) 10(5e15) 12.5(10e15)
0.700 0.313 0.998 0.015 0.087 0.126
4.05(-4.5e10.525) 6.15(-1.425e13.85) 9(4.225e15.125) 7.4(1.7e13.8) 12.5(2,45e17.175) 14(4.9e18.525) 8.9(-25.25e-1.725)
8,2(0.175e13.725) 8,05(4.625e16.425) 11.2(1.325e16.225) 9(1.1e12.7) 11.95(6.775e16.175) 12.4(4e15.75) 5.75(-21.175e0)
3,3(-3.625e6.425) 4.75(-5.4e8.8) 3.7(-0.625e8.85) 2.65(-11.05e5.325) 5.7(-1.95e14.8) 7.25(4.125e13.875) 5.3(-24.375e0.125)
0.113 0.046 0.071 0.015 0.269 0.382 0.559
4.85(-2.825e13.1) 9.85(1.8e18.975) 17.05(9.475e23.3) 15.75(10.625e23.55) 24.85(14.5e28.6) 27.45(17.15e30.775) 7.35(-8.725e13.075)
9.1(-1.85e16.8) 15.7(5.65e24.6) 18.55(8.725e25.35) 21.25(8.05e26.8) 24.4(17.875e28.725) 23.95(15.65e29.55) 9.75(-9.3e16.4)
6.7(-0.35e11.925) 11.05(-1.85e16.55) 12.4(5.425e20.125) 13.75(-1.15e18.225) 20.65(7.775e26.45) 20.25(11.475e27.675) 11.95(-10,95e14.375)
0.421 0.094 0.349 0.083 0.279 0.335 0.786
P1a
P2b
P3c
0.695
0.006
0.024
0.024
0.181
0.296
0.005
0.875
0.019
P1 (mild - severe). P2 (mild - moderate). P3 (mild - severe).
treatment duration was found to be 5.1 ± 3.7 years. The PTA values of patient group with 5 year treatment period were significantly higher at 250 and 500 Hz frequencies (p < 0.05) (Table 3). There were no significant differences when patients' DPOAE and SNR results were compared with the treatment periods (p > 0.05) (Table 3). 4. Discussion Familial Mediterranean Fever is observed at similar frequency in both males and females. In our study, male/female ratio was found Table 3 Comparison of the patients' audiometry, DPOAE and SNR results with treatment durations. Tests
PTA 250 Hz 500 Hz 1000 Hz 2000 Hz 4000 Hz 8000 Hz DPOAE 1 khz 1.4 khz 2 khz 2.8 khz 4 khz 6 khzl 8 khz 1 khz SNR 1.4 khz 2 khz 2.8 khz 4 khz 6 khz 8 khz
FMF course
p
<5 year
5 year
10(5e15)X 10(5e15) 10(5e10) 10(5e10) 10(5e15) 10(10e15)
15(10e20) 15(10e15) 10(10e15) 10(5e10) 10(5e15) 15(10e20)
0,008 0,034 0.160 0.695 0.951 0.171
7.2(1,05e11,525) 6.95(3.95e14.45) 5,9(1,2e15,6) 6.35(-3.475e12.775) 10.75(4.575e15.05) 13.25(3.275e15.2) 4.2(23.45e0.675) 6.85(2.225e17.65)
6(-2e11.75) 8.05(2.975e15.525) 9,85(1575e15,575) 8.35(1.325e11.7) 12.35(5.675e16.025) 12.4(5.25e16.075) 7.9(21.3e0.125) 8.05(1.6e15.425)
0.586 0.980 0.816 0.773 0.466 0.712 0.717 0.997
13.65(5.4e21.9) 17.45(6.6e23.6) 18.05(5.825e23.55) 23.95(15.95e27.3) 25.65(10.9e28.825) 11.7(8.325e16.775)
15.4(4.725e23.55) 16.65(9.55e24.225) 20(10.625e25.75) 24.5(17.625e28.725) 23.65(16.8e30,575) 8.7(9.975e15.325)
0.660 0.768 0.335 0.488 0.588 0.479
to be 1.08/1. The ratio is similar to the 2005 study conducted by Turkish FMF study group [8]. Additionally, our study has a similar ratio to the 1999 study carried out by Majeed et al. [9] in Arab society. Despite the differences in ethnic origins, FMF is observed at a similar frequency in both males and females. Cochlear function plays a particularly important role in the development of language skills in children. FMF, which is categorized in the systemic auto-inflammatory disease group is thought to affect the cochlea due to vasculitis and thrombophilia complications. In our study, pure tone averages of participants were studied with audiometric testing separately for the right and the left ear at different frequencies. FMF patients had significantly higher pure tone averages at 500, 4000 and 8000 Hz frequencies when compared with the control group. This data suggests that particularly at high frequencies the disease affects cochlear function. DPOAE signal values of FMF patients at 6 kHz and 8 kHz and the SNR values of FMF patients at 8 kHz were high. These results shows that the hearing function of FMF patients is unaffected. However, the audiometry test is more objective and it is considered to be more sensitive than the DPOAE test in demonstrating cochlear influences. It is thought that FMF patients may have cochlear involvement especially at high frequencies if audiometry test results are considered. There are few studies in literature which have evaluated the cochlear function in FMF patients at pediatric age. The study performed with 34 pediatric FMF patients was the first study on the pediatric age group [10]. In this study it has shown that FMF disease affects cochlear function as in our study. In 2011 Uysal et al. [11] examined the hearing function of 56 FMF patients between 5 and 17 years of age and 30 healthy individuals using only the TEOAE method but did not find a significant difference between the two groups. Similarly, in 2012 Polat et al. [12] did not find significant effects on cochlea in adult FMF patients with TEOAE and audiometry testing. In 2006 Hornigold et al. [13] published a case report in which they demonstrated an adult patient who developed amyloidosis also had bilateral hearing loss. Another hypothesis
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trying to explain the observed effects on cochlea emphasizes the development of hypercoagulability [14]. In this hypothesis, it is thought that increased fibrinogen levels during FMF episodes play a role in the coagulation cascade and affect the blood flow of the cochlea [15]. Recently, Keskindemirci et al. [7]. compared cochlear functions according to severity scores and no significant differences were shown between the groups and controls. In our study, the audiometry and DPOAE test results of mild, moderate and severe FMF patients, based on the disease severity scoring system developed by Pras et al. [5], were compared with each other. Pure tone averages of moderate and severe patients were found to be high in the right ear at 2000 Hz frequency. High pure tone average results especially at high frequencies suggested that as the clinical severity of the disease increases cochlear function deteriorates relatively. Yalçinkaya et al. [16] showed that early onset disease has a more severe course than late onset disease. In our study, comparison of the patients' audiometry results with treatment durations revealed significant increase at 250 and 500 Hz frequencies showing that a prolonged treatment periods increase the possibility of ear complications.
References [1] C. Fonnesu, C. Cerquaglia, M. Giovinale, et al., Familial Mediterranean Fever: a review for clinical management, Jt. Bone Spine 76 (2009) 227e233. € [2] E. Yılmaz, S. Ozen, B. Balcı, et al., Mutation frequency of familial mediterranean
[3]
[4] [5] [6] [7]
[8] [9] [10]
[11]
5. Conclusion Our study contributes to scientific literature with the evaluation of cochlear functions in respect to the severity scores of the disease and treatment durations. Our study shows that FMF affects cochlear function especially at higher frequencies and prolonged course of illness. Disclosure There is no financial disclosure. There is no conflict of interest.
[12] [13]
[14] [15] [16]
fever and evidence for high carrier rate in the Turkish population, Eur. J. Hum. Genet. 9 (2001) 553e555. € ı ve AmiE. Orün, F. Yalçınkaya, Türk Tıbbında Ailevi Akdeniz Ates¸i Hastalıg loidoz. Familial Mediterranean Fever and amyloidosis in Turkish medical literature, Turk. Neph. Dial. Transpl. 12 (2003) 1e7. A. Livneh, P. Langevitz, D. Zemer, et al., Criteria for the diagnosis of familial mediterranean fever, Arthritis-Rheumatism 40 (1997) 1879e1885. M. Pras, J. Gafhi, E. Jacop, et al., Recent advances in familial mediterranean fever, Adv. Nephrol. 13 (1984) 261e271. E. Ben-Chetrit, M. Levy, Familial mediterranean fever, Lancet 351 (1998) 659e664. lu-Karaaltın, et al., Cochlear functions in G. Keskindemirci, N.A. Ayaz, A. Batıog children with familial Mediterranean fever: any role of the severity of the disease? Int. J. Pediatr. Otorhinolaryngol. 79 (2015) 1566e1570. Turkish FMF Study Group, Familial mediterranean fever in Turkey. results of a nationwide multicenter study, Medicine 84 (2005) 1e11. H.A. Majeed, M. Rawashdeh, H. El-Shanti, et al., Familial Mediterranean Fever in children: the expanded clinical profile, Q. J. Med. 92 (1999) 309e318. S. Koybası, H.I. Atasoy, Y.O. Bicer, E. Tug, Cochlear involvement in familial mediterranean fever: a new feature of an old disease, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 244e247. I. Uysal, L. Gürbüzler, A. Kaya, et al., Evaluation of cochlear function using transient evoked otoacoustic emission in children with Familial Mediterranean Fever, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 379e381. _ Uysal, S. S¸enel, et al., Evaluation of hearing in patients with familal K. Polat, I. mediterranean fever, Eur. Arch. Otorhinolaryngol. 270 (2013) 2871e2874. R. Hornigold, A.V. Patel, V.M. Ward, A.F. O'Connor, Familial systemic amyloidosis associated with bilateral sensorineural hearing loss and bilateral facial palsies, J. Laryngol. Otol. 120 (2006) 778e780. O.E. Tayer-Shifman, E. Ben-Chetrit, Familial mediterranean fever and hypercoagulability, Mediterr. J. Hematol. Infect. Dis. 3 (2011) e2011017. A. Demirel, T. Celkan, O. Kasapcopur, et al., Is familial mediterranean fever a thrombotic disease or not? Eur. J. Pediatr. 167 (2008) 279e285. F. Yalçinkaya, Z.B. Ozcakar, M. Tanyıldız, A.H. Elhan, Familial mediterranean fever in small children in Turkey, Clin. Exp. Rheumatol. 29 (2011) 87e90.