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Study of audiovestibular dysfunction in children with systemic lupus erythematosus
International Journal of Pediatric Otorhinolaryngology 77 (2013) 1561–1566
Contents lists available at SciVerse ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Study of audiovestibular dysfunction in children with systemic lupus erythematosus Ghada Ibrahim Gad a,*, Somaia Tawfik Mohamed b, Khaled Salah Awwad a, Rehab Fetoh Mohamed c a b c
Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt ENT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Pediatrics Hospital, Ain Shams University, Egypt
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 April 2013 Received in revised form 2 July 2013 Accepted 3 July 2013 Available online 2 August 2013
Objective: Inner ear dysfunction in systemic lupus erythematosis patients has been reported but audiovestibular involvement is not well documented especially in pediatrics. This study was designed to evaluate silent audiovestibular dysfunction among SLE children. Methods: Case control study examined in allergy and immunology clinic; pediatrics hospital and audiovestibular clinic; Ain Shams University from January 2009 to December 2010. Thirty-five systemic lupus erythematosus children (diagnosed according to American College of Rheumatology); age group 8–16 years, were randomly selected. Five of them were excluded due to one or more exclusion criteria (previous otitis media, stroke, lupus cerebritis, meningitis or encephalitis, audiovestibular symptom). Ten of them refused enrollment or could not complete full battery. Seventeen females and three males, mean age 12.9 2.6 years, completed the study. Control group included 20 normal subjects, age and sex matched. Full clinical assessment, basic audiological evaluation and vestibular testing (videonystagmography VNG and computerized dynamic posturography CDP) were conducted for children included in the study. Results: Five systemic lupus erythematosus patients had sensorineural hearing loss strongly associated with +ve antiphospholipid antibody and two had conductive hearing loss. Two children in control group had conductive hearing loss (p = 0.05). Abnormal VNG findings was significantly higher among systemic lupus erythematosus children (40%) compared to controls (0%) and associated with +ve antiphospholipid antibodies (x2 = 10, p = 0.002, Fisher exact test = 0.003). Twenty-five percentage of systemic lupus erythematosus children had abnormal CDP findings reflecting impaired balance function associated with positive antiphospholipid antibodies showing significant statistical difference compared to controls (0% affection) (x2 = 5.7, p = 0.017, Fisher exact test = 0.047). Conclusion: Silent audiovestibular dysfunction is prevalent among systemic lupus erythematosus children especially those positive for antiphospholipid antibodies necessitating routine regular evaluation. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Systemic lupus erythematosus Audiovestibular Antiphospholipid antibody
1. Introduction Systemic lupus erythematosus (SLE) is increasingly recognized in pediatrics population. Immune complexes and autoantibodies are the main causes of multiorgan involvement characteristic of the disease. Sensorineural hearing loss (SNHL) and inner ear dysfunction in SLE patients were first identified by Kastanioudakis et al. [1] and Sperling et al. [2]. Inner ear damage in SLE patients has been occasionally reported but frequency and extent of audio-
* Corresponding author at: Department of Pediatrics, Ain Shams University, Ramses Street, Cairo 11566, Egypt. Tel.: +20 1145746064. E-mail address: [email protected] (G.I. Gad). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.07.004
vestibular involvement are not well documented especially in pediatrics. Previous studies were conducted for audiovestibular function in adults with SLE [2,3]. They were conducted using basic audiological evaluation and electronystagmography (ENG). However, evaluation of audiovestibular function in pediatric patients with SLE was not thoroughly investigated. In addition, functional evaluation of balance was not previously investigated. This can be conducted by computerized dynamic posturography which is the only method validated by controlled research studies to isolate the functional contributions of vestibular inputs, visual inputs, somatosensory inputs, central integrating mechanisms, and neuromuscular system outputs for postural and balance control [4].
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Accordingly, this study was designed to assess audiovestibular functions as a part of systemic autoimmune disorder in children with SLE. 2. Methods The present study was carried out in allergy and immunology clinic in pediatrics hospital and audiovestibular clinic, Ain Shams University. The study was a case–control one, 35 SLE patients (diagnosed clinically and laboratory according to American College of Rheumatology [5]) in the age group 8–16 years were randomly selected and approached (simple randomization). Five of them were excluded due to one or more of exclusion criteria, and 10 refused enrollment or could not complete the full battery. A control group consisting of 20 healthy children age and sex matched with the study group were recruited over a period of 24 months from January 2009 to December 2010. Patients with history of otitis media with effusion, chronic suppurative otitis media (CSOM), previously diagnosed as having stroke or lupus cerebritis, meningitis or encephalitis, any audiovestibular complaint (tinnitus, hearing problem, vertigo, etc.) were excluded from the study. The study was approved by the ethical committee of Pediatrics Hospital, Ain Shams University. An informed consent was taken from parents of all children before enrollment in the study. The study & control groups were subjected to the following: (1) Full history taking, thorough clinical examination with special emphasis on duration of illness, type of medications and SLE disease activity index (SLEDAI) score. (2) Record of SLE investigations (already registered in the file) - Stranded deoxyribonucleic acid antibody. - Antinuclear antibody. - Antiphospholipid antibodies. (3) Otological examination: - Audiological evaluation: Pure tone audiometry by air conduction and bone conduction and speech audiometry were done using two Channel Audiometer Madsen model Orbiter 922. - Immittancemetry to assess middle ear function using interacoustic Imittancemeter model AZ7. (4) Vestibular evaluation: I Videonystagmography (VNG) Test battery: Using computerized VNG Micromedical, Meta 4, with a light bar designed to ensure a large visual field at both horizontal and vertical planes. Water caloric irrigator model, Hortman was used to do caloric testing. The test was done as follows: The patient sat on the test chair 1 m away from the center of the light bar with infrared goggles on his eyes and then started the VNG subtests to measure. 1. Spontaneous/gaze nystagmus. 2. Oculomotor tests: including random Saccade test, tracking test and optokinetic test. 3. Positional and positioning testing. 4. Bithermal Caloric testing. II Computerized dynamic posturography (CDP): During CDP testing, the patient stands on a movable, dual forceplate support surface within a moveable surround (enclosure). Under control of a computer, the force platform can either move in a horizontal plane (translate), or rotate out of the horizontal plane [6]. Standardized test protocols expose the patient to support surface and visual surround motions, during which the patient’s postural stability and motor reactions are recorded. These test protocols include: (Fig. 1)
1. Sensory organization test (SOT): testing for six challenging conditions. 2. Motor control test (MCT): testing for forward and backward movements. 3. Adaptation test (ADT): testing for toes up and toes down movements.
During the SOT, the utility of visual, vestibular, and proprioceptive inputs in controlling spontaneous sway is eliminated without provoking motor reactions by moving the support surface and the visual enclosure in response to the patient’s postural movements. During the motor control protocols (MCT and ADT), reactions are provoked by unexpected abrupt movements of the support surface. Because the measures of postural stability, as well as the motions of the support surface and visual surround, are precisely controlled and calibrated relative to the patient’s height and weight, standardized graphical summaries can compare the patient’s results to those of age-matched asymptomatic (normal) individuals. 2.1. Statistical analysis Standard computer program SPSS for Windows, release 13.0 (SPSS Inc., USA) was used for data entry and analysis. All numeric variables were expressed as mean standard deviation (SD). Comparison of different variables in various groups was done using Mann Whitney test for nonparametric variables. Chi-square (x2) test was used to compare frequency of qualitative variables among the different groups with Fisher exact test if indicated. Spearman’s correlation test was used for correlating non-parametric variables. For all tests a probability (p) less than 0.05 was considered significant. 3. Results Demographic characteristics of studied children are shown in Table 1. Pure tone audiometry revealed that 5 cases (25%) suffered from moderate sensorineural hearing loss (SNHL) and 2 (10%) with mild conductive hearing loss (CHL) among SLE patients. Control group showed normal hearing in all children except 2 cases with mild CHL (Table 2). All subjects had speech reception threshold matched with pure tone average with excellent speech discrimination scores proportionate to degree of hearing loss. They showed type A tympanograms reflecting normal middle ear function except 2 patients with conductive hearing loss who showed type B flat reflecting middle ear effusion. Non-significant statistical association was detected between either sex (x2 = 1.9, p = 0.168) or type of medications whether steroids alone or with cytotoxic drugs (x2 = 0.64, p = 0.42) and hearing loss among SLE patients. SLEDAI score (active or inactive) showed non-significant association with SNHL (x2 = 1.1, p = 0.29). All SLE patients with +ve antiphospholipid antibodies had SNHL (100%). Vestibular test results revealed abnormal video nystagmography in 40% of SLE children compared to controls (0%) with peripheral affection (involving end organ in labyrinth and peripheral nerve) in 1 (5%) patient and central affection (starting at relay station between vestibular nerve and vestibular nuclei in brain stem) in 3 (15%) patients, and combined in 4 (20%) patients. Regarding VNG subset results, 7 (35%) patients had abnormal oculomotor subset (4 of them had abnormal saccade, 6 abnormal tracking), 2 (10%) had abnormal positional subset and 3 (15%) had abnormal caloric subtest. Active SLEDAI was significantly associated with abnormal peripheral vestibular testing (x2 = 4.444; p = 0.035), but not with central one (x2 = 2.96; p = 0.085).
G.I. Gad et al. / International Journal of Pediatric Otorhinolaryngology 77 (2013) 1561–1566
Fig. 1. Computerized dynamic posturography tests.
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Table 1 Demographic characteristics of studied children.
Table 2 Comparison between cases and controls as regards audiovestibular functions. Z/x2
Study group
Control
n = 20
N = 20
Mean SD/ n (%)
Mean SD/ n (%)
Age in years
12.90 2.673
12.85 2.368
Sex Male Female Duration of disease in years
3 (15%) 17 (85%) 4.40 1.875
3 (15%) 17 (85%)
SLEDAI Active (6) Inactive (<6)
9.15 6.968 12 (60%) 8 (40%)
Drugs Steroid Steroids + cytotoxics
11 (55%) 9 (45%)
APL Positive Negative
0.150 0.000
p-Value
0.881
1.00
Study group
Control group
n (%)
n (%)
Normal hearing SNHL CHL
13 (65.0%) 5 (25.0%) 2 (10.0%)
18 (90.0%) 0 (0.0%) 2 (10.0%)
VNG Normal Abnormal
12 (60%) 8 (40%)
20 (100%) 0 (0%)
CDP Normal Abnormal
15 (75%) 5 (25%)
20 (100%) 0 (0%)
x2 5.806
10
5.7
p
0.055
0.002*
0.017y
SNHL, sensorineural hearing loss; CHL, conductive hearing loss; VNG, videonystagmography; CDP, computerized dynamic posturography. * Fisher exact test: 0.003. y Fisher exact test: 0.047.
5 (25%) 15 (75%)
SLEDAI, systemic lupus erythematosus disease activity index; APL, antiphospholipid antibodies.
Similarly, SLE patients receiving steroids and cytotoxic drugs showed highly significant association with peripheral vestibular affection (x2 = 8.148; p = 0.004) and not with central one (x2 = 3.03; p = 0.08). Another significant statistical association was detected between positive antiphospholipid antibodies and abnormal VNG test (x2 = 4.44; p = 0.035; 4 out of 5 SLE patients with +ve antiphospholipid antibodies had abnormal VNG). Five (25%) SLE children revealed abnormal computerized dynamic posturography (CDP) with significant difference compared to controls (0% affection) (x2 = 5.7; p = 0.017, Fisher exact test = 0.047). Significant statistical association between abnormal CDP and positive antiphospholipid antibodies was reported (x2 = 4.36; p = 0.037; 3 out of 5 positive antiphospholipid antibodies had abnormal CDP).
Audiovestibular evaluation and antiphospholipid profile of the studied SLE patients is shown in Table 3. Regarding sensory organization test (SOT), SLE patients had significantly lower values in C5 and C6 compared to control group (Table 4). There was abnormality in conditions C4, C5 and C6 among 15% of SLE patients reflecting visual/vestibular pattern of dysfunctions, while 10% had abnormality in conditions C5 and C6 reflecting vestibular pattern of dysfunction. Non-significant statistical difference was detected between studied patients taking steroids only and those taking steroids and cytotoxics as regards SOT. SLE patients showed non-significant difference compared to controls as regards latency in motor control tests (MCT) (Table 5), whereas all amplitude measures were significantly lower among patients (Table 6). On the other hand, adaptation test was significantly higher among cases in toes down position (z = 0.748; p = 0.006). Significant positive correlation was detected between large backward (LB) movement amplitude in MCT and both duration of SLE (r = 0.238; p = 0.023) and SLEDAI score (r = 0.166; p = 0.011). In addition, disease duration showed significant positive correlation with large forward (LF) movement amplitude in MCT (r = 0.174; p = 0.042).
Table 3 Audiologic, vestibular and antiphospholipid profile of studied SLE patients. Case number
Duration Of SLE (years)
SLEDAI
Audiologic assessment
VNG
CDP
Antiphospholipid antibodies
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
4 2 5 2 4 5 4 2 2 6 4 4 6 3 7 4 3 8 8 5
4 0 14 8 3 10 8 0 2 18 4 18 20 5 15 6 4 24 11 9
Normal CHL Normal Normal SNHL SNHL Normal Normal Normal SNHL Normal SNHL Normal Normal SNHL Normal CHL Normal Normal Normal
Normal Normal Normal Normal Abnormal Abnormal Normal Normal Normal Abnormal Normal Abnormal Abnormal Normal Normal Abnormal Normal Abnormal Abnormal Normal
Normal Normal Normal Abnormal Abnormal Abnormal Normal Normal Normal Abnormal Normal Normal Normal Normal Normal Abnormal Normal Normal Normal Normal
Negative Negative Negative Negative Positive Positive Negative Negative Negative Positive Negative Positive Negative Negative Positive Negative Negative Negative Negative Negative
(active) (active) (active) (active)
(active) (active) (active) (active) (active) (active) (active) (active)
(central) (peripheral)
(central) (combined) (combined)
(central) (combined) (combined)
CDP: computerized dynamic posturography; VNG: videonystagmography; Central vestibular affection: begins at relay station between vestibular nerve and nuclei in brain stem; Peripheral vestibular affection: at end organ in labrynth and peripheral nerve; Combined: central and peripheral vestibular affection; SLEDAI: systemic lupus erythematosus disease activity index; SNHL: sensorineural hearing loss; Stero: steroids; CHL: conductive hearing loss.
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Table 4 Comparison between studied patients and control group as regards SOT. Study group
Control
C1 C2 C3 C4 C5 C6 Composite score
Mean
SD
95% Cl
91.10 89.75 87.90 84.90 82.30 81.35 84.40
6.299 6.121 6.585 8.097 11.112 10.996 6.855
88.15 86.89 84.82 80.11 75.10 70.23 81.19
94.05 92.61 90.98 88.69 87.50 86.47 87.61
Mean
SD
95% Cl
90.35 89.70 87.70 81.0 71.40 64.75 78.25
4.234 4.092 6.165 8.790 16.139 18.615 10.867
88.37 87.78 84.81 76.89 63.85 56.04 73.16
92.33 91.62 90.59 85.11 78.95 73.40 83.34
z-Value
p-Value
1.324 0.547 0.014 1.524 2.330 2.978 1.620
0.185 0.585 0.989 0.128 0.020 0.003 0.105
C1 means condition 1. Bold font indicates statistical significance.
4. Discussion The frequency of asymptomatic hearing defect in this study was 35% of SLE children, among which 10% had conductive hearing loss due to middle ear effusion and 25% had sensorineural hearing loss, while only 10% of the control group had conductive hearing loss. Previous studies involving adult SLE patients showed (70%) frequency of asymptomatic impaired hearing; (66%) with sensorineural and (4%) with conductive alterations while (16%) in the control group had alterations of audiometric tests: (12%) conductive and (4%) asymptomatic SNHL [7]. Sensorineural hearing loss was found in (21%) of a population of SLE patients among which (67%) reported audiovestibular symptoms [3]. Adult SLE patients with (17.1%) frequency of symptomatic hearing loss revealed (28.6%) symmetric SNHL affection [8]. Auditory symptoms were present in (55.5%) of adult SLE patients, with a diagnosis of SNHL in (15.6%) of them [9]. The pathogenesis of SNHL in SLE remains obscure. However, the strong association of SNHL in SLE patients with +ve antiphospholipid antibodies might postulate that micro infarctions of the capillaries or arterioles, and thrombosis affecting blood supply to the inner ear may be the cause of SNHL and not only vasculitis. Previous reports documented such association [10–12], while others did not [7,9]. Antiphospholipid antibodies are found in approximately 24% as lupus anticoagulant and 27% as anticardiolipin antibodies in children with SLE [13] and an association with sudden SNHL has been reported although a direct causal relationship remains unconfirmed and definite pathogenesis still obscure [10,11]. Hishashi et al. [14] were the first to report association between profound SNHL in patients with autoimmune diseases and antiphospholipid antibodies. The cochlea, vestibule, semicircular canals and vestibular aqueduct were filled with dense fibrous tissue and new bone formation among SLE patient [15]. Audiological findings in our patients showed non-significant association with type of medication or SLEDAI score, in agreement with previous reports [1,7,9]. Several reports showed that many audiovestibular pathologies in the pediatrics population may be immune-mediated. This might
be of more significance in cases of coexisting systemic autoimmune disorder. The present study showed that 8 patients (40%) had abnormal videonystagmography results, 3 of them (15%) had only central vestibular lesion, 1 patient (5%) had only peripheral vestibular lesion while the majority (4) (20%) had combined central and peripheral lesions. This reflects that central vestibular dysfunction was more frequent than peripheral affection in children with SLE which might be due to vasculitis affecting central vestibular pathways. We found only one report in the literature investigating vestibular function in adult SLE patients using electronystagmography and revealed significantly more frequent abnormal results in SLE group (50%) compared with the control group (7.14%) (p < 0.01), SLE group had significantly more peripheral type vestibular pathology compared with the control group (p < 0.05) [3]. Lower frequency of vestibular dysfunction in the present study might be due to difference in the sample of the studied group. The present study was conducted on pediatric patients with no history of audiovestibular symptoms while over 70% of adults studied by Karatas et al. [3] reported vertigo and dizziness. In our SLE patients we found significant association between active SLEDAI and use of steroids and cytotoxic drugs with peripheral vestibular system affection. To the best of our knowledge, no previous studies investigated the balance function in SLE patients using dynamic posturography (CDP). In the present study 5 patients (25%) of the studied SLE cases had abnormal CDP results. Sensory organization test (SOT) was performed and (15%) of patients had reduced scores in conditions (C4, C5 and C6) reflecting inability to use visual and vestibular cues to maintain balance and postural control. In addition, 10% had reduced scores in condition (C5 and C6) indicating inability to use vestibular information for balance control. Motor control tests (MCT) done for further analysis showed significant difference between cases and controls in amplitude measures and adaptation test (toes down) whereas latency did not differ significantly. This reflects SLE patients cannot use central integrating mechanisms, and neuromuscular system outputs for postural and balance control.
Table 5 Comparison between studied patients and control group as regards (latency) in MCT. Study group
SB MB LB SF MF LF
Control group
Mean
SD
95% Cl
132.25 124.75 120.25 133.50 134.25 128.75
19.566 12.511 9.244 15.483 18.516 23.835
123.09 118.89 115.92 126.25 125.58 117.60
141.41 130.61 124.58 140.75 142.92 139.90
Mean
SD
95% Cl
122.25 120.75 122.00 125.50 130.75 123.75
7.860 7.993 8.944 9.583 11.616 8.565
118.57 117.01 117.81 121.50 125.31 119.74
125.93 124.49 126.19 129.99 136.19 127.76
z-Value
p-Value
1.636 0.735 0.496 1.698 0.547 0.165
0.102 0.462 0.620 0.090 0.565 0.869
MCT, motor control test; SB, small backward; SF, small forward; MB, medium backward; MF, medium forward; LB, large backward; LF, large forward.
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Table 6 Comparison between studied patients and control group as regards (amplitude) in MCT. Study group
SB MB LB SF MF LF
Control group
Mean
SD
95% Cl
0.48 1.70 2.60 0.58 2.150 2.33
0.389 1.005 1.603 0.654 1.606 1.830
0.30 1.23 1.85 0.27 1.398 1.47
0.65 2.17 3.35 0.88 2.902 3.18
Mean
SD
95% Cl
0.83 2.40 3.18 0.88 2.225 2.88
0.295 0.503 0.406 0.275 0.525 0.626
0.71 2.16 8.98 0.75 1.979 2.58
0.94 2.64 3.37 1.00 2.471 3.17
z-Value
p-Value
2.977 3.083 1.908 2.277 1.361 2.762
0.003 0.002 0.056 0.023 0.174 0.007
MCT, motor control test; SB, small backward; SF, small forward; MB, medium backward; MF, medium forward; LB, large backward; LF, large forward.
The present study proved statistically significant association between antiphospholipid antibodies and impaired vestibular test results (VNG and CDP tests). However, clinical significance of these results should be interpreted cautiously due to small sample size. In conclusion, silent audiovestibular dysfunction is prevalent in a significant proportion of SLE children especially those positive for antiphospholipid antibodies. It is recommended to regularly evaluate audiovestibular function among these children aiming at early detection and management of audiovestibular disorders to minimize patient handicap. Systemic blood testing for antiphospholipid antibodies in case of non-explained auditive or vestibular abnormalities in pediatrics population is also recommended. Conflict of interest statement The authors declare that they have no competing interests. Acknowledgements There was No writing assistance in preparing the manuscript. The study was not supported by any funding source; equipments in Audiology Unit, ENT Department were used. References [1] I. Kastanioudakis, N. Ziavra, P.V. Voulgari, G. Exarchakos, A. Skevas, A.A. Drosos, Ear involvement in systemic lupus erythematosus patients: a comparative study, J. Laryngol. Otol. 116 (2) (2002) 103–107. [2] N.M. Sperling, K. Tehrani, A. Liebling, E. Ginzler, Aural symptoms and hearing loss in patients with lupus, Otolaryngol. Head Neck Surg. 118 (1998) 762–765.
[3] E. Karatas, A.M. Onat, C. Durucu, T. Baglam, M. Kanlikama, O. Altunoren, et al., Audiovestibular disturbance in patients with systemic lupus erythematosus, Otolaryngol. Head Neck Surg. 136 (1) (2007) 82–86. [4] F.O. Black, What can posturography tell us about vestibular function? Ann. N.Y. Acad. Sci. 942 (2001) 446–464. [5] M.C. Hochberg, Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum. 40 (9) (1997) 1725. [6] E.M. Monsell, J.M. Furman, S.J. Herdman, H.R. Konrad, N.T. Shepard, Computerized dynamic platform posturography, Otolaryngol. Head Neck Surg. 117 (4) (1997) 394–398. [7] S. Roverano, G. Cassano, S. Paira, J. Chiavarini, C. Graf, L. Rico, et al., Asymptomatic sensorineural hearing loss in patients with systemic lupus erythematosus, J. Clin. Rheumatol. 12 (5) (2006) 217–220. [8] K. Maciaszczyk, T. Durko, E. Waszczykowska, A. Erkiert-Polqui, A. Pajor, Auditory function in patients with systemic lupus erythematosus, Auris Nasus Larynx 38 (1) (2011) 26–32. [9] A.P. Gomides, E.J. do Rosario, H.M. Borqes, H.H. Gomides, P.M. de Padua, P.D. Sampaio-Barros, Sensorineural dysacusis in patients with systemic lupus erythematosus, Lupus 16 (12) (2007) 987–990. [10] G.C. Compadretti, C. Brandolini, I. Tasca, Sudden sensorineural hearing loss in lupus erythematosus associated with antiphospholipid syndrome: case report and review, Ann. Otol. Rhinol. Laryngol. 114 (3) (2005) 214–218. [11] L. Green, E.B. Miller, Sudden sensorineural hearing loss as a first manifestation of systemic lupus erythematosus: association with anticardiolipin antibodies, Clin. Rheumatol. 20 (3) (2001) 220–222. [12] M. Naarendorp, H. Spiera, Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus like syndromes and antiphospholipid antibodies, J. Rheumatol. 25 (3) (1998) 589–592. [13] C. Berube, L. Mitchell, E. Silverman, M. David, C. Saint Cyr, R. Laxer, The relationship of antiphospholipid antibodies to thromboembolic events in pediatric patients with systemic lupus erythematosus: a cross sectional study, Pediatr. Res. 44 (3) (1998) 351–356. [14] K. Hisashi, S. Komune, TairaT, T. Uemura, S. Sadoshima, H. Tsuda, Anticardiolipin antibody-induced sudden profound sensorineural hearing loss, Am. J. Otolaryngol. 14 (4) (1993) 275–277. [15] N. Fukushima, H. Fukushima, S. Cureoglu, P.A. Schachern, M.M. Paparella, Hearing loss associated with systemic lupus erythematosus: temporal bone histopathology, Otol. Neurotol. 27 (1) (2006) 127–128.
Contents lists available at SciVerse ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Study of audiovestibular dysfunction in children with systemic lupus erythematosus Ghada Ibrahim Gad a,*, Somaia Tawfik Mohamed b, Khaled Salah Awwad a, Rehab Fetoh Mohamed c a b c
Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt ENT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Pediatrics Hospital, Ain Shams University, Egypt
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 April 2013 Received in revised form 2 July 2013 Accepted 3 July 2013 Available online 2 August 2013
Objective: Inner ear dysfunction in systemic lupus erythematosis patients has been reported but audiovestibular involvement is not well documented especially in pediatrics. This study was designed to evaluate silent audiovestibular dysfunction among SLE children. Methods: Case control study examined in allergy and immunology clinic; pediatrics hospital and audiovestibular clinic; Ain Shams University from January 2009 to December 2010. Thirty-five systemic lupus erythematosus children (diagnosed according to American College of Rheumatology); age group 8–16 years, were randomly selected. Five of them were excluded due to one or more exclusion criteria (previous otitis media, stroke, lupus cerebritis, meningitis or encephalitis, audiovestibular symptom). Ten of them refused enrollment or could not complete full battery. Seventeen females and three males, mean age 12.9 2.6 years, completed the study. Control group included 20 normal subjects, age and sex matched. Full clinical assessment, basic audiological evaluation and vestibular testing (videonystagmography VNG and computerized dynamic posturography CDP) were conducted for children included in the study. Results: Five systemic lupus erythematosus patients had sensorineural hearing loss strongly associated with +ve antiphospholipid antibody and two had conductive hearing loss. Two children in control group had conductive hearing loss (p = 0.05). Abnormal VNG findings was significantly higher among systemic lupus erythematosus children (40%) compared to controls (0%) and associated with +ve antiphospholipid antibodies (x2 = 10, p = 0.002, Fisher exact test = 0.003). Twenty-five percentage of systemic lupus erythematosus children had abnormal CDP findings reflecting impaired balance function associated with positive antiphospholipid antibodies showing significant statistical difference compared to controls (0% affection) (x2 = 5.7, p = 0.017, Fisher exact test = 0.047). Conclusion: Silent audiovestibular dysfunction is prevalent among systemic lupus erythematosus children especially those positive for antiphospholipid antibodies necessitating routine regular evaluation. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Systemic lupus erythematosus Audiovestibular Antiphospholipid antibody
1. Introduction Systemic lupus erythematosus (SLE) is increasingly recognized in pediatrics population. Immune complexes and autoantibodies are the main causes of multiorgan involvement characteristic of the disease. Sensorineural hearing loss (SNHL) and inner ear dysfunction in SLE patients were first identified by Kastanioudakis et al. [1] and Sperling et al. [2]. Inner ear damage in SLE patients has been occasionally reported but frequency and extent of audio-
* Corresponding author at: Department of Pediatrics, Ain Shams University, Ramses Street, Cairo 11566, Egypt. Tel.: +20 1145746064. E-mail address: [email protected] (G.I. Gad). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.07.004
vestibular involvement are not well documented especially in pediatrics. Previous studies were conducted for audiovestibular function in adults with SLE [2,3]. They were conducted using basic audiological evaluation and electronystagmography (ENG). However, evaluation of audiovestibular function in pediatric patients with SLE was not thoroughly investigated. In addition, functional evaluation of balance was not previously investigated. This can be conducted by computerized dynamic posturography which is the only method validated by controlled research studies to isolate the functional contributions of vestibular inputs, visual inputs, somatosensory inputs, central integrating mechanisms, and neuromuscular system outputs for postural and balance control [4].
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Accordingly, this study was designed to assess audiovestibular functions as a part of systemic autoimmune disorder in children with SLE. 2. Methods The present study was carried out in allergy and immunology clinic in pediatrics hospital and audiovestibular clinic, Ain Shams University. The study was a case–control one, 35 SLE patients (diagnosed clinically and laboratory according to American College of Rheumatology [5]) in the age group 8–16 years were randomly selected and approached (simple randomization). Five of them were excluded due to one or more of exclusion criteria, and 10 refused enrollment or could not complete the full battery. A control group consisting of 20 healthy children age and sex matched with the study group were recruited over a period of 24 months from January 2009 to December 2010. Patients with history of otitis media with effusion, chronic suppurative otitis media (CSOM), previously diagnosed as having stroke or lupus cerebritis, meningitis or encephalitis, any audiovestibular complaint (tinnitus, hearing problem, vertigo, etc.) were excluded from the study. The study was approved by the ethical committee of Pediatrics Hospital, Ain Shams University. An informed consent was taken from parents of all children before enrollment in the study. The study & control groups were subjected to the following: (1) Full history taking, thorough clinical examination with special emphasis on duration of illness, type of medications and SLE disease activity index (SLEDAI) score. (2) Record of SLE investigations (already registered in the file) - Stranded deoxyribonucleic acid antibody. - Antinuclear antibody. - Antiphospholipid antibodies. (3) Otological examination: - Audiological evaluation: Pure tone audiometry by air conduction and bone conduction and speech audiometry were done using two Channel Audiometer Madsen model Orbiter 922. - Immittancemetry to assess middle ear function using interacoustic Imittancemeter model AZ7. (4) Vestibular evaluation: I Videonystagmography (VNG) Test battery: Using computerized VNG Micromedical, Meta 4, with a light bar designed to ensure a large visual field at both horizontal and vertical planes. Water caloric irrigator model, Hortman was used to do caloric testing. The test was done as follows: The patient sat on the test chair 1 m away from the center of the light bar with infrared goggles on his eyes and then started the VNG subtests to measure. 1. Spontaneous/gaze nystagmus. 2. Oculomotor tests: including random Saccade test, tracking test and optokinetic test. 3. Positional and positioning testing. 4. Bithermal Caloric testing. II Computerized dynamic posturography (CDP): During CDP testing, the patient stands on a movable, dual forceplate support surface within a moveable surround (enclosure). Under control of a computer, the force platform can either move in a horizontal plane (translate), or rotate out of the horizontal plane [6]. Standardized test protocols expose the patient to support surface and visual surround motions, during which the patient’s postural stability and motor reactions are recorded. These test protocols include: (Fig. 1)
1. Sensory organization test (SOT): testing for six challenging conditions. 2. Motor control test (MCT): testing for forward and backward movements. 3. Adaptation test (ADT): testing for toes up and toes down movements.
During the SOT, the utility of visual, vestibular, and proprioceptive inputs in controlling spontaneous sway is eliminated without provoking motor reactions by moving the support surface and the visual enclosure in response to the patient’s postural movements. During the motor control protocols (MCT and ADT), reactions are provoked by unexpected abrupt movements of the support surface. Because the measures of postural stability, as well as the motions of the support surface and visual surround, are precisely controlled and calibrated relative to the patient’s height and weight, standardized graphical summaries can compare the patient’s results to those of age-matched asymptomatic (normal) individuals. 2.1. Statistical analysis Standard computer program SPSS for Windows, release 13.0 (SPSS Inc., USA) was used for data entry and analysis. All numeric variables were expressed as mean standard deviation (SD). Comparison of different variables in various groups was done using Mann Whitney test for nonparametric variables. Chi-square (x2) test was used to compare frequency of qualitative variables among the different groups with Fisher exact test if indicated. Spearman’s correlation test was used for correlating non-parametric variables. For all tests a probability (p) less than 0.05 was considered significant. 3. Results Demographic characteristics of studied children are shown in Table 1. Pure tone audiometry revealed that 5 cases (25%) suffered from moderate sensorineural hearing loss (SNHL) and 2 (10%) with mild conductive hearing loss (CHL) among SLE patients. Control group showed normal hearing in all children except 2 cases with mild CHL (Table 2). All subjects had speech reception threshold matched with pure tone average with excellent speech discrimination scores proportionate to degree of hearing loss. They showed type A tympanograms reflecting normal middle ear function except 2 patients with conductive hearing loss who showed type B flat reflecting middle ear effusion. Non-significant statistical association was detected between either sex (x2 = 1.9, p = 0.168) or type of medications whether steroids alone or with cytotoxic drugs (x2 = 0.64, p = 0.42) and hearing loss among SLE patients. SLEDAI score (active or inactive) showed non-significant association with SNHL (x2 = 1.1, p = 0.29). All SLE patients with +ve antiphospholipid antibodies had SNHL (100%). Vestibular test results revealed abnormal video nystagmography in 40% of SLE children compared to controls (0%) with peripheral affection (involving end organ in labyrinth and peripheral nerve) in 1 (5%) patient and central affection (starting at relay station between vestibular nerve and vestibular nuclei in brain stem) in 3 (15%) patients, and combined in 4 (20%) patients. Regarding VNG subset results, 7 (35%) patients had abnormal oculomotor subset (4 of them had abnormal saccade, 6 abnormal tracking), 2 (10%) had abnormal positional subset and 3 (15%) had abnormal caloric subtest. Active SLEDAI was significantly associated with abnormal peripheral vestibular testing (x2 = 4.444; p = 0.035), but not with central one (x2 = 2.96; p = 0.085).
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Fig. 1. Computerized dynamic posturography tests.
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Table 1 Demographic characteristics of studied children.
Table 2 Comparison between cases and controls as regards audiovestibular functions. Z/x2
Study group
Control
n = 20
N = 20
Mean SD/ n (%)
Mean SD/ n (%)
Age in years
12.90 2.673
12.85 2.368
Sex Male Female Duration of disease in years
3 (15%) 17 (85%) 4.40 1.875
3 (15%) 17 (85%)
SLEDAI Active (6) Inactive (<6)
9.15 6.968 12 (60%) 8 (40%)
Drugs Steroid Steroids + cytotoxics
11 (55%) 9 (45%)
APL Positive Negative
0.150 0.000
p-Value
0.881
1.00
Study group
Control group
n (%)
n (%)
Normal hearing SNHL CHL
13 (65.0%) 5 (25.0%) 2 (10.0%)
18 (90.0%) 0 (0.0%) 2 (10.0%)
VNG Normal Abnormal
12 (60%) 8 (40%)
20 (100%) 0 (0%)
CDP Normal Abnormal
15 (75%) 5 (25%)
20 (100%) 0 (0%)
x2 5.806
10
5.7
p
0.055
0.002*
0.017y
SNHL, sensorineural hearing loss; CHL, conductive hearing loss; VNG, videonystagmography; CDP, computerized dynamic posturography. * Fisher exact test: 0.003. y Fisher exact test: 0.047.
5 (25%) 15 (75%)
SLEDAI, systemic lupus erythematosus disease activity index; APL, antiphospholipid antibodies.
Similarly, SLE patients receiving steroids and cytotoxic drugs showed highly significant association with peripheral vestibular affection (x2 = 8.148; p = 0.004) and not with central one (x2 = 3.03; p = 0.08). Another significant statistical association was detected between positive antiphospholipid antibodies and abnormal VNG test (x2 = 4.44; p = 0.035; 4 out of 5 SLE patients with +ve antiphospholipid antibodies had abnormal VNG). Five (25%) SLE children revealed abnormal computerized dynamic posturography (CDP) with significant difference compared to controls (0% affection) (x2 = 5.7; p = 0.017, Fisher exact test = 0.047). Significant statistical association between abnormal CDP and positive antiphospholipid antibodies was reported (x2 = 4.36; p = 0.037; 3 out of 5 positive antiphospholipid antibodies had abnormal CDP).
Audiovestibular evaluation and antiphospholipid profile of the studied SLE patients is shown in Table 3. Regarding sensory organization test (SOT), SLE patients had significantly lower values in C5 and C6 compared to control group (Table 4). There was abnormality in conditions C4, C5 and C6 among 15% of SLE patients reflecting visual/vestibular pattern of dysfunctions, while 10% had abnormality in conditions C5 and C6 reflecting vestibular pattern of dysfunction. Non-significant statistical difference was detected between studied patients taking steroids only and those taking steroids and cytotoxics as regards SOT. SLE patients showed non-significant difference compared to controls as regards latency in motor control tests (MCT) (Table 5), whereas all amplitude measures were significantly lower among patients (Table 6). On the other hand, adaptation test was significantly higher among cases in toes down position (z = 0.748; p = 0.006). Significant positive correlation was detected between large backward (LB) movement amplitude in MCT and both duration of SLE (r = 0.238; p = 0.023) and SLEDAI score (r = 0.166; p = 0.011). In addition, disease duration showed significant positive correlation with large forward (LF) movement amplitude in MCT (r = 0.174; p = 0.042).
Table 3 Audiologic, vestibular and antiphospholipid profile of studied SLE patients. Case number
Duration Of SLE (years)
SLEDAI
Audiologic assessment
VNG
CDP
Antiphospholipid antibodies
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
4 2 5 2 4 5 4 2 2 6 4 4 6 3 7 4 3 8 8 5
4 0 14 8 3 10 8 0 2 18 4 18 20 5 15 6 4 24 11 9
Normal CHL Normal Normal SNHL SNHL Normal Normal Normal SNHL Normal SNHL Normal Normal SNHL Normal CHL Normal Normal Normal
Normal Normal Normal Normal Abnormal Abnormal Normal Normal Normal Abnormal Normal Abnormal Abnormal Normal Normal Abnormal Normal Abnormal Abnormal Normal
Normal Normal Normal Abnormal Abnormal Abnormal Normal Normal Normal Abnormal Normal Normal Normal Normal Normal Abnormal Normal Normal Normal Normal
Negative Negative Negative Negative Positive Positive Negative Negative Negative Positive Negative Positive Negative Negative Positive Negative Negative Negative Negative Negative
(active) (active) (active) (active)
(active) (active) (active) (active) (active) (active) (active) (active)
(central) (peripheral)
(central) (combined) (combined)
(central) (combined) (combined)
CDP: computerized dynamic posturography; VNG: videonystagmography; Central vestibular affection: begins at relay station between vestibular nerve and nuclei in brain stem; Peripheral vestibular affection: at end organ in labrynth and peripheral nerve; Combined: central and peripheral vestibular affection; SLEDAI: systemic lupus erythematosus disease activity index; SNHL: sensorineural hearing loss; Stero: steroids; CHL: conductive hearing loss.
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Table 4 Comparison between studied patients and control group as regards SOT. Study group
Control
C1 C2 C3 C4 C5 C6 Composite score
Mean
SD
95% Cl
91.10 89.75 87.90 84.90 82.30 81.35 84.40
6.299 6.121 6.585 8.097 11.112 10.996 6.855
88.15 86.89 84.82 80.11 75.10 70.23 81.19
94.05 92.61 90.98 88.69 87.50 86.47 87.61
Mean
SD
95% Cl
90.35 89.70 87.70 81.0 71.40 64.75 78.25
4.234 4.092 6.165 8.790 16.139 18.615 10.867
88.37 87.78 84.81 76.89 63.85 56.04 73.16
92.33 91.62 90.59 85.11 78.95 73.40 83.34
z-Value
p-Value
1.324 0.547 0.014 1.524 2.330 2.978 1.620
0.185 0.585 0.989 0.128 0.020 0.003 0.105
C1 means condition 1. Bold font indicates statistical significance.
4. Discussion The frequency of asymptomatic hearing defect in this study was 35% of SLE children, among which 10% had conductive hearing loss due to middle ear effusion and 25% had sensorineural hearing loss, while only 10% of the control group had conductive hearing loss. Previous studies involving adult SLE patients showed (70%) frequency of asymptomatic impaired hearing; (66%) with sensorineural and (4%) with conductive alterations while (16%) in the control group had alterations of audiometric tests: (12%) conductive and (4%) asymptomatic SNHL [7]. Sensorineural hearing loss was found in (21%) of a population of SLE patients among which (67%) reported audiovestibular symptoms [3]. Adult SLE patients with (17.1%) frequency of symptomatic hearing loss revealed (28.6%) symmetric SNHL affection [8]. Auditory symptoms were present in (55.5%) of adult SLE patients, with a diagnosis of SNHL in (15.6%) of them [9]. The pathogenesis of SNHL in SLE remains obscure. However, the strong association of SNHL in SLE patients with +ve antiphospholipid antibodies might postulate that micro infarctions of the capillaries or arterioles, and thrombosis affecting blood supply to the inner ear may be the cause of SNHL and not only vasculitis. Previous reports documented such association [10–12], while others did not [7,9]. Antiphospholipid antibodies are found in approximately 24% as lupus anticoagulant and 27% as anticardiolipin antibodies in children with SLE [13] and an association with sudden SNHL has been reported although a direct causal relationship remains unconfirmed and definite pathogenesis still obscure [10,11]. Hishashi et al. [14] were the first to report association between profound SNHL in patients with autoimmune diseases and antiphospholipid antibodies. The cochlea, vestibule, semicircular canals and vestibular aqueduct were filled with dense fibrous tissue and new bone formation among SLE patient [15]. Audiological findings in our patients showed non-significant association with type of medication or SLEDAI score, in agreement with previous reports [1,7,9]. Several reports showed that many audiovestibular pathologies in the pediatrics population may be immune-mediated. This might
be of more significance in cases of coexisting systemic autoimmune disorder. The present study showed that 8 patients (40%) had abnormal videonystagmography results, 3 of them (15%) had only central vestibular lesion, 1 patient (5%) had only peripheral vestibular lesion while the majority (4) (20%) had combined central and peripheral lesions. This reflects that central vestibular dysfunction was more frequent than peripheral affection in children with SLE which might be due to vasculitis affecting central vestibular pathways. We found only one report in the literature investigating vestibular function in adult SLE patients using electronystagmography and revealed significantly more frequent abnormal results in SLE group (50%) compared with the control group (7.14%) (p < 0.01), SLE group had significantly more peripheral type vestibular pathology compared with the control group (p < 0.05) [3]. Lower frequency of vestibular dysfunction in the present study might be due to difference in the sample of the studied group. The present study was conducted on pediatric patients with no history of audiovestibular symptoms while over 70% of adults studied by Karatas et al. [3] reported vertigo and dizziness. In our SLE patients we found significant association between active SLEDAI and use of steroids and cytotoxic drugs with peripheral vestibular system affection. To the best of our knowledge, no previous studies investigated the balance function in SLE patients using dynamic posturography (CDP). In the present study 5 patients (25%) of the studied SLE cases had abnormal CDP results. Sensory organization test (SOT) was performed and (15%) of patients had reduced scores in conditions (C4, C5 and C6) reflecting inability to use visual and vestibular cues to maintain balance and postural control. In addition, 10% had reduced scores in condition (C5 and C6) indicating inability to use vestibular information for balance control. Motor control tests (MCT) done for further analysis showed significant difference between cases and controls in amplitude measures and adaptation test (toes down) whereas latency did not differ significantly. This reflects SLE patients cannot use central integrating mechanisms, and neuromuscular system outputs for postural and balance control.
Table 5 Comparison between studied patients and control group as regards (latency) in MCT. Study group
SB MB LB SF MF LF
Control group
Mean
SD
95% Cl
132.25 124.75 120.25 133.50 134.25 128.75
19.566 12.511 9.244 15.483 18.516 23.835
123.09 118.89 115.92 126.25 125.58 117.60
141.41 130.61 124.58 140.75 142.92 139.90
Mean
SD
95% Cl
122.25 120.75 122.00 125.50 130.75 123.75
7.860 7.993 8.944 9.583 11.616 8.565
118.57 117.01 117.81 121.50 125.31 119.74
125.93 124.49 126.19 129.99 136.19 127.76
z-Value
p-Value
1.636 0.735 0.496 1.698 0.547 0.165
0.102 0.462 0.620 0.090 0.565 0.869
MCT, motor control test; SB, small backward; SF, small forward; MB, medium backward; MF, medium forward; LB, large backward; LF, large forward.
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Table 6 Comparison between studied patients and control group as regards (amplitude) in MCT. Study group
SB MB LB SF MF LF
Control group
Mean
SD
95% Cl
0.48 1.70 2.60 0.58 2.150 2.33
0.389 1.005 1.603 0.654 1.606 1.830
0.30 1.23 1.85 0.27 1.398 1.47
0.65 2.17 3.35 0.88 2.902 3.18
Mean
SD
95% Cl
0.83 2.40 3.18 0.88 2.225 2.88
0.295 0.503 0.406 0.275 0.525 0.626
0.71 2.16 8.98 0.75 1.979 2.58
0.94 2.64 3.37 1.00 2.471 3.17
z-Value
p-Value
2.977 3.083 1.908 2.277 1.361 2.762
0.003 0.002 0.056 0.023 0.174 0.007
MCT, motor control test; SB, small backward; SF, small forward; MB, medium backward; MF, medium forward; LB, large backward; LF, large forward.
The present study proved statistically significant association between antiphospholipid antibodies and impaired vestibular test results (VNG and CDP tests). However, clinical significance of these results should be interpreted cautiously due to small sample size. In conclusion, silent audiovestibular dysfunction is prevalent in a significant proportion of SLE children especially those positive for antiphospholipid antibodies. It is recommended to regularly evaluate audiovestibular function among these children aiming at early detection and management of audiovestibular disorders to minimize patient handicap. Systemic blood testing for antiphospholipid antibodies in case of non-explained auditive or vestibular abnormalities in pediatrics population is also recommended. Conflict of interest statement The authors declare that they have no competing interests. Acknowledgements There was No writing assistance in preparing the manuscript. The study was not supported by any funding source; equipments in Audiology Unit, ENT Department were used. References [1] I. Kastanioudakis, N. Ziavra, P.V. Voulgari, G. Exarchakos, A. Skevas, A.A. Drosos, Ear involvement in systemic lupus erythematosus patients: a comparative study, J. Laryngol. Otol. 116 (2) (2002) 103–107. [2] N.M. Sperling, K. Tehrani, A. Liebling, E. Ginzler, Aural symptoms and hearing loss in patients with lupus, Otolaryngol. Head Neck Surg. 118 (1998) 762–765.
[3] E. Karatas, A.M. Onat, C. Durucu, T. Baglam, M. Kanlikama, O. Altunoren, et al., Audiovestibular disturbance in patients with systemic lupus erythematosus, Otolaryngol. Head Neck Surg. 136 (1) (2007) 82–86. [4] F.O. Black, What can posturography tell us about vestibular function? Ann. N.Y. Acad. Sci. 942 (2001) 446–464. [5] M.C. Hochberg, Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum. 40 (9) (1997) 1725. [6] E.M. Monsell, J.M. Furman, S.J. Herdman, H.R. Konrad, N.T. Shepard, Computerized dynamic platform posturography, Otolaryngol. Head Neck Surg. 117 (4) (1997) 394–398. [7] S. Roverano, G. Cassano, S. Paira, J. Chiavarini, C. Graf, L. Rico, et al., Asymptomatic sensorineural hearing loss in patients with systemic lupus erythematosus, J. Clin. Rheumatol. 12 (5) (2006) 217–220. [8] K. Maciaszczyk, T. Durko, E. Waszczykowska, A. Erkiert-Polqui, A. Pajor, Auditory function in patients with systemic lupus erythematosus, Auris Nasus Larynx 38 (1) (2011) 26–32. [9] A.P. Gomides, E.J. do Rosario, H.M. Borqes, H.H. Gomides, P.M. de Padua, P.D. Sampaio-Barros, Sensorineural dysacusis in patients with systemic lupus erythematosus, Lupus 16 (12) (2007) 987–990. [10] G.C. Compadretti, C. Brandolini, I. Tasca, Sudden sensorineural hearing loss in lupus erythematosus associated with antiphospholipid syndrome: case report and review, Ann. Otol. Rhinol. Laryngol. 114 (3) (2005) 214–218. [11] L. Green, E.B. Miller, Sudden sensorineural hearing loss as a first manifestation of systemic lupus erythematosus: association with anticardiolipin antibodies, Clin. Rheumatol. 20 (3) (2001) 220–222. [12] M. Naarendorp, H. Spiera, Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupus like syndromes and antiphospholipid antibodies, J. Rheumatol. 25 (3) (1998) 589–592. [13] C. Berube, L. Mitchell, E. Silverman, M. David, C. Saint Cyr, R. Laxer, The relationship of antiphospholipid antibodies to thromboembolic events in pediatric patients with systemic lupus erythematosus: a cross sectional study, Pediatr. Res. 44 (3) (1998) 351–356. [14] K. Hisashi, S. Komune, TairaT, T. Uemura, S. Sadoshima, H. Tsuda, Anticardiolipin antibody-induced sudden profound sensorineural hearing loss, Am. J. Otolaryngol. 14 (4) (1993) 275–277. [15] N. Fukushima, H. Fukushima, S. Cureoglu, P.A. Schachern, M.M. Paparella, Hearing loss associated with systemic lupus erythematosus: temporal bone histopathology, Otol. Neurotol. 27 (1) (2006) 127–128.