SPECIAL ISSUE ARTICLE

Pediatric Autoimmune Inner Ear Disease:

A Rare, But Treatable Condition
Rotem Semo Oz, MD; Michael Gluth, MD; and Melissa S. Tesher, MD

vention may result in improved rates of

ABSTRACT hearing loss reversal.6
Autoimmune inner ear disease (AIED) is a rare, but treatable cause of sudden sen-
sorineural hearing loss in children. Most cases present acutely and involve both ears. EPIDEMIOLOGY
The precise mechanism of hearing loss in AIED is not known. Many suspected etiolo- AIED is a rare disease with an esti-
gies have been proposed including infections, vascular abnormalities, and trauma. How- mated yearly incidence of less than 5
ever, 70% of cases are defined as idiopathic. There are no standardized diagnostic crite- cases per 100,000.7 However, because
ria for AIED, and the diagnostic process may be challenging. Positive auto antibodies there are no standardized criteria or de-
and response to immunosuppressive therapy support the diagnosis. Treatment may finitive diagnostic tests, the exact preva-
include corticosteroids and steroid-sparing immunosuppressive medications. A high lence remains unknown.7
index of suspicion is recommended as the hearing loss may be stabilized or even re-
versed with early treatment. Long-term medical treatment failures generally have CLINICAL PRESENTATION
good outcomes with cochlear implantation. [Pediatr Ann. 2019;48(10):e391-e394.] AIED typically presents as bilateral
asymmetric sensorineural hearing loss

A
utoimmune inner ear disease den. Sudden sensorineural hearing loss that progresses over a period of days to
(AIED), also known as auto- (SSNHL) is defined hearing loss of more months. This contrasts with pediatric
immune sensorineural hearing than 30 dB in less than 3 days.3 AIED is nonautoimmune sudden onset hearing
loss, is a rare form of bilateral sensori- unlike most cases of SSNHL in that it is loss, in which most cases are unilat-
neural hearing loss that responds to im- usually bilateral at the time of presenta- eral.4.8 Serial audiometry in AIED pa-
munosuppressive therapy.1 This condi- tion. This rare occurrence among cases tients usually depicts fluctuating hearing
tion, as first described by McCabe1 in of SSNHL should prompt clinicians to thresholds that follow a trend of pro-
1979, is usually recognized as a specific consider the diagnosis of AIED as well gressive deterioration. Although 80%
pattern of sensorineural hearing loss as underlying systemic conditions such of AIED patients have bilateral, asym-
that is uniquely bilateral, asymmetric, as infection (Lyme, cytomegalovirus metrical SSNHL at initial presentation, a
and fluctuating.2 Sensorineural hearing [CMV], Epstein-Barr virus [EBV], small minority will initially present with
loss attributed to AIED was originally syphilis), vasculitis, paraneoplastic hearing loss only in one ear, before later
characterized by responsiveness to treat- syndrome, drug ototoxicity, or other (weeks to months) developing hearing
ment with systemic corticosteroids and systemic autoimmune diseases.4,5 Early loss on the contralateral side.2 One-half
cyclophosphamide. The presentation of diagnosis and treatment of this disorder of patients with AIED have associated
AIED-related hearing loss is often sud- is extremely important as early inter- vestibular symptoms such as imbalance
and vertigo.2 Tinnitus is also a common
presenting symptom. Data describing
Rotem Semo Oz, MD, is a Fellow in Pediatric Rheumatology, Comer Children’s Hospital, The Universi- AIED specifically in children are sparse.
ty of Chicago. Michael Gluth, MD, is an Associate Professor of Surgery, Section of Otolaryngology-Head Huang et al.9 presented seven children
& Neck Surgery, The University of Chicago. Melissa S. Tesher, MD, is an Assistant Professor of Pediatrics, age 4 to 13 years who were diagnosed
Section of Pediatric Rheumatology, The University of Chicago Medical Center. with AIED based on the finding of
Address correspondence to Rotem Semo Oz, MD, The University of Chicago, 5841 S. Maryland Av- SSNHL and positive antibodies. Five of
enue, MC 5044, Room C-1041, Chicago, IL 60637; email: rotem.semooz@uchospitals.edu. the seven children presented with bilat-
Disclosure: The authors have no relevant financial relationships to disclose. eral hearing loss, and 5 of 7 complained
doi:10.3928/19382359-20190923-01 of tinnitus.9

PEDIATRIC ANNALS • Vol. 48, No. 10, 2019 e391


PATHOGENESIS AND EVIDENCE
FOR AUTOIMMUNITY
The precise mechanism of hearing
loss in AIED is not fully understood.
Numerous clinical observations and
animal studies seem to support an au-
toimmune mechanism for this entity.10
Hearing loss is known to occur at
a higher-than-normal rate in patients
with several autoimmune diseases such
as systemic lupus erythematosus, ul-
cerative colitis, Sjogren’s syndrome,
and Cogan’s syndrome. Interestingly,
children with juvenile idiopathic ar-
thritis (JIA) may have subtle hearing
impairment more frequently than is
commonly appreciated. Céspedes et
al.11 found that 78 of 124 ears in 62
patients with JIA had a mild degree of
hearing impairment. Ikiz et al.12 found
middle and/or inner ear involvement in
32% of ears in a cohort of 38 patients
with JIA. He attributed this finding to
rheumatic process in the middle ear
joints or to immune-complex medi-
ated vasculitis in the inner ear. Simi-
lar results were reported among adults
with rheumatoid arthritis. Lidar et al.13
reported three cases of vasculitis that
initially presented as sudden hearing
loss.13
Harris et al.,14 using guinea pig
models, showed that the inner ear can
produce antibodies in response to sen-
sitization. They later isolated a 68-kD
protein, using Western blot analysis
on serum from patients with SSNHL
and from animals with experimental
autoimmune hearing loss. Inner ear
proteins were found to be the target
of this 68-kD protein.14 Boulassel et
al.15 found several additional antibod-
ies (including 30- and 42-kD protein)
that reacted with the guinea pig inner
ear. These findings suggest that several
populations of antibodies contribute to
the enhanced immunologic activity in
AIED.
e392
SPECIAL ISSUE ARTICLE
The precise immune pathogenesis
of the inner ear injury process is un-
clear. Type II (cytotoxic), type III (im-
mune complex), and type IV (delayed
type) immune response were suggested
as potential mechanisms.10
DIAGNOSIS
There are no standardized diagnos-
tic criteria for AIED and the diagnostic
process may be challenging. A high in-
dex of suspicion is recommended when
sudden bilateral asymmetric sensori-
neural hearing loss is encountered. The
diagnosis is mainly clinical based on
hearing loss pattern and responsiveness
to immunosuppressant therapy. Posi-
tive serum autoantibodies and exclu-
sion of other potential causes further
support the diagnosis. The diagnostic
assessment consists of four parts.2,4,9
Otologic Assessment
Audiologic testing demonstrates the
presence of acute sensorineural hear-
ing loss (bone-conduction thresholds
>30 dB for at least three frequencies);
usually present in both ears. Speech
audiometry typically demonstrates
diminished word recognition scores.
Vestibular function testing may de-
pict evidence of unilateral or bilateral
peripheral vestibular weakness. Oto-
scopic examination is usually normal,
as is head and neck examination. If the
patient is experiencing acute vestibular
symptoms, spontaneous jerk nystag-
mus in the horizontal plane may be ob-
served and gait may be unstable.
Evaluation for Underlying
Autoimmune/Infectious Disease
Clinical history of autoimmune
disease. Suggested laboratory evalu-
ation includes compete blood count,
erythrocyte sedimentation rate,
antinuclear antibody, antineutrophil
cytoplasmatic antibody, rheumatic fac-
tor, anti-Sjögren syndrome-related an-
tigen A, anti-Sjögren syndrome-related
antigen B, and angiotensin converting
enzyme level. Lyme serology, fluores-
cent treponemal-antibody absorption
for syphilis, and/or anti-CMV and EBV
immunoglobulin G (IgG) and IgM, as
clinically indicated to rule out infec-
tious etiology, may also be considered.
Eye examination to rule out interstitial
keratitis/uveitis (Cogan syndrome) or
branch retinal artery occlusion (Susac
syndrome) could also be another
element.
Testing for Specific Inner Ear
Autoantibodies
Serologic testing for inner ear an-
tibodies can be helpful as a positive
finding supports the suspected diag-
nosis of AIED, but sensitivity is lim-
ited and the significance of a positive
versus a negative test is unclear. The
most well-known antibody is the heat
shock protein 70 against the 68-kDa
antigen, which is present on hair cells
and supporting cells in the inner ear.16
This antibody was found in 35% of pa-
tients with AIED17 and in 92% of pa-
tients with Cogan’s syndrome, which
presents with corneal inflammation
and audiovestibular dysfunction that is
otherwise similar to AIED.18 Presence
of these antibodies has been proposed
as a marker for steroid responsiveness,
but animal studies have failed to defini-
tively support this assertion, and practi-
cally speaking, most patients suspected
of having AIED have been treated with
a steroid trial well before laboratory
test results are known. Other antibodies
such as anti-beta tubulin and anti-coch-
lin have also been suggested as possible
markers of AIED.
Radiologic Imaging
Magnetic resonance imaging  (MRI)
with contrast of the brain and internal
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auditory canals should be considered
to rule out rare primary causes such as
cranial nerve tumor (bilateral vestibular
schwanomma, in type 2 neurofibroma-
tosis), neurodegenerative disease (mul-
tiple sclerosis), superficial siderosis,
or inner ear developmental malforma-
tions. Susac syndrome includes the
combination of AIED-like hearing loss,
visual loss due to retinal artery occlu-
sion, and encephalopathy due to diffuse
vasculitic white matter lesions that are
apparent on MRI.19 In the acute phase
of AIED, contrasted MRI imaging may
reveal enhancement of the cochlea or
vestibular labyrinth.
TREATMENT
Corticosteroids have remained
the standard of care for treatment of
AIED since it was first suggested by
McCabe;1 however, it is worth noting
that this original report included a few
cases that did not respond to steroids,
but did respond to cyclophosphamide.1
Various dosing regimens and treatment
durations have been reported. Reported
doses range between 1 mg/kg per day
and 60 mg daily9,20,21 and can be giv-
en orally or intravenously. Xenellis et
al.22 found that intratympanic steroid
treatment after 10 days of intravenous
solumedrol had a favorable outcome
compared to intravenous steroids alone.
The duration of treatment varied from
a minimum of 14 days to 1 month or
longer. The overall reported response
to steroid treatment is 60% to 70%, but
response was temporary in some cases.
A variety of steroid-sparing immuno-
suppressive treatments have also been
tried. Methotrexate, cyclophospha-
mide, anti-TNF antibody biologics, and
rituximab (anti-CD20 antibody) have
all been used in small studies, with
inconclusive results.23 A randomized
control study found that methotrexate
was not more effective than placebo in
PEDIATRIC ANNALS • Vol. 48, No. 10, 2019
SPECIAL ISSUE ARTICLE
maintaining the hearing improvement
achieved in 60 patients with AIED.24
Unfortunately, not all patients with
AIED will respond adequately to medi-
cal therapy even if applied promptly
in the acute setting. Further, some pa-
tients that do respond will experience
slow deterioration of hearing over time
despite maintenance immunosuppres-
sant therapy. Also, some patients who
respond to immunosuppressant therapy
will later develop intolerable side ef-
fects. In each of these instances, it is
common for patients to be first treated
with hearing aid fitting. Later, as hear-
ing thresholds worsen, many patients
with AIED eventually undergo cochlear
implantation when the benefit from
hearing aids is insufficient with respect
to speech understanding.25 In general,
cochlear implant outcomes in the AIED
patient population are quite good, if
not better than, the general cochlear
implant recipient population. However,
cochlear fibrosis and ossification are
possible obstacles if implantation is
delayed and, although no contraindi-
cations to implantation, these specific
findings may portend a worse prognosis
in each patient.
CONCLUSION
Autoimmune hearing loss is a rare,
but potentially treatable form of sud-
den hearing loss in children. Most
cases present acutely and involve both
ears with differing degrees of hearing
impairment. Positive response to cor-
ticosteroid or other immunosuppres-
sive treatment supports the diagnosis.
Unfortunately, there are no definitive
diagnostic criteria or reliable serologic
markers. Therefore, a high index of sus-
picion for the diagnosis is appropriate
when acute bilateral asymmetric sen-
sorineural hearing loss is encountered,
and other possible etiologies have been
ruled out. Consideration of an early
trial of corticosteroid therapy is a rea-
sonable approach to suspected cases,
whereas cochlear implantation is a vi-
able option for most long-term treatment
failures.
REFERENCES
1. McCabe BF. Autoimmune sensorineu-
ral hearing loss. Ann Otol Rhinol Lar-
yngol. 1979;88(5):585-589. https://doi.
org/10.1177/000348947908800501
2. Ciorba A, Corazzi V, Bianchini C, et al.
Autoimmune inner ear disease (AIED):
a diagnostic challenge. Int J Immuno-
pathol Pharmacol. 2018;32. https://
d o i . o rg / 1 0 . 1 1 7 7 / 2 0 5 8 7 3 8 4 1 8 8 0 8 6 8 0
PMID:30376736
3. Stew BT, Fishpool SJ, Williams H. Sud-
den sensorineural hearing loss. Br J Hosp
Med (Lond). 2012;73(2):86-89. https://
d o i . o rg / 1 0 . 1 2 9 6 8 / h m e d . 2 0 1 2 . 7 3 . 2 . 8 6
PMID:22504750
4. Pitaro J, Bechor-Fellner A, Gavriel H, Ma-
rom T, Eviatar E. Sudden sensorineural hear-
ing loss in children: Etiology, management,
and outcome. Int J Pediatr Otorhinolaryngol.
2016;82:34-37. https://doi.org/10.1016/j.
ijporl.2015.12.022 PMID:26857312
5. Tarshish Y, Leschinski A, Kenna M. Pediatric
sudden sensorineural hearing loss: diagnosed
causes and re-sponse to intervention. Int J Pe-
diatr Otorhinolaryngol. 2013;77(4):553-559.
https://doi.org/10.1016/j.ijporl.2013.01.004
PMID:23369615
6. Ruckenstein MJ. Autoimmune inner ear
disease. Curr Opin Otolaryngol Head Neck
Surg. 2004;12(5):426-430. https://doi.
org/10.1097/01.moo.0000136101.95662.aa
PMID:15377956
7. Vambutas A, Pathak S. AAO: autoimmune
and autoinflammatory (disease) in otology:
what is new in immune-mediated hearing
loss. Laryngoscope Investig Otolaryngol.
2016;1(5):110-115. https://doi.org/10.1002/
lio2.28 PMID:27917401
8. Kim JY, Han JJ, Sunwoo WS, et al. Sud-
den sensorineural hearing loss in children
and adolescents: clinical characteristics and
age-related prognosis. Auris Nasus Lar-
ynx. 2018;45(3):447-455. doi:10.1016/j.
anl.2017.08.010
9. Huang NC, Sataloff RT. Autoimmune in-
ner ear disease in children. Otol Neu-
rotol. 2011;32(2):213-216. https://doi.
org/10.1097/MAO.0b013e318204ac01
PMID:21178803
10. Li G, You D, Ma J, Li W, Li H, Sun S.
The role of autoimmunity in the patho-
genesis of sudden sensorineural hearing
loss. Neural Plast. 2018;2018:7691473.
e393

https://doi.org/10.1155/2018/7691473
PMID:30008743 34. doi:10.1080/000164801300006236
11. Céspedes Cruz AI, Méndez Núñez M, Solís
Vallejo E, et al. Frequency of auditory
involvement and of associated factors in
patients with juvenile idiopathic arthri-
tis. Rheumatol Clin. 2019;15(3):152-155.
doi:10.1016/j.reuma.2017.07.003
12. Ikiz AO, Unsal E, Kirkim G, Erdag TK,
Guneri EA. Hearing loss and middle ear
involvement in patients with juvenile id-
iopathic arthritis. Int J Pediatr Otorhino-
laryngol. 2007;71(7):1079-1085. https://
d o i . o rg / 1 0 . 1 0 1 6 / j . i j p o r l . 2 0 0 7 . 0 3 . 0 1 7
PMID:17482280
13. Lidar M, Carmel E, Kronenberg Y, Lan-
gevitz P. Hearing loss as the present-
ing feature of systemic vasculitis. Ann
N Y Acad Sci. 2007;1107(1):136-141.
https://doi.org/10.1196/annals.1381.015
PMID:17804541
14. Harris JP, Sharp PA. Inner ear autoanti-
bodies in patients with rapidly progres-
sive sensorineural hearing loss. Laryngo-
scope. 1990;100(5):516-524. https://doi.
org/10.1288/00005537-199005000-00015
PMID:2329911
15. Boulassel MR, Deggouj N, Tomasi JP, Gers-
dorff M. Inner ear autoantibodie s and their
targets in patients with autoimmune, inner
e394
SPECIAL ISSUE ARTICLE
ear diseases. Acta Otolaryngol. 2001;121:28-
16. Bloch DB, San Martin JE, Rauch SD,
Moscicki RA, Bloch KJ. Serum antibodies
to heat shock protein 70 in sen-sorineural
hearing loss. Arch Otolaryngol Head Neck
Surg. 1995;121(10):1167-1171. https://doi.
org/10.1001/archotol.1995.01890100075013
PMID:7546586
17. Yoo TJ, Stuart JM, Kang AH, Townes AS,
Tomoda K, Dixit S. Type II collagen auto-
immunity in otosclerosis and Meniere’s dis-
ease. Science. 1982;217(4565):1153-1155.
https://doi.org/10.1126/science.7112122
PMID:7112122
18. Bonaguri C, Orsoni J, Russo A, et al. Cogan’s
syndrome: anti-Hsp70 antibodies are a sero-
logical marker in the typical form. Isr Med As-
soc J. 2014;16(5):285-288. PMID:24979832
19. Kleffner I, Dörr J, Ringelstein M, et al; Euro-
pean Susac Consortium (EuSaC). Diagnostic
criteria for Susac syn-drome. J Neurol Neu-
rosurg Psychiatry. 2016;87(12):1287-1295.
https://doi.org/10.1136/jnnp-2016-314295
PMID:28103199
20. Berrocal JR, Ramírez-Camacho R. Sud-
den sensorineural hearing loss: supporting
the immunologic theory. Ann Otol Rhinol
Laryngol. 2002;111(11):989-997. https://
doi.org/10.1177/000348940211101107
PMID:12450172
21. Niparko JK, Wang NY, Rauch SD, et al. Serial
audiometry in a clinical trial of AIED treatment.
Otol Neurotol. 2005;26(5):908-917. https://doi.
org/10.1097/01.mao.0000185081.28598.5c
PMID:16151337
22. Xenellis J, Papadimitriou N, Nikolopou-
los T, et al. Intratympanic steroid treatment
in idiopathic sudden senso-rineural hear-
ing loss: a control study. Otolaryngol Head
Neck Surg. 2006;134(6):940-945. https://
doi.org/10.1016/j.otohns.2005.03.081
PMID:16730534
23. Matteson EL, Fabry DA, Facer GW, et al. Open
trial of methotrexate as treatment for autoimmune
hearing loss. Arthritis Rheum. 2001;45(2):146-
150. https://doi.org/10.1002/1529-0131(2001
04)45:2<146::AID-ANR167>3.0.CO;2-I
PMID:11324778
24. Harris JP, Weisman MH, Derebery JM,
et al. Treatment of corticosteroid-respon-
sive autoimmune inner ear disease with
methotrexate: a randomized controlled
trial. JAMA. 2003;290(14):1875-1883.
https://doi.org/10.1001/jama.290.14.1875
PMID:14532316
25. Sakano H, Harris JP. Emerging options in im-
mune-mediated hearing loss. Laryngoscope In-
vestig Otolaryngol. 2018;4(1):102-108. https://
doi.org/10.1002/lio2.205 PMID:30828626
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