Autoimmunity Reviews 10 (2011) 756761

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Review

Sudden sensorineural hearing loss: An autoimmune disease?

A. Greco , M. Fusconi, A. Gallo, C. Marinelli, G.F. Macri, M. De Vincentiis
ENT Department, Hospital Policlinico Umberto I University of Rome, Sapienza, Italy

a r t i c l e

i n f o

a b s t r a c t
Objectives: To review our current knowledge of the pathogenesis of sudden sensorineural hearing loss,
including viral infection, vascular occlusion and immune system-mediated mechanisms, and to discuss the
pathogenesis as it relates to pharmacotherapy.
Systematic review methodology: Relevant publications on the pathogenesis of sudden sensorineural hearing
loss from 1944 to 2010 were analysed.
Results and conclusions: Sudden sensorineural hearing loss is dened as hearing loss of 30 dB in three
sequential frequencies over 3 days or less. It can be an isolated symptom or the presenting symptom of a
systemic disease. The aetiology and pathogenesis remain unknown. Detailed investigation typically reveals a
specic cause in about 10% of patients. Proposed theories of causation include viral infections, vascular
occlusion and immune system-mediated mechanisms. A variety of therapies have been proposed based on
the various proposed aetiologies.
2011 Elsevier B.V. All rights reserved.

Article history:
Received 1 May 2011
Accepted 5 May 2011
Available online 18 May 2011
Keywords:
Measles virus
Hearing loss
Autoimmunity

Contents
1.

Introduction . . . . . . . . . .
1.1.
Aetiology . . . . . . . .
1.2.
Viral hypothesis . . . . .
1.3.
Vascular theory . . . . .
1.4.
Immunologic theory . . .
1.5.
Therapeutic considerations
2.
Conclusions . . . . . . . . . .
Take-home messages . . . . . . . .
References . . . . . . . . . . . . .

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1. Introduction
Sudden sensorineural hearing loss was described for the rst time
by De Klein in 1944, and it is dened as hearing loss of at least 30 dB in
three sequential frequencies in the standard pure tone audiogram
over 3 days or less [1]. It occurs abruptly and is a frightening
experience for patients.
The incidence of sudden sensorineural hearing loss (SSHL) has
been reported to range from 5 to 20 cases per 100,000 persons per
year [2]. British surveys have estimated between 5 and 30 cases per
100,000 per year [3,4]. However, a German study reported an
incidence of up to 160 cases per 100,000 per year [5]. The disease

Corresponding author at: P.zza Acilia no. 4, 00100 Rome, Italy. Tel.: +39 3355948375.
E-mail addresses: antonio.greco@uniroma1.it, giano1979@hotmail.com (A. Greco).
1568-9972/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2011.05.005

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has a wide age distribution, with an average of 5060 years, but is

equally distributed between genders. The hearing loss is unilateral in
most cases, with bilateral involvement reported in less than 5% [6].
Tinnitus occurs in about 80% of patients, and vertigo in about 30% [7].
Up to 80% of patients report a feeling of aural fullness [8].
Sudden sensorineural hearing loss can be an isolated problem or
the presenting symptom of a systemic disease, such as Wegener's
granulomatosis [9], Sjogren's syndrome [10], relapsing polychondritis
[11], polyarteritis nodosa [12], systemic lupus erythematous [13] or
Behet's disease [14].
1.1. Aetiology
Although it has a high spontaneous recovery rate of 4065% [15],
the aetiology and pathogenesis of sudden deafness remains unknown
[16]. For this reason, SSHL remains one of the most controversial and

A. Greco et al. / Autoimmunity Reviews 10 (2011) 756761

challenging issues in otology. Detailed investigation show a specic

cause in about 10% of patients [17]. The term idiopathic sudden
sensorineural hearing loss is often used to describe the remainder of
patients.
Proposed theories of causation include viral infection [18], vascular
occlusion [19] and immune system-mediated mechanisms [20]. A
variety of medical and surgical therapies have been proposed over the
past several decades that have been based on these aetiologic
theories. Some of these therapies have resulted in signicant
morbidity or even mortality [21,22]. Therefore, elucidation of the
pathogenesis responsible for this enigmatic entity is vital if progress is
to be made in treating this condition.
1.2. Viral hypothesis
There are three mechanisms that have been proposed to explain
how a viral infection can lead to sudden sensorineural hearing loss
[23]. One possible mechanism is viral infection of the cochlea
(cochleitis) or of the cochlear nerve (neuritis). The virus is presumed
to reach the inner ear from haematogenous spread, although other
routes of spread are possible, such as from the cerebrospinal uid
space or from the middle ear.
The second proposed mechanism is reactivation of a latent viral
infection of the inner ear. The third mechanism by which a virus could
trigger SSHL is an indirect mechanism. This third mechanism involves
a systemic or distant viral infection that triggers an antibody response
that cross-reacts with an inner ear antigen. This is an example of the
immune system-mediated hypothesis. In this third scenario there is
not a direct viral attack on the inner ear.
The viral hypothesis of SSHL typically refers collectively to the
rst two mechanisms, which involve direct viral invasion of the inner
ear or reactivation of a latent virus within the ear. The mumps virus
has been reported to cause sudden deafness in clinical and serologic
studies [24,25]. However, many studies have found that mumps
infections accounted only for a small fraction (less than 10%) of cases
of SSHL [25,26]. Measles and rubella have also been associated with
sudden deafness [26,27].
With widespread immunisation against mumps, measles and
rubella viruses the incidence of these infections has fallen drastically
and SSHL due to these aetiologic agents has nearly been eradicated.
However, there has not been a concomitant decline in the overall
incidence of SSHL [28], further supporting the argument that these
particular viruses are not the primary cause of SSHL.
Members of the Herpesviridae family of viruses have been
proposed as a cause of SSHL [2931]. The herpes virus family includes
the following: herpes simplex types 1 and 2, varicella zoster virus

757

(VZV), cytomegalovirus (CMV), EpsteinBarr virus, and human

herpesviruses 6, 7 and 8 (HHV-6, HHV-7, and HHV-8). All of these
viruses, once acquired, persist in their latent forms for the duration of
an infected person's life. Most adults are seropositive for several of
these viruses, having acquired them during childhood. These adults
are, therefore, not susceptible to new (acute), and SSHL in a
seropositive patient can only be explained by reactivation of latent
virus. Unfortunately, there are no reliable serologic tests to diagnose
reactivation. Once an individual is seropositive for a latent herpes
virus, an increase in his or her titre does not diagnose reactivation.
Other types of viruses, such as respiratory viruses, adenoviruses
and arenaviruses, have also been implicated in SSHL based on
anamnestic or serological data [18,26,28]. Pitkaranta and Julkunen
could not detect production of interferon or interferon-induced gene
expression in peripheral blood samples of patients with SSHL [32],
both of which are useful diagnostic markers for systemic viral
infections. Pitkaranta and Julkunen's study is signicant because it
did not target specic viruses, but rather it assayed for sensitive
markers of a systemic viral infection in general. Their study supports
the argument that SSHL is not commonly associated with a systemic
viral infection.
Westmore et al. [33] were able to isolate live mumps virus from
the perilymph of a young woman who presented with SSHL after
mumps parotitis. This is the only report that has demonstrated a
direct role of a virus as a causative agent in SSHL. Not all cases of
mumps-induced sensorineural hearing loss occur after mumps
parotitis [34,35]. In a study of meningitis and hearing loss [36],
Nadol did not nd hearing loss in any of 304 patients with viral
meningitis. Given the close communication between CSF and inner
ear uids, this lack of association argues against one specic group of
viruses, the enteroviruses, as the aetiology of SSHL. Enteroviruses
(e.g., coxsackievirus, echovirus, etc.) are the causative agents of 90% of
cases of viral meningitis [37].
A number of reports have described the histopathological ndings
in the temporal bones of patients who had SSHL during their lifetime
[21,22,38,39] (see Fig. 1). In all these studies, evidence of viral
infections of the inner ear was lacking. Evidence of viral infection
includes the following: isolation of a virus from the labyrinth,
demonstration of typical viral cytopathological abnormalities, demonstration of viral particles by electron microscopy, or identication
of specic viral antigens.
Many studies have been performed using direct inoculation of
pathogenic viruses into the inner ears of experimental animals to
study SSHL. Unfortunately, these studies have not replicated the
clinical or histopathological features observed in patients with SSHL
[40]. In many studies, viral inoculation resulted in a progressive form

Fig. 1. Photomicrographs of cochleas. A cochlea in patient with sensorineural hearing loss with decrease in spiral ganglion. B normal cochlea. Picture taken from: Vasama JP,
Linthicum FH. Idiopatic sudden sensorineural hearing loss: temporal bone hystopathologic study. Ann. Otol. Rhinol. Laryngol 109: 2000. 527532.

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A. Greco et al. / Autoimmunity Reviews 10 (2011) 756761

of hearing loss, rather than a sudden onset of the disorder. Moreover,

the histopathological ndings within the cochlea were characterised
by leukocytic inltration, haemorrhage and degeneration of sensory
and neural structures, followed by brosis and new bone formation in
some cases [41,42]. In other studies, experimental inoculation of
viruses into the labyrinth had little or no pathogenic effects [43,44].
1.3. Vascular theory
Vascular occlusion has been proposed as a mechanism for sudden
deafness [45] based on the catastrophic nature of the event, which is
similar to a thromboembolic stroke. However, the many clinical and
experimental observations reported in the literature do not support a
vascular aetiology of SSHL. Thromboembolic events could be expected
to be more common in elderly patients with SSHL, but this is not the
case [46]. Furthermore, SSHL frequently occurs in young, healthy
people.
The labyrinthine artery is a terminal artery that supplies both the
cochlea and the vestibular sensory organ [47]. Therefore, it is difcult
to explain cases of SSHL without vertigo using the vascular theory.
Experimental compromise of the cochlear blood supply results in an
irreversible hearing loss after 1 h of occlusion, even if blood ow is
restored subsequently [48]. In contrast, patients with SSHL may
experience recovery of function over the course of days to weeks. In
addition, the hallmark of a vascular insult to the cochlea consists of
deposition of connective tissue and new bone within the cochlea
[49,50]. (see Fig. 2). However, connective tissue and new bone was
found in only 1 of 17 cases in a temporal bone collection [51] and has
been reported in only 2 of 29 patients with SSHL in the literature
[52,53]. Under physiological conditions, blood supply to the inner ear
is provided by the labyrinthine artery, which is a functional end artery
of the anterior inferior cerebellar artery (AICA).
Recent studies [54] have shown the involvement of genetic
mutations associated with thrombotic, micro-angiopathic disorders
in the development of SSHL. It has been suggested that congenital
and/or acquired thrombophilia may have a pathogenic role in the
development of SSHL. Congenital thrombophilias are represented by
well-described gene polymorphisms, such as factor V Leiden, which is
characterised by a G169 A mutation. Other known polymorphisms
that have already been studied include a mutated prothrombin
characterised by G 2021 A in the promoter region of the gene.
The most common acquired thrombophilia is characterised by the
presence of lupus anticoagulant or antiphospholipid antibodies.

Fig. 2. Midmodiolar section showing complete degeneration of sensory and neural

structures with replacement by brous tissue and new bone. The cochlear duct is not
affected in the lower basal turn, where hair cells are present with innervating dendrites.
Picture taken from: Saumil NM, Joe CA, Nadol JB. Pathology and pathophysiology of
idiopathic sudden sensorineural hearing loss. Otology & Neurotology 2005; 26:151160.

Hyperhomocysteinemia is another condition that predisposes to the

development of arteriovenous thrombosis that may be genetic (i.e.,
MTHFR C677T homozygosity, homocystinuria) or acquired (e.g.,
eating disorders, thyroid disorders, kidney disease) [55]. The blood
ow in the labyrinthine artery is regulated by adrenergic receptors,
particularly in the smooth muscle cells of the modiolus. Distal blood
ow is poorly regulated and strongly dependent on plasma viscosity
and platelet function.
Recently, it was reported that LDL and brinogen apheresis
treatment improves outcomes in patients with SSHL, suggesting
that vascular factors may play a greater role in the pathogenesis of
SSHL than was previously assumed [56,57]. Fibrinogen is a major
determinant of plasma viscosity; elevated brinogen levels are
associated with an increased risk of cardiovascular and atherothrombotic disease [58,59]. Reduction in the level of LDL results in more
efcient release of nitric oxide, the main mediator of blood vessel
diameter, and reduces platelet aggregation potential [60,61].
Increased LDL and reduced HDL cholesterol plasma concentrations
are amongst the most predictive coronary risk factors [62]. However,
patients with SSHL had neither elevated LDL cholesterol levels nor
reduced HDL cholesterol levels. Fibrinogen concentrations have been
reported to be increased in SSHL patients [63]. Higher brinogen
levels may contribute to SSHL by increasing the plasma viscosity and
enhancing platelet activity [64].
Some authors have found that the risk of stroke was 1.6 times
greater among SSHL patients, and the risk was particularly high for
strokes involving the AICA [65]. Therefore, SSHL may be a predictor of
subsequent stroke, a fact that has important clinical implications for
the care of SSHL patients [66]. Some authors suggest that SSHL
patients, particularly those who are elderly or have other vascular
conditions, should undergo haematological and neurological examinations to help clinicians identify those who are potentially at risk for
stroke in the near future [67].
1.4. Immunologic theory
The immunologic hypothesis is based on the theory that
circulating antibodies cross-react with inner ear antigens [68,69] or
activated T cells, thereby damaging the inner ear [69]. Such antibodies
may be triggered by viruses or other agents. A number of inner ear
antigens have been proposed as targets of such antibodies, including
type 2 collagen [70], Beta-actin [71], Cochlin [72,73] and Beta-tectorin
[73]. The best documented of these antibodies is against choline
transporter-like protein 2 (CTL2), an inner ear glycoprotein [74]. Out
of a group of 20 patients with SSHL, 9 were found to have antibodies
against CTL2 [75]. In Cogan's syndrome, immunoglobulins against a
supporting cell protein (DEP-1/CD148) and connexin 26 (a gap
junction protein) have been detected within the sensory epithelia of
the inner ear, and these antibodies led to sensorineural hearing loss in
mice [76].
In patients with SSHL, autoantibodies against antigens of the inner
ear, like types 2 and 9 collagen [77,78], P30 [72] and P80 cochlear
proteins [68], cardiolipin [79], serotonin and ganglioside [80], have
been detected. In addition, reductions in the T lymphocyte subpopulations C3, C4 and C8 [81,82] and an increase in the level of C3bc
complement factor [83] have been found in patients with SSHL. Antiendothelial cell antibodies (AECAs) are a heterogeneous group of
antibodies directed against endothelial cells. They have been detected
in several diseases that all involve vessel wall damage [84]. There is an
increasing body of evidence that AECAs might play a role in triggering
autoimmune vascular diseases. In fact, experimental in vitro and in
vivo models have supported a pathogenic role for AECAs in sustaining
immune-mediated vessel damage.
Anti-endothelial cell antibodies have been described in a variety of
diseases, including connective tissue disorders and systemic vasculitis
[85,86]. Some authors have reported the presence of serum anti-

A. Greco et al. / Autoimmunity Reviews 10 (2011) 756761

endothelial cell autoantibodies in patients with SSHL [87]. The

relationship between the inner ear and the immune system was
originally established by McCabe [88], who described a clinical entity
characterised by steroid-responsive, rapidly-progressive sensorineural hearing loss. Serological evidence supporting the involvement of
the immune system in SSHL was provided by Harris and Sharp [89],
who found circulating antibodies against several cochlear antigens in
patients with idiopathic, progressive, bilateral sensorineural hearing
loss (IPBSNHL). One of these antigens is a 68-kDa protein that was
originally believed to be specic to the inner ear but was later
identied as heat shock protein-70 (HSP70), which is also expressed
in other tissues [9092]. Anti-HSP70 antibodies have been reported to
occur in 10.519% of patients with SSHL [93,94].
Previous publications have established an association between
SSNHL and autoantibodies directed against phospholipids (anti-PLs)
in systemic lupus erythematosus patients [95,96]. These autoantibodies,
mainly anti-cardiolipin (anti-CL) and anti-beta-2-glycoprotein-1 (antibeta-2-GP1), are associated with thrombotic phenomena in antiphospholipid syndromes (APSs) and are considered pro-atherogenic. AntiPL antibodies have a pathogenic effect on platelets and vascular
endothelial cells, resulting in vaso-occlusive manifestations. The actual
targets of the anti-PLs antibodies are cardiolipin and the binding protein
cofactor beta-2-GP-1 (also called apolipoprotein H).
It has been suggested that these autoantibodies induce thrombosis
in the labyrinthine vessels, thereby causing subsequent damage to the
inner ear that results in SNHL [95]. Anti-CL and anti-beta-2-GP-1
antibodies have been detected in 12.931% and 6.612% of patients
with SSHL, respectively [9799]. Another study has reported anti-PL
(33.3%) and anti-HSP70 (25.4%) antibodies in SNHL patients [100].
Velmann found anti-HSP70 antibodies in 40% of SNHL patients [101].
Anti-PL antibodies can be induced by human viruses [102,103]. Viral
peptides trigger an immune response and, as a result, lead to the
development of pathogenic anti-PL antibodies, particularly in predisposed individuals.
A similar mechanism may underlie the production of anti-PL
antibodies in idiopathic SNHL patients. Acute obstruction of the small
vessels of the labyrinthine circulation is one possible cause of SNHL,
and such a mechanism would account for its immediate onset. The
dissolution of a thrombus and reperfusion of the labyrinthine vessel
hours or days after the thrombotic event might offer a partial
explanation of the clinical course of the SNHL [104]. HSPs are
ubiquitous proteins in phylogeny, and their presence in a diverse
array of species, including microorganisms, may increase the
possibility of an immune response to microbial HSPs that can crossreact with human HSPs [105,106]. However, further studies are
necessary in order to clarify the immunologic role of antibodies found
in SNHL patients and their impact on the treatment of these patients.
1.5. Therapeutic considerations
In most cases of SNHL, no specic cause is identied, and the
following empirical treatments can be considered. Oral corticosteroids
are widely used, and their main effect is suppression of the inner ear's
immune response [106,107]. Patients can be treated with a short course
of oral prednisolone (e.g., 1 mg/kg per day or a maximum of 60 mg daily
for adults for 10 days) [107]. Although the greatest extent of hearing
recovery occurs when corticosteroid therapy is initiated 12 weeks after
the onset of symptoms, a response to prednisolone started as late as
2 months after SNHL onset has been reported [108].
Intra-tympanic dexamethasone has been used as an experimental
therapy in patients with SSHL because it achieves a high concentration
of steroids in the labyrinth in animal models [109] In a multi-centre,
randomised controlled trial [110], methotrexate was no more
effective than placebo in patients with progressive bilateral hearing
loss [111]. Case reports have shown benets to using immunosuppressants (e.g., cyclophosphamide, azathioprine, mycophenolate

759

mofetil) in patients with progressive sensorineural hearing loss, but

no studies have studied these drugs in patients with sudden
sensorineural hearing loss. In cases in which a vascular cause cannot
be excluded, a low dose of oral aspirin may be benecial [112]. To our
knowledge, there is little evidence supporting the use of heparin and
intravenous thrombolytics in SNHL [113].
A systematic review showed no benets to using hyperbaric
oxygen therapy for the treatment of SNHL [114]. Treatment with
carbogen, a gaseous mixture of 5% carbon dioxide and 95% oxygen, has
been investigated and found to have variable benets [115]. Several
other treatments have been investigated because of speculation about
the pathogenesis of SNHL. Treatment with antiviral agents (e.g.,
acyclovir, valacyclovir) has not shown benet in randomised
controlled trials [116].
2. Conclusions
We reviewed the most important theories of causation of sudden
sensorineural hearing loss, with an emphasis on the immunologic
theory. We analysed the published evidence for and against the
various theories. The evidence indicates that viral and vascular
aetiologies can, in some cases, lead to sudden deafness. However,
the published evidence supports the idea that the immunologic
theory is a more common cause. Therefore, we recommend that
patients with idiopathic SNHL should be treated with corticosteroids
or immunosuppressants.
There is much that remains to be understood about the pathogenesis
of SSNHL, and more clinical trials are necessary to establish evidencebased treatments. Further studies are necessary to identify and clarify
the immunologic role of antibodies found in SNHL patients and their
impact on the treatment of the disease.
Take-home messages
Sudden sensorineural hearing loss is an autoimmune disease. Its
pathogenesis includes viral infection and vascular disorders.
Due to the possible autoimmune pathogenesis of the disease,
pharmacotherapy for sudden SNHL may include corticosteroids and
immunosuppressants. The use of antiviral agents aligns with the
viral hypothesis, and low-dose aspirin and carbogen align with the
vascular theory.
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Is SF-36 a reliable outcome of neurophychiatric events in patients affected with systemic lupus erythematosus?
Neuropsychiatric events in patients affected with systemic lupus erythematosus (SLE) represent a poor prognostic factor and until now none
of the known approaches for the outcome assessment of these patients, such as neuroimaging alone or in combination with clinical variable
have been validated.
The Systemic Lupus International Collaborating Clinics (SLICC) proposes the short form SF-36 as reliable outcome measure for the study of
neuropsychiatric events in SLE patients (Ann Rheum Dis 2011; 50:961-67). The Authors consider a large cohort of 1,400 SLE patients and
identied 274 patients that had one or more neuropsychiatric events. The SF-36, particularly the mental component summary, changed in
the appropriate direction in association with both clinical improvement and worsening.
In conclusion SF-36 should be considered as a reliable outcome of neuropsychiatric events in SLE patients.
Luca Iaccarino