Autoimmunity Reviews 10 (2011) 756–761

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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

Article history: Objectives: To review our current knowledge of the pathogenesis of sudden sensorineural hearing loss,
Received 1 May 2011 including viral infection, vascular occlusion and immune system-mediated mechanisms, and to discuss the
Accepted 5 May 2011 pathogenesis as it relates to pharmacotherapy.
Available online 18 May 2011 Systematic review methodology: Relevant publications on the pathogenesis of sudden sensorineural hearing
loss from 1944 to 2010 were analysed.
Keywords:
Results and conclusions: Sudden sensorineural hearing loss is defined as hearing loss of 30 dB in three
Measles virus
Hearing loss
sequential frequencies over 3 days or less. It can be an isolated symptom or the presenting symptom of a
Autoimmunity systemic disease. The aetiology and pathogenesis remain unknown. Detailed investigation typically reveals a
specific 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.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
1.1. Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
1.2. Viral hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
1.3. Vascular theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
1.4. Immunologic theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
1.5. Therapeutic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759

1. Introduction has a wide age distribution, with an average of 50–60 years, but is
equally distributed between genders. The hearing loss is unilateral in
Sudden sensorineural hearing loss was described for the first time most cases, with bilateral involvement reported in less than 5% [6].
by De Klein in 1944, and it is defined as hearing loss of at least 30 dB in Tinnitus occurs in about 80% of patients, and vertigo in about 30% [7].
three sequential frequencies in the standard pure tone audiogram Up to 80% of patients report a feeling of aural fullness [8].
over 3 days or less [1]. It occurs abruptly and is a frightening Sudden sensorineural hearing loss can be an isolated problem or
experience for patients. the presenting symptom of a systemic disease, such as Wegener's
The incidence of sudden sensorineural hearing loss (SSHL) has granulomatosis [9], Sjogren's syndrome [10], relapsing polychondritis
been reported to range from 5 to 20 cases per 100,000 persons per [11], polyarteritis nodosa [12], systemic lupus erythematous [13] or
year [2]. British surveys have estimated between 5 and 30 cases per Behçet's disease [14].
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 1.1. Aetiology

Although it has a high spontaneous recovery rate of 40–65% [15],

⁎ Corresponding author at: P.zza Acilia no. 4, 00100 Rome, Italy. Tel.: +39 3355948375. the aetiology and pathogenesis of sudden deafness remains unknown
E-mail addresses: [email protected], [email protected] (A. Greco). [16]. For this reason, SSHL remains one of the most controversial and

1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2011.05.005
 A. Greco et al. / Autoimmunity Reviews 10 (2011) 756–761 757

challenging issues in otology. Detailed investigation show a specific (VZV), cytomegalovirus (CMV), Epstein–Barr virus, and human
cause in about 10% of patients [17]. The term idiopathic sudden herpesviruses 6, 7 and 8 (HHV-6, HHV-7, and HHV-8). All of these
sensorineural hearing loss is often used to describe the remainder of viruses, once acquired, persist in their latent forms for the duration of
patients. an infected person's life. Most adults are seropositive for several of
Proposed theories of causation include viral infection [18], vascular these viruses, having acquired them during childhood. These adults
occlusion [19] and immune system-mediated mechanisms [20]. A are, therefore, not susceptible to new (acute), and SSHL in a
variety of medical and surgical therapies have been proposed over the seropositive patient can only be explained by reactivation of latent
past several decades that have been based on these aetiologic virus. Unfortunately, there are no reliable serologic tests to diagnose
theories. Some of these therapies have resulted in significant reactivation. Once an individual is seropositive for a latent herpes
morbidity or even mortality [21,22]. Therefore, elucidation of the virus, an increase in his or her titre does not diagnose reactivation.
pathogenesis responsible for this enigmatic entity is vital if progress is Other types of viruses, such as respiratory viruses, adenoviruses
to be made in treating this condition. and arenaviruses, have also been implicated in SSHL based on
anamnestic or serological data [18,26,28]. Pitkaranta and Julkunen
1.2. Viral hypothesis could not detect production of interferon or interferon-induced gene
expression in peripheral blood samples of patients with SSHL [32],
There are three mechanisms that have been proposed to explain both of which are useful diagnostic markers for systemic viral
how a viral infection can lead to sudden sensorineural hearing loss infections. Pitkaranta and Julkunen's study is significant because it
[23]. One possible mechanism is viral infection of the cochlea did not target specific viruses, but rather it assayed for sensitive
(cochleitis) or of the cochlear nerve (neuritis). The virus is presumed markers of a systemic viral infection in general. Their study supports
to reach the inner ear from haematogenous spread, although other the argument that SSHL is not commonly associated with a systemic
routes of spread are possible, such as from the cerebrospinal fluid viral infection.
space or from the middle ear. Westmore et al. [33] were able to isolate live mumps virus from
The second proposed mechanism is reactivation of a latent viral the perilymph of a young woman who presented with SSHL after
infection of the inner ear. The third mechanism by which a virus could mumps parotitis. This is the only report that has demonstrated a
trigger SSHL is an indirect mechanism. This third mechanism involves direct role of a virus as a causative agent in SSHL. Not all cases of
a systemic or distant viral infection that triggers an antibody response mumps-induced sensorineural hearing loss occur after mumps
that cross-reacts with an inner ear antigen. This is an example of the parotitis [34,35]. In a study of meningitis and hearing loss [36],
immune system-mediated hypothesis. In this third scenario there is Nadol did not find hearing loss in any of 304 patients with viral
not a direct viral attack on the inner ear. meningitis. Given the close communication between CSF and inner
The “viral hypothesis” of SSHL typically refers collectively to the ear fluids, this lack of association argues against one specific group of
first two mechanisms, which involve direct viral invasion of the inner viruses, the enteroviruses, as the aetiology of SSHL. Enteroviruses
ear or reactivation of a latent virus within the ear. The mumps virus (e.g., coxsackievirus, echovirus, etc.) are the causative agents of 90% of
has been reported to cause sudden deafness in clinical and serologic cases of viral meningitis [37].
studies [24,25]. However, many studies have found that mumps A number of reports have described the histopathological findings
infections accounted only for a small fraction (less than 10%) of cases in the temporal bones of patients who had SSHL during their lifetime
of SSHL [25,26]. Measles and rubella have also been associated with [21,22,38,39] (see Fig. 1). In all these studies, evidence of viral
sudden deafness [26,27]. infections of the inner ear was lacking. Evidence of viral infection
With widespread immunisation against mumps, measles and includes the following: isolation of a virus from the labyrinth,
rubella viruses the incidence of these infections has fallen drastically demonstration of typical viral cytopathological abnormalities, dem-
and SSHL due to these aetiologic agents has nearly been eradicated. onstration of viral particles by electron microscopy, or identification
However, there has not been a concomitant decline in the overall of specific viral antigens.
incidence of SSHL [28], further supporting the argument that these Many studies have been performed using direct inoculation of
particular viruses are not the primary cause of SSHL. pathogenic viruses into the inner ears of experimental animals to
Members of the Herpesviridae family of viruses have been study SSHL. Unfortunately, these studies have not replicated the
proposed as a cause of SSHL [29–31]. The herpes virus family includes clinical or histopathological features observed in patients with SSHL
the following: herpes simplex types 1 and 2, varicella zoster virus [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. 527–532.
758 A. Greco et al. / Autoimmunity Reviews 10 (2011) 756–761

of hearing loss, rather than a sudden onset of the disorder. Moreover, Hyperhomocysteinemia is another condition that predisposes to the
the histopathological findings within the cochlea were characterised development of arteriovenous thrombosis that may be genetic (i.e.,
by leukocytic infiltration, haemorrhage and degeneration of sensory MTHFR C677T homozygosity, homocystinuria) or acquired (e.g.,
and neural structures, followed by fibrosis and new bone formation in eating disorders, thyroid disorders, kidney disease) [55]. The blood
some cases [41,42]. In other studies, experimental inoculation of flow in the labyrinthine artery is regulated by adrenergic receptors,
viruses into the labyrinth had little or no pathogenic effects [43,44]. particularly in the smooth muscle cells of the modiolus. Distal blood
flow is poorly regulated and strongly dependent on plasma viscosity
1.3. Vascular theory and platelet function.
Recently, it was reported that LDL and fibrinogen apheresis
Vascular occlusion has been proposed as a mechanism for sudden treatment improves outcomes in patients with SSHL, suggesting
deafness [45] based on the catastrophic nature of the event, which is that vascular factors may play a greater role in the pathogenesis of
similar to a thromboembolic stroke. However, the many clinical and SSHL than was previously assumed [56,57]. Fibrinogen is a major
experimental observations reported in the literature do not support a determinant of plasma viscosity; elevated fibrinogen levels are
vascular aetiology of SSHL. Thromboembolic events could be expected associated with an increased risk of cardiovascular and atherothrom-
to be more common in elderly patients with SSHL, but this is not the botic disease [58,59]. Reduction in the level of LDL results in more
case [46]. Furthermore, SSHL frequently occurs in young, healthy efficient release of nitric oxide, the main mediator of blood vessel
people. diameter, and reduces platelet aggregation potential [60,61].
The labyrinthine artery is a terminal artery that supplies both the Increased LDL and reduced HDL cholesterol plasma concentrations
cochlea and the vestibular sensory organ [47]. Therefore, it is difficult are amongst the most predictive coronary risk factors [62]. However,
to explain cases of SSHL without vertigo using the vascular theory. patients with SSHL had neither elevated LDL cholesterol levels nor
Experimental compromise of the cochlear blood supply results in an reduced HDL cholesterol levels. Fibrinogen concentrations have been
irreversible hearing loss after 1 h of occlusion, even if blood flow is reported to be increased in SSHL patients [63]. Higher fibrinogen
restored subsequently [48]. In contrast, patients with SSHL may levels may contribute to SSHL by increasing the plasma viscosity and
experience recovery of function over the course of days to weeks. In enhancing platelet activity [64].
addition, the hallmark of a vascular insult to the cochlea consists of Some authors have found that the risk of stroke was 1.6 times
deposition of connective tissue and new bone within the cochlea greater among SSHL patients, and the risk was particularly high for
[49,50]. (see Fig. 2). However, connective tissue and new bone was strokes involving the AICA [65]. Therefore, SSHL may be a predictor of
found in only 1 of 17 cases in a temporal bone collection [51] and has subsequent stroke, a fact that has important clinical implications for
been reported in only 2 of 29 patients with SSHL in the literature the care of SSHL patients [66]. Some authors suggest that SSHL
[52,53]. Under physiological conditions, blood supply to the inner ear patients, particularly those who are elderly or have other vascular
is provided by the labyrinthine artery, which is a functional end artery conditions, should undergo haematological and neurological exami-
of the anterior inferior cerebellar artery (AICA). nations to help clinicians identify those who are potentially at risk for
Recent studies [54] have shown the involvement of genetic stroke in the near future [67].
mutations associated with thrombotic, micro-angiopathic disorders
in the development of SSHL. It has been suggested that congenital 1.4. Immunologic theory
and/or acquired thrombophilia may have a pathogenic role in the
development of SSHL. Congenital thrombophilias are represented by The immunologic hypothesis is based on the theory that
well-described gene polymorphisms, such as factor V Leiden, which is circulating antibodies cross-react with inner ear antigens [68,69] or
characterised by a G169 A mutation. Other known polymorphisms activated T cells, thereby damaging the inner ear [69]. Such antibodies
that have already been studied include a mutated prothrombin may be triggered by viruses or other agents. A number of inner ear
characterised by G 2021 A in the promoter region of the gene. antigens have been proposed as targets of such antibodies, including
The most common acquired thrombophilia is characterised by the type 2 collagen [70], Beta-actin [71], Cochlin [72,73] and Beta-tectorin
presence of lupus anticoagulant or antiphospholipid antibodies. [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 sub-
populations C3, C4 and C8 [81,82] and an increase in the level of C3bc
complement factor [83] have been found in patients with SSHL. Anti-
endothelial 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
Fig. 2. Midmodiolar section showing complete degeneration of sensory and neural immune-mediated vessel damage.
structures with replacement by fibrous tissue and new bone. The cochlear duct is not
affected in the lower basal turn, where hair cells are present with innervating dendrites.
Anti-endothelial cell antibodies have been described in a variety of
Picture taken from: Saumil NM, Joe CA, Nadol JB. Pathology and pathophysiology of diseases, including connective tissue disorders and systemic vasculitis
idiopathic sudden sensorineural hearing loss. Otology & Neurotology 2005; 26:151–160. [85,86]. Some authors have reported the presence of serum anti-
 A. Greco et al. / Autoimmunity Reviews 10 (2011) 756–761 759

endothelial cell autoantibodies in patients with SSHL [87]. The mofetil) in patients with progressive sensorineural hearing loss, but
relationship between the inner ear and the immune system was no studies have studied these drugs in patients with sudden
originally established by McCabe [88], who described a clinical entity sensorineural hearing loss. In cases in which a vascular cause cannot
characterised by steroid-responsive, rapidly-progressive sensorineu- be excluded, a low dose of oral aspirin may be beneficial [112]. To our
ral hearing loss. Serological evidence supporting the involvement of knowledge, there is little evidence supporting the use of heparin and
the immune system in SSHL was provided by Harris and Sharp [89], intravenous thrombolytics in SNHL [113].
who found circulating antibodies against several cochlear antigens in A systematic review showed no benefits to using hyperbaric
patients with idiopathic, progressive, bilateral sensorineural hearing oxygen therapy for the treatment of SNHL [114]. Treatment with
loss (IPBSNHL). One of these antigens is a 68-kDa protein that was carbogen, a gaseous mixture of 5% carbon dioxide and 95% oxygen, has
originally believed to be specific to the inner ear but was later been investigated and found to have variable benefits [115]. Several
identified as heat shock protein-70 (HSP70), which is also expressed other treatments have been investigated because of speculation about
in other tissues [90–92]. Anti-HSP70 antibodies have been reported to the pathogenesis of SNHL. Treatment with antiviral agents (e.g.,
occur in 10.5–19% of patients with SSHL [93,94]. acyclovir, valacyclovir) has not shown benefit in randomised
Previous publications have established an association between controlled trials [116].
SSNHL and autoantibodies directed against phospholipids (anti-PLs)
in systemic lupus erythematosus patients [95,96]. These autoantibodies, 2. Conclusions
mainly anti-cardiolipin (anti-CL) and anti-beta-2-glycoprotein-1 (anti-
beta-2-GP1), are associated with thrombotic phenomena in antipho- We reviewed the most important theories of causation of sudden
spholipid syndromes (APSs) and are considered pro-atherogenic. Anti- sensorineural hearing loss, with an emphasis on the immunologic
PL antibodies have a pathogenic effect on platelets and vascular theory. We analysed the published evidence for and against the
endothelial cells, resulting in vaso-occlusive manifestations. The actual various theories. The evidence indicates that viral and vascular
targets of the anti-PLs antibodies are cardiolipin and the binding protein aetiologies can, in some cases, lead to sudden deafness. However,
cofactor beta-2-GP-1 (also called apolipoprotein H). the published evidence supports the idea that the immunologic
It has been suggested that these autoantibodies induce thrombosis theory is a more common cause. Therefore, we recommend that
in the labyrinthine vessels, thereby causing subsequent damage to the patients with idiopathic SNHL should be treated with corticosteroids
inner ear that results in SNHL [95]. Anti-CL and anti-beta-2-GP-1 or immunosuppressants.
antibodies have been detected in 12.9–31% and 6.6–12% of patients There is much that remains to be understood about the pathogenesis
with SSHL, respectively [97–99]. Another study has reported anti-PL of SSNHL, and more clinical trials are necessary to establish evidence-
(33.3%) and anti-HSP70 (25.4%) antibodies in SNHL patients [100]. based treatments. Further studies are necessary to identify and clarify
Velmann found anti-HSP70 antibodies in 40% of SNHL patients [101]. the immunologic role of antibodies found in SNHL patients and their
Anti-PL antibodies can be induced by human viruses [102,103]. Viral impact on the treatment of the disease.
peptides trigger an immune response and, as a result, lead to the
development of pathogenic anti-PL antibodies, particularly in predis-
Take-home messages
posed individuals.
A similar mechanism may underlie the production of anti-PL
• Sudden sensorineural hearing loss is an autoimmune disease. Its
antibodies in idiopathic SNHL patients. Acute obstruction of the small
pathogenesis includes viral infection and vascular disorders.
vessels of the labyrinthine circulation is one possible cause of SNHL,
• Due to the possible autoimmune pathogenesis of the disease,
and such a mechanism would account for its immediate onset. The
pharmacotherapy for sudden SNHL may include corticosteroids and
dissolution of a thrombus and reperfusion of the labyrinthine vessel
immunosuppressants. The use of antiviral agents aligns with the
hours or days after the thrombotic event might offer a partial
viral hypothesis, and low-dose aspirin and carbogen align with the
explanation of the clinical course of the SNHL [104]. HSPs are
vascular theory.
ubiquitous proteins in phylogeny, and their presence in a diverse
array of species, including microorganisms, may increase the
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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
identified 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