# Combination Immunosuppressive Therapy in Primary Autoimmune Inner Ear Disease in Pregnancy

Authors: Saikrishna Ananthapadmanabhan; Joe Jabbour; David Brown; Vanaja Sivapathasingam
Journal: Case Reports in Otolaryngology
 (2022)

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## Abstract

Objective. Autoimmune inner ear disease (AIED) is a rare disorder characterized by rapidly progressive, sensorineural hearing loss that demonstrates good responsiveness to corticosteroid and immunosuppressive therapy. The pathophysiology is likely driven by chronic trafficking of immune cells into the inner ear, targeting inner ear proteins to coordinate inflammation. Suppression or modulation of the immune response can minimize cochleitis allowing for potential recovery of hearing. It is an otologic emergency requiring a multidisciplinary approach to management to commence immunosuppressive therapy. This can be achieved using steroids, immunomodulators, plasmapheresis, intravenous immunoglobulin, or biologic agents. Treatment decisions are further complicated in pregnancy and require supervision by an obstetrician and maternal-fetal medicine (MFM) specialist. Concerns include safe dosing of steroids and potential for transplacental migration of immune complexes. We provide the first comprehensive literature review on AIED and its implications in pregnancy. We frame our discussion in the context of the second reported case of primary AIED in pregnancy and the first to show excellent response to immunosuppressive therapy. Methods. We reviewed the presented case and literature on AIED. Results. A 27-year-old, pregnant, HSP-70 positive woman was diagnosed with AIED and had excellent recovery of hearing and balance following a combination of steroid treatment, augmented by oral immunomodulators, plasmapheresis, and IVIG. Conclusion. AIED is a diagnostic challenge, and treatment considerations are complex when encountered in pregnancy. Management requires multidisciplinary involvement between otolaryngologists, immunologists, and obstetricians to balance maternal and fetal health outcomes.


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## Body

## 1. Introduction

Autoimmune inner ear disease (AIED) is an exceptionally rare occurrence during pregnancy. It presents challenging diagnostic and management paradigms. AIED is defined as rapidly progressive, typically bilateral, hearing loss that demonstrates responsiveness to corticosteroid and immunosuppressive therapy as demonstrated by McCabe in 1979 [1, 2]. It was first described by Lehnhardt and Cogan in 1958 [3, 4]. Clinically, symptoms develop over weeks to months, which is too rapid for presbycusis and too gradual for sudden SNHL.AIED may be primary, in which the disease process is confined to the inner ear, or secondary, accounting for 30% of cases, in which cochleovestibular damage occurs in the context of a systemic autoimmune process with circulating immune complexes [5]. Inner ear involvement secondary to multisystem inflammation has been seen in multiple conditions including Cogan’s syndrome, rheumatologic conditions, and granulomatous disease [5]. The underlying immunological mechanisms are not well elucidated in the literature [6]. Autoimmune conditions may manifest during pregnancy, triggered by hormonal and physiological changes [7]. AIED should be recognized as an otologic emergency with urgent multidisciplinary management coordinated by otolaryngologists and immunologists in initiating immunosuppressive treatment that improves chance of hearing and balance recovery. Disease manifesting in pregnancy requires specialty input from obstetricians and MFM specialists [8] as treatment considerations must balance maternal and fetal health.


## 2. Case Presentation

A 27-year-old pregnant female, in the 19th week of gestation, presented to the outpatient ENT clinic with a 1-week history of bilateral SNHL, vertigo, and tinnitus. She had presented to the emergency department the previous week with flu-like symptoms, headache, photophobia, and neck stiffness, when she was discharged with a presumptive diagnosis of migraines. She was otherwise well with no medical history or regular medications. Her obstetric history was G9P1, including 6 miscarriages, 2 terminations, and 1 term pregnancy. There was no personal or family history of autoimmune disease, vasculitis, thrombophilia, or genetic conditions.Otoscopy revealed patent external auditory canals, intact and noninflamed tympanic membranes, and no evidence of middle ear pathology. She was unsteady in her gait. There was horizontal nystagmus on left lateral gaze, and head impulse testing was positive to the left. Free field voice testing indicated bilateral hearing impairment. Tuning fork assessment was equivocal for Weber’s test and Rinne’s positive bilaterally. The remainder of the neurological examination was unremarkable.Baseline pure tone audiogram showed bilateral moderate sensorineural hearing loss with flat morphology, affecting low and high frequencies (Figure1). Speech discrimination was good with an appropriate level of amplification.Figure 1
Audiogram pretreatment: bilateral mild sloping to moderate-severe sensorineural hearing loss.The provisional diagnosis of bilateral acute cochleovestibular inflammation was made, and urgent multidisciplinary consultations were sought from obstetrics, MFM, neurology and immunology.The lumbar puncture showed CSF-restricted oligoclonal bands and pleocytosis with mononuclear cells (Table1). Autoimmune encephalitis was considered based on Graus criteria [9].Table 1
CSF studies.
Cerebrospinal fluid analysisCSF glucose2.8 mmol/L2.2–3.9CSF protein0.43 g/L0.15–0.45CSF LDH24 U/LCSF cell countLeukocytes36 × 106/LErythrocytes2 × 106/LPolymorphonuclear cellsNilMononuclear cells36 × 106/LOligoclonal bandsPositive, CSF restrictedCultureNo bacterial growthMycobacterial cultureNegativeMycobacterial NATNegativeNucleic acid testing for EBV, VZV CMV, enterovirus, HSV, and polyomavirusNegativeCerebrospinal fluid immunologic testsNeuronal antibodies: Purkinje (Yo), PCA 2, ANNA-1, ANNA-2, Ma 1, Ma 2, amphiphysin, CV2, Tr, SOX-1NegativeNMDA receptor antibodiesNegativeCASPR2 antibodiesNegativeLGI-1 antibodiesNegativeGABA-B antibodiesNegativeDPPX antibodiesNegativeIgLON5 antibodiesNegativeAlbumin0.21 g/L0–0.35Immunoglobulin G0.03 g/L0–0.03IgG/albumin ratio0.140–0.25An urgent MRI brain and spine was arranged which showed normal cerebellopontine angles, vestibulocochlear nerves, labyrinthine signal intensity, and architecture, with the absence of demyelination features. Serial imaging taken 2 weeks apart excluded interval cochlear fluid signal changes. Blood tests showed elevated acute phase reactants and excluded viral etiology (Tables2–4). Autoimmune screen returned speckled antinuclear antibodies in 1 : 640 and positive HSP-70 antibodies (Table 5). The diagnosis of primary AIED was established.Table 2
Baseline laboratory tests.
Full blood countHaemoglobin127 g/L115–165White cell count5.5 × 109/L4.0–11.0Platelets159 × 109/L150–400Haematocrit0.37 L/L0.36–0.44Mean corpuscular volume87 fL82–98Mean corpuscular Hb30 pg27–32Mean corpuscular Hb concentration345 g/L300–350Red cell distribution width12.3%11.0–15.0Serum biochemistrySodium136 mmol/L135–145Potassium3.6 mmol/L3.2–5.0Chloride107 mmol/L95–110Bicarbonate20 mmol/L22–32Urea2.7 mmol/L2.5–6.5Creatinine52 umol/L45–90eGFR>90 mL/min/1.73 m2>90Calcium2.42 mmol/L2.15–2.55Magnesium0.83 mmol/L0.70–1.10Phosphate1.09 mmol/L0.75–1.50C-reactive protein<3 mg/L<3Erythrocyte sedimentation rate50 mm/hr3–19Table 3
Viral and infectious diseases serology.
Viral serologyCMV IgGNot detectedCMV IgMNot detectedEBV IgGDetectedEBV IgMEquivocalHSV1 IgGDetectedHSV2 IgGNot detectedHSV IgMNot detectedVaricella zoster IgGDetectedVaricella zoster IgMNot detectedHIV Ag/Ab screenNot detectedHBsAgNot detectedHCV antibodyNot detectedRoss River virus IgMNot detectedBarmah Forest virus IgMNot detectedArbovirus serologyNot detectedInfectious disease serologySyphilis EIA total antibodyNonreactiveAnti-DNase B titre<100<200Antistreptolysin O titre91.4 IU/mL<200TB gamma interferonNot detectedTable 4
Metabolic and endocrinologic profile.
Metabolic and endocrine profileIron level5.9 umol/L7.0–29.0Transferrin2.7 g/L1.8–3.3Transferrin saturation10%10–45Ferritin29 ug/L15–150HbA1c%5.0%4.0–6.0Vitamin B12117 pmol/L>150Holotranscobalamin level61 pmol/L>36Serum folate18.9 nmol/L>10.0TSH2.57 mIU/L0.40–3.50Free thyroxine14.0 pmol/L9.0–19.0Angiotensin converting enzyme32 UL20–70Urate0.18 mmol/L0.12–0.38Homocysteine6.2 umol/L4.5–13.5Chromogranin A1.9 nmol/L<3.0Neopterin12 nmol/L0–13Total bile acids8 umol/L≤8.0Apolipoprotein A11.68 g/L1.11–2.09Apolipoprotein B1.18 g/L0.63–1.32Apolipoprotein A1/B ratio1.420.87–2.85Lipoprotein EPGNormal limitsTable 5
Immunologic and cell markers, including flow cytometry profile and genetic studies.
Cell markersCD19 pan B cell7%CD20 mature B cell7%Kappa light chain3%Lambda light chain3%CD3 T cells69%CD4 helper subset34%CD8 cytotoxic subset32%Flow commentNo evidence of lymphoproliferative diseaseImmunologic markersRheumatoid factor<10 IU/mL<15Anti-CCP antibodies3 U/mL<5IgG8.7 g/L6.6–15.6IgA1.73 g/L0.75–3.80IM1.56 g/L0.40–3.10IgE19 U/mL<113IgG13.76 g/L3.92–9.12IgG22.60 g/L1.50–6.40IgG30.48 g/L0.25–1.38IgG40.27 g/L0.04–0.70C1Q complement component155 mg/L118–244C2 complement29.9 mg/L14.0–5.0C3 complement1.30 g/L0.74–1.57C4 complement0.28 g/L0.13–0.41C5 complement>200.0 mg/L100–169C6 complement120 mg/L45–96C7 complement>110 mg/L55–85C8 complement172.0 mg/L112–172C9 complement500.0 mg/L125–265Haptoglobin1.53 g/L0.30–2.15A1 antitrypsin level2.38 g/L0.90–1.90Serum total protein63 g/L46–70Albumin EPG36 g/L37–51Alpha1 globulin2.9 g/L0.9–2.0Alpha2 globulin8.9 g/L2.8–7.7Beta globulin8.9 g/L5.1–14.0Gamma globulin6.9 g/L5.1–14.0B2 microglobulin1.9 mg/L1.0–2.6Glutamic acid decarboxylase antibody<5 U/mL≤5Islet cell antigen 512 antibodies<8 U/mL0–15Nuclear antibodiesDetected 1 : 640 speckleddsDNA antibodiesPatternRNP antibodies7 IU/mL0–29SM (Smith) antigen antibodiesNot detectedSSA/Ro 60 antibodiesNot detectedRo-52/TRIM 21 antibodiesNot detectedSSB/La antibodiesNot detectedScleroderma 70 antibodiesNot detectedJo-1 antibodiesNot detectedNeuronal antibodies: PurkinjeNot detected(Yo), PCA 2, ANNA-1, ANNA-2, Ma 1, Ma 2, amphiphysin, CV2, Tr, and SOX-1Not detectedSmooth muscle antibodiesNot detected <1 : 40Mitochondrial antibodiesNot detected <1 : 40Parietal cell antibodiesNot detected <1 : 40Intrinsic factor antibody4 U/mL<20Thyroglobulin antibodies<20 IU/mL0–60Thyroid peroxidase antibodies<10 IU/mL0–35Heat shock protein 70 antibodiesDetected APancreatic islet cell antibodiesNot detectedGliadin IgG deamidated antibodies2 units<20Transglutaminase IgA antibodies<1 U/mL<4Neutrophil cytoplasm PR3 and MPO antibodiesNot detectedRo-52, Mi-2, Ku, PM-Scl 100, PM-Scl 75, SRP, EJ, OJ, Jo-1, PL-7, and PL-12NegativeZinc transporter 8 antibodiesNegative <10 U/mLGenetic diagnosticsThiopurine methyltransferase genotypeNo TMPT variant allelesFactor V DNANo factor V Leiden mutationSystemic steroid treatment was commenced immediately following neurology, immunology, and MFM consultations. The patient received intravenous methylprednisolone pulsing with 1 g daily for three days. She received intravenous acyclovir 900 mg three times daily for three days as prophylactic HSV coverage on advice from neurologists. Obstetric and MFM advised on safety of medications in pregnancy. She received one dose of intratympanic dexamethasone, by which state there was marked improvement in her balance and hearing thresholds (Figure2). Ophthalmology review excluded ocular inflammation. She was discharged on 100 mg daily azathioprine and 50 mg daily prednisolone, which was slowly weaned under immunology guidance. She remained under the combined supervision of the MFM, immunology, and ENT disciplines throughout her pregnancy. Her hearing and balance remained stable on maintenance therapy. Due to concerns of poor fetal growth, she received five sessions of plasmapheresis followed by monthly IVIG therapy.Figure 2
Audiogram posttreatment: mild sensorineural hearing loss (right greater than the left).A healthy baby was born at term. The patient’s newborn initially failed the newborn hearing test but passed the following week. There are no further concerns regarding the toddler’s hearing. At three years, the patient remains on maintenance immunomodulator therapy, supervised by her immunologist, with azathioprine 100 mg and sirolimus 1 mg daily. Her recent audiogram showed hearing recovery stabilized to baseline (Figure3).Figure 3
Audiogram two years posttreatment: hearing thresholds returned to baseline with mild sensorineural hearing loss at higher frequencies.


## 3. Discussion

### 3.1. Clinical Manifestations and Diagnosis of AIED

AIED is a rare entity first described by McCabe in a case series of 18 patients with progressive bilateral SNHL without identifiable etiology who were steroid responsive [1]. The incidence of AIED is estimated at <5 cases per 100,000 with an estimated prevalence of 45000 in the US [10]. Cochlear neuritis may initially be unilateral and then progress to the other ear, with patients often showing asymmetric audiometric profiles. The pattern of hearing loss can be fluctuant, but generally deteriorates with time. Vestibular involvement is common with 50% of patients experiencing ataxia or positional vertigo [5]. Balance disorders may be underestimated due to the slow development of vestibular dysfunction and compensation by somatosensory and visual systems [11]. Aural fullness and tinnitus are reported in 25–50% of patients [2].Due to its low incidence combined with our limited understanding of pathophysiology and inability to establish reliable biomarkers, there is no formal diagnostic criterion [12]. AIED is a diagnosis of exclusion in a patient with a suggestive history, favorable response to immunosuppression, or known autoimmune disease. Diagnosis is suspected on audiogram with bilateral sensorineural hearing loss of at least 30 dB at any frequency and evidence of progression in at least one ear on two serial audiograms performed 3 months apart [13, 14]. Serial audiograms are required as the pattern of sensorineural hearing loss may be fluctuant and to monitor response to steroid therapy. The audiometric pattern is an important prognostic indicator for recovery of hearing. Isolated low-frequency hearing loss is associated with better treatment outcomes compared to a flat audiogram or high-frequency losses [15]. The severity of hearing loss prior to treatment has an inverse correlation with recovery. All patients should undergo MRI evaluation to exclude retrocochlear and demyelinating pathology.


### 3.2. Serological Markers in AIED

Laboratory testing can include nonspecific markers of inflammation and autoimmunity including C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, and complement protein. Specific inner ear antigen tests include the migration inhibition test (MIT), lymphocyte transformation test (LTT), and Western blot analysis. The MIT and LTT have inherent technical difficulties, and results may be heterogeneous [12]. More specific tests for autoreactivity to inner ear antigens such as HSP-70 should be considered. HSP-70 is a constitutively expressed protein that is upregulated in conditions of stress and found in the spiral limbus, spiral prominence, and organ of Corti within the inner ear, and in peripheral organs [6]. Suspicion of AIED should be raised in HSP-70 positive patients; however, it may also be present in the general population and in Meniere’s disease—hence, its use as a biomarker is disputed. A diagnostic dilemma between AIED and Meniere’s disease exists, and spontaneous recovery of hearing in Meniere’s disease may be mistaken as a positive response to immunosuppression in AIED [16]. An extensive immunologic workup is not mandated and should be coordinated by an immunologist with expertise in interpretation of results, as testing can be expensive [17].


### 3.3. Pathogenesis of AIED

Our current understanding regarding the immunological basis of AIED is limited. The inner ear is not immunologically privileged as previously thought, and inflammatory stimuli can recruit immune competent lymphocytes into the labyrinth and endolymphatic sac [18]. Cells enter the scala tympani via the spiral modiolar vein, coordinating labyrinthitis [2, 5, 6, 12]. Studies have shown the presence of autoantibodies directed against inner ear proteins such as HSP-70, cochlin (spiral ganglion), type II collagen (spiral ligament, endolymphatic duct), and KHRI-3 (otolith organs and endolymphatic sac) [2, 6]. Chronic and persistent trafficking of immune cells into the inner ear results in destructive changes including cochlear ischemia and fibrosis, spiral ganglion degeneration, otic capsule spongiosis, and endolymphatic hydrops [2, 5]. Rarely, secondary AIED may induce arthritis of the incudostapedial joint causing conductive hearing loss [6]. Molecular mimicry and shared epitopes between viral antigens and inner ear proteins can cause cross-reactivity, directing an autoimmune response following viral infection [5, 12, 19]. Although plausible, there is currently no evidence of positive viral serology in AIED.


### 3.4. Treatment Modalities in AIED

Corticosteroids remain the primary medical therapy in autoimmune SNHL, with activation of glucocorticoid receptors within the cochlear hair cells causing downregulation of local cytokines and reducing autoantibody production and inflammation [20]. This attenuates cochleitis and hair cell death, with potential recovery of function. Steroids increase microvascular blood flow in the cochlea and reduce endolymphatic hydrops. Almost 70–90% are steroid responsive, although adjunctive immunosuppressive agents may be indicated in relapses of hearing loss during the maintenance or steroid weaning phase [14]. Azathioprine, a purine analog, has demonstrated improvement in hearing in combination with prednisone in a cohort study of 12 patients [21]. We used azathioprine because of compatibility with pregnancy. In later pregnancy after organogenesis, cyclophosphamide or tacrolimus can be considered [22]. Management of vestibular dysfunction and balance disorders involves balance physiotherapy and treatment of the autoimmune process.Plasmapheresis removes circulating immune complexes and autoantibodies and is an adjunct in managing autoimmune diseases [5]. It can be considered in severe hearing impairment or as salvage treatment in steroid-resistant cases and involves thrice weekly treatment for 2 weeks and then weekly for four weeks [23]. IVIG therapy provides immunoregulatory action by altering complement-mediated destruction, neutralizing autoantibodies, and modulating autoreactive B cells [24].Nonsteroidal immunomodulators and biologics have been used in treatment in patients who are not candidates for high-dose steroid therapy, who fail first-line steroid therapy, and to encourage steroid weaning. A recent systematic review revealed steroid nonresponders may benefit from biologics, although studies are limited by small cohorts and variable efficacy [20]. TNF-alpha inhibitors such as systemic etanercept 25 mg twice weekly have shown significant improvement in hearing thresholds [25]. Local instillation of infliximab weekly for 4 weeks revealed stable improvement in hearing at 10–38 weeks after treatment [26]. Anakinra, an interleukin-1β blocker, demonstrated improvement in hearing thresholds in a clinical trial of 14 patients with AIED who were nonresponders to steroids [27]. Rituximab, a CD20 antagonist, has been shown to reduce corticosteroid dosage and improve symptoms in AIED [28]. It has demonstrated ability to maintain hearing improvement after corticosteroid use [29], but it has limited use after the first trimester of pregnancy [30].Patients with destructive inner ear changes have poor outcomes, even with maximal medical management [6, 17, 31]. Time sensitive cochlear implantation should be considered in cases when useful hearing is not restored and maintained [31]. Cochlear implantation does not address the underlying disease process and can be challenging in immune-mediated labyrinthitis ossificans and intracochlear fibrosis [32]. Future treatment strategies include gene and stem cell therapy aimed at neuronal preservation within the cochlea and hair cells [33]. In vivo models using human adipose-derived mesenchymal stem cells demonstrated improvement in hearing in AIED [34].


### 3.5. AIED in Pregnancy

Therapeutic decisions in pregnancy are complicated by the potential risk of treatment on maternal and fetal outcomes and the concern for autoimmune targeting of the fetal inner ear. Combination modalities should be incorporated to minimize systemic corticosteroid dosing. Long-term, high-dose steroid therapy has an unfavorable side effect profile. The literature is inconclusive on the safety of prolonged steroid administration in pregnancy, and there is currently insufficient evidence to suggest an increased risk of fetal malformations or gestational diabetes mellitus [35]. Multidisciplinary discussion between otolaryngology, immunology, and MFM facilitates sharing of expertise and ensuring optimal management of the immune-mediated hearing loss without compromising maternal or fetal outcomes. Due to limited evidence on the management of AIED, a collaborative approach is preferred [14].The obstetrician provides expertise to guide safe dosing of steroids in pregnancy and whether steroid-sparing or steroid-minimizing treatment should be utilized. Alternate options include intratympanic dexamethasone, oral immunomodulator therapy, plasmapheresis, and IVIG [20]. Intratympanic steroid injection can achieve higher perilymph steroid concentrations compared to oral or intravenous administration [36, 37]. Systemic therapy is indicated to ameliorate the underlying multisystem autoimmune response. In pregnancy, there is concern for transplacental transfer of autoantibodies to the fetus-plasmapheresis or IVIG may provide benefit. Similar to our case, one study reported a higher incidence of abnormal auditory brainstem response findings in the children of women who developed AIED during pregnancy [38]. Hence, we must recognize that autoimmune hearing loss in pregnancy may also have implications on the newborn’s hearing. There are no data on whether the hearing deficits persisted in childhood.Hill et al. described the first case of primary AIED in pregnancy, reporting that oral steroids minimized further deterioration in hearing, but the patient did not recover to baseline levels [8]. In that case, the patient presented late and treated only with oral prednisone. In our case, early initiation of intensive steroids, including pulsed methylprednisolone and intratympanic dexamethasone, and multimodal long-term treatment showed great efficacy. Cogan’s syndrome, a form of secondary AIED characterized by bilateral cochleovestibulitis and keratitis, has been described in pregnancy in two case reports. One study maintained disease stability with hydroxychloroquine and prednisone, whilst the other treated symptomatic flares with oral and ophthalmic steroids [39, 40].


## 3.1. Clinical Manifestations and Diagnosis of AIED

AIED is a rare entity first described by McCabe in a case series of 18 patients with progressive bilateral SNHL without identifiable etiology who were steroid responsive [1]. The incidence of AIED is estimated at <5 cases per 100,000 with an estimated prevalence of 45000 in the US [10]. Cochlear neuritis may initially be unilateral and then progress to the other ear, with patients often showing asymmetric audiometric profiles. The pattern of hearing loss can be fluctuant, but generally deteriorates with time. Vestibular involvement is common with 50% of patients experiencing ataxia or positional vertigo [5]. Balance disorders may be underestimated due to the slow development of vestibular dysfunction and compensation by somatosensory and visual systems [11]. Aural fullness and tinnitus are reported in 25–50% of patients [2].Due to its low incidence combined with our limited understanding of pathophysiology and inability to establish reliable biomarkers, there is no formal diagnostic criterion [12]. AIED is a diagnosis of exclusion in a patient with a suggestive history, favorable response to immunosuppression, or known autoimmune disease. Diagnosis is suspected on audiogram with bilateral sensorineural hearing loss of at least 30 dB at any frequency and evidence of progression in at least one ear on two serial audiograms performed 3 months apart [13, 14]. Serial audiograms are required as the pattern of sensorineural hearing loss may be fluctuant and to monitor response to steroid therapy. The audiometric pattern is an important prognostic indicator for recovery of hearing. Isolated low-frequency hearing loss is associated with better treatment outcomes compared to a flat audiogram or high-frequency losses [15]. The severity of hearing loss prior to treatment has an inverse correlation with recovery. All patients should undergo MRI evaluation to exclude retrocochlear and demyelinating pathology.


## 3.2. Serological Markers in AIED

Laboratory testing can include nonspecific markers of inflammation and autoimmunity including C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, and complement protein. Specific inner ear antigen tests include the migration inhibition test (MIT), lymphocyte transformation test (LTT), and Western blot analysis. The MIT and LTT have inherent technical difficulties, and results may be heterogeneous [12]. More specific tests for autoreactivity to inner ear antigens such as HSP-70 should be considered. HSP-70 is a constitutively expressed protein that is upregulated in conditions of stress and found in the spiral limbus, spiral prominence, and organ of Corti within the inner ear, and in peripheral organs [6]. Suspicion of AIED should be raised in HSP-70 positive patients; however, it may also be present in the general population and in Meniere’s disease—hence, its use as a biomarker is disputed. A diagnostic dilemma between AIED and Meniere’s disease exists, and spontaneous recovery of hearing in Meniere’s disease may be mistaken as a positive response to immunosuppression in AIED [16]. An extensive immunologic workup is not mandated and should be coordinated by an immunologist with expertise in interpretation of results, as testing can be expensive [17].


## 3.3. Pathogenesis of AIED

Our current understanding regarding the immunological basis of AIED is limited. The inner ear is not immunologically privileged as previously thought, and inflammatory stimuli can recruit immune competent lymphocytes into the labyrinth and endolymphatic sac [18]. Cells enter the scala tympani via the spiral modiolar vein, coordinating labyrinthitis [2, 5, 6, 12]. Studies have shown the presence of autoantibodies directed against inner ear proteins such as HSP-70, cochlin (spiral ganglion), type II collagen (spiral ligament, endolymphatic duct), and KHRI-3 (otolith organs and endolymphatic sac) [2, 6]. Chronic and persistent trafficking of immune cells into the inner ear results in destructive changes including cochlear ischemia and fibrosis, spiral ganglion degeneration, otic capsule spongiosis, and endolymphatic hydrops [2, 5]. Rarely, secondary AIED may induce arthritis of the incudostapedial joint causing conductive hearing loss [6]. Molecular mimicry and shared epitopes between viral antigens and inner ear proteins can cause cross-reactivity, directing an autoimmune response following viral infection [5, 12, 19]. Although plausible, there is currently no evidence of positive viral serology in AIED.


## 3.4. Treatment Modalities in AIED

Corticosteroids remain the primary medical therapy in autoimmune SNHL, with activation of glucocorticoid receptors within the cochlear hair cells causing downregulation of local cytokines and reducing autoantibody production and inflammation [20]. This attenuates cochleitis and hair cell death, with potential recovery of function. Steroids increase microvascular blood flow in the cochlea and reduce endolymphatic hydrops. Almost 70–90% are steroid responsive, although adjunctive immunosuppressive agents may be indicated in relapses of hearing loss during the maintenance or steroid weaning phase [14]. Azathioprine, a purine analog, has demonstrated improvement in hearing in combination with prednisone in a cohort study of 12 patients [21]. We used azathioprine because of compatibility with pregnancy. In later pregnancy after organogenesis, cyclophosphamide or tacrolimus can be considered [22]. Management of vestibular dysfunction and balance disorders involves balance physiotherapy and treatment of the autoimmune process.Plasmapheresis removes circulating immune complexes and autoantibodies and is an adjunct in managing autoimmune diseases [5]. It can be considered in severe hearing impairment or as salvage treatment in steroid-resistant cases and involves thrice weekly treatment for 2 weeks and then weekly for four weeks [23]. IVIG therapy provides immunoregulatory action by altering complement-mediated destruction, neutralizing autoantibodies, and modulating autoreactive B cells [24].Nonsteroidal immunomodulators and biologics have been used in treatment in patients who are not candidates for high-dose steroid therapy, who fail first-line steroid therapy, and to encourage steroid weaning. A recent systematic review revealed steroid nonresponders may benefit from biologics, although studies are limited by small cohorts and variable efficacy [20]. TNF-alpha inhibitors such as systemic etanercept 25 mg twice weekly have shown significant improvement in hearing thresholds [25]. Local instillation of infliximab weekly for 4 weeks revealed stable improvement in hearing at 10–38 weeks after treatment [26]. Anakinra, an interleukin-1β blocker, demonstrated improvement in hearing thresholds in a clinical trial of 14 patients with AIED who were nonresponders to steroids [27]. Rituximab, a CD20 antagonist, has been shown to reduce corticosteroid dosage and improve symptoms in AIED [28]. It has demonstrated ability to maintain hearing improvement after corticosteroid use [29], but it has limited use after the first trimester of pregnancy [30].Patients with destructive inner ear changes have poor outcomes, even with maximal medical management [6, 17, 31]. Time sensitive cochlear implantation should be considered in cases when useful hearing is not restored and maintained [31]. Cochlear implantation does not address the underlying disease process and can be challenging in immune-mediated labyrinthitis ossificans and intracochlear fibrosis [32]. Future treatment strategies include gene and stem cell therapy aimed at neuronal preservation within the cochlea and hair cells [33]. In vivo models using human adipose-derived mesenchymal stem cells demonstrated improvement in hearing in AIED [34].


## 3.5. AIED in Pregnancy

Therapeutic decisions in pregnancy are complicated by the potential risk of treatment on maternal and fetal outcomes and the concern for autoimmune targeting of the fetal inner ear. Combination modalities should be incorporated to minimize systemic corticosteroid dosing. Long-term, high-dose steroid therapy has an unfavorable side effect profile. The literature is inconclusive on the safety of prolonged steroid administration in pregnancy, and there is currently insufficient evidence to suggest an increased risk of fetal malformations or gestational diabetes mellitus [35]. Multidisciplinary discussion between otolaryngology, immunology, and MFM facilitates sharing of expertise and ensuring optimal management of the immune-mediated hearing loss without compromising maternal or fetal outcomes. Due to limited evidence on the management of AIED, a collaborative approach is preferred [14].The obstetrician provides expertise to guide safe dosing of steroids in pregnancy and whether steroid-sparing or steroid-minimizing treatment should be utilized. Alternate options include intratympanic dexamethasone, oral immunomodulator therapy, plasmapheresis, and IVIG [20]. Intratympanic steroid injection can achieve higher perilymph steroid concentrations compared to oral or intravenous administration [36, 37]. Systemic therapy is indicated to ameliorate the underlying multisystem autoimmune response. In pregnancy, there is concern for transplacental transfer of autoantibodies to the fetus-plasmapheresis or IVIG may provide benefit. Similar to our case, one study reported a higher incidence of abnormal auditory brainstem response findings in the children of women who developed AIED during pregnancy [38]. Hence, we must recognize that autoimmune hearing loss in pregnancy may also have implications on the newborn’s hearing. There are no data on whether the hearing deficits persisted in childhood.Hill et al. described the first case of primary AIED in pregnancy, reporting that oral steroids minimized further deterioration in hearing, but the patient did not recover to baseline levels [8]. In that case, the patient presented late and treated only with oral prednisone. In our case, early initiation of intensive steroids, including pulsed methylprednisolone and intratympanic dexamethasone, and multimodal long-term treatment showed great efficacy. Cogan’s syndrome, a form of secondary AIED characterized by bilateral cochleovestibulitis and keratitis, has been described in pregnancy in two case reports. One study maintained disease stability with hydroxychloroquine and prednisone, whilst the other treated symptomatic flares with oral and ophthalmic steroids [39, 40].


## 4. Conclusion

AIED is an otologic emergency that rarely manifests during pregnancy and requires urgent treatment, supervised by otolaryngologists, immunologists, and MFM specialists. Multimodal combination therapy is effective and minimizes long-term systemic corticosteroid exposure. We report a rare case of primary AIED in pregnancy with remarkable hearing outcomes following combination (IV, oral, and intratympanic) steroid therapy, augmented by immunomodulators, plasmapheresis, and IVIG.



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*Source: 9210780-2022-03-18.xml*