Journal of Otology & RhinologyISSN: 2324-8785

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Review Article, J Otol Rhinol Vol: 4 Issue: 5

Cogan's Syndrome: A Retrospective Study of 22 Years

Sandra Agostinho1*, Marta Canas Marques1,2, Marco Alveirinho Simão1,2 and Óscar Dias1,2
1Department of Otorhinolaryngology, Voice and Communication Disorders, Santa Maria Hospital, Lisbon, Portugal
2Otorhinolaringology Clinic University, Faculty of Medicine, University of Lisbon, Hospital of Santa Maria, Lisbon, Portugal
Corresponding author :Sandra Filomena da Silva Agostinho MD
Department of Otolaryngology, Voice and Communication Disorders, Hospital of Santa Maria, Avenida Professor Egas Moniz, 1649-035, Lisboa – Portugal
Tel: 21 780 5000; Fax: 21 780 5610
E-mail: [email protected]
Received: February 12, 2015 Accepted: June 09, 2015 Published: June 15,2015
Citation: Agostinho S, Marques MC, Simão MA, Dias O (2015) Cogan’s Syndrome: A Retrospective Study of 22 Years. J Otol Rhinol 4:4. doi:10.4172/2324-8785.1000233

Abstract

Introduction: Cogan’s syndrome (CS) is a rare clinical entity, of presumptive autoimmune etiology, typically characterized by a non-syphilitic interstitial keratitis (IK) associated with a Menière-like vestibuloauditory dysfunction.

Objective: Since only few cases have been published to current date and considering the variable presentation, clinical course and absence of specific diagnostic tests, we aim to potentially bring further insight for diagnosis and management.

Materials and Methods: We conducted a retrospective study of all cases of CS followed at the Department of Otorhinolaryngology, Voice and Communication Disorders in Santa Maria Hospital, Lisbon, from 1992 to 2013. Patient’s demographics, otolaryngologic, ophthalmologic and systemic manifestations, presenting symptoms, audiovestibular and laboratory testing, imaging assessment, performed treatment, disease course and hearing outcomes were analyzed.

Results: We review a group of six patients, two with typical and four with atypical CS. Five patients evolved to profound hearing loss, bilateral in two cases. No patient had permanent visual deficit. The Erythrocyte Sedimentation Rate (ESR) increase was the most consistent laboratory finding. Only one patient had positive anti- Heat Shock Protein (HSP) 70 antibodies. All patients were treated with corticosteroids. Methotrexate was associated in three, with some hearing loss stabilization. Three patients underwent cochlear implantation.

Discussion and Conclusions: In our series, morbidity was mainly related to the vestibuloauditory dysfunction. In implanted patients, there was a significant improvement of hearing function. We highlight the need of a multidisciplinary approach to this pathology for better therapeutic outcomes and quality of life.

Keywords: Cogan’s syndrome; Autoimmune hearing loss; Interstitial keratitis

Keywords

Cogan’s syndrome; Autoimmune hearing loss; Interstitial keratitis

Introduction

CS is a rare clinical entity, of presumptive autoimmune etiology, typically characterized by a non-syphilitic IK associated with a Menière-like vestibuloauditory dysfunction.
It was first described in 1945 by the ophthalmologist David Cogan [1]. In 1980, Haynes et al. [2] proposed clinical diagnostic criteria for the “atypical” variants of the disease: a delay of more than two years between the onset of typical ocular and audiovestibular dysfunction; presence within a two-year range, of atypical ocular manifestations with or without non-syphilitic IK, in association with typical audiovestibular symptoms; or the occurrence of typical ocular manifestations in association with atypical audiovestibular symptoms also within a two-year range since the initial clinical presentation.
Hearing loss has usually a sudden onset and may be unilateral or bilateral, asymmetrical, fluctuating or rapidly progressive, and is often combined with tinnitus, vertigo, dizziness, and nausea and vomiting [1-5]. IK may present with red eye, photophobia, ocular foreign-body sensation or ocular pain [2,5,6]. In typical CS, the time range between the onset of ocular and cochleovestibular symptoms is highly variable [1,4,7], usually being between one to three months [4], though they can occur within a few days up to two years apart [4-6].
Considering the variable presentation and clinical course as well as the absence of specific diagnostic tests, diagnosis of CS is frequently delayed, being a challenge in clinical practice. The incidence of CS is certainly underestimated because the diagnosis is based on high clinical suspicion. In fact, only few cases have been published to current date [1-6].
We report all cases followed at our department, assessing epidemiologic features, clinical presentation, performed treatment and disease course, aiming to potentially bring further insight for its diagnosis and management.

Materials and Methods

We conducted a retrospective study of patients diagnosed with CS followed at the Department of Otorhinolaryngology, Voice and Communication Disorders in Santa Maria Hospital, Lisbon, from 1992 to 2013. Written informed consent was obtained from all participants in this study. Medical records of all patients diagnosed as having CS, and identified as such, were reviewed.
Patients with documentation of non-syphilitic IK and other inflammatory eye diseases, sudden-onset or rapidly progressive hearing loss and vestibular complaints were included and classified in typical and atypical disease according to Haynes criteria [2]. A negative serologic test for syphilis was also required.
Authors used the following exclusion criteria: if a delay of more than two years between the onset of atypical ocular and audiovestibular dysfunction was reported or if positive serologic tests for syphilis were obtained. Based on these criteria, one patient was excluded from the study, since the presentation of his atypical ocular and audiovestibular symptoms occurred eight years apart.
Demographic data, otolaryngologic, ophthalmologic and systemic manifestations, presenting symptoms, audiovestibular and laboratory testing, imaging assessment, performed treatment, disease course and hearing outcomes were analyzed. All patients were evaluated and followed by an Otolaryngologist, an Ophthalmologist and a Rheumatologist for an adequate multidisciplinary approach.

Results

Six patients were included, two with typical and four with atypical CS (Table 1), with ages between 17 and 42 years at time of diagnosis (average age: 28.2 years). The average follow-up period was 10.3 years (range: 4-18 years).
Table 1: Results (I); F: Female, M: Male.
In four patients, first symptoms were ophthalmologic (Table 2). A viral infection in the few weeks preceding disease onset was reported in two cases, namely an upper respiratory tract infection in one patient and a gastrenteritis in the other. In the initial audiovestibular flare, all patients experienced severe vertigo and imbalance lasting from hours to days with acute, persistent, non-pulsatile tinnitus and, sometimes, aural fullness. In all cases, sensorineural hearing loss (SNHL) was reported, with bilateral ear involvement, initially asymmetric, flutuating and rapidly progressive. The severity and course of hearing loss differed between the right and left ears, with an interaural difference superior to 15 dB at the last audiometric evaluation in half of our cases (Table 3). Five patients evolved to profound hearing loss, bilateral in two cases and unilateral in three (Table 3). The mean period of time between diagnosis and progression to profound deafness was 7.5 years.
Table 2: Results (II); SNHL: Sensorineural hearing loss.
Table 3: Results (III); PTA: Pure Tone Average; CT: Computed Tomography; MRI: Magnetic Ressonance Imaging; ESR: Erythrocyte Sedimentation Rate; ANCA: Antineutrophil Cytoplasmatic Antibodies; Anti-HSP 70: Anti-Heat Shock Protein 70 antibody.
Ocular symptoms most commonly reported were photophobia, hyperemia and ocular pain. After ophthalmologic observation, three patients were diagnosed non-syphilitic IK, with concomitant anterior uveitis in one case, classifying it as an atypical case. The remaining three atypical cases had anterior uveitis and conjunctivitis. No patient had permanent visual deficit. The period between the onset of ocular and audiovestibular manifestations ranged from one day to two years.
Systemic manifestations were reported in four patients, being the musculoskeletal ones (polyarthralgias and myalgias) common to all. Two patients were diagnosed rheumatologic co-morbidities (erythema nodosum and De Quervain syndrome). No patient developed symptoms of large vessel vasculitis.
Complementary diagnostic tests included laboratory testing, pure-tone audiometry, caloric vestibular function testing, brain and temporal bone Computed Tomography (CT), brain Magnetic Ressonance Imaging (MRI) and Doppler echocardiogram.
Laboratory tests included complete blood count, ESR, Thyroid- Stimulating Hormone, free Thyroxine 4, serologic tests for Treponema pallidum, Borrelia burgdorferi, Toxoplasma gondii, Epstein-Barr Virus, Cytomegalovirus, Varicella-Zoster Virus, Herpes Simplex Virus, Anti-neutrophil cytoplasmic antibodies (ANCA), Anti-nuclear antibodies (ANA), anti-HSP 70 antibody. ESR increase was the most consistent laboratory finding. Only one patient had positive anti-HSP 70 antibodies (Case 5).
Three patients also performed brainstem-evoked auditory potentials, which were normal in cases 4 and 5. In case 2, waves I to IV were absent on the right ear and no response was elicited on the left ear. With a 100 dB click stimulus, wave V was evoked on the right ear, but with a delayed absolute latency (6,20 ms) and low amplitude. Caloric vestibular function testing documented 1 case of bilateral areflexia, 1 case of bilateral hyporeflexia, 2 cases of unilateral hyporeflexia and 2 cases of bilateral normoreflexia. Imaging exams and Doppler echocardiogram were unremarkable.
In 5 patients, oral corticotherapy was given in acute audiovestibular dysfunction (predinosone, 1-2 mg/kg/day, 7 days, with progressive tappering) (Table 4). The sixth patient was admitted to perform pulses of methylprednisolone (3 cycles), followed by oral prednisone after hospital discharge. Although an initially favorable response to corticosteroids was observed in all patients, particularly of vestibular complaints, only in three patients some degree of long term stabilization of auditory deficit was obtained and methotrexate was associated to allow corticoid dose reduction (Table 4). No toxicity due to methotrexate was reported.
Table 4: Results (IV).
All patients were initially rehabilitated with bilateral hearing aids. Three of them underwent unilateral cochlear implantation, with good functional outcome, adopting a strategy of bimodal rehabilitation. One patient (Case 2) refused cochlear implantation.

Discussion

CS is a rare clinical entity, of presumptive autoimmune etiology, affecting mostly young Caucasian adults between the second and fourth decades of life [3,4,6,8,9], with similar prevalence in both sexes [4-7]. In our series, the average age at diagnosis was 28,2 years, though there was a predominance of female patients.
Audiovestibular dysfunction
About 90% of patients experience an initial flare of acute peripheral audiovestibular disorder with vertigo, dizziness, nausea and vomiting followed by tinnitus and hearing loss [3,5-7]. Symptoms are usually pronounced persisting days to weeks or even months [10] and complete peripheral vestibular dysfunction with ataxia and oscillopsia may be present [3,5]. In our series, all patients presented in acute phase with vertigo, nausea and vomiting lasting hours to few days with concurrent tinnitus and aural fullness in three cases. Although audiovestibular symptoms may be initially unilateral, usually disease course progresses to bilateral cochleovestibular involvement. In general, we found that acute vestibular symptoms tended to subside when hearing impairment arised, though they might be present at the same time, which is in agreement with other series [4]. Hearing loss is typically sensorineural, bilateral and asymmetrical, with a fluctuating pattern and progressive worsening over time [3-7]. In some published series, there was a predominance of a downsloping audiometric configuration [5]. All patients in our series had bilateral cochlear involvement and no typical audiometric configuration was noted.
Generally, after the initial flare some patients reach a slowly progressing chronic stage with few symptoms [4,10], whereas others have fluctuations in hearing levels and exacerbations of vestibular symptoms at varying intervals [10]. In our cohort, two patients (cases 2 and 5) reported triggering factors, such as stress, fatigue, menstruation and upper respiratory tract infections associated with exacerbations of vestibulo-auditory dysfunction.
Ophthalmologic manifestations
Non-syphilitic IK is the typical ocular inflammatory disease [11], which in association with vestibulocochlear dysfunction and in the setting of negative serologic tests for syphilis, it’s pathognomonic of CS [1-9]. It is a non-ulcerative, non-suppurative inflammation of the corneal stroma [12]. The natural history has two phases, an acute and a cicatricial one [12]. First, it manifests with ocular pain, conjunctival hyperaemia, fotofobia and blurred vision, being rarely asymptomatic [4,11]. Infrequently, it may be associated with transitory reduced visual acuity [4,7]. An irregular, granular corneal infiltration is observed, particularly in the posterior part of the cornea, near the limbus [11]. IK tends to present in acute and recurrent episodes, with bilateral ocular involvement [2,5-9]. Initial inflammation may take several months to solve, leaving mild-to-severe scarring and thinning in the cornea. Regression of stromal neovascularization often leaves behind remnants known as “ghost vessels”. Endothelial disfunction may follow, resulting in central corneal edema later in life [13]. Even if IK goes unnoticed in the active phase, these late phase ophtalmological findings in a context of audiovestibular dysfunction may raise the diagnosis of CS. Other documented eye inflammatory diseases include conjunctivitis, uveitis, scleritis, episcleritis, iritis, retinitis, papillary edema, retinal artery occlusion, with or without associated interstitial keratitis, falling in atypical Cogan’s syndrome spectrum [7-9].
Systemic involvement
Systemic involvement occurs in about 66% of typical cases and up to 90% of patients with atypical disease [7,9]. The most common manifestations are constitutional (fatigue, fever, weight loss), musculoskeletal (myalgias, arthralgias, arthritis), cardiovascular (aortitis, aortic insufficiency), neurological (headache, meningismus, peripheral neuropathy) and gastrointestinal (abdominal pain, splenomegaly) [3-7,9]. Some authors suggest that atypical CS patients, having a higher prevalence of systemic involvement as well as other rheumatological co-morbidities, may constitute a potential subtype of patients with worse prognosis [2,3,5,8]. Large vessel vasculitis, namely of aorta with consequent aortic valve insufficiency, renal and iliac arteries is associated with a worse prognosis [7]. In our series, three patients reported systemic manifestations, which occurred both in the acute and chronic phases, and there were no cases of large vessel vasculitis.
Diagnosis
So far, diagnosis of CS is based on clinical elements [3] with no specific diagnostic tests [4,14,15]. The ESR is often elevated during the disease’s active phase, as we found in our cohort, though it’s not a specific marker [3-9].
There is conflicting evidence regarding the usefullness of anti- HSP 70 antibody in the diagnosis of autoimmune inner ear disease (AIED) [16,17] as also to predict steroid responsiveness [17]. In CS, it can be present in up to 50% of cases [18]. One study showed positivity for anti-HSP70 antibody in 92.9% of typical CS patients comparing to 16.6% in atypical CS ones [19]. Considering this, Anti-Hsp70 antibodies can be a serological marker of typical CS and a negative result, in the absence of immunosuppressive treatment, may exclude the diagnosis in its typical form. In our series, only one patient (with a typical CS) showed positivity to Anti-HSP 70 antibodies (Case 5) and she presented a corticosteroid-dependent hearing loss.
It was demonstrated that, during the acute phase of disease, the MRI of the brain could show an increase of gadolinium uptake in the vestibular area, semicircular canals, vestibular nerve or cochlea and in a chronic stage, there is a narrowing of the semicircular canals and cochlea, with no contrast enhancement [15]. As these findings are inespecific, we and others [5] agree that brain and temporal bone CT or MRI should be used to exclude other causes of audiovestibular dysfunction.
PET-CT seems to play a role on diagnosis and follow-up of patients with large vessel vasculitis and on documentation of response to treatment [7,20].
Treatment and prognosis
Systemic corticotherapy is, to current date, the first-line treatment of CS [4,6]. Early diagnosis of CS is crucial for a timely steroid treatment to prevent irreversible eye lesions and it has been shown that hearing is less likely to improve when the patient presents with deafness [10]. The route of drug administration, dosage and duration of treatment course varied in published series [2,3,5,6,9].
Intratympanic corticosteroid is a minimally invasive therapeutic approach, with few side effects, that has been used in AIED. However, there is no consensus regarding doses and length of treatment and its efficacy has so far not been fully determined [16]. Moreover, no studies were found concerning effectiveness of intratympanic steroid injection in patients with CS. Systemic corticotherapy (prednisone or methylprednisolone) should be given (1-1.5 mg/kg/day) for 2-4 weeks, with progressive tapering, until a low maintenance dosage is achieved [4,7]. If no clinical improvement occurs after two weeks, treatment should be discontinued [4]. Favorable responses in auditory function can be initially observed, but with subsequent deterioration despite maintenance of therapy [5], which is consistent with our results. Suprapharmacological dosages (superior to 1 mg/ kg/day of prednisone) might be needed in the acute flares and longterm hearing stablility may be achieved with a low maintenance dosage of corticosteroids, as we saw in two patients (Cases 5 and 6).
When prolonged or high dosages are needed to control active stages of the disease, association of an immunosuppressive agent will be suitable, allowing also a reduction of corticosteroid’s dosage [7]. For this purpose, methotrexate was chosen for our patients. Among other immunosuppressant agents used in CS, with variable sucess rates, cyclophosphamide (used particularly in inflamatory ocular disease), azathioprine, mycophenolate mofetil and cyclosporine (used to controll audiovestibular symptoms) are the most commonly used [3,4,7].
So far, there aren’t any therapeutic protocols with proven effectiveness in improving or stabilizing the auditory deficit with 37- 60% of CS patients evolving to profound deafness [2,4-6,7,10] – about 54% with typical CS and 37% with atypical CS [10]. Five of our 6 patients developed profound deafness, bilateral in two of them. In spite of these poor functional hearing outcomes, in the last decades, cochlear implantation has stood out as a rehabilitation strategy in Cogan’s syndrome with good results [5,21], as we could see in our series.
Concerning the vestibular complaints, good symptomatic control was achieved with corticotherapy in most patients of our series, though two of them reported persistence of ataxia after the initial vertigo attack and one of them also oscillopsia, improved after vestibular rehabilitation.
Ophthalmologic and systemic manifestations seem to respond better and faster to corticotherapy than audiovestibular symptoms [7,8]. IK is effectively treated with topical corticosteroids in most patients. Although corneal inflammation associated with IK resolves spontaneously, topical corticosteroid shortens the duration and severity of corneal inflammation [13]. Considering this, it seems that timely and adequate ocular treatment can change IK´s natural history by preventing late sequelae. However, it was reported that patients with atypical inflammatory ocular disease might need systemic corticotherapy to achieve full regression of ocular findings [3]. In our series, all patients presented a satisfactory control of ocular complaints with topical corticotherapy, regardless of the type of disease.
Complications arising from prolonged systemic corticotherapy are an important cause of morbidity in CS, sometimes neglected [5]. Their prevalence was reported to be around 30% [5]. Two patients of our cohort developed bilateral cataracts secondary to prolonged use of corticosteroids, one of which required surgical correction. Iatrogenic Cushing syndrome was also noted in two cases. To prevent peptic ulcer disease, all patients were given a proton pump inhibitor. No toxicity due to methotrexate was reported.
Cardiovascular complications arising from aortitis, involvement of the coronary arteries and aortic insufficiency, with subsequent left ventricular insufficiency, seem to be the main cause of mortality related to disease [7].

Conclusion

In our series, similar to what is reported in literature, morbidity was primarily related to audiovestibular dysfunction, having five of six patients progressed to profound deafness. Patients submitted to cochlear implantation, showed significant improvement of hearing function, allowing in all three cases better professional readaptation, reaffirming its importance as a rehabilitation strategy in CS. We also highlight the need of a multidisciplinary collaboration between Otolaryngology, Audiovestibulogy, Ophthalmology, Rheumatology and Radiology for a better therapeutic approach to this pathology.

References

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