Service de Médecine Interne, Hôpital Louis Mourier, Colombes, 1 Service de Médecine Interne, Hôpital Claude Huriez, Lille, 2 Service de Médecine Interne, Hôpital Foch, Suresnes and 3 Service de Médecine Interne, Hôpital Bichat, Paris, France.
Correspondence to: A. Grasland, Service de Médecine Interne, Hôpital Louis Mourier, 178 rue des Renouillers, 92700 Colombes, France. E-mail: anne.grasland{at}lmr.ap-hop-paris.fr
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Patients were identified from a survey conducted with physicians affiliated to the French National Society for Internal Medicine, and were classified into typical or atypical Cogan's syndrome according to the Haynes criteria. Clinical data were collected in a standardized manner. A comprehensive literature review using the Medline database and the reference lists of identified articles was performed.
Results. Seventeen patients had typical Cogan's syndrome and 15 had atypical Cogan's syndrome. Apart from non-syphilitic interstitial keratitis, the ocular manifestations of patients with atypical Cogan's syndrome were mainly uveitis and episcleritis. All but one patient presented with Ménière-like syndrome, and at the end of follow-up 11 were deaf and 19 additional patients had developed a significant decrease in auditory acuity. Twenty-five patients (78%) developed systemic manifestations, including aortitis in four. Comparison of typical and atypical Cogan's syndrome showed that some systemic manifestations were more common in atypical Cogan's syndrome, but these differences may be explained by reporting bias in the literature.
Conclusion. Differences regarding the associated systemic manifestations of typical and atypical Cogan's syndrome may reflect reporting bias in the literature. However, the diversity of the ocular and audiovestibular manifestations and the acceptable lengthy delay between the two types of involvement in atypical Cogan's syndrome should make one cautious before accepting this diagnosis as the diagnosis may mimic various other systemic diseases.
KEY WORDS: Cogan's syndrome, Sensorineural hearing loss, Aortitis, Vasculitis, Interstitial keratitis
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cogan's syndrome is a rare entity, mostly described in young adult Caucasian patients of either sex, and fewer than 250 cases have been reported in the literature. Interstitial keratitis is rarely asymptomatic, and most of the patients present with eye redness, photophobia or eye pain [2, 3]. On examination of patients with IK, an irregular, granular corneal infiltration is observed, affecting particularly the posterior part of the cornea, near the limbus. Secondary neovascularization may frequently ensue [3]. In most cases, both eyes are affected during the disease course, with great variability in symptoms from one eye to the other and from day to day. Rarely, the ocular symptoms remain unilateral [25]. In atypical Cogan's syndrome, many ocular lesions have been reported to be either isolated or associated with IK, and include episcleritis or scleritis, retinitis, optical neuritis, glaucoma, papillary oedema, cataracts, ocular motor palsy, exophthalmia, central retinal artery occlusion, xerophthalmia, ptosis and tendonitis [611]. A moderate and usually transient decrease in visual acuity is not uncommon in Cogan's syndrome, but amaurosis or blindness may also occur. In the series reported by Vollertsen et al. [3], blindness affected eight out of 156 eyes and was bilateral in two patients.
The audiovestibular manifestations of Cogan's syndrome are similar to those of Ménière's syndrome, with an abrupt onset including vertigo, instability, nausea, vomiting and tinnitus [13]. Generally, the vestibular manifestations are secondarily associated with an often severe and definitive hearing loss, leading commonly to deafness. Hearing loss is often bilateral from onset but in some patients it may be unilateral initially, becoming bilateral later. In the review by Vollertsen et al. [3], which included 78 patients with typical Cogan's syndrome, bilateral deafness affected 43.5% of patients and occurred a mean of 3 months after the onset of the initial symptoms. Investigations reveal a sensorineural deafness, and radiographic studies of mastoid bone and auditory canals are normal. However, magnetic resonance imaging and computed tomographic scanning may show narrowing or obliteration of parts of the vestibular labyrinth that are related to the risk of permanent hearing loss [12, 13].
In addition to the ocular and audiovestibular symptoms, various systemic manifestations, including aortitis and necrotizing vasculitis, have been reported in patients with this syndrome. We report our experience of a multicentre series of 32 patients with either typical or atypical Cogan's syndrome, which we combined with a detailed review of the literature. A comparison of the clinical manifestations of typical and atypical Cogan's syndrome was also performed.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Typical Cogan's syndrome was defined using Cogan's original criteria [1] with the following three conditions: (i) ocular symptoms, typically an isolated non-syphilitic IK that could be associated with conjunctivitis, conjunctival or subconjunctival bleeding, or iritis; (ii) audiovestibular symptoms similar to those of Ménière's syndrome (sudden onset of nausea, vomiting, tinnitus and vertigo, accompanied by gradual hearing loss), usually progressing to deafness in 13 months; (iii) an interval between the onset of ocular and audiovestibular manifestations of less than 2 yr.
According to the criteria of Haynes et al. [2], patients with any of the following associations were classified as having atypical Cogan's syndrome: (i) inflammatory ocular manifestations, including episcleritis, scleritis, retinal artery occlusion, choroiditis, retinal haemorrhage, papilloedema, exophthalmos or tendonitis, with or without IK; patients with isolated conjunctivitis, subconjunctival haemorrhage or iritis were also classified as having atypical Cogan's syndrome if these inflammatory ocular manifestations were associated with Ménière-like episodes within an interval of 2 yr; (ii) typical ocular manifestations associated, within 2 yr, with audiovestibular symptoms different from Ménière-like episodes; (iii) a delay of more than 2 yr between the onset of typical ocular and audiovestibular manifestations.
We carried out a comprehensive literature review using the Medline database (keyword: Cogan's syndrome) and the reference lists of identified articles. Since the literature review by Haynes et al. [2] published in 1980, which reported on 111 patients with Cogan's syndrome (typical, n = 78; atypical, n = 33), we were able to identify in the English and French literature 79 additional patients with either typical (n = 35) [1439] or atypical (n = 44) [411, 4075] Cogan's syndrome with sufficient details to be analysed.
The design of this study conformed to ethical standards currently applied in France.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Clinical characteristics, pattern of disease at onset, and ocular and audiovestibular manifestations (Table 1)
|
A possible precipitating factor was identified in 10 of our patients: six in the typical Cogan's syndrome group (rhinitis and pharyngitis, tonsillitis, otitis, flu-like syndrome, cold exposure and dental abscesses) and four in the atypical Cogan's syndrome group [Chlamydia pneumonia, flu-like syndrome (two patients) and desensitization]. In a few cases in the literature, Cogan's syndrome has been triggered by upper respiratory tract infection (27%) or, less commonly, by diarrhoea [2, 3, 5], dental infection [1, 4] or immunization [2, 3].
The presenting manifestations were ocular in seven patients (four typical Cogan's syndrome, three atypical Cogan's syndrome), audiovestibular in 15 (seven typical Cogan's syndrome, eight atypical Cogan's syndrome) and articular in two (one typical Cogan's syndrome, one atypical Cogan's syndrome). In the remaining eight patients (five typical Cogan's syndrome, three atypical Cogan's syndrome) the ocular and audiovestibular manifestations were concomitant. The literature review showed that patients presented predominantly with isolated ocular or audiovestibular manifestations, and more rarely with concomitant organ involvement. The mean delay between involvement of the two organs was 3 months in typical Cogan's syndrome.
Ocular manifestations
By definition, all 17 patients in the typical Cogan's syndrome group presented IK, which was bilateral in 16. The IK was isolated in 13 patients and associated with conjunctivitis in three patients or a superficial keratitis in two. In the atypical Cogan's syndrome group, the ocular manifestations were bilateral in 14 of the 15 patients: six patients presented IK, which was isolated in one case and associated in five cases with conjunctivitis, uveitis, episcleritis or glaucoma. Of the remaining nine patients, seven presented uveitis, associated with conjunctivitis in two, superficial keratitis in two and descemetitis in one; the last two patients presented superficial keratitis with conjunctivitis.
Audiovestibular manifestations
In the two groups the audiovestibular manifestations were typical, with a vestibular syndrome of sudden onset associated with various signs, including vertigo, tinnitus, ataxia, nausea and vomiting, often resolving after several days but followed by progressive hearing loss of variable severity. In only one patient with atypical Cogan's syndrome were vestibular manifestations lacking (patient 32). In the typical Cogan's syndrome group, the delay between the onset of ocular and audiovestibular manifestations was, by definition, less than 2 yr. However, in most cases, both manifestations occurred closely or even simultaneously in five patients (mean 2 months, median 4 weeks, range 012 months). In the atypical Cogan's syndrome group, the mean interval between ocular and audiovestibular manifestations was 27.1 months (median 4 weeks, range 015 yr).
Systemic manifestations (Table 2)
|
Later in the disease course, five patients (two typical Cogan's syndrome and three atypical Cogan's syndrome) developed new systemic manifestations: aortic aneurysm requiring surgery (one patient, 3 yr after the diagnosis of Cogan's syndrome), aortitis, carotid and subclavian artery stenosis (one patient, 6 months after the diagnosis of Cogan's syndrome), renal amyloidosis associated with monoclonal gammopathy, manifesting as a nephrotic syndrome (one patient, 12 yr after the diagnosis of Cogan's syndrome), polychondritis (one patient, 2 yr after the diagnosis of Cogan's syndrome) and sarcoidosis (one patient, 2 yr after the diagnosis of Cogan's syndrome).
Cogan's syndrome has been associated with various systemic manifestations, and the disease remained restricted to eye and ear in 17/52 (33%) of the patients with typical Cogan's syndrome and 7/59 (12%) (P<0.01) of those with atypical Cogan's syndrome published since the review by Haynes et al. [2] in 1980 and including the patients of our series. The comparison of the distribution of clinical features between reported cases of typical Cogan's syndrome and atypical Cogan's syndrome shows that patients having atypical Cogan's syndrome present significantly more frequent musculoskeletal and neurological manifestations, and lymphadenopathy (Table 2).
Laboratory investigations
In all but four patients, an elevated erythrocyte sedimentation rate (ESR; >15 mm/h) was reported at the time of diagnosis. The mean ESR was 65 mm/h in the two groups (range 4 120 mm/h). Most of the patients underwent extensive investigations looking for an infection at the time of disease onset. There was no serological evidence for infection with Treponema pallidum, blood cultures remained sterile, and serology (not all performed in all patients) was negative in all but one patient for various organisms (Chlamydia, Borrelia burgdorferi, brucellosis, toxoplasmosis, tularaemia, Coxiella, Rickettsia, Bartonella, EpsteinBarr virus, cytomegalovirus, HIV, herpes virus, hepatitis A, B and C viruses, mumps, Coxsackie virus, parvovirus B19). One patient had a positive serology that suggested a recent chlamydial infection. Two patients (patients 7 and 21) were tested for anti-cochlear antibodies and one had a positive result. In the other patients, immunological studies were not contributory. One patient had a moderate positive antinuclear antibody (ANA) titre (1/160) while in the others ANA was negative or present at only low titres. Two out of 16 patients (patients 11 and 24) had a circulating anticoagulant antibody, and only one (patient 9) of the six patients for whom tests for anticardiolipin antibodies were performed tested positive. Two out of 20 patients tested positive for antineutrophil cytoplasmic antibodies (ANCA) and had low titres (1/40) (patient 8 had peripheral ANCA and patient 15 had cytoplasmic ANCA), but antigen specificity could not be elicited by enzyme-linked immunosorbent assay. Rheumatoid factor was positive in one out of 29 patients (patient 8). Only two out of 24 patients had cryoglobulinaemia (patients 8 and 9).
Treatment and outcome (Table 3)
|
During the disease course, comorbid conditions were identified in four patients with atypical Cogan's syndrome (inflammatory bowel disease, thrombocytopenic purpura, HLA-B27-positive spondylarthritis and sarcoidosis; one case each).
All but one (patient 30) patients were treated with corticosteroids. Corticosteroids were administered orally (prednisone) at a dose ranging from 0.5 to 2 mg/kg per day. Eighteen patients also received initially intravenous administration of high-dose methylprednisolone for 15 days. In 17 patients, corticosteroid treatment controlled the ophthalmological and systemic signs. However, four patients only (patients 3, 4, 18 and 22) reported an improvement in hearing acuity on corticosteroid treatment. In the remaining 15 patients (six typical Cogan's syndrome and nine atypical Cogan's syndrome), the lack of efficacy of corticosteroids or dependence on high doses of prednisone justified additional therapy, usually with an immunosuppressive drug, that was rarely successful. Various drugs were prescribed, including cyclophosphamide in 10 cases (successful in two patients, in one of which it was given in association with intravenous immunoglobulins), azathioprine in six cases, cyclosporin in three cases, methotrexate in six cases (successful in two), mercaptopurine in one case, chlorambucil in one case, and disulone in two cases.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The most characteristic cardiovascular manifestation of Cogan's syndrome is aortitis with aortic insufficiency, which has been reported in 23/222 (10%) patients. Lesions may involve the entire aortic wall and may be associated with aneurysmal dilation. An aortic valve replacement is sometimes needed [3, 22, 33, 52, 56, 68]. The microscopic lesions are diverse and non-specific. Giant cells may be present. Aortitis in Cogan's syndrome is indistinguishable from Takayasu's disease [75]. A few cases of coronary insufficiency and myocardial infarction have been attributed to specific vasculitis of coronary arteries, aneuzrysmal dilation or ostial stenosis [6, 22, 48, 56, 65, 71, 75]. Mitral valve involvement has been reported rarely [5, 6, 52]. Pericarditis has been reported in four patients [5, 11, 48, 67]. Specific involvement of large arteries has been reported in Cogan's syndrome. Arteritis may be asymptomatic or associated with a bruit or the absence of a pulse, abdominal pain related to mesenteric arteritis, upper or lower limb claudication, high blood pressure due to renal artery involvement, or even necrosis of the extremities [3, 38, 54, 67, 68, 75]. Arteritis may develop many years after the onset of Cogan's syndrome, even if the disease seems quiescent [68]. Radiographic investigations may show local arterial stenosis, occlusion or aneurysmal dilation. A few cases of aortic arch syndrome have been reported [22, 56, 65, 75], including one with Takayasu's arteritis [65].
Most of the rheumatic manifestations that have been reported in Cogan's syndrome have been polyarthralgias, but a few cases of arthritis have been published [30, 34, 52, 69]. A few patients with atypical Cogan's syndrome associated with rheumatoid arthritis, idiopathic juvenile arthritis or ankylosing spondylitis have been reported [40, 46, 49, 51, 61]. Patients may also present with myalgias, and muscle biopsy may reveal vasculitis or evidence of myositis [3, 4, 24, 69].
Neurological manifestations were present in 29 of the 222 published cases (13%). Central nervous system involvement is more common and may include hemiparesis or hemiplegia due to a cerebral vascular accident, aphasia due to a transient ischaemic event, cerebellar syndrome [31, 37], myelopathy [3], seizures [3], meningitis [4, 14, 44] or encephalitis [3]. Computed tomographic scanning may provide evidence of localized cerebral ischaemia with infarction [20, 55] and MRI may also show multiple lesions of the white matter consistent with cerebral vasculitis [20]. Reported peripheral nerve involvement includes paraesthesia of the extremities, trigeminal neuralgia or motor deficits affecting the cranial nerves, the phrenic nerve or several nerve trunks, resulting in mononeuritis multiplex [3, 9, 24, 33, 38]. Lumbar puncture may demonstrate meningitis with elevated protein and pleocytosis even in the absence of clinical manifestations.
Various gastrointestinal manifestations, including diarrhoea, melena and abdominal pain, sometimes related to mesenteric arteritis, have been reported [3, 38, 54]. Hepatomegaly and splenomegaly were reported in a few patients [1, 3, 6, 62, 72]. Reported cutaneous lesions include a non-specific erythematous or urticarial rash, purpura, nodules or ulceration of the limbs, genitals or mouth, and pyoderma gangrenosum [3, 18, 19, 34, 62, 72]. Histological examination showed non-specific or leucocytic vasculitis [3, 18]. The presence of sinusitis or auricular or nasal chondritis, with cartilage destruction in some cases, raises questions about the distinction between Cogan's syndrome, relapsing polychondritis and Wegener's granulomatosis [34, 53]. Miscellaneous other manifestations have been reported, including pleuropulmonary involvement and lymphadenopathy.
None of the reported laboratory abnormalities is specific. By definition, serological tests for syphilis are negative. Leucocytosis with neutrophilia is common and the ESR is often elevated. Surveying for infections is usually negative, but evidence for Chlamydia infection has been reported in a few cases [2, 62]. Rheumatoid factor and antinuclear antibodies are usually negative. A low complement level was reported in five patients and cryoglobulinaemia in four. Antibodies directed against a corneal antigen or the constituents of the inner ear have been detected by some authors [4, 16, 46, 52].
The disease course of Cogan's syndrome is variable. Most commonly, after an initial flare lasting several weeks or months, the condition becomes chronic and progresses slowly. In other cases, there are recurrent ocular or vestibular flares, at variable intervals, in some cases seeming to be triggered by an infection, with apparent complete remission during the interval. If deafness occurs, it is usually permanent although a secondary improvement in hearing has been observed in a few patients. Of the 111 cases with detailed follow-up reported since the review by Haynes et al. [2] and including our series, 28/52 (54%) and 22/59 (37%) with typical and atypical Cogan's syndrome respectively were deaf in both ears. Conversely, a permanent decrease in visual acuity has been reported only rarely in Cogan's syndrome [2, 3]. Several deaths have been reported, due to cardiac failure, myocardial infarction, cerebrovascular accident, subarachnoid haemorrhage, rupture of the renal artery, and sepsis attributed to immunosuppressive treatment [29, 38, 54, 67, 69]. Amongst the 78 cases studied by Vollertsen et al. [3], with a mean follow-up duration of 22 months, an unfavourable disease course was observed in 49 (63%): 34 patients developed deafness, 12 diffuse vasculitis, 11 aortic insufficiency and six blindness, and seven patients had died. Weight loss, cardiovascular and abdominal manifestations, increased ESR, anaemia, leucocytosis and thrombocytosis appeared to be significantly associated with unfavourable prognosis.
Corticosteroids are often effective in controlling the ocular, vascular or other visceral manifestations of Cogan's syndrome but have much less reliable effects on hearing [3, 4, 6, 35]. An initial dose of 1 mg/kg per day of prednisone is usually recommended. The probability of recovering hearing loss may be higher when corticosteroids are given early in the disease course [3]. In the reported cases, corticosteroid treatment is rapidly discontinued in the absence of an improvement. If an improvement is observed, corticosteroids are gradually tapered over 26 months [3]. If corticosteroids are not effective, immunosuppressive drugs are commonly used [6, 7, 11, 16, 24, 35, 37, 38, 44, 54, 68, 69]. Azathioprine, cyclophosphamide and cyclosporin have been prescribed. The best results seem to have been obtained with methotrexate, which led to an improvement in four published cases [16, 35, 36, 68] and stabilized hearing in two other cases [7, 65]. However, in the absence of controlled clinical trials no definitive therapeutic recommendation could be offered, especially concerning the use of cytotoxic agents. In a few cases, deafness was improved by the use of hearing aids [23, 27, 34] or cochlear implants [28, 41].
The aetiology of Cogan's syndrome remains unknown. Exposure to a toxic substance preceded the onset of symptoms in a few cases [1, 3]. Infection has often been considered a possible trigger. However, antibiotic treatment has never proved effective. Although Cogan's syndrome is clearly linked to vasculitis, its assimilation to periarteritis nodosa does not seem acceptable. Indeed, vasculitis is not constantly found in Cogan's syndrome, and when it is present its histological appearance is not always consistent with periarteritis nodosa. Giant cell arteritis lesions and lesions similar in appearance to those of Buerger's disease have been described [3, 75]. Finally, the role of vasculitis in the pathogenesis of the ocular and audiovestibular lesions of Cogan's syndrome remains to be demonstrated. The relationship between Cogan's syndrome and the manifestations of autoimmune sensorineural hearing loss described by McCabe in 1979 [76] remains unclear. The audiovestibular symptoms of this condition are very similar to those of Cogan's syndrome. It is therefore possible that, in some patients, autoimmune sensorineural hearing loss could be the first symptom of Cogan's syndrome. Only a close follow-up of these patients will make it possible to determine if autoimmune sensorineural hearing loss is merely one aspect of a more general disease. Moreover, the presence of autoantibodies against inner ear and endothelial antigens found in some patients with Cogan's syndrome adds further evidence for the autoimmune nature of this disease [4, 16, 28, 46, 52, 77]. A recent study used pooled immunoglobulin G obtained from eight patients with Cogan's syndrome to screen a random peptide library. Antibodies directed against an immunodominant peptide showing similarity with autoantigens, including SSA/Ro and CD148, which is expressed in the inner ear and on endothelial cells, were identified in all eight patients and none of the controls. The same antibodies also bound to connexin 26, which is implicated in congenital deafness. After intravenous administration to mice, these autoantibodies were capable of inducing the features of Cogan's syndrome, with tissue damage of the inner ear and endothelial cells, and also corneal involvement [77].
Since the initial description of Cogan's syndrome, its definition has been debated. Haynes et al. [2] proposed that a diagnosis of atypical Cogan's syndrome should be considered in the presence of ocular manifestations other than non-syphilitic IK or symptoms delayed by more than 2 yr with respect to the audiovestibular manifestations. Patients reported with atypical Cogan's syndrome had systemic manifestations more commonly than those with typical Cogan's syndrome. Comparison of the distribution of clinical features between reported cases of typical Cogan's syndrome and atypical Cogan's syndrome shows that patients having atypical Cogan's syndrome present musculoskeletal and neurological manifestations and lymphadenopathy significantly more frequently, but this may well be a consequence of reporting bias in the literature. However, atypical Cogan's syndrome has also been associated with other systemic disease, including sarcoidosis [2, 43], rheumatoid arthritis [3, 46, 49], juvenile idiopathic arthritis [51, 61], Sjögren's syndrome [7], Crohn's disease [40, 38, 42, 52], ulcerative colitis [75] and Wegener's granulomatosis [53]. Caution should be exercised before accepting the diagnosis of atypical Cogan's syndrome, as this entity may share common manifestations with other systemic diseases.
|
The authors have declared no conflicts of interest.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|