Introduction. Clinical manifestations

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1 Cogan syndrome Heather E Moss MD PhD (Dr. Moss of Stanford University has no relevant financial relationships to disclose.) Raymond P Roos MD, editor. (Dr. Raymond Roos of the University of Chicago Medical Center serves on the Scientific Advisory Board of Revalesio Corporation and a Data and Safety Monitoring Board for a clinical trial of a Mallinckrodt Pharmaceuticals product, has received consulting fees from M-T Pharmacy and Best Doctors and holds shares in Amgen, Merck, Ionis, and GE.) Originally released May 13, 1996; last updated March 13, 2017; expires March 13, 2020 Introduction This article includes discussion of Cogan syndrome, Cogan keratitis syndrome, keratitis-deafness syndrome, nonsyphilitic interstitial keratitis, oculovestibulo-auditory syndrome, and atypical Cogan syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Cogan syndrome is a rare, likely autoimmune, inflammatory disease that affects the inner ear and ocular cornea. It is characterized by an acute phase of relapsing ocular and aural involvement lasting months to years, followed by a chronic phase of relatively low disease activity. Patients typically recover from the ocular symptoms, but many develop permanent hearing loss. Some also develop systemic necrotizing vasculitis that affects vital organs, such as the aorta and aortic valves, brain, and kidneys, with life-threatening complications. Oral glucocorticoid therapy is the mainstay of treatment. Key points Cogan syndrome is characterized by ocular disease and audiovestibular dysfunction. Typical ocular disease is interstitial keratitis. Typical audiovestibular symptoms are acute attacks resembling Ménière disease and progressive hearing loss. A large proportion of patients have systemic manifestations, with a minority having life threatening sequelae of vasculitis. Immunosuppressive therapy is used to control symptoms. Historical note and terminology The syndrome of nonsyphilitic interstitial keratitis in association with audiovestibular dysfunction was first reported in 1934 (Morgan and Baumgartner 1934); shortly thereafter it was classified as a distinct clinical entity by David Cogan (Cogan 1945). Oliner and colleagues were the first group to hypothesize that Cogan syndrome was a manifestation of a generalized arteritis (Oliner et al 1953). Atypical Cogan syndrome is defined on the basis of atypical audiovestibular or ocular symptoms. Haynes and colleagues defined as atypical those cases with audiovestibular symptoms that were not Ménière-like or that occurred more than 2 years before or after the onset of eye symptoms (Haynes et al 1980). Cody and Williams defined atypical Cogan syndrome as the presence of an inflammatory eye lesion in addition to or instead of interstitial keratitis (Cody and Williams 1960). The synonyms of Cogan syndrome include Cogan keratitis syndrome, keratitis-deafness syndrome, nonsyphilitic interstitial keratitis, and oculovestibulo-auditory syndrome. Clinical manifestations Presentation and course Cogan syndrome is characterized by inflammatory ocular disease and audio-vestibular symptoms occurring

2 simultaneously or sequentially within 6 months. A large proportion of patients also have systemic manifestations. Most patients have multiple relapses, with a minority having monophasic disease with remission or progressive disease without remission (Gluth et al 2006). Firm diagnostic criteria have not been established, and this leads to heterogeneity in the literature. Papers describing 60 patients seen at the Mayo Clinic (Gluth et al 2006) and reviewing 23 pediatric cases (Pagnini et al 2012) are literature surveying presentation and outcomes of Cogan syndrome. A review by Kessel and colleagues succinctly summarizes the symptoms by organ system (Kessel et al 2014). Typical ocular symptoms consist of acute unilateral or bilateral interstitial keratitis in almost 80% of affected individuals, causing photophobia, excessive lacrimation, and eye pain. Examination of the eyes early in the course of the disease reveals a patchy, granular corneal infiltrate, predominantly in the posterior half of the cornea, more pronounced close to the limbus (Oliner et al 1953). The corneal endothelium may be boggy, but the cornea is not thickened, and little or no reaction occurs in the anterior chamber or the iris. Later in the disease, corneal neovascularization develops. Cogan pointed out the differences between his cases and congenital syphilis: onset of interstitial keratitis was not abrupt, the cornea was not thickened, ground-glass or opalescent opacities did not develop, iridocyclitis was absent, and vascularization was much less in Cogan syndrome (Cogan 1945). Atypical Cogan syndrome is characterized by significant eye disease in the absence or presence of the more typical interstitial keratitis. The most common atypical ocular symptoms are iritis or uveitis (37%), scleritis or episcleritis (23%), and conjunctivitis (10%) (Gluth et al 2006). Retinal artery occlusion, choroiditis, retinal hemorrhages, optic nerve edema, superficial keratitis, deep stromal keratitis, sclerosing keratitis, pars planitis, retinitis, choroiditis, optic neuritis, optic nerve head edema, central retinal artery occlusion, retinal angiomatosis, cystoid macular edema, and orbital inflammatory syndrome have been described (Cody 1960; Cody and Williams 1962; Haynes et al 1980; Cobo and Haynes 1984; Majoor et al 1992; Shah et al 1994; Semeraro et al 2011). Typical audiovestibular symptoms include Ménière-like attacks of severe vertigo, nausea, emesis, ataxia, oscillopsia, tinnitus, and fluctuating, progressive hearing loss. In Gluth's report, 100% of patients had hearing loss, and 93% had abnormal vestibular function testing at some point in their disease. Atypical audio-vestibular symptoms include slowly progressive deafness without vestibular symptoms. Sudden onset of binaural deafness has been described, preceding ocular symptoms in 1 case (Cote et al 1993). In Gluth's series, more than 20% experienced nonspecific symptoms (at least 1 of headaches, arthralgias, fevers, arthritis, or myalgias) (Gluth et al 2006). The same series reported vasculitis in 13% of patients. A systemic vasculitis usually affects medium-sized vessels although any sized vessel may be affected (Gaubitz 2001). Vollertsen and colleagues reported that the median time from disease onset to vasculitis was 7 months, and vasculitis occurred within 1 year in two thirds of those who developed it (Vollertsen 1986). Cardiac manifestations are vasculitic in nature, and most deaths are due to the sequelae of aortitis. In Gluth's series, 12% had aortic disease (Gluth et al 2006). Coronary artery involvement of 2 types has been described: (1) occlusion of coronary ostia by aortic inflammation and (2) vasculitis of the coronary arteries themselves (Livingston et al 1992). Multiple aortic arch vessel stenoses have been reported (Cochrane and Tatoulis 1991). Aortic dilatation and pericarditis also occur (Livingston et al 1992). Beyond audio-vestibular dysfunction, other central nervous system manifestations are seen in 7% and peripheral nervous system manifestations in 1% of patients (Haynes et al 1980). Reported findings include seizures, EEG abnormalities, cerebral infarcts, hyperreflexia, cranial neuropathies, trigeminal neuralgia, transverse myelitis, peripheral neuropathies, cerebellar lesions, encephalitis, meningitis, and cerebral sinus thrombosis (Bicknell and Holland 1978; Karni et al 1991; Manto and Jacquy 1996; Antonios and Silliman 2012). Almost all organ systems have been reported to be affected. Dermatologic manifestations are seen in about 10% of patients and include rashes, some with ulceration, and urticarial vasculitis (Ochonisky et al 1991). Other reported manifestations include gastrointestinal bleeding, lymphadenopathy, hepatosplenomegaly, glomerulonephritis, renal vasculitis, pleuritis, pulmonary nodules, arthritis, polychondritis, hypogonadism, hypothyroidism, and Budd-Chiari syndrome (Haynes et al 1980; Vollertsen et al 1986; Vollertsen 1990; Davis et al 2006; O'Brien et al 2006; Radman et al 2008). There are many reports of co-occurrence of Cogan syndrome with other autoimmune diseases. Eight percent of patients had established rheumatological diagnoses in Gluth's series (Gluth et al 2006). Inflammatory bowel disease

3 has been described in 13 patients with Cogan syndrome (Scharl et al 2011). Several reports have documented Cogan syndrome within the spectrum of extra-articular vasculitic manifestations of rheumatoid arthritis (Dekker et al 1996), periarteritis nodosa (Oliner et al 1953), Takayasu arteritis (Raza et al 1998), Wegener granulomatosis (Gran et al 1999), and tubulointerstitial nephritis uveitis (TINU) syndrome (Brogan et al 2012). Twenty-three cases of Cogan syndrome in the pediatric age group were reviewed by Pagnini and colleagues (Pagnini et al 2012). At time of onset, almost half had systemic symptoms, over 90% had ocular involvement, and almost 75% had audio-vestibular features. Approximately 20% only had 1 system involved at onset. Cardiovascular involvement was present in 17% of patients at onset and did not develop in any patients during follow up. The disease course was characterized by improvement in ocular and vestibular manifestations and nonspecific symptoms and persistence of auditory and cardiovascular characteristics. Prognosis and complications The acute ocular symptoms gradually resolve, and the visual sequelae of typical Cogan syndrome are usually benign. The audiovestibular dysfunction leads to progressive hearing loss and deafness in 60% of patients (Haynes et al 1980). Audiograms are always abnormal and usually reveal hearing loss, more pronounced at higher frequencies (Haynes et al 1981). A review of 111 patients, 13 of whom were extensively studied at the National Institutes of Health, found 5- year survival to be 85% for typical but only 64% for atypical Cogan syndrome (Haynes et al 1980). Serious outcomes in Cogan syndrome include bilateral deafness in 42%, vasculitis in 15%, aortic insufficiency in 14%, blindness in 8%, and death in 9% (Vollertsen et al 1986). The major disease-related morbidities were due to vestibuloauditory disease and only infrequently due to systemic manifestations, such as vasculitis with or without aortitis (Gluth et al 2006). Most life-threatening complications occur as a result of the systemic necrotizing vasculitis that affects vital organs, such as the aorta and aortic valves, brain, and kidneys, resulting in congestive heart failure, myocardial infarction, stroke, renal failure, and death. Pediatric outcomes are similar to those in adults with long-terms symptoms related to auditory and circulatory dysfunction, with vestibular and ocular symptoms generally resolving (Pagnini et al 2012). Clinical vignette A 56-year-old man was referred for confirmation of Cogan syndrome. He had a history of episodic photophobia as well as red and painful eyes (worse on the left) that dated back to the mid-1970s. He had been treated with numerous courses of topical and oral glucocorticoids. The attacks, which had been frequent and severe in the initial years, had abated with the passage of time. He had been followed in the Ophthalmology Clinic of our institution for the past 10 years, and again intermittently treated with glucocorticoid eyedrops for scleritis, episcleritis, and interstitial keratitis. He also had noted tinnitus for the previous 10 years with gradual worsening of his hearing, such that he was having increasing difficulty using a stethoscope. Two months prior to the referral, he developed acute positional vertigo (worse with left ear down) that woke him up from sleep. He had nausea and vomiting and worsened hearing in both ears. He also noted concomitant worsening of vision in both eyes, described as looking through a fog." He was diagnosed with labyrinthitis and treated with oral prednisone 60 mg daily, tapered over a week. His vision and hearing improved and his vertigo resolved within a couple of days. He was put on daily topical glucocorticoid eye drops, increasing in frequency to 3 to 4 times a day when he relapsed. His general health was excellent. Past medical history was significant for a right lung lesion discovered 33 years previously that, on excision, was found to be histoplasmosis. He suffered damage to the inferior vena cava during surgery. He had no residual respiratory problems. He was employed as a visiting physical therapist and covered a large rural territory. He denied current or previous neurologic or cardiac problems. On examination his mental status and affect were normal. His vision was 20/20 in the right eye and 20/25 in the left eye. Visual fields were full to confrontation. He had no ptosis or proptosis. Pupils were 3 mm, equal and briskly reactive; he had no relative afferent papillary defects. Cranial nerves were normal except for slightly decreased hearing in both ears. Slit lamp exam revealed central subepithelial stromal corneal haziness and primarily inferior midstromal haziness with ghost vessels. Intraocular pressures were normal. The iris and anterior chamber were normal. Both lenses had 1+ nuclear sclerosis and 1+ posterior subcapsular cataracts. Dilated retinal exam revealed normal discs with mild peripapillary atrophy, normal vessels, and maculae. General motor, coordination, gait, reflex,

4 and sensory exams were normal. Biological basis Etiology and pathogenesis No etiology of Cogan syndrome has been identified, although its association with vasculitis and other autoimmune diseases implies an autoimmune basis. Genetics. A genetic association has not been reported. Cell biology and immunology. The exact mechanism for the immune response has not been elucidated. Char and colleagues demonstrated leukocyte migration inhibition in patients who were exposed to pooled allogenic normal corneal extract and, therefore, postulated a cell-mediated response (Cogan and Sullivan 1975). Similar results were obtained with inner ear membranes extracted from semicircular canals and vestibules (Hughes et al 1983). One patient with atypical Cogan syndrome had an increased lymphocyte stimulation index with S antigen, outer rod segment, and scleroprotein (Peeters et al 1986). Antibodies against corneal epithelium (Majoor et al 1992) and both inner ear tissue and corneal epithelium (Arnold and Gebbers 1984) have been demonstrated. However, their significance has been questioned (Helmchen et al 1999). Subsequent studies have suggested immune activity against a so-called Cogan peptide (Lunardi et al 2002; Benvenga et al 2003). Cogan peptide is homologous to autoantigens such as Connexin 26 and DEP-1/CD148 on the sensory epithelia of inner ear and endothelial cells, as well as other antigens such as SSA/Ro, laminin, ladinin, kinesin, and calcineurin (Lunardi et al 2002; Benvenga et al 2003). The association between Cogan peptide antibodies and autoimmune hearing loss is being explored (Berti et al 2013). Circulating immune complexes have been found by a microconsumption complement method (Manto and Jacquy 1996). Circulating autoantibodies against heat shock protein (HSP-70), a 68 kd protein, have been reported to be present in approximately 40% of patients with active autoimmune inner ear diseases, including Cogan syndrome, and the specificity of the test compared with healthy patients may approach 90% (Kiang 1998). A study of anti-hsp 70 found 92.9% sensitivity in typical Cogan syndrome (n=24). However, it was also elevated in over 50% of patients with autoimmune hearing loss, over 15% of patients with atypical Cogan syndrome, and 5% of patients with other autoimmune diseases (Bonaguri et al 2014). The similarity of the syndrome to syphilis has prompted a search for infectious etiologies. No spirochetal etiology has been found (Vollertsen 1990). Chlamydia organisms, known to cause chronic eye infections, have been implicated in a few cases of Cogan syndrome based on isolation of Chlamydia psittaci (Vollertsen 1990), IgM antibody to Chlamydia trachomatis during active disease with subsequent falling titers (Haynes et al 1980), and Chlamydia pneumoniae IgA titers, plus a 4-fold increase in IgG titers after 1 month (Ljungstrom et al 1997). Haynes and colleagues noted an association with preceding upper respiratory infection in 42% of typical cases and 65% of atypical cases (Haynes et al 1980). An early association with HLA-B17 antigen (Cogan and Sullivan 1975) has not been borne out by later investigations (Kaiser-Kupfer et al 1978). A single case has been reported in an HIV-positive patient (Kleeberg et al 2008) though data suggest that the syndrome was neither due to immunosuppression nor to an immune reconstitution inflammatory syndrome (IRIS). Pathology. Corneal pathology in Cogan syndrome has been examined in specimens obtained at penetrating keratoplasty and a few autopsied cases, and reveals lymphocyte and plasma cell infiltration into deeper layers of the cornea, with evidence of neovascularization but no vasculitis (Leff 1967; Haynes et al 1980; Majoor et al 1992). Confocal microscopic evaluation of affected corneas in vivo showed stromal deposits and sparing of the outer layers and endothelium in all cases. Seventy-five percent of cases had interruptions in the subepithelial plexus (Pellistri et al 2010). Pathological study of the temporal bone in Cogan syndrome has demonstrated retrograde degeneration of the vestibular and auditory nerves, endolymphatic hydrops of the cochlea and semicircular canals, focal and diffuse proliferation of fibrous tissue and bone, and atrophy of inner ear tissues, including sense organs (Fisher and Hellstrom 1961; Schuknecht and Nadol 1994). Vasculitis of the vestibulocochlear nerves has been described (Haynes et al 1980).

5 Biopsy and autopsy studies of resected aorta show moderate intimal thickening due to fibrous connective tissue deposition, degeneration of the media with focal fibrinoid necrosis of collagen, and acute and chronic inflammatory changes with occasional multinucleated giant cells. Aortic valves show degeneration and thickening due to dense fibroconnective tissue, but no inflammation (Gelfand et al 1972). A consensus statement on aortic pathology defined 4 inflammatory patterns in aortitis with Cogan syndrome having a mixed inflammatory pattern (Stone et al 2015). Vascular lesions in the extremities and viscera have demonstrated a systemic necrotizing vasculitis, which has been likened to that of periarteritis nodosa or to thromboangiitis obliterans (Fisher and Hellstrom 1961). Focal areas of necrosis, fibrinoid degeneration, and leukocyte infiltration involving small arteries and veins in various organs have been described at autopsy (Crawford 1957). Epidemiology" Cogan syndrome is viewed as a rare syndrome, but no estimate of its incidence or prevalence is available. Over 300 patients have been reported in the world literature. It occurs without gender predominance and has been described in all races. The median age of onset in the National Institutes of Health and Mayo Clinic groups was 22 years and 38 years, with a range of 13 to 31 and 9 to 70 years, respectively (Haynes 1980; Gluth et al 2006). The youngest reported patient was 2 years of age (Chynn and Jakobiec 1996). Differential diagnosis The differential diagnosis of Cogan syndrome includes disorders that cause interstitial keratitis and audiovestibular dysfunction. The following list includes most of these disorders: Congenital syphilis Acquired syphilis Tuberculosis Sarcoidosis Onchocerciasis Chlamydial infections Congenital rubella Congenital mumps Viral labyrinthitis Viral infections (Herpes simplex virus, Herpes zoster virus, mumps, rubella, influenza, measles, variola) Periarteritis nodosa Wegener granulomatosis Rheumatoid arthritis Giant cell arteritis Sjögren syndrome Behçet disease Ankylosing spondylitis Relapsing polychondritis Takayasu arteritis Vogt-Koyanagi-Harada syndrome 3-methyl-1-pentyn-3-yl acid phthalate (Whipside) toxicity Diagnostic workup Making the diagnosis of Cogan syndrome is important, not only because hearing is often lost and vision can be lost but also because 10% of cases are complicated by aortic insufficiency, which can be life-threatening (Garcia Berrocal et al 1999). Firm diagnostic criteria have not been established, and there are no tests that prove or disprove the diagnosis. In particular, the role of this testing for Cogan peptide antibodies regarding diagnosis and treatment of Cogan syndrome has not yet been established. Therefore, diagnosis is made on clinical grounds following exclusion of other conditions with similar presentations. Negative serologic and treponemal tests for syphilis are mandatory to rule out congenital and acquired syphilis, the conditions most similar to Cogan syndrome. Sarcoidosis is the next most likely diagnosis to be excluded. To enable

6 diagnosis of immune-mediated inner ear disorders, the diagnostic protocol should include antinuclear, antineutrophil cytoplasmic, antiendothelial cell, antiphospholipid, anticardiolipin, and antithyroid antibody testing (Agrup 2006). Up to 75% of patients have leukocytosis (mostly neutrophils) and an elevated erythrocyte sedimentation rate, with smaller percentages having anemia, thrombocytosis, and lymphopenia; relative monocytosis and eosinophilia are occasionally found (Vollertsen et al 1986). The anemia and elevated erythrocyte sedimentation rate tend to normalize after an acute attack, but the leukocytosis tends to persist (Hughes et al 1983). Rheumatoid factor and a biologically false-positive Venereal Disease Research Laboratories test have been described in 8% of patients; antinuclear antibody and lupus erythematosus preparation are generally negative (Haynes et al 1980). C-reactive protein is often elevated and has been advocated as a marker of the therapeutic response (Cote et al 1993). Elevated serum levels of other acute phase reactants, such as immunoglobulin, fibrinogen, haptoglobin (Vollertsen et al 1986), as well as antineutrophil cytoplasmic antibodies (Yamanishi et al 1996) have been observed. Elevated liver enzymes are present in 8% (Haynes et al 1980). Cutaneous anergy and decreased numbers of T cells and complement levels (C3, C4) have been described (Edstrom and Vahlne 1976). One series found positive cryoglobulins in 23% (Haynes et al 1980), although this was not noted in other series. Positive titers for Chlamydia trachomatis were found in 9 of 13 patients (Haynes et al 1980), and for Chlamydia pneumoniae in 1 patient in another series (Ljungstrom et al 1997). Mild abnormalities in urinalysis have been described in 17% of patients (Vollertsen et al 1986). Abnormalities of the cerebrospinal fluid have been described in case reports. Pathologic findings of necrotizing vasculitis have been demonstrated by biopsy of the skin, kidney, liver, spleen, gastrointestinal tract, subcutaneous nodules, muscle, myocardium, and coronary arteries (Vollertsen et al 1986). Bone marrow and brain biopsy generally have nonspecific findings (Vollertsen et al 1986). The audiogram test is abnormal in 95% of patients with Cogan syndrome; the hearing loss is more pronounced at the extreme frequencies, with relative sparing of the midrange, and a pattern indicating cochlear pathology. Auditory evoked potentials are also reduced or absent and suggestive of sensorineural deafness. The caloric test response is also absent in 70% of patients. High-resolution, gadolinium-enhanced, T1-weighted MRI studies have shown enhancement of the vestibule, semicircular canals, vestibular nerve, and cochlea in patients with acute disease, whereas patients with chronic deficits but no acute disease have narrowing or occlusion of semicircular canals on images obtained by the 3-dimensional constructive interference in steady-stage technique (Helmchen et al 1998; Bursztejn 2005; Fugate et al 2009). PET, especially when combined with HSP-70 determination, may be a useful technique for assessing activity of disease in patients with autoimmune inner ear disease (Mazlumzadeh et al 2003). Cerebral angiographic findings of vasculitis, including alternating segments of stenosis and ectasia in intracranial arteries as well as a small aneurysm at the vertebrobasilar junction, have been described (Albayram et al 2001). Management A systematic review of systemic therapy was published by Mora and colleagues (Mora et al 2017). Topical glucocorticoids and atropine generally control the interstitial keratitis of Cogan syndrome. Eighty percent of patients treated with topical or systemic glucocorticoids have improvement of their ocular symptoms within 1 week (Vollertsen et al 1986). Oral glucocorticoids are the treatment of choice for the prevention of hearing loss when used early in the course of the disease before substantial loss has occurred; low- and middle-frequency hearing is best preserved (Haynes et al 1980; Haynes et al 1981). Oral glucocorticoids are also useful in treating the vasculitic manifestations of Cogan syndrome; in 1 series, 22% of patients treated with glucocorticoids died, compared to 67% of untreated patients (Vollertsen et al 1986). Alternatives to steroid therapy have been successfully used in glucocorticoid-unresponsive or -dependent patients to improve hearing, control vasculitis, and reduce relapses. These include methotrexate (Richardson 1994; Matteson et al 2001), cyclosporin A (Allen et al 1990; Covelli et al 1999), cyclophosphamide (Haynes et al 1980), rituximab (Orsoni et al 2010), infliximab (Fricker et al 2007), mycophenolate mofetil (Hautefort et al 2009), leflunomide (Xie et al 2009), tocilizumab, an IL-6 receptor antibody (Shibuya et al 2013), and plasma exchange (Best et al 2013). Hearing fluctuations that occur late in the course of the disease respond to oral thiazide diuretics (Haynes et al 1980;

7 Haynes et al 1981). Cochlear implantation with excellent results up to 5 years following implantation has been reported in several studies (Gluth et al 2006; Wang et al 2010; Bacciu et al 2015). In patients with symptomatic aortitis and aortic insufficiency, aortic valve replacement can be life-saving. Coronary artery bypass grafting has been used successfully in patients with coronary arteritis (Vollertsen et al 1986). Splenectomy has been demonstrated to be useful in patients with splenomegaly (Pinals 1978). Outcomes The treatment literature is case report based, which limits conclusions regarding the comparative effectiveness of treatments. Treatment related complications are those specific to the treatment methodology chosen. Special considerations Pregnancy Three cases of pregnancy associated with Cogan syndrome have been reported, with none reporting obstetric or postpartum complications (Deliveliotou et al 2007; Currie et al 2009; Tarney et al 2014). Pregnancy associated with inflammatory or autoimmune diseases requires an individualized therapeutic approach (Gordon 2004). References cited Agrup C, Luxon LM. Immune-mediated inner-ear disorders in neuro-otology. Curr Opin Neurol 2006;19(1): PMID Albayram MS, Wityk R, Yousem DM, Zinreich SJ. The cerebral angiographic findings in Cogan syndrome. Am J Neuroradiol 2001;22: PMID Allen NB, Cox CC, Cobo M, et al. Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogan's syndrome. Am J Med 1990;88(3): PMID Antonios N, Silliman S. Cogan syndrome: an analysis of reported neurological manifestations. Neurologist 2012;18: PMID Arnold W, Gebbers JO. [Serum antibodies against corneal and internal ear tissues in Cogan's syndrome]. Laryngol Rhinol Otol (Stuttg) 1984;63: PMID Bacciu A, Pasanisi E, Di Lella F, Guida M, Bacciu S, Vincenti V. Cochlear implantation in patients with Cogan syndrome: long-term results. Eur Arch Otorhinolaryngol 2015;272(11): PMID Benvenga S, Trimarchi F, Facchiano A. Cogan's syndrome as an autoimmune disease. Lancet 2003;361: PMID Berti E, Vannucci G, Lunardi C, et al. Identification of autoantibodies against inner ear antigens in a cohort of children with idiopathic sensorineural hearing loss. Autoimmunity 2013;46(8): PMID Best C, Thomke F, Hitzler W, Dieterich M. Plasmapheresis as effective treatment in chronic active Cogan-I-syndrome. Immunol Lett 2013;150(1-2);87-8. PMID Bicknell JM, Holland JV. Neurologic manifestations of Cogan syndrome. Neurology 1978;28: PMID Bonaguri C, Orsoni J, Russo A, et al. Cogan's syndrome: anti-hsp70 antibodies are a serological marker in the typical form. Isr Med Assoc J 2014;16(5): PMID Brogan K, Eleftheiou D, Rajput K, Edelsten C, Sebire NJ, Brogan PA. Tubulointerstitial nephritis, uveitis, hearing loss and vestibular failure: TINU-atypical Cogan's overlap syndrome. Rheumatology 2012;51: PMID Bursztejn AC, Lesens O, Hansmann Y, et al. Cogan's syndrome revealed by haemorrhagic glairous diarrhoea. Presse Med 2005;34(4): PMID

8 Chynn EW, Jakobiec FA. Cogan's syndrome: ophthalmic, audiovestibular, and systemic manifestations and therapy. Int Ophthalmol Clin 1996;36: PMID Cobo LM, Haynes BF. Early corneal findings in Cogan's syndrome. Ophthalmology 1984;91: PMID Cochrane AD, Tatoulis J. Cogan's syndrome with aortitis, aortic regurgitation, and aortic arch vessel stenoses. Ann Thorac Surg 1991;52: PMID Cody DT, Williams HL. Cogan's syndrome. Laryngoscope 1960;70: PMID Cody DT, Williams HL. Cogan's syndrome. Mayo Clin Proc 1962;37: PMID Cogan DG. Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol 1945;33: Cogan DG, Sullivan WR Jr. Immunologic study of nonsyphilitic interstitial keratitis with vestibuloauditory symptoms. Am J Ophthalmol 1975;80: PMID Cote DN, Molony TB, Waxman J, Parsa D. Cogan's syndrome manifesting as sudden bilateral deafness: diagnosis and management. South Med J 1993;86: PMID Covelli M, Lapadula G, Pipitone V. Cogan's syndrome: unsuccessful outcome with early combination therapy. Clin Exp Rheumatol 1999;17: PMID Crawford WJ. Cogan's syndrome associated with polyarteritis nodosa. Penn Med J 1957;60: PMID Currie C, Wax JR, Pinette MG, Blackstone J, Cartin A. Cogan's syndrome complicating pregnancy. J Matern Fetal Neonatal Med 2009;22(10): PMID Davis N, Lunardi C, Shield JP. Sensori-neural deafness and hypothyroidism: autoimmunity causing 'pseudo-pendred syndrome.' Horm Res 2006;65(6): PMID Dekker JJ, Dinant HJ, Van Soesbergen RM. Cogan's syndrome as an extra-articular manifestation of rheumatoid arthritis. Clin Rheumatol 1996;15: PMID Deliveliotou A, Moustakarias T, Argeitis J, Vaggos G, Vitoratos N, Hassiakos D. Successful full-term pregnancy in a woman with Cogan's syndrome: a case report. Clin Rheumatol 2007;26(12): PMID Edstrom S, Vahlne A. Immunologic findings in a case of Cogan's syndrome. Acta Otolaryngol 1976;82: PMID Fisher ER, Hellstrom HR. Cogan's syndrome and systemic vascular disease. Arch Pathol 1961;72: PMID Fricker M, Baumann A, Wermelinger F, Villiger PM, Helbling A. A novel therapeutic option in Cogan diseases. TNF-alpha blockers. Rheumatol Int 2007;27(5): PMID Fugate JE, Smith JH, Claassen DO. Bilateral cochlear enhancement in Cogan syndrome. Neurology 2009;73(1):75. PMID Garcia Berrocal JR, Vargas JA, Vaquero M, Ramón y Cajal S, Ramírez-Camacho RA. Cogan's syndrome: an oculoaudiovestibular disease. Postgrad Med J 1999;75(883): PMID Gaubitz M, Lubben B, Seidel M, Schotte H, Gramley F, Domschke W. Cogan's syndrome: organ specific autoimmune disease or systemic vasculitis. A report of two cases and review of the literature. Clin Exp Rheumatol 2001;19: PMID Gelfand ML, Kantor T, Gorstein F. Cogan's syndrome with cardio-vascular involvement: aortic insufficiency. Bull N Y Acad Med 1972;48: PMID

9 Gluth MB, Baratz KH, Matteson EL, Driscoll CL. Cogan syndrome: a retrospective review of 60 patients throughout a half century. Mayo Clin Proc 2006;81(4): PMID Gordon C. Pregnancy and autoimmune diseases. Best Pract Res Clin Rheum 2004;18: PMID Gran JT, Nordvag BY, Storesund B. An overlap syndrome with features of atypical Cogan syndrome and Wegener's granulomatosis. Scand J Rheumatol 1999;28:62-4. PMID Hautefort C, Loundon N, Montchilov M, Marlin S, Garabedian EN, Ulinski T. Mycophenolate mofetil as a treatment of steroid dependent Cogan's syndrome in childhood. Int J Ped Otorhinolaryngology 2009;73: PMID Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan's syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine (Baltimore) 1980;59: PMID Haynes BF, Pikus A, Kaiser-Kupfer MI, Fauci AS. Successful treatment of sudden hearing loss in Cogan's syndrome with corticosteroids. Arthritis Rheum 1981;24: PMID Helmchen C, Arbusow V, Jaeger L, Strupp M, Stoecker W, Schulz P. Cogan's syndrome: clinical significance of antibodies against the inner ear and cornea. Acta Otolaryngol 1999;119: PMID Helmchen C, Jaeger L, Buttner U, Raiser M, Brandt T. Cogan's syndrome. High resolution MRI indicators of activity. J Vestib Res 1998;8: PMID Hughes GB, Kinney SE, Barna BP, Tomsak RL, Calabrese LH. Autoimmune reactivity in Cogan's syndrome: a preliminary report. Otolaryngol Head Neck Surg 1983;91: PMID Kaiser-Kupfer MI, Mittal KK, Del Valle LA, Haynes BF. The HLA antigens in Cogan's syndrome. Am J Ophthalmol 1978;86: PMID Karni A, Sadeh M, Blatt I, Goldhammer Y. Cogan's syndrome complicated by lacunar brain infarcts. J Neurol Neurosurg Psychiatry 1991;54: PMID Kessel A, Vadasz Z, Toubi E. Cogan syndrome--pathogenesis, clinical variants and treatment approaches. Autoimm Rev 2014;13(4-5): PMID Kiang JG, Tsokos GC. Heat shock protein 70 kda: molecular biology, biochemistry, and physiology. Pharmacol Ther 1998;80: PMID Kleeberg J, Maire R, Chave JP, Pournaras JA, Guex-Crosier Y, Du Pasquier RA. Inaugural description of Cogan syndrome in an HIV-infected person. J Neurol 2008;255(9): PMID Leff IL. Cogan's syndrome. Ocular pathology. N Y State Med J 1967;67: PMID Livingston JZ, Casale AS, Hutchins GM, Shapiro EP. Coronary involvement in Cogan's syndrome. Am Heart J 1992;123: PMID Ljungstrom L, Franzen C, Schlaug M, Elowson S, Viidas U. Reinfection with chlamydia pneumoniae may induce isolated and systemic vasculitis in small and large vessels. Scand J Infect Dis Suppl 1997;104: PMID Lunardi C, Bason C, Leandri M, et al. Autoantibodies to inner ear and endothelial antigens in Cogan's syndrome. Lancet 2002;360: PMID Majoor MH, Albers FW, Van der Gaag R, Gmelig-Meyling F, Huizing EH. Corneal autoimmunity in Cogan's syndrome. Report of two cases. Ann Otol Rhinol Laryngol 1992;101: PMID Manto MU, Jacquy J. Cerebellar ataxia in Cogan syndrome. J Neurol Sci 1996;136: PMID Matteson EL, Fabry DA, Facer GW, et al. Open trial of Methotrexate as treatment for autoimmune hearing loss. Arthritis Care Res 2001;45: PMID

10 Mazlumzadeh M, Lowe VJ, Mullan BP, Fabry DA, McDonald TJ, Matteson EL. The utility of positron emission tomography in the evaluation of autoimmune hearing loss. Otol Neurotol 2003;24(2): PMID Mora P, Calzetti G, Ghirardini S, Rubino P, Fandolfi S, Orsoni J. Cogan's syndrome: state of the art of systemic immunosuppressive treatment in adult and pediatric patients. Autoimmun Rev 2017;16(4): PMID Morgan RF, Baumgartner CJ. Meniere's disease complicated by recurrent interstitial keratitis: excellent result following a cervical ganglionectomy. West J Surg 1934;42: O'Brien MJ, Bloom A, LaBerge JM, et al. SIR 2006 Annual Meeting Film Panel Case: Budd-Chiari syndrome in a patient with Cogan syndrome. J Vasc Interv Radiol 2006;17(12): PMID Ochonisky S, Chosidow O, Kuentz M, et al. Cogan's syndrome. An unusual etiology of urticarial vasculitis. Dermatologica 1991;183: PMID Oliner L, Taubenhaus M, Shapira TM, Leshin N. Nonsyphilitic interstitial keratitis and bilateral deafness (Cogan's syndrome) associated with essential polyangiitis (periarteritis nodosa). N Engl J Med 1953;248: PMID Orsoni JG, Laganà B, Rubino P, Zavota L, Bacciu S, Mora P. Rituximab ameliorated severe hearing loss in Cogan's syndrome: a case report. Orphanet J Rare Dis 2010;5:18. PMID Pagnini I, Zannin ME, Vittadello F, et al. Clinical features and outcome of Cogan syndrome. J Pediatr 2012;160: PMID Peeters GJ, Pinckers CW, Cremers AJ, Hoefnagels WH. Atypical Cogan's syndrome: an autoimmune disease. Ann Otol Rhinol Laryngol 1986;95: PMID Pellistri I, Mora P, Ponzin D, Coggiola A, Nubile M, Orsoni JG. Cogan syndrome: confocal microscopy assessment of corneal damage. Eur J Ophthalmol 2010;20: PMID Pinals RS. Cogan's syndrome with arthritis and aortic insufficiency. J Rheumatol 1978;5: PMID Radman M, Kraus O, Solter M. Male hypogonadism in a patient with Cogan syndrome. Ann Saudi Med 2008;28(6): PMID Raza K, Karokis D, Kitas GD. Cogan's syndrome with Takayasu's arteritis. Br J Rheumatol 1998;37: PMID Richardson B. Methotrexate therapy for hearing loss in Cogan's syndrome. Arthrit Rheumat 1994;37(10): PMID Scharl M, Frei P, Fried M, Rogler G, Vavricka SR. Association between Cogan's syndrome and inflammatory bowel disease: a case series. J Crohn's Colitis 2011;5:64-8. PMID Schuknecht HF, Nadol JB. Temporal bone pathology in a case of Cogan's syndrome. Laryngoscope 1994;104: PMID Semeraro F, Fusso A, Duse S, Romano V, Cotagliola C. Retinal angiomatosis and cystoid macular oedema in Cogan's syndrome. Optom Vis Sci 2011;88:E PMID Shah P, Luqmani RA, Murray PI, Honan WP, Corridan PGJ, Emery P. Posterior scleritis--an unusual manifestation of Cogan's syndrome. Br J Rheumatol 1994;33: PMID Shibuya M, Fujio K, Morita K, Harada H, Kanda H, Yamamoto K. Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis. Mod Rheumatol 2013;23(3): PMID Stone JR, Bruneval P, Angelini A, et al. Consensus statement on surgical pathology of the aorta from the Society of Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovasc Pathol 2015;24(5): PMID

11 Tarney CM, Wilson K, Sewell MF. Cogan syndrome in pregnancy. Obstet Gynecol 2014;124(2 Pt 2 Suppl 1): PMID Vollertsen RS. Vasculitis and Cogan's syndrome. Rheum Dis Clin North Am 1990;16: PMID Vollertsen RS, McDonald TJ, Younge BR, Banks PM, Stanson AW, Ilstrup DM. Cogan's syndrome: 18 cases and a review of the literature. Mayo Clin Proc 1986;61: PMID Wang JR, Yuen HW, Shipp DB, et al. Cochlear implantation in patients with autoimmune inner ear disease including Cogan syndrome: a comparison with age- and sex-matched controls. Laryngoscope 2010;120: PMID Xie L, Cai Y, Bao X, Vao L. Leflunomide for the successful management of juvenile Cogan's syndrome. Clin Rheumatol 2009;28: PMID Yamanishi Y, Ishioka S, Takeda M, Maeda H, Yamakido M. Atypical Cogan's syndrome associated with antineutrophil cytoplasmic auto-antibodies. Br J Rheumatol 1996;35: PMID **References especially recommended by the author or editor for general reading. Former authors Sarkis M Nazarian MD (original author), Tarakad S Ramachandran MD, Sarika Shirsat MD, and Arun Ramachandran ICD and OMIM codes ICD codes ICD-9: Cogan syndrome: ICD-10: Cogan syndrome: H16.3 Profile Age range of presentation years years years Sex preponderance male=female Family history none Heredity none Population groups selectively affected none selectively affected Occupation groups selectively affected none selectively affected

12 Differential diagnosis list congenital syphilis acquired syphilis tuberculosis sarcoidosis onchocerciasis chlamydial infections congenital rubella congenital mumps viral labyrinthitis viral infections Herpes simplex virus infection Herpes zoster virus infection mumps rubella influenza measles variola periarteritis nodosa Wegener granulomatosis rheumatoid arthritis giant cell arteritis Sjögren syndrome Behçet disease ankylosing spondylitis relapsing polychondritis Takayasu arteritis Vogt-Koyanagi-Harada syndrome 3-methyl-1-pentyn-3-yl acid phthalate (Whipside) toxicity Associated disorders Aortic insufficiency Arthritis Crohn disease Inflammatory bowel disease Interstitial keratitis Systemic necrotizing vasculitis Other topics to consider Ataxia Lacunar infarction Neurologic complications of diseases of the aorta Neurologic manifestations of Crohn disease Copyright MedLink Corporation. All rights reserved.