Cogan syndrome is a rare autoimmune disease characterized by non-syphilitic interstitial keratitis and vestibuloauditory symptoms. It was first reported in 1945 by David G. Cogan at the Massachusetts Eye and Ear Infirmary. To date, only a few hundred cases have been reported in the literature 1).
This syndrome predominantly affects young white adults in their 20s to 30s, but can occur at any age 4). The etiology is unknown, but infectious triggers such as upper respiratory tract infections, diarrhea, dental infections, and vaccinations have been reported.
It is characterized by recurrent ocular inflammation and progressive hearing loss that can lead to deafness if left untreated. Up to 80% of patients have systemic symptoms, and up to 15% develop vasculitis 3). The mortality rate is 10%, mainly due to vasculitis. Deaths from stroke, gastrointestinal bleeding, cardiac complications, and systemic vasculitis have been reported 1).
Vestibuloauditory symptoms include sudden nausea, vomiting, tinnitus, vertigo, and progressive hearing loss that usually leads to deafness within 1 to 3 months.
Cogan syndrome is classified into typical and atypical forms 1).
| Classification | Ocular Findings | Vestibuloauditory Symptoms |
|---|---|---|
| Typical | Interstitial keratitis | Appears within 2 years |
| Atypical | Various inflammatory lesions | Interval of 2 years or more |
Typical Cogan syndrome
Interstitial keratitis: The most common ocular finding, present in 77% of cases 1). It rapidly progresses from peripheral subepithelial keratitis.
Ring-shaped corneal opacity: Presents with 360° peripheral corneal opacity, accompanied by deep stromal neovascularization and crystalline deposits 1).
Iritis: May be accompanied by anterior chamber inflammation.
Subconjunctival hemorrhage: Can be a feature of the typical form.
Atypical Cogan syndrome
Scleritis/episcleritis: May or may not be accompanied by interstitial keratitis.
Uveitis: Can involve either anterior or posterior uveitis.
Retinal vasculitis: One of the posterior segment findings.
Optic nerve involvement: Optic disc edema, optic neuritis, and vasculitic optic neuropathy have been reported.
Cotton-wool spots: May be observed around the optic nerve 7).
Anterior segment optical coherence tomography (AS-OCT) shows hyperreflectivity in the anterior two-thirds of the corneal stroma and compensatory focal epithelial thickening corresponding to areas of stromal thinning. This finding is useful for differentiating from corneal ectasia, where the epithelium over the protruding area is thinned, whereas in Cogan syndrome the epithelium thickens compensatorily 2).
Typical Cogan syndrome is characterized by non-syphilitic interstitial keratitis and Meniere-like vestibuloauditory symptoms, with the vestibuloauditory symptoms appearing within 2 years of the ocular symptoms. Atypical Cogan syndrome presents with inflammatory eye diseases other than interstitial keratitis (such as scleritis, choroiditis, uveitis, retinal vasculitis) and has an interval of more than 2 years between ocular and vestibuloauditory symptoms. Atypical cases tend to have more systemic symptoms.
The etiology of Cogan syndrome is not fully understood. It is presumed to be an autoimmune disease involving autoantibodies targeting corneal, inner ear, and endothelial antigens. Infiltration of lymphocytes and plasma cells has been confirmed in the corneal tissue and cochlea of patients.
Cogan peptide has homology with CD148 and connexin 26, which are expressed in the sensory epithelium of the inner ear and cornea. Autoantibodies against this peptide have been detected in some cases, which may explain the mechanism by which the cornea and inner ear are simultaneously affected 1).
Reported infectious triggers include upper respiratory tract infections, gastroenteritis, dental infections, and vaccinations. A molecular mimicry mechanism is presumed 1). IL-6 may play a central role in disease onset 7).
There is no single test to confirm the diagnosis of Cogan syndrome. It is a diagnosis of exclusion; when interstitial keratitis is detected, syphilis, herpes, chlamydia, tuberculosis, measles, mumps, and Lyme disease must be excluded.
| Differential diagnosis | Key points for differentiation |
|---|---|
| Syphilitic keratitis | Differentiate by serological testing |
| Vogt-Koyanagi-Harada disease | Primarily uveitis |
| Susac syndrome | Characteristic corpus callosum lesions |
There is no single definitive test. Diagnosis is made based on the clinical combination of interstitial keratitis and vestibuloauditory symptoms, after excluding infectious etiologies such as syphilis and herpes. Elevated inflammatory markers (CRP, ESR) indicate disease activity. Anti-heat shock protein antibodies may be positive in 50% of patients.
Treatment of Cogan syndrome depends on the severity and extent of systemic involvement. Multidisciplinary management by an ophthalmologist, otorhinolaryngologist, and rheumatologist is necessary 4).
First-Line Agents
Steroids: Prednisolone 1 mg/kg/day is started and tapered after 2–4 weeks 4). If administered within 2 weeks of hearing loss onset, hearing improvement is achieved in 55% of patients; beyond 2 weeks, the improvement rate drops to 8% 7).
Methotrexate: Used in recurrent cases or when steroid tapering is difficult, but randomized trials have not supported its efficacy 4).
Cyclophosphamide: Reported to protect hearing in autoimmune inner ear disease, but caution is needed for toxicity (infection, malignancy risk) 4).
Biologic Agents
Infliximab: Recommended for cases unresponsive to combination therapy with steroids and DMARDs. Steroid tapering is possible in 86% of patients 4).
Tocilizumab: IL-6 receptor antibody. Improvement in scleritis and sensorineural hearing loss has been reported. Early administration may prevent irreversible sensory organ damage 7).
Rituximab: Efficacy for severe hearing loss has been reported4)
Etanercept: Hearing improvement is limited, but improvement in speech discrimination has been observed4)
Steroid monotherapy should not be maintained for more than 3 weeks due to toxicity risks and difficulty in maintaining disease control1).
Cochlear implants are effective for severe sensorineural hearing loss. However, in Cogan syndrome, inflammatory ossification and fibrosis of the inner ear may make surgery difficult. Since ossification can occur within 8 weeks after the onset of hearing loss, it is necessary to consider imaging evaluation of ossification and the status of immunosuppressive drug administration when determining the timing of surgery6).
Hearing recovery strongly depends on the timing of treatment initiation. When steroids are administered within 2 weeks of hearing loss onset, hearing improvement is achieved in 55% of cases, but after 2 weeks, the improvement rate drops to 8%7). Irreversible complete deafness occurs in 43–52% of patients4). Cochlear implants are an effective option for severe hearing loss and can provide long-term stable speech perception6).
Cogan syndrome is considered an autoimmune disease, but the detailed pathogenic mechanism remains unknown.
Infiltration of lymphocytes and plasma cells has been confirmed in corneal tissue and the cochlea. Cogan peptide shares homology with CD148 (receptor-type tyrosine phosphatase) and connexin 26 (gap junction protein) expressed in the sensory epithelium of the inner ear and cornea. Autoantibodies against this peptide have been detected in some cases, providing a molecular basis for simultaneous damage to the cornea and inner ear1).
In the 2012 revised International Chapel Hill Consensus Conference, Cogan syndrome was classified as a variable vessel vasculitis7). It can affect small, medium, and large vessels. About 10% of patients develop aortitis, leading to complications such as aortic regurgitation, coronary artery stenosis, and limb ischemia3).
Regarding the mechanism of vestibulocochlear dysfunction, endolymphatic hydrops similar to Meniere’s disease was previously assumed. However, recent MRI (HYDROPS method) has reported cases showing contrast enhancement of the cochlea and vestibule without endolymphatic hydrops, suggesting that labyrinthitis may be the cause of auditory and vestibular dysfunction6).
IL-6 may play a central role in the pathogenesis of the disease. Serum IL-6 levels are markedly elevated in patients with Cogan syndrome, and the efficacy of tocilizumab, an IL-6 inhibitor, supports this hypothesis 7).
The molecular basis is that the Cogan peptide shares homology with CD148 and connexin 26, which are commonly expressed in the sensory epithelium of the cornea and inner ear 1). When autoantibodies against this peptide are produced, both the cornea and inner ear become targets. Molecular mimicry triggered by an infectious agent is presumed to be the trigger for autoantibody production.
The role of biologic agents in the treatment of Cogan syndrome is gaining attention. In particular, early administration of tocilizumab, an IL-6 receptor antibody, may be effective in preventing irreversible sensory organ damage 7).
The efficacy of tofacitinib, a JAK inhibitor, has also been reported. It selectively inhibits JAK1/JAK3 and suppresses tissue-resident memory T cells and angiogenic pathways in medium- and large-vessel vasculitis 4).
In inner ear imaging, HYDROPS MRI can directly assess the presence of endolymphatic hydrops and inflammation of the cochlea and vestibule. This has advanced the understanding of the pathomechanisms of vestibular and auditory disorders 6).
Future research is expected to further elucidate the role of inflammatory cytokines including IL-6 and establish early therapeutic intervention to prevent sensory organ damage.
