Cogan’s Syndrome

• Bradley Schlussel, M.D.

 Basic Information

Definition

Cogan’s syndrome is a very rare autoimmune inner ear disorder that is temporally associated with an inflammatory eye disease, usually interstitial keratitis, and is thought to be mediated by a hypersensitivity response to infectious agents associated with vasculitis.

Synonyms

1. Cogan syndrome

ICD-10CM CODES
H16.3	Interstitial and deep keratitis

Epidemiology & Demographics

Incidence

No population studies are available for incidence calculation. Approximately 250 cases have been described in the literature to date.

Prevalence

No population studies are available for prevalence analysis. The classic form of Cogan’s syndrome tends to affect Caucasian individuals.

Predominant Sex

No gender preference. Affects men and women equally in case reports.

Predominant Age

Median age of onset is 22 years with cases reported in children and older adults.

Genetics

Unknown

Risk Factors

Cogan’s syndrome may have increased prevalence in patients with inflammatory bowel disease. In many case reports, infectious processes have been implicated, such as previous upper respiratory tract infections that led to cross-reactive autoantibodies.

Physical Findings & Clinical Presentation

See Table E1 for systemic manifestations of Cogan’s syndrome.

Clinical hallmarks:

1. •

   Cogan’s syndrome is characterized by an acute, subacute, or recurrent onset of inner ear loss of function resembling Meniere’s disease (tinnitus, vertigo, and gradual hearing loss). The resultant hearing loss typically is sensorineural, bilateral, and progressive. This is temporally related to the onset of keratitis manifested as pain, redness, and blurry vision in the affected eye. Systemic vasculitis features are marked by large-vessel vasculitis and can occur in up to 10% of patients. Medium-vessel vasculitis resembling polyarteritis nodosa to small-vessel vasculitis manifestations are possible.

2. •

   Constitutional: fever, headache, weight loss, malaise.

3. •

   Ocular: redness, pain, photophobia, and blurred vision as a result of interstitial keratitis (72%-100%). Scleritis or episcleritis (23%). The gap between involvement of audiovestibular and ocular symptoms is usually one to six months and not more than two years.

4. •

   Hearing/vestibular: hearing loss progressing to deafness, usually bilateral (100%), vertigo (90%), and tinnitus (80%). Imbalance may be associated with nausea and vomiting.

5. •

   Cardiovascular: aortitis, aortic aneurysm, aortic insufficiency.

6. •

   Musculoskeletal: arthralgia, arthritis, myalgia.

7. •

   Neurological: hemiparesis and hemiplegia.

8. •

   Gastrointestinal: abdominal pain (13%-16%), diarrhea, melena.

9. •

   Renal: hematuria (7%), glomerulonephritis (3%).

10. •

    Dermatologic: cutaneous nodules, rash.

Etiology

The exact etiology of Cogan’s syndrome is unknown. Evidence of an autoimmune mechanism includes binding of autoantibodies from patients with Cogan’s syndrome to the cochlea of mice in passive transfer studies. Autopsy specimens show nonspecific lymphocytic and plasma cell infiltration. Infection is thought to be a trigger for Cogan’s syndrome. Some HLA loci, including HLA-B17, HLA-A9, HLA-Bw35, and HLA-Cw4, correlate with the disorder.

Diagnosis

Differential Diagnosis

1. •

   Infectious diseases

   1. 1.

      Syphilis

   2. 2.

      Tuberculosis, Lyme disease, chlamydia, leprosy, brucellosis, mumps, EBV, herpes zoster, and herpes simplex; rubeola should be considered in the differential for interstitial keratitis.

2. •

   Rheumatology

   1. 1.

      ANCA-associated vasculitis: granulomatosis with polyangiitis (Wegener’s granulomatosis)

   2. 2.

      Takayasu’s arteritis

   3. 3.

      Giant cell arteritis

   4. 4.

      Rheumatoid arthritis with vasculitis

   5. 5.

      Polyarteritis nodosa

   6. 6.

      Behçet’s disease

   7. 7.

      Sarcoidosis

3. •

   Neurology

   1. 1.

      Susac syndrome

4. •

   Neoplastic

   1. 1.

      Lymphoma (CNS)

5. •

   Miscellaneous

   1. 1.

      Vogt-Koyanagi-Harada syndrome

Laboratory Tests

1. •

   Diagnosis of Cogan’s syndrome is usually made on clinical evidence.

2. •

   Inflammatory markers are often elevated, including the erythrocyte sedimentation rate (ESR) and C-reactive protein.

3. •

   Complete blood cell count with differential; may show leukocytosis.

4. •

   ANCA serology test to exclude ANCA-associated vasculitis.

5. •

   Serologic test result should be negative for syphilis.

6. •

   Anti-Hsp 70 antibodies have been suggested as possible markers of typical Cogan’s syndrome, although relevance remains to be confirmed.

Imaging Studies

1. •

   Initial tone audiogram shows a hearing loss, especially at high frequencies.

2. •

   MRI with gadolinium of the brain to rule out non–inner ear causes for acute or subacute hearing loss and vestibular dysfunction. Brain MRI can range from normal to gadolinium enhancement of the vestibular-cochlear structures.

3. •

   MRA of the aorta and its proximal branches may be used to assess for vascular inflammation that may support the diagnosis of large-vessel vasculitis.

Treatment

Nonpharmacologic Therapy

1. •

   Cochlear implant

Acute General Rx

1. •

   Treatment guidelines are based on grade C (fair evidence from ancillary studies) recommendations.

2. •

   Early treatment is critical for a favorable prognosis.

3. •

   Eye symptoms: Unlike audiovestibular symptoms, ocular manifestations typically respond to topical corticosteroids. Mydriatics may be considered.

4. •

   Vestibuloauditory symptoms: Oral prednisone 1 to 2 mg/kg/day is recommended.

5. •

   Vasculitis symptoms: Oral prednisone 1 to 2 mg/kg/day is recommended. Oral or IV cyclophosphamide should be considered for life-threatening features.

Chronic Rx

1. •

   Methotrexate, cyclophosphamide or azathioprine may be considered as steroid-sparing agents.

2. •

   Treatment options such as TNF-alpha inhibitors (infliximab and etanercept), plasmapheresis, rituximab, tocilizumab, cyclosporine, and mycophenolate mofetil have been reported in the literature.

Disposition

1. •

   Ocular outcomes are good.

2. •

   Hearing loss may occur in up to 50% of cases.

Referral

1. •

   Ophthalmology for complete ocular examination, including slit-lamp examination.

2. •

   Rheumatology/immunology for all patients with suspected disease.

3. •

   Audiology for complete hearing assessment.

4. •

   Otolaryngology for confirmation of sensorineural hearing loss.

Suggested Readings

• N.B. Allen, et al.: Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogan’s syndrome. Am J Med. 88:296 1990 2309745

• N. Antonios, et al.: Cogan syndrome: an analysis of reported neurological manifestations. Neurologist. 18:55–63 2012 22367829

• G.M. Espinoza, A. Prost: Cogan’s syndrome and other ocular vasculitides. Curr Rheumatol Rep. 17:24 2015 25854487

• A. Greco, et al.: Cogan’s syndrome: an autoimmune inner ear disease. Autoimmun Rev. 12:396–400 2013 22846458

• L. Maiolino, et al.: Autoimmune ear disease: clinical and diagnostic relevance in Cogan’s Syndrome. Audiol Res. 7 (1):162 2017 28458810

• P. Mora, et al.: Cogan’s syndrome: state of the art of systemic immunosuppressive treatment in adult and pediatric patients. Autoimmun Rev. 16 (4):385–390 2017 28232169

• O. Singer: Cogan and Behcet syndromes. Rheum Dis Clin North Am. 41:75–91 2015 25399941

• O.E. Tayer-Shifman, et al.: Cogan’s syndrome-clinical guidelines and novel therapeutic approaches. Clin Rev Allergy Immunol. 47:65–72 2014 24385257