Cogan syndrome

Cogan syndrome is a rare autoimmune or inflammatory disease that affects the eyes and inner ears. Cogan syndrome is a very rare type of ANCA-negative vasculitis affecting the eyes and vestibulocochlear system ¹. Symptoms of Cogan’s syndrome include inflammation and pain in the eyes, decreased vision, hearing loss, and vertigo. Other symptoms may include joint or muscle pain or inflammation of the blood vessels ². It is not clear that Cogan’s syndrome is a primary vasculitis ³. Large vessel vasculitis predominates in the aorta and its branches and resembles Takayasu’s arteritis. Inflammation of the proximal aorta (aortitis) may occur in 10% of patients. Medium vessel vasculitis often can involve many organs, as is seen in polyarteritis nodosa ³.

The exact cause of Cogan’s syndrome is not well-understood. It is thought that Cogan syndrome is caused by an autoimmune response that causes the immune system to attack the tissues of the eyes and ears. Cogan syndrome is not known to run in families ⁴. Diagnosis of Cogan syndrome is based on observing symptoms associated with the syndrome and ruling out other possible causes of the symptoms. Treatment options generally include corticosteroids and immunosuppressive agents ⁴.

Cogan syndrome can occur in people of any age and race, and it most frequently starts in young adults in their late 20’s or early 30’s. It can start with eye inflammation (red and painful eyes irritated by the light), with hearing loss and vertigo, or with both within a one month period of time. The hearing loss can be profound and is frequently associated with the sensation of pressure in the ear. Vertigo can also be severe. Vasculitis signs and symptoms can be present at presentation or may develop later in the course of the syndrome. Large vessel vasculitis and aortitis symptoms often include the heart sounds of a leaky aortic heart valve diminished pulses, and peripheral claudication (pain in muscles with use from poor blood flow). Medium vessel vasculitis symptoms are non-specific and are similar to those seen in polyarteritis nodosa. The eye and ear disease have never been pathologically documented to be secondary to vasculitis.

Untreated disease may lead to corneal scarring and vision loss and, in 60 to 80% of patients, permanent hearing loss.

Permanent hearing loss occurs in almost all patients with Cogan syndrome and is profound in up to two-thirds. Vertigo is more severe with the initial episodes than later attacks, tending to improve with time. A vague unsteadiness can persist in some patients and evidence of vestibular damage can be found in all patients (abnormal electronystagmography). Permanent eye damage and visual loss are rare. Aortitis can lead to aortic insufficiency and congestive heart failure.

Keratitis, episcleritis, and anterior uveitis can usually be treated with topical prednisolone acetate 1% every 1 hour to four times daily for 2 to 3 weeks. To treat deeper ocular inflammation and especially to treat vestibuloauditory symptoms before they become permanent, prednisone 1 mg/kg oral once/day is begun as soon as possible and continued for 2 to 6 months. Some clinicians add cyclophosphamide, methotrexate, cyclosporine, or infliximab for recalcitrant cases.

Cogan syndrome cause

Cogan syndrome is an autoimmune disease, which means that it occurs when the immune system begins to attack the tissues of the body. This is called an autoimmune response. Specifically, the immune systems of people with Cogan syndrome begin to attack the tissues of the eyes and the inner ears. In some cases, the autoimmune response may also be directed against blood vessels ². The exact reason that people with Cogan syndrome have an autoimmune response against the tissues of the eyes and the inner ears is not well-understood  ⁴. For some people, it may be that symptoms of Cogan syndrome begin after an infection ⁵.

Cogan syndrome inheritance pattern

Changes (mutations) in a specific gene are not known to cause Cogan syndrome. This means that Cogan syndrome is not thought to be passed directly from parent to child, and the syndrome is not thought to run in families ⁴.  In general, family members of an individual with an autoimmune disease are thought to be at an increased risk to develop an autoimmune disease themselves. Although there are not reports of Cogan syndrome running in families, it is possible that family members of people with Cogan syndrome are at an increased risk to develop other autoimmune diseases.

Cogan syndrome symptoms

Cogan syndrome primarily affects the eyes and the inner ears. Cogan syndrome presenting symptoms involve the ocular system in 38% of patients, the vestibuloauditory system in 46%, and both in 15%. By 5 months, 75% of patients have both ocular and vestibuloauditory symptoms. Nonspecific systemic complaints include fever, headache, joint pain, and myalgia.

Ocular symptoms

Ocular involvement includes any combination of the following:

• Bilateral interstitial keratitis or other corneal stromal keratitis
• Episcleritis or scleritis
• Uveitis
• Papillitis
• Other orbital inflammation (eg, vitritis, choroiditis)

Ocular symptoms include irritation, pain, photophobia, and decreased vision. Ocular examination shows a patchy corneal stromal infiltrate typical of interstitial keratitis, ocular redness, optic nerve edema, proptosis, or a combination of these symptoms.

Vestibuloauditory symptoms

• Vestibuloauditory symptoms include sensorineural hearing loss, tinnitus, and vertigo.

Vascular symptoms

• A diastolic heart murmur may be present when aortitis is significant. Claudication may be present if limb vessels are affected.

Symptoms of Cogan syndrome generally begin in adolescence to mid-adulthood. The first symptoms typically either affect only the inner ears or only the eyes but often progress to affect both the eyes and the ears. Symptoms affecting the eyes include redness, irritation and pain, excessive tear production, sensitivity to light (photophobia), and decreased vision. When the eyes are examined by an ophthalmologist, swelling of specific tissues of the eye (interstitial keratitis) may be identified ². Symptoms affecting the ears may include sensorineural hearing loss, ringing in the ears (tinnitus) and dizziness (vertigo) ².

Cogan syndrome can also affect the blood vessels. This can cause symptoms in other parts of the body including pain or cramping in the muscles (myalgia), fever, headache, diarrhea, and stomach pain. In some cases, people with Cogan syndrome may have a heart murmur or other heart problems ².

Cogan’s syndrome diagnosis

Cogan syndrome is diagnosed when a doctor observes signs and symptoms consistent with the syndrome. If Cogan syndrome is suspected, other diseases that may have similar signs and symptoms must be excluded. These diseases include syphilis, Lyme disease, Epstein-Barr virus, and Meniere disease ². Laboratory tests to exclude other diseases may include blood tests, urinalysis, and studies to analyze liver function ⁴. In some cases, blood tests for a specific antibody related to Cogan syndrome may be completed ⁴.

If a diagnosis of Cogan syndrome is suspected, it is suggested that the affected individual see an ophthalmologist and otolaryngologist to determine if there are other symptoms consistent with Cogan syndrome ⁴.

Most patients have an elevated erythrocyte sedimentation rate (ESR) and leukocytosis (elevated white blood count) at presentation. Anemia is present, initially, in one-third of patients, and about 20% have cryoglobulinemia (cold precipitating proteins in the blood) or eosinophilia (increased number of eosinophil white blood cells in the blood).

The diagnosis of Cogan syndrome requires the presence of eye inflammation and inner ear dysfunction that is not explained by another illness. Other major illnesses with similar symptoms include infections (Lyme disease, syphilis, Chlamydia, and Whipple’s disease), other systemic inflammatory diseases (Crohn’s disease, Behçet’s disease, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, Sjogren’s syndrome, systemic lupus, vasculitis, and Vogt-Koyanagi-Harada syndrome), cancers (central nervous system lymphoma and chronic lymphocytic leukemia), antiphospholipid antibody syndrome and multiple sclerosis. The diagnosis of vasculitis is suspected based on the symptoms above and proven in patients with Cogan syndrome via echocardiography, angiography, and/or biopsy of affected tissues.

Cogan syndrome treatment

Corticosteroids are the cornerstone of Cogan syndrome therapy ⁴. Topical glucocorticoids in association with cycloplegics may be considered for the management of isolated, mild eye involvement, while systemic corticosteroids should be considered for more severe eye involvement, hearing impairment, and systemic manifestations. Treatment with high doses of systemic corticosteroids (1-1.5 mg/kg of prednisone daily) are expected to prevent deafness, with a beneficial response usually within 2-3 weeks. However corticosteroids have proven to be of short-term benefit, and they carry a risk of serious side effects, therefore in patients with refractory or steroid-dependent disease, a second line treatment with immunosuppressants should be considered, although conventional immunosuppressive drugs such as methotrexate, cyclophosphamide, azathioprine, or cyclosporin A seem to have a limited efficacy. There are increasing reports of successful response to Infliximab, a tumor necrosis alpha (TNFalpha) blocker. Infliximab showed cochleovestibular symptoms improvement and allowed corticosteroid tapering, with a significantly difference when compared to patients treated with steroids alone or conventional disease-modifying anti-rheumatic drugs (DMARDs). The early use of infliximab as first line therapy in severe cases seems to be even more effective. Cochlear implantation is a valuable rescue surgical strategy in cases of severe sensorineural hearing loss unresponsive to intensive immunosuppressive regimens.

Recurrent drops in hearing can be secondary to recurrent inner ear inflammation or the changes in swelling due to damage done to the inner ear, called cochlear hydrops. If hearing loss is associated with eye inflammation or fails to improve after 3-5 days, increased doses of glucocorticoids should be considered.

Proven aortitis and/or vasculitis should be treated with glucocorticoids and immunosuppressive therapy. Cyclosporine, cyclophosphamide, and methotrexate have all been effective initial agents in patients with aortitis and/or large vessel vasculitis. Medium-size vessel vasculitis is treated similarly to the approach taken with PAN. Symptomatic aortic valve disease may lead to the need for aortic valve replacement, chronically or sub-acutely. Peripheral ischemia can require balloon dilatation and/or vascular by-pass procedures in the rare patient.

Adverse effects of glucocorticoids are well known and include glucose intolerance, diabetes, easy bruising, increased infections, rounded faces, loss of calcium from bones, central nervous system effects (particularly at high dose), and thinning of skin. Immunosuppressive drugs can lower blood counts, increase likelihood of infections, damage the liver, cause urinary bleeding, and increase the risk of malignancies.

Cogan syndrome prognosis

Most people with Cogan syndrome respond well to corticosteroids or immunosuppressive agents. However, in some cases the medications may not be effective, or the syndrome may have progressed too quickly for the medications to relieve symptoms. In these cases, the symptoms of Cogan syndrome may lead to permanent vision or hearing loss ². Permanent hearing loss is more common than permanent vision loss, and hearing loss may not be improved with the use of medications. The medications used to treat Cogan syndrome may have side-effects, so the risks and benefits of each medication must be considered ³.

The long-term outlook for people with Cogan syndrome also depends on the involvement of the blood vessels. If the blood vessels are affected by the autoimmune response associated with Cogan syndrome and the treatment is not effective, symptoms such as stomach pain or headaches may persist. Life-threatening complications of Cogan syndrome are rare, but may include an aneurysm of the aorta ⁴. Severe internal organ involvement and cardiovascular complications-related deaths are rare.

References

1. Houriet C, Haneke E. Nail Lichen Planus in a Patient with Cogan Syndrome: Report of a Case and Discussion. Case Rep Dermatol. 2019;11(2):175–179. Published 2019 Jun 26. doi:10.1159/000500946 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616199
2. Cogan Syndrome. https://www.merckmanuals.com/professional/eye-disorders/corneal-disorders/cogan-syndrome
3. Cogan’s Syndrome. https://www.vasculitisfoundation.org/mcm_article/cogans-syndrome
4. Cogan syndrome. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=1467
5. Greco A, Gallo A, Fusconi M, Magliulo G, Turchetta R, Marinelli C, Macri GF, De Virgilio A, and de Vincentiis M. Cogan’s syndrome: An autoimmune inner ear disease. Autoimmunity Reviews. January 2013; 12(3):396-400. https://www.ncbi.nlm.nih.gov/pubmed/22846458