Cogan syndrome

INTRODUCTION — Cogan syndrome (CS) is a chronic inflammatory disorder that most commonly affects young adults. Clinical hallmarks are interstitial keratitis (IK) and vestibuloauditory dysfunction [1]. Associations between CS and systemic vasculitis, as well as aortitis, also exist [2-4].

The pathology, pathogenesis, clinical manifestations, and treatment of CS will be presented here.

PATHOLOGY — Limited autopsy data derived from temporal bone specimens of patients with Cogan syndrome (CS) reveal a range of findings, including [5-7]:

●Lymphocyte and plasma cell infiltration of the spiral ligament

●Loss of cochlear neurons

●Endolymphatic hydrops

●Degenerative changes in the organ of Corti

●Extensive new bone formation in the inner ear

●Demyelination and atrophy of the vestibular and cochlear branches of the eighth cranial nerve

Histopathologic examination of corneal tissue from patients with interstitial keratitis (IK) reveals lymphocytic and plasma cell infiltration in the deeper layers [8].

Despite an association with systemic vasculitis, eye and inner ear specimens of those with CS generally do not reveal any evidence of vasculitis. However, a single autopsy case has found histopathologic evidence of vasculitis in both the cochlear and vestibular systems [9]. In cases with systemic vasculitis, affected vessel walls outside the eye and inner ear show typical histopathologic changes of acute and chronic inflammation depending upon the nature of involvement (Takayasu-like or polyangiitis-like) [2,5,10-13]. (See "Clinical features and diagnosis of Takayasu arteritis".)

Additional pathologic findings are relatively nonspecific and are compatible with a chronic inflammatory process. As an example, damaged aortic valves in cases of aortitis grossly manifest cusp detachments and outpouchings, fenestrations, thinning, thickening, and retraction [10,11,13,14]. Microscopic examination of affected valvular tissue shows lymphoid cell infiltration, fibrinoid necrosis, and myxomatous degeneration [10,11,13-15].

PATHOGENESIS — The mechanisms responsible for the eye and inner ear disease in Cogan syndrome (CS) are unknown. Some evidence suggests that the disease is a result of inner ear autoimmunity. A few patients display reactivity against antigens expressed in the inner ear [16]. These antigens share sequence homology with Ro/SSA autoantigen, laminin, cell density-enhanced protein tyrosine-1 (DEP-1/CD148), connexin 26, and the reovirus III major core protein lambda 1 [17].

In animals, passive transfer of the autoantibodies reproduced features of CS in mice; this supports a hypothesis that infection, perhaps from reovirus type III, may be involved in triggering this autoimmune disease through molecular mimicry [16]. This is further supported by the observations that one-quarter to one-third of patients with CS have an antecedent viral-like illness [2,18,19].

In addition, antibodies to Hsp-70 have been detected in some patients with CS and other forms of autoimmune sensorineural hearing loss [20].

An additional trigger may be cigarette smoking [19].

EPIDEMIOLOGY — The peak incidence of Cogan syndrome (CS) occurs in the third decade of life. In the two largest series, the median age of onset was 22 years (range 5 to 63 years) [2,3]. CS may also occur in children and in older adults [21-23]. There is no known sex or racial predominance.

CLINICAL FEATURES — A definite diagnosis of Cogan syndrome (CS) is based upon characteristic involvement of both the eye and the inner ear. Both organs are nearly equally likely to be the cause of presenting symptoms.

Less than 5 percent of patients initially present with systemic manifestations. In these cases, the diagnosis of CS can only be established after the development of eye or inner ear disease [2,3,19].

Ocular disease — The predominant ocular feature of CS is interstitial keratitis (IK), which typically causes eye redness, pain, photophobia, and blurred vision. Slit-lamp examination commonly demonstrates a patchy, deep, granular corneal infiltrate (image 1).

Cases of early IK may produce a faint peripheral, anterior stromal, subepithelial keratitis [24]; these manifestations may be confused with a viral or chlamydial infection [24]. Rarely, uncontrolled corneal inflammation may lead to neovascularization and corneal clouding, resulting in permanent visual loss [19,25].

Although IK is the classic eye finding, it is not essential for the diagnosis. Ocular inflammation may involve other parts of the eye and may lead to iridocyclitis, conjunctivitis, episcleritis, anterior or posterior scleritis, or retinal vasculitis (image 2) [3,19,21,26,27].

Retinal vasculitis and posterior scleritis are serious conditions that frequently cause visual impairment; when present, they demand urgent treatment. (See 'Posterior ocular inflammation' below.)

Inner ear disease — The inner ear manifestations of CS are characterized by Ménière-like attacks consisting of vertigo, ataxia, nausea, vomiting, tinnitus, and hearing loss [28]. Vestibular dysfunction may also cause oscillopsia, which is the perception of objects jiggling back and forth after abruptly turning the head to one side or the other. Caloric testing often reveals absent vestibular function. (See "Evaluation of the patient with vertigo".)

Some patients with CS may present with inner ear disease prior to the development of the ocular manifestations, typically within a couple of years. Thus, such patients may initially be thought to have autoimmune inner ear disease.

Recurrent episodes of inner ear disease frequently result in profound hearing loss. In a retrospective series of 60 patients from one center, hearing loss was typically sudden, bilateral, fluctuating, and progressive, resulting in complete hearing loss in 73 of 120 ears [19]. Hearing loss in both ears was noted at some point in all patients. Two smaller studies both found bilateral deafness in approximately two-thirds of patients [2,3]. In the one author's experience, the hearing loss is incremental with periods of relatively stable reduced hearing between episodes of sudden down-fluctuations in hearing that may respond to steroids.

Recurrent episodes of inner ear disease may also result in cochlear hydrops [2,9]; this condition may be associated with down-fluctuations in hearing because of changes in the cochlear pressure independent of inflammation [29]. Such noninflammatory down-fluctuations are difficult to distinguish from those of inflammatory origin after several episodes of active CS.

Down-fluctuation in hearing associated with an upper respiratory infection or menses may be monitored without change in therapy to observe if it will resolve in three to five days, since a noninflammatory down-fluctuation frequently abates within this time frame. If hearing loss is associated with eye inflammation or other features of active CS, then a down-fluctuation in hearing is most likely due to inflammation.

Typically, audiometry testing demonstrates a sensorineural hearing loss, preferentially involving the low- and high-range frequencies; poor speech discrimination is also observed (figure 1A-B). In one preliminary study, at least 30 percent of patients had a pure-tone audiometry threshold of greater than or equal to 60 dB, a threshold value indicative of moderately severe hearing loss [4].

Systemic vasculitis — When present, the systemic vasculitis associated with CS is a large- or medium- to small-sized vessel vasculitis or an aortitis. The pattern of vessel involvement may be overlapping.

Aortitis, which may develop within weeks to years of disease onset, has been described in approximately 10 percent of patients [2,3,28]. It may cause proximal aorta dilation, aortic valvular regurgitation, ostial coronary artery disease, and thoracoabdominal aortic aneurysms [10,11,28,30-32]. A coronary arteritis has also been described [3,12,29].

The large-vessel vasculitis associated with CS may also resemble Takayasu arteritis, causing an occlusion of the aortic arch vessels with resultant upper and/or lower limb claudication or renal artery stenosis [10,12,33,34]. A small- or medium-sized vessel arteritis has been described in some cases [35]. (See "Clinical features and diagnosis of Takayasu arteritis".)

Other findings — Nonspecific systemic manifestations of CS include fever, fatigue, weight loss, lymphadenopathy, hepatomegaly, hepatitis, splenomegaly, pulmonary nodules, pericarditis, abdominal pain, arthralgia, arthritis, myalgia, and urticaria [4,19,27,28]. The disorder has also been described in patients with inflammatory bowel disease [36-38].

EVALUATION — Evaluation of the patient with possible Cogan syndrome (CS) requires the following steps:

●Ophthalmologic examination to establish the presence of interstitial keratitis (IK), scleritis, or episcleritis and to exclude other diseases and ocular pathology

●Neurologic and otologic examination to establish the presence of vestibuloauditory abnormalities

●Rheumatologic examination to seek evidence of systemic vasculitis

DIAGNOSIS — The diagnosis of Cogan syndrome (CS) is based upon the presence of characteristic inflammatory eye disease and vestibuloauditory dysfunction. The previously used modifying terms "typical" and "atypical" CS have been abandoned because this distinction no longer appears to carry prognostic significance [2].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Cogan syndrome (CS) includes diverse conditions that cause similar eye and inner ear manifestations (table 1), such as sarcoidosis, polyarteritis nodosa, granulomatosis with polyangiitis, and rheumatoid arthritis. The occurrence of uveitis in particular raises the diagnostic possibility of Behçet syndrome, Crohn disease, sarcoidosis, and Lyme disease. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of sarcoidosis".)

Infectious causes of interstitial keratitis (IK) include congenital syphilis, tuberculosis, chlamydial infection, and viral infection. Infectious agents can be differentiated from CS by serologic testing (eg, fluorescent treponemal antibody absorption [FTA-ABS] test for syphilis), skin tests (eg, tuberculin skin testing), serum TB tests, cultures, therapeutic trials of antimicrobial treatment, and characteristic clinical signs (eg, dendritic pattern in herpetic corneal infections). (See "The red eye: Evaluation and management", section on 'Viral keratitis' and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on 'Late congenital syphilis' and "Tuberculosis and the eye" and "Conjunctivitis".)

CS also must be distinguished from Susac syndrome, which occurs predominately in adults between the ages of 20 and 40, and is characterized by subacute encephalopathy, sensorineural hearing loss, and retinal arteriolar occlusions due to an occlusive nonvasculitic vasculopathy [39]. The major findings in this disorder, which differ from those in CS, include the presence of retinal and neuropsychiatric findings and the absence of IK or other inflammation of the anterior segment of the eye.

TREATMENT — Therapeutic options for the treatment of Cogan syndrome (CS) include the use of topical agents for limited ocular disease and immunosuppressive therapy for more extensive ocular disease, inner ear involvement, and/or systemic vasculitis.

Systemic vasculitis — Systemic vasculitis associated with CS is treated with prednisone. This agent is administered at 1 mg/kg per day given in divided doses to produce a short period of intense immunosuppression; this induction dose may result in more rapid disease control with subsequent consolidation to once per day dosing with clinical improvement. The glucocorticoid taper is approached in a manner similar to that generally utilized for systemic vasculitis. (See "Treatment and prognosis of polyarteritis nodosa".)

Additional immunosuppressive therapy may be required depending upon the severity of disease and upon the nature of organ system involvement [29,40].

●For the treatment of large-vessel vasculitis, weekly methotrexate (15 to 25 mg/week) is our first choice as an additional immunosuppressive agent (see "Use of methotrexate in the treatment of rheumatoid arthritis"). If there is no response to methotrexate after three to six months, azathioprine (1.5 to 2.5 mg/kg/day) and mycophenolate mofetil (2 to 3 g/day) are among the non-biologics used in this setting [41]. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Dose titration and monitoring'.)

Large vessel vasculitis associated with CS has also been treated with cyclophosphamide (750 mg/m² intravenously every month or 2 to 3 mg/kg orally per day) [12]. We generally prefer intravenous over oral administration because of the lower risk of hemorrhagic cystitis and ease of monitoring. Cyclophosphamide is typically given for four to six months, and patients are subsequently transitioned to an alternative therapeutic agent described above. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

If there is no response to cyclophosphamide after three to six months, cyclosporine (4 mg/kg/day or less) may be used [12]. Cyclosporine is usually continued for one year after clinical and laboratory parameters of the vasculitis have become inactive, with a subsequent taper over three months.

Treatment with tumor necrosis factor (TNF) inhibitors has been associated with improvement in refractory cases of Takayasu arteritis [42]. Tocilizumab (4 to 8 mg/kg every four weeks), an interleukin (IL) 6 receptor antagonist, has also produced a favorable treatment response in some cases [43]. Treatment with additional immunosuppressive agents is generally continued for 6 to 12 months after all evidence of disease activity has resolved.

●For the treatment of medium-sized vessel vasculitis, we initially treat with high-dose glucocorticoids as described above. After tapering of the prednisone dose, recalcitrant mild disease may require the addition of methotrexate or azathioprine. Moderate and severe disease is typically treated with intravenous or oral cyclophosphamide over four to six months, with subsequent transition to either azathioprine or methotrexate for remission maintenance [12,29,40]. The cyclophosphamide regimen is similar to that used for the treatment of polyarteritis nodosa. (See "Treatment and prognosis of polyarteritis nodosa".)

Surgical bypass grafting or aortic valve replacement may be required in some patients with severe ischemic symptoms or heart failure. If possible, such procedures should be performed during periods of disease quiescence [29,40].

Ocular disease — In those with CS, anterior ocular inflammation and posterior ocular inflammation are treated quite differently. Anterior disease usually responds to topical glucocorticoids, while posterior involvement requires systemic therapy.

Anterior ocular inflammation — Anterior ocular inflammation, such as interstitial keratitis (IK) and anterior uveitis, should initially be treated with topical ocular glucocorticoids. Prednisolone acetate at 1 percent (lower potency formulations are also frequently adequate) and mydriatics are administered to decrease ocular inflammation and photophobia, prevent synechiae, and relieve ocular discomfort [29,40]. The symptoms and signs of IK and anterior uveitis usually improve within three to seven days with topical glucocorticoid therapy [3].

Patients with IK who fail to respond to the above regimen should be evaluated and treated for other potential causes of corneal inflammation, particularly chlamydia. A trial of oral doxycycline (200 mg daily for two to three weeks) should be considered in such cases [29,40,44]. Rarely, treatment of IK or anterior uveitis may require systemic glucocorticoid therapy if the above treatments are ineffective after 2 to 2.5 weeks [45]. Topical glucocorticoids do not exacerbate a chlamydial infection as long as the patient is receiving oral tetracycline therapy.

Other forms of anterior ocular inflammation, including conjunctivitis, scleritis, and episcleritis, should also be treated with topical glucocorticoid therapy. Topical or systemic nonsteroidal antiinflammatory drug (NSAID) therapy may benefit some patients with episcleritis and scleritis [40]. Nodular scleritis or scleritis unresponsive to topical glucocorticoids and oral NSAIDs may require treatment with systemic glucocorticoids [40]. Uveitis refractory to these other therapies may be managed with anti-TNF treatment [46].

Posterior ocular inflammation — Posterior ocular inflammation requires treatment with systemic glucocorticoids beginning at a dose of prednisone 1 mg/kg per day. Failure to respond within two to three weeks to high-dose glucocorticoids, inability to taper the glucocorticoids to a dose equivalent to 10 mg of prednisone/day or less, or the development of significant glucocorticoid-induced toxicity are indications for the use of other immunosuppressive drugs, such as methotrexate (15 to 25 mg/week), azathioprine (1.5 to 2 mg/kg per day), mycophenolate (1000 to 1500 mg twice daily), cyclophosphamide (750 mg/m² intravenously every month or 2 to 3 mg/kg orally per day), rituximab, cyclosporine (5 mg/kg/day), or a TNF inhibitor [12,40,47-50].

Since methotrexate is probably the safest option, it is frequently chosen first. When used together with another immunosuppressive agent, the glucocorticoid dose should be tapered to the lowest possible dose or should be discontinued, as tolerated, over the next three to four months. If the patient remains free of active disease for six to nine months, consideration should be given to tapering the additional agent over the next three to four months [47].

Progressive corneal opacification may require corneal transplantation. Cataracts that develop in this setting may require extraction to correct the loss of visual acuity [25,40]. The threshold for such procedures may be lower in deaf patients with CS than in other individuals because they may rely upon lip reading or sign language for communication [29,40].

Inner ear disease — Compromised auditory acuity and vestibular dysfunction in a patient with newly diagnosed CS are indications for a therapeutic trial of systemic glucocorticoids. The degree of hearing loss should be quantified by audiometry. For initial therapy, we recommend prednisone (1 to 2 mg/kg per day) administered in divided doses to produce a short period of intense immunosuppression [3,4,18,40,51]. With clinical improvement, the dose may be consolidated to a single morning administration [29,40].

Subjective hearing improvement and decreased hearing thresholds after two to three weeks of high-dose therapy warrant gradual tapering of the dose over the next four to eight weeks. However, reductions in the glucocorticoid dose are contingent upon stable auditory acuity and vestibular function [40].

Worsening hearing loss judged to be inflammatory in nature should be documented by audiometry and should be treated with prednisone (0.5 to 2.0 mg/kg per day); the dose chosen depends upon the severity of the change and upon the dose of prednisone at which the hearing loss occurred. Some patients may require long-term glucocorticoid therapy because of recurrent hearing loss during attempts to taper the prednisone dose (figure 1A-B) [29].

Intratympanic glucocorticoids may be effective in some patients with idiopathic sensorineural hearing loss [52]. This approach can be considered, although it is uncertain whether intratympanic glucocorticoids will benefit patients with CS [52].

When hearing loss is not believed to be caused by inflammation, auditory acuity should be monitored without change in the prednisone dose. Since these patients may have hearing loss due to cochlear hydrops, a course of diuretic therapy should be considered [29]. Both hydrochlorothiazide at 25 mg/day and furosemide at 10 to 20 mg/day have been used. Failure to improve after four to seven days of diuretic therapy, along with the absence of any other explanation for the hearing loss (such as an upper respiratory tract infection), justifies a trial of an increased dose of prednisone [29].

The use of glucocorticoid-sparing immunosuppressive therapy should be considered in patients for whom excessive glucocorticoid doses either are required to control hearing loss or result in toxicity [29,40]. In this setting, cyclophosphamide, methotrexate, azathioprine, tacrolimus, leflunomide, mycophenolate mofetil, and TNF inhibitors have been successfully utilized as adjunctive immunosuppressive therapy, but their efficacies remain uncertain [18,29,53-58]. Infliximab may be more effective than other TNF inhibitors [59]. There has also been anecdotal experience using rituximab and IL-1 antagonists in the setting of autoimmune hearing loss [60].

Our first preference is methotrexate (15 to 25 mg/week), while our second option is azathioprine (1.5 to 2.5 mg/kg per day). Any of the medications above may be tried if these two agents are ineffective. A retrospective study of treatment and outcomes of 60 patients with CS suggested vestibuloauditory responses were better with infliximab compared with other therapies [61]. The duration of therapy depends upon the response. If the glucocorticoid-sparing therapy stabilizes the hearing loss and allows tapering of the glucocorticoids, we continue such therapy for six to nine months after tapering off the glucocorticoids, if possible. Some patients may require chronic glucocorticoid-sparing therapy.

Cochlear implants (CI) have been beneficial in patients with CS who fail to respond to pharmacologic therapy, resulting in severe hearing loss [19,62,63]. Outcomes of CI for patients with CS appear to be similar to those receiving a CI due to nonimmune-mediated hearing loss [63,64]. CI functional deterioration may occur without evident technical issues and improve with immunosuppressive therapy, implying that ongoing cochlear inflammation is the etiologic factor [65].

Vestibular dysfunction — Acute vestibular dysfunction is treated using antihistamines (such as meclizine hydrochloride, 12.5 to 25 mg every 6 to 12 hours) or benzodiazepines (such as diazepam, 2 to 10 mg four times per day), as well as bedrest. Recurrent vestibular dysfunction is virtually always accompanied by hearing loss and should be treated as described above, using glucocorticoids and, if needed, glucocorticoid-sparing therapy.

Significant recurrent vestibular dysfunction without concomitant hearing loss is very unusual and should be treated with antihistamines or benzodiazepines, as discussed above. A trial of glucocorticoids should be considered if this treatment fails. Long-term glucocorticoid therapy has generally not been required to control recurrent vestibular dysfunction.

Chronic vestibular dysfunction occurs in a few patients with CS and can be treated with antihistamines, benzodiazepines, and vestibular therapy, which includes exercise activities aimed at maximizing central nervous system compensation for vestibular dysfunction [2,18,19,66].

PROGNOSIS — The disease course of Cogan syndrome (CS) is typically characterized by multiple relapses of inflammatory eye disease and inner ear disease, or both, although some may exhibit a monophasic illness and fewer yet display persistently active disease. In a retrospective review of 60 patients with CS who had received their care at the Mayo Clinic between 1940 and 2002, progression to complete hearing loss was noted in both ears and in one ear in 52 and 18 percent of cases, respectively [19]. The outcomes of the ocular manifestations of CS depend on the type of inflammatory eye disease. However, in this study, the vast majority of patients had normal or near normal vision at the final follow-up [19].

The prognosis of CS appears to have improved with more aggressive use of immunosuppressive drugs and biologic agents. For comparison, a retrospective study of 62 patients with CS that came from two nationwide networks in France (n = 40) and were combined with case reports reported in the literature between 2004 and 2015 (n = 22) showed lower relapse rates (13 and 31 percent of patients relapsed at 5 and 10 years, respectively) than the relapse rates from the patients in the Mayo Clinic study (78 percent relapsed during an average of 7.1 years of follow-up) [61]. Both groups of patients were uniformly treated with high doses of glucocorticoids at initial presentation and during the subsequent clinical course. However, the patients from the French study had greater use of immunosuppressive agents compared with those managed at the Mayo Clinic; 10 of the patients in the French study were treated with infliximab, which was only approved for use in late 1998. Caution must be exercised in interpreting these apparent differences in relapse rates between the two studies since these two groups of patients that were studied over these nonoverlapping time periods may not be strictly comparable in terms of clinical features and disease severity.

Premature death is not a usual feature of CS. When deaths occur in this setting, they mostly result from either a complication of immunosuppressive treatment or an associated systemic vasculitis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Cogan syndrome (CS) is a chronic inflammatory disorder that most commonly affects young adults. Clinical hallmarks are interstitial keratitis (IK) and vestibuloauditory dysfunction, and associations between CS and systemic vasculitis, as well as aortitis, also exist. There are a range of pathologic findings, most of which reflect immune-mediated injury of the affected tissues; however, despite an association with systemic vasculitis, eye and inner ear specimens of those with CS infrequently reveal any evidence of vasculitis. The underlying mechanisms responsible for the eye and inner ear disease in CS are unknown. (See 'Introduction' above and 'Pathology' above and 'Pathogenesis' above and 'Epidemiology' above.)

●The predominant ocular feature of CS is IK, which typically causes eye redness, pain, photophobia, and blurred vision. Slit-lamp examination commonly demonstrates a patchy, deep, granular corneal infiltrate. IK is not essential for the diagnosis; ocular inflammation may involve other parts of the eye and may lead to iridocyclitis, conjunctivitis, episcleritis, anterior or posterior scleritis, or retinal vasculitis. (See 'Ocular disease' above.)

●The inner ear manifestations of CS are Ménière-like attacks consisting of vertigo, ataxia, nausea, vomiting, tinnitus, and hearing loss. Vestibular dysfunction may also cause oscillopsia, and caloric testing often reveals absent vestibular function. Recurrent episodes of inner ear disease frequently result in profound sensorineural hearing loss. Noninflammatory down-fluctuations in hearing may be difficult to distinguish from those of inflammatory origin. If hearing loss is associated with eye inflammation or other features of active CS or does not resolve within three to five days, an inflammatory origin is more likely. (See 'Inner ear disease' above.)

●When present, the systemic vasculitis associated with CS is a large- or medium- to small-sized vessel vasculitis or an aortitis. The pattern of vessel involvement may be overlapping. Other systemic manifestations of CS include fever, fatigue, weight loss, lymphadenopathy, hepatomegaly, hepatitis, splenomegaly, pulmonary nodules, pericarditis, abdominal pain, arthralgia, arthritis, myalgia, and urticaria. An association with inflammatory bowel disease has also been observed. (See 'Systemic vasculitis' above and 'Other findings' above.)

●Evaluation of the patient with possible CS requires ophthalmologic examination to establish the presence of IK, scleritis, or episcleritis and to exclude other diseases and ocular pathology; neurologic and otologic examination to establish the presence of vestibuloauditory abnormalities; and rheumatologic examination to seek evidence of systemic vasculitis. We diagnose CS based upon the presence of characteristic inflammatory eye disease and vestibuloauditory dysfunction. The eye and inner ear are nearly equally likely to be the cause of presenting symptoms, while less than 5 percent of patients initially present with systemic manifestations. (See 'Clinical features' above and 'Evaluation' above and 'Diagnosis' above.)

●The differential diagnosis of CS includes diverse conditions that cause similar eye and inner ear manifestations, such as sarcoidosis, polyarteritis nodosa, granulomatosis with polyangiitis, and rheumatoid arthritis. Other diagnostic possibilities include the infectious causes of IK and a syndrome of subacute encephalopathy, sensorineural hearing loss, and retinal arteriolar occlusions in young adults that is due to an occlusive nonvasculitic vasculopathy. (See 'Differential diagnosis' above.)

●Therapeutic options for the treatment of CS include the use of topical agents for limited (usually anterior) ocular disease and systemic immunosuppressive therapy for more extensive (usually posterior) ocular disease, inner ear involvement, and/or systemic vasculitis. Immunosuppressive therapy typically includes glucocorticoids; adjunctive immunosuppressive therapy is guided by the severity of disease and upon the nature of organ system involvement. Surgical bypass grafting or aortic valve replacement may be required in some patients. (See 'Treatment' above and 'Systemic vasculitis' above and 'Ocular disease' above and 'Anterior ocular inflammation' above and 'Posterior ocular inflammation' above.)

●In a newly diagnosed patient with CS, we treat compromised auditory acuity or vestibular dysfunction with a therapeutic trial of systemic glucocorticoids. Glucocorticoid-sparing immunosuppressive therapy, such as methotrexate, azathioprine, or tumor necrosis factor (TNF) inhibitors (eg, infliximab) may also be required to minimize disease progression. We generally treat acute vestibular dysfunction using antihistamines (such as meclizine hydrochloride) or benzodiazepines, as well as bedrest. Recurrent vestibular dysfunction is virtually always accompanied by hearing loss and should be treated using glucocorticoids and, if needed, glucocorticoid-sparing therapy. Chronic vestibular dysfunction should be treated with antihistamines, benzodiazepines, and vestibular therapy. Cochlear implants (CI) have been beneficial in patients with severe hearing loss who have not responded to pharmacologic therapy. (See 'Inner ear disease' above and 'Vestibular dysfunction' above.)