Patients typically manifest with either ocular or vestibuloauditory involvement on initial presentation. In adults, 25–50 % of CS patients present with ocular manifestations, 32–36 % with vestibuloauditory symptoms, and 5 % with both organ involvement [7, 8, 32, 33].

In pediatric CS, ocular and vestibuloauditory symptoms are the predominant presenting symptoms [12]. In one series, two-thirds of patients had evidence of IK [12]. Compared to adults, IK in children may be more diffuse, and likely to involve the central cornea [36, 57]. For these reasons, pediatric CS may result in devastating visual consequences, such as amblyopia.

The largest series of pediatric CS reported included 23 children with a mean age of 11.4 years: 47.8 % experienced constitutional symptoms (fever, weight loss, arthralgias, myalgias, and headaches); 91.3 % had ocular symptoms (interstitial keratitis, episcleritis/conjunctivitis, uveitis); 39.1 % had vestibular symptoms (vertigo, nausea/vomiting, dizziness), 65.2 % had auditory involvement (SNHL, tinnitus, and deafness), 17.3 % experienced cardiac valve complications, and 13 % had skin manifestations [12]. The majority of patients (69.6 %) experienced permanent complications from the disease including SNHL, vestibular dysfunction, ocular sequelae, and cardiac valve damage [12].

The first description of corneal histopathology in CS was published in 1961 [58]. Thickening of the corneal epithelium; neovascularization, lymphocytic and plasma cells infiltration; crystalline lipids, and hyalinization of the optic nerve have been described in CS patients [2, 4, 7, 15, 26]. A conjunctiva biopsy from a suspected case of IK revealed plasma cell and monocyte infiltration [2].

SNHL is attributable to lymphocytic and plasma cell infiltration resulting in degeneration and atrophy of cells in the semicircular canals, spiral ligament of the cochlea, organ of Corti, utricle, saccule, and proximal portion of the eight cranial nerve [7, 12, 18, 21, 59]. Endolymphatic hydrops of the temporal bone and osteogensis of the round window membrane secondary to chronic inflammation have also been detected on histological exam [7, 41, 60]. The role of vasculitis in hearing loss is debatable. Pathological samples have not shown evidence of vasculitis, but rather chronic inflammatory changes [18].

Grossly, dilatation of the aorta and narrowing of the coronary ostia near the aortic valve have been found on autopsies [33, 39]. Fibrinoid necrosis, degradation of the elastic lamellae, and fibromyxoid changes of the aorta can result in deformation and aneurysms of the aorta and aortic valve leaflets [7, 39, 61]. Thickening and inflammatory cell infiltration of the pericardium, myocardium, and endocardium have been described, with resultant fibrosis and infarction of the involved tissues [2, 7].

Inflammation of the vessels of the kidneys, dura, brain, mesentery, bowel, skin, and muscles resulting have also been reported [7, 39, 43].

Skin biopsies from CS patients have shown vasculitis, leukocytic evasion, ulceration, and fibrosis [7, 8, 22]. Lymph node biopsies have shown granulomatous inflammation with nonspecific inflammatory hyperplasia [7]. Pathologic findings of abdominal organs in CS patients have included hepatic granulomas, bile duct proliferation, glomerulonephritis, renal cortical infarction, caseating necrosis of the spleen, and inflammation of the lamina propria and submucosa of the bowel [7]. In the brain, hemosiderin deposit in the subarachnoid, cerebral petechiae and edema, and gliosis of the occipital lobe have been reported [7].

The corneal manifestations of congenital syphilis tend to be significantly more severe than CS [19]. Congenital syphilis can cause bilateral, progressive IK, with significant posterior corneal scarring, edema, and neovascularization in the presence of other luetic stigmata (skin, dental, skeletal) [1, 30]. Hearing loss may also be associated, but vestibular function is typically not affected, unlike CS [1, 19, 30].

Other infectious etiologies that may present with similar symptoms as CS include tuberculosis, chlamydia, Borrelia burgdorferi, and certain viruses. Tuberculosis rarely causes IK; however, when it occurs, there is usually minimal corneal infiltration with mild neovascularization [1]. Associated hearing loss can result from treatment with streptomycin [2, 30]. The chlamydia species, in particular, have been investigated for its possible role in the pathogenesis of CS. It is a known infectious cause of ocular, otolaryngologic, and cardiovascular complications in humans [2, 13]. Lyme disease, caused by the spirochete Borrelia burgdoreferi, can cause skin changes (erythema migrans, borrelia lymphocytoma, achrodermatitis chronica atrophicans), carditis (resulting in conduction abnormalities), neurological symptoms (aseptic meningitis and peripheral nerve palsies), arthritis, and, rarely, ocular manifestations (conjunctivitis, episcleritis, keratitis, endophthalmitis) that may mimic CS [62]. HSV/VZV can cause hearing loss due to involvement of CN VIII, as it can become strangulated in the auditory canal due to mass effect from swelling [30]. Herpetic viruses can also cause corneal lesions, but they are usually dendritic in appearance. Mumps and rubella may affect the ear and can rarely cause IK [7]. Viral labyrinthitis is a common cause of unilateral inner ear dysfunction, associated with vertigo, nausea, and vomiting [63].

Inflammatory causes of both vestibuloauditory and ocular symptoms include PAN, granulomatosis with polyangiitis (GPA, formerly known as Wegener granulomatosis), temporal arteritis, Bechet’s disease, Grave’s disease, lupus, and relapsing polychondritis [7, 18]. Relapsing polychondritis is a systemic inflammatory disorder affecting cartilaginous tissues of the body, which may result in auricular collapse, ear pain, otitis media, SNHL, and vestibular dysfunction [64]. Associated ocular manifestations of relapsing polychondritis include episcleritis, scleritis, corneal infiltrates, peripheral ulcerative keratitis, iridocyclitis, and rarely, posterior segment involvement [65]. Takayasu’s arteritis, like CS, affects large vessels [13]. Underlying granulomatous inflammation of the aorta in Takayasu’s arteritis may lead to nonspecific constitutional symptoms, claudication of the extremities, aorta aneurysms, coronary artery ischemia, and renal artery stenosis [66]. However, unlike CS, Takaysu’s arteritis rarely affects the eyes and ears [13]. Sarcoidosis characteristically affects the lungs, heart, skin, eye, and lymph nodes, but seldomly results in vestibuloauditory symptoms [26].

Vogt– Koyanagi–Harada (VLH) disease is a systemic process that targets melanin-containing tissue that can result in meningitis, decreased vision, and hearing loss [31]. However, the ocular inflammatory manifestations (iritis, choroiditis, and retinal detachments) in VKH tend to be much more severe compared to CS [19]. VKH patients also present with poliosis and vitiligo, which is not typical of CS [67].

Aminoglycosides, antimalarials (quinine), diuretics, salicylates, heavy metals can all cause hearing loss [7, 26]. Streptomycin can cause Ménière-like vestibular symptoms. 3-methyl-1-pentyn-3-yl-acid phthalate (Whipcide) is used for whip worm treatment, and can induce CS-like symptoms such as IK and hearing loss [2, 19]. Symptoms tend to wane after drug discontinuation [19].

Symptoms of Meniere’s disease include vertigo, hearing loss, tinnitus, and aural fullness [8, 10, 52]. CS can present very similarly to Ménière’s disease; however, there are certain key differences. The symptoms in CS tend to be bilateral, more acute on onset, rapidly progressive, and chronic in duration [41]. Whereas in Ménière’s disease, symptoms tend to be unilateral, last for only minutes to hours at a time, and result in more mild vestibuloauditory dysfunction compared to CS [8, 10, 52].

Laboratory data is typically not helpful in the diagnosis of CS [5]. Nonspecific markers of inflammation include leukocytosis (36–70 %), thrombocytosis (12–33 %), elevated erythrocyte sedimentation rate (ESR, 25–100 %) and C-reactive protein (CRP, 33 %), anemia (15–39 %), and abnormal liver enzymes (16 %) [2, 7, 8, 14, 55]. In the assessment of suspected CS patients, basic laboratory assessment includes a complete blood count (CBC); complete metabolic panel; urine analysis; ESR/CRP levels, and, treponemic pallidum and chlamydia titers. In cases of positive chlamydia titers, treatment should be initiated with azithromycin or doxycycline [14]. In endemic areas, Lyme disease serology should also be obtained. Surveillance of ESR and CRP levels may be helpful in monitoring disease activity in CS patients [14, 29].

Given CS’s association with other inflammatory disorders, additional testing should be performed based on clinical presentation and suspicion. Other inflammatory markers that may be elevated include antiphospholipid antibodies (APA), anti-DNA antibodies myeloperoxidase (MPO), proteinase 3 (PR3), antineutrophil cytoplasmic antibodies (ANCA), and rheumatoid factor (RF) [6, 14]. However, these non- specific antibodies are not consistently elevated in CS patients. For instance, in one series, less than 11 % of patients had positive APA, ANCA, or RF levels [8]. Several studies have reported detection of antibodies against heat shock protein 70 in CS patients, but they are not routinely obtained in clinical practice [33]. Decreased albumin, IgG, and complement levels have been reported, along with increased IgA, IgM, and haptoglobin levels in association with chronic inflammation [7, 22]. In cases complicated by meningoencephalitis, cerebrospinal fluid (CSF) may shows pleocytosis, lymphocytosis, or increased protein levels [52].