Cogan syndrome was first described in 1945 by Dr. David Cogan, an ophthalmologist, who described four patients who developed near simultaneously interstitial keratitis and vestibular-auditory symptoms, which led to deafness in three women. Later reports, in particular a series of 60 patients seen at the Mayo Clinic, widened the scope of this syndrome to include features of systemic and large-vessel vasculitis with classic and atypical presentations. There are reports on about 30 pediatric cases with a maximum of 3 from individual centers, of which 23 were summarized in 2012.
There is no formal definition or classification of this syndrome. Historically, classic cases were defined as patients with interstitial keratitis who developed both ocular and vestibular-auditory symptoms within 2 years. Patients with ophthalmological manifestations other than interstitial keratitis or with more than 2 years between the development of ocular and vestibular-auditory symptoms were considered to have “atypical” syndrome. Signs of large-vessel vasculitis, particularly of the proximal aorta and aortic valve insufficiency, were also considered “atypical.”
Most cases occur in young adulthood with rare cases in childhood. The median onset in childhood is approximately 11 years of age, with the youngest reported case at 6 months of age. Nearly two thirds of childhood cases are in males, whereas in adults there is no gender predilection. In adults there is no ethnic predilection. Familial cases are rare. Adult series reported human leukocyte antigen (HLA) associations with A9, Bx17, Bw35, and Cw4.
The etiology is unknown. However, similarities to syphilitic keratitis have led to searches for infectious etiologies. Studies from the National Institutes of Health (NIH) found serologic evidence for infection by Chlamydia trachomatis in many patients, but this has not been replicated by other investigators. Other investigated organisms included other species of Chlamydia and Borrelia burgdoferi . The Mayo Clinic series found that smoking rates among patients were twice that of the general population.
The pathogenesis is considered to be autoimmune. Usually relatively protected from the immune system, the eye and inner ear may develop an immune response to various undetermined insults resulting in T- and B-lymphocyte activation and the formation of autoantibodies. However, most adult studies did not find evidence of autoantibody formation to antigens of the inner ear, including to 68 kDa, frequently found in idiopathic progressive bilateral sensorineural hearing loss. Other adult studies found in some patients with Cogan syndrome antibodies to the density-enhanced protein tyrosine phosphatase 1 (DEP-1) expressed on endothelial cells, which has a peptide with partial homology to the SS-A antigen.
No specific pathology has been found in eye and inner ear structures. Large-vessel vasculitis resembles that of Takayasu’s arteritis and polyarteritis nodosa.
Often the disease onset is preceded by an infection, most commonly an upper respiratory infection. There does not appear to be significant differences between adult and childhood disease. The median time from onset to diagnosis is about 8 months. Table 38-1 details the proportion of children with ocular, vestibular-auditory, musculoskeletal, and systemic symptoms at onset and at follow-up. Signs of large-vessel vasculitis, particularly proximal aortitis and aortic valve insufficiency, are present in 10% to 15% of children.
|Median age (years)||10.5 (range 0.5-18)||12.5 (range 1-16)|
|Systemic features||12 (40%)||0|
|Musculoskeletal symptoms||13 (43.3%)||0|
|Ocular||28 (93.3%)||3 (10%)|
|Interstitial keratitis||17 (56.7%)||1 (3.3%)|
|Uveitis||7 (23.3%)||1 (3.3%)|
|Conjunctivitis/episcleritis||6 (20%)||1 (3.3%)|
|Vestibular/auditory||21 (70%)||14 (46.7%)|
|Vertigo/nausea/dizziness||10 (33.3%)||1 (3.3%)|
|Sensorineural hearing loss||14 (46.7%)||4 (13.3%)|
|Deafness||2 (6.7%)||7 (23.3%)|
|Tinnitus/hyperacusia||8 (26.7%)||2 (6.7%)|
|Cardiovascular||4 (13.3%)||4 (13.3%)|
More than 50% of the children have multisystem disease with approximately 25% of cases involving two systems; in approximately 20% of the cases, only one system is involved. The interval between development of ocular and vestibular-auditory symptoms is generally less than 2 years. However, several children were already deaf by the time ocular symptoms started.
Acute phase reactants are usually elevated but can be normal in patients with isolated ocular and vestibular-auditory disease. Autoantibodies are usually negative, but in a few patients antiphospholipid antibodies and antineutrophil cytoplasmic antibodies may be found, the latter in a perinuclear pattern. Repeated audiometry testing is crucial, with hearing loss noted initially in the high and low frequencies, similar to Ménière’s syndrome. Brain stem auditory evoked potentials are abnormal in advanced disease.
Echocardiography may demonstrate aortic valve insufficiency with thickening and proximal aortitis. Inner ear magnetic resonance imaging (MRI) with gadolinium may show cochlear enhancement. Proximal aorta MRI is useful to search for evidence of aortitis. Calcific obliteration of cochlear and vestibular structures can be found in computed tomography.
The association of interstitial keratitis with vestibular-auditory inflammatory disease can be seen in many other conditions. Infections include Chlamydia, Lyme disease, and congenital syphilis. Inflammatory diseases include sarcoidosis, polyangiitis with granulomatosis, relapsing polychondritis, Behçet disease, Sjögren syndrome, Susac syndrome, and antiphospholipid antibody syndrome. Other conditions include lymphoma, Vogt–Kouangi–Harada syndrome, mitochondrial cytopathies, and Whipple disease.
Treatment and Outcome
There are no controlled therapeutic trials. However, early diagnosis and institution of high-dose corticosteroids (between 1 and 2 mg/kg/day) is crucial to save hearing or prevent further loss of hearing. It is often hard to wean corticosteroids, and steroid-sparing medications are often necessary, methotrexate being the most commonly used in children. Other options used in children include mycophenolate mofetil, leflunomide, azathioprine, cyclosporine A, and cyclophosphamide (the latter mainly in cases of large-vessel vasculitis). In adults anti-tumor necrosis factor (TNF) agents have been used with some success. Ocular corticosteroid drops are commonly used. Cochlear implants are beneficial in patients with established deafness.
Only about 30% patients achieve complete, damage-free remission. Ocular outcomes are usually excellent with rare permanent damage. However, permanent partial hearing loss or deafness residua occur in nearly 50% of childhood cases. Delayed diagnosis of more than 2 months was the most important factor related to a poor outcome in pediatric cases. Aortic valve damage is usually not reversible, although it rarely leads to the need for surgical replacement. Only one case of death, from subarachnoid hemorrhage, was seen in childhood cases.
Immune Complex Small-Vessel Vasculitis
Antiglomerular Basement Membrane Disease
Antiglomerular basement membrane (GBM) disease, formerly called Goodpasture syndrome, is one of the pulmonary-renal syndromes resulting from antibodies to the non-collagenous-1 (NC1) domain alpha 3 chain of type IV collagen in alveolar and glomerular basement membranes.
Clinically and histologically the disease is similar to microscopic polyangiitis (see Chapter 36 ). Overlap cases with both anti-GBM and perinuclear antineutrophil cytoplasmic antibodies (pANCAs) with specificity for myeloperoxidase have been reported in children, with a worse prognosis than isolated anti-GBM disease. Immunofluorescence demonstrating a linear deposition of IgG along the capillary basement membrane can differentiate between the two conditions.
This disease predominantly affects young men and has been reported in approximately 25 children and adolescents. Anti-GBM disease has occurred after therapy with d -penicillamine, in cases of heavy metal and hydrocarbon exposure, and in patients with a variety of rheumatic diseases.
Treatment includes corticosteroids, plasmapheresis, and immunosuppressive agents. Recently, rituximab has shown promise. The survival rate is about 90%, but many children progress to end-stage renal disease. In children, the disease is almost always monophasic.
This disease is defined by the Chapel Hill Consensus Conference as vasculitis with immune deposits in capillaries, venules, or arterioles of the skin and kidney associated with cryoglobulins in the serum. The two types of cryoglobulins seen in children are type II (monoclonal immunoglobulin M [IgM] rheumatoid factor [RF]) and type III (polyclonal IgM RF). Clinically, both resemble other forms of leukocytoclastic vasculitis. The most common and earliest manifestation is distal extremity purpura (>75%), often precipitated by exposure to cold, which can lead to ulceration. Other manifestations include musculoskeletal disease, more arthralgia (~67%) than frank arthritis (~10%), polyneuropathy, Raynaud phenomenon, and liver enzyme abnormalities. Renal involvement with hypertension occurs later in the disease course (~50%), mainly in the form of membranoproliferative glomerulonephritis.
Laboratory findings include low C4 levels and positive RF (both >65%), hematuria, proteinuria, and mixed type II or III cryoglobulins in the serum. Pathology shows leukocytoclastic vasculitis with deposits of IgM, IgG, and complement seen by immunofluorescence.
Cryoglobulinemic vasculitis is rare in children. In one series (n = 18), children had a significantly higher prevalence of prolonged fever, arthralgia, arthritis, and cutaneous involvement compared with adults. The etiology is primarily secondary to hepatitis C infection (see below). Hepatitis B, chronic salmonella infections, and other conditions such as DiGeorge syndrome, sickle-cell anemia, thalassemia, and even Henoch–Schönlein purpura (HSP) have been associated with childhood cryoglobulinemia. One case of symptomatic cryoglobulinemia in an infant was related to transplacental transmission. Traditional treatment includes combinations of corticosteroids, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin (IVIG). Recently, the efficacy of rituximab has been demonstrated. Progressive renal disease is the principal cause of long-term morbidity.
Cryofibrinogenemia, secondary to infection or in one instance occurring in three family members, can cause similar clinical and pathological phenomena to cryoglobulinemia.
Urticarial vasculitis (UV) should be suspected in children with individual lesions lasting in one location for 24 hours or longer, with associated purpura, fever, arthralgia/arthritis, and glomerulonephitis. UV is a very rare cause of chronic urticaria in children (<1%). It can present with normal or decreased complement levels (hypocomplementemic).
Hypocomplementemic UV (HUV), first described in the 1970s, tends to be more severe than normocomplementemic UV. Diagnostic criteria include recurrent urticaria and low complement levels as major criteria and at least two minor criteria, including demonstration of venulitis on skin biopsy, arthritis, ocular inflammation, abdominal pain, positive C1q antibodies, and glomerulonephritis. Positive antinuclear antibody (ANA) and double-stranded DNA antibodies are exclusion criteria.
UV occurs mostly in girls at all ages and can even occur in infants. Children have recurrent episodes of urticaria associated more with a burning sensation than pruritus. The urticaria resolves over 2 to 4 days, leaving residual pigmentation ( Fig. 38-1 ). Other skin lesions include purpura, papules, and vesicles. Fever, nausea, vomiting, and abdominal pain may accompany cutaneous exacerbations (~25%). Arthralgias occur in approximately 60% of patients, and arthritis, usually of small joints, in approximately 30%. Arthritis episodes are short with no long-term residua. Pulmonary disease (e.g., cough, dyspnea, hemoptysis) occurs in approximately 30% of patients and clinical glomerulonephritis in approximately 15%. Less commonly, uveitis and episcleritis, fever, angioedema, Raynaud phenomenon, pseudotumor cerebri, and seizures are seen. In children, rapidly progressive glomerulonephritis and pulmonary hemorrhage have been described.
HUV has been associated with systemic lupus erythematosus (SLE), Sjögren syndrome, hepatitis B and C antigenemia (cryoglobulinemia), drug reactions, and excessive exposure to sun. In fact, many patients subsequently develop full-blown SLE.
The pathogenesis of this condition is thought to result from the binding of IgG C1q antibodies to immune complexes with activation of the classic complement pathway. Levels of C3, C4, and C1q are reduced in 18% to 50% of patients; the complement level often parallels the severity of the disease. In two Turkish families with an autosomal recessive inheritance pattern, loss of function mutations in DNASE1L3 (deoxyribonuclease 1-like 3), a protein coding gene, were the cause of HUV. Skin biopsy documents a leukocytoclastic vasculitis, predominantly venulitis, with the deposition of IgM and C3 in affected vessels. Various types of renal lesions including mesangial, focal, membranoproliferative, and membranous glomerulonephritis are seen in approximately 50% of children.
Management consists of supportive measures and treatment of any associated disorders. Antihistamines, dapsone, hydroxychloroquine, colchicine, and indomethacin have been used with variable success. Corticosteroids, IVIG, or other immunosuppressive drugs may be required in children with severe disease, especially those with crescentic glomerulonephritis. The course of the disease depends on the associated disorders and extent of systemic involvement.
Normocomplementemic UV can also accompany other forms of vasculitis (for example, early HSP) and can be seen as part of neutrophilic urticaria such as the cryopyrin-associated periodic syndromes and Schnitzler syndrome.
Vasculitis Associated With Systemic Disease
Vasculitis may occur as part of systemic inflammatory diseases, mainly due to immune complex deposition, but also in part a result of accelerated atherosclerosis related to vascular inflammation.
Vasculitis in Juvenile Idiopathic Arthritis
Small- and medium-sized vessel vasculitis, first described in children and adolescents by Ansell in 1978, is a rare phenomenon in patients with RF-positive polyarthritis juvenile idiopathic arthritis (JIA) and is associated with a poor prognosis. The most common findings are nailfold and digital cutaneous vasculitis, representing microinfarctions. Digital and leg ulcers, scleritis, keratitis, mononeuritis multiplex, and aortic valve insufficiency are among other features. The prevalence of this complication appears to have decreased dramatically, perhaps due to earlier aggressive therapy. Long-standing ankylosing spondylitis (almost always in adulthood) is associated with proximal aortitis with valve insufficiency.
Vasculitis Related to Systemic Lupus Erythematosus and Other Systemic Autoimmune Diseases
Leukocytoclastic vasculitis may occur in SLE, and present as palpable purpura, nodules, punctuate erythema, urticaria, livedo reticularis, panniculitis, and chilblains/pernio (see below). Ulcerative skin lesions tend to be painful and are most frequently found on fingers or toes. Resistant ulcers have been associated with complement deficiencies. Vasculitis can be the cause of several of the severe and life-threatening features related to SLE, especially central nervous system involvement (see Chapter 23 ). In dermatomyositis and scleroderma, fibroproliferative and thrombotic vasculopathy, rather than vasculitis, are the hallmarks of vascular involvement and the base for Raynaud phenomenon. Skin ulcers and gastrointestinal involvement in dermatomyositis and renal/pulmonary artery involvement in scleroderma indicate a poor prognosis (see Chapters 26 and 27 ). Sarcoidosis is also associated with vasculitis (all vessel sizes), particularly in patients with central nervous system, aorta, and renal vessel involvement. A variety of skin lesions are seen in sarcoidosis, including leukocytoclastic vasculitis (see Chapter 39 ).
Familial Mediterranean Fever and Vasculitis
Approximately 5% to 7% of patients with familial Mediterranean fever (FMF) develop HSP, often prior to the development of classic FMF attacks (see Chapter 47 ). Ten percent of HSP patients in ethnic groups with high prevalence of FMF were found to have asymptomatic homozygous mutations in the MEFV gene and 17% to 34% had heterozygote mutations. The course of HSP in FMF patients is more “inflammatory,” with higher fever and inflammatory markers, than idiopathic HSP.
Polyarteritis nodosa (PAN) is also more common among patients with FMF, especially in children. Perinephric hematoma is a characteristic finding ( Fig. 38-2 ). The course of PAN is usually milder than in idiopathic disease.
Lymphoproliferative disease is rarely (1% to 3%) accompanied by a paraneoplastic vasculitis, within 12 months of onset. The most common type (45% to 60%) is leukocytoclastic vasculitis of the skin with arthralgia/arthritis. There are rare cases of PAN, granulomatosis with polyarteritis, Sjögren syndrome, and HSP. Occasionally, vasculitis precedes the diagnosis or can be the first sign of a relapse. Treatment is aimed primarily at the malignancy with careful use of corticosteroids. Lymphocytic lymphoma and Waldenström macroglobulinemia, both rare in children, can result in a cryoglobulinemic vasculitis (the latter type I). Atrial myxoma can mimic vasculitis, through systemic symptoms and emboli dissemination. Leukemia vasculitis is a result of direct invasion of dermal blood vessels.
Vasculitis Associated With Probable Etiology
The various types of viral-induced vasculitis are summarized in .
Hepatitis B Virus
Shortly before the icteric phase of hepatitis B, 5% to 15% of patients develop an immune complex small-vessel vasculitis. Features include fever, a polymorphic rash (purpura, urticaria, maculopapular rash), symmetric and predominantly small-joint arthritis, myalgia, and nephritis. Low levels of C3, C4 (~40%), and RF (~25%) can be found. The presence of liver enzyme abnormalities, hepatitis B surface antigen (HBsAg) and IgM anti-hepatitis B core (HBc) antibodies is diagnostic. These features self-remit without specific treatment within 2 to 3 weeks, with the appearance of jaundice.
Hepatitis B–related PAN is extremely rare in childhood. PAN usually occurs during the first year after infection and has a similar presentation to idiopathic disease but perhaps a more severe course. Treatment consists of combined antiviral and immunosuppressive medications. The disease is usually monophasic for those that attain remission.
Hepatitis C Virus Cryoglobulinemic Vasculitis
Cryoglobulins are found in 40% to 50% of patients with hepatitis C, although cryoglobulinemic vasculitis, is seen in less than 5% of patients. However, hepatitis C infection is responsible for 80% to 90% of cases of cryoglobulinemic vasculitis. Clinical and laboratory manifestations are similar to other causes of cryoglobulinemic vasculitis (see above).
Treatment of mild disease includes combination of antiviral therapy with low-dose corticosteroids. In severe disease plasmapheresis, cyclophosphamide and rituximab are added to corticosteroids. Recent data suggest that rituximab as monotherapy or in combination with antiviral therapy may lead to complete remission in more than 60% of cases. Interferon-α use should be delayed in severe disease as it may initially worsen vasculitis.
Parvovirus B19 is associated with a small-vessel vasculitis that occurs during the second phase of an acute infection. Clinical features include fever, purpuric rash and polyarthritis. Resolution of symptoms usually occurs within days to few weeks. IVIG has been beneficial in persistent cases.
Vasculitis has been reported in 1% to 2% of infections with human immunodeficiency virus (HIV) type 1. The most common presentation is a PAN-like disease. Rarely HIV-related vasculitis presents as leukocytoclastic, large vessel, central nervous system (CNS), or Kawasaki disease. In one series, 33% of cases of adult Kawasaki disease were associated with HIV. Immunosuppressive treatment should be as “light” and short as possible and needs to be coordinated with HIV specialists.
Varicella-zoster (VZ) infection of the face and neck has been associated with medium to large-vessel CNS vasculitis 4 to 6 weeks following infection. The estimated prevalence in children is 1 in 6500. Ipsilateral involvement of the carotid, anterior, and middle cerebral arteries is most common. The disease is usually monophasic but recurrent or progressive cases have been described. VZ is one of the most common causes of acute retinal vasculitis. Purpura fulminans is a form of vasculitis associated with severe varicella infection. Rare cases of vasculitis related to hepatitis A, influenza A, cytomegalovirus, Epstein-Barr virus and herpes simplex virus have been reported, some in immunocompromised patients.
Bacterial infections can cause vasculitis either as part of the infection, secondary to sepsis or as a postinfectious immune complex process.
The most common is related to Neisseria infections. Isolated infected vesicular and purpura lesions, occasionally leading to bullae and ulceration are seen in the early phase of gonococcal infections. These usually occur on the volar aspect of the wrists but can occur elsewhere. Widespread purpura is seen both in acute and chronic (the latter most commonly seen in Australia) meningococcal infections. An immune complex vasculitis including purpura, arthritis, and peripheral neuropathy can occur 5 to 9 days from the start of a meningococcal infection, following initial improvement after start of antibiotic treatment. Rickettsial disease, particularly Rocky Mountain spotted fever, is associated with distal small-vessel vasculitis. Case reports or series of vasculitis related to a variety of other bacterial infections have been reported. Most are associated with small-vessel vasculitis, but other size vessel involvement may occur in rare instances, including aortitis and coronary arteritis. Aortitis is a major feature of tertiary syphilis. Cat scratch disease (Bartonella henselae) is associated with leukocytoclastic vasculitis and can resemble HSP. Infectious endocarditis can result in immune complex small-vessel vasculitis in the skin (Osler and Janeway nodes), retina, kidney, and spleen. Neonatal necrotizing enterocolitis can also cause an immune complex vasculitis. Leukocytoclastic vasculitis can be a feature of mycobacterium and salmonella infections related to IL-12 receptor deficiency.