Ophthalmic Manifestations of Kawasaki Disease
Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute, self-limited medium vessel childhood vasculitis. It has a particular predilection for the coronary arteries, which makes it the most common cause of acquired heart disease in children in developed countries. Ocular manifestations of KD are distinct and usually include anterior segment lesions. KD is a potentially fatal disease as it can lead to myocarditis, aneurysm formation and rupture, myocardial infarction(MI) and sudden death.
Ophthalmologists and other health care providers should be aware of the ocular manifestations of KD as they can be critical in helping to distinguish the disease from other less severe diseases with similar presentations. By creating awareness of the ocular findings in KD, we hope to decrease the time to diagnosis and lifesaving intervention in patients.
KD most commonly affects young children that are between the ages of 6 months and 4 years, with the highest incidence seen with Asian descent (1). However, it can present at any age, and can even be seen in adults. There is a slight male predominance (2), with males facing higher rates of complications (3). It is rare to see Kawasaki disease in children less than 4 months, possibly pointing to protection from maternal antibodies (4). About 9% of patients will experience acute phase cardiac complications, while about 3% will experience cardiac sequelae (5).
The etiology of KD is still not completely understood. Recent studies have shown an association with certain genetic markers such as HLA-B51 and HLA-Bw22j2 serotypes, chemokine receptor gene-cluster CCR2-CCR5 haplotypes and FCGR3A polymorphism of the IgG receptor IIIa. These discoveries point towards a potential genetic predisposition to the disease (2, 7).
Specific factors that lead to an increased risk of coronary artery aneurysms include (2, 4-6): Fever >5 days Recurrence of fever after a period of being afebrile for 48 hours Male Cardiomegaly <1 year old of age Asian or Pacific Islander descent Hispanic ethnicity Lower IgG levels Increased pro-BNP levels Increased TNF-alpha levels Thrombocytopenia at initial presentation
A biopsy is rarely performed and is not necessary to make a diagnosis. However, histopathology shows granulomatous inflammation and destruction of the media of arteries by neutrophil invasion. Later in the disease there is arterial remodeling as neutrophils get replaced by lymphocytes, monocytes, and fibroblasts.
The underlying genetic predisposition is thought to be triggered by an environmental stimulus, potentially a wind- or water-borne vector. It is believed that an infectious agent leads to the overactivation of the innate immune system that results in endothelial damage of the tunica media, the medial layer of medium sized arteries. This cascade ends in the pathognomonic myocarditis, arteritis, and coronary aneurysm formation of KD. Increasing recruitment of inflammatory cells and mediators to the arterial media leads to subsequent stenosis and thrombosis formation that can result in MI, rupture, ischemia-related dysrhythmias or death (2).
KD does not have a single diagnostic testing modality to confirm disease. However, it is a clinical diagnosis that has key signs that suggest a patient may be suffering from this condition. According to the National Institute for Health and Care Excellence (NICE), patient's may have Kawasaki disease if they have: 1. a high temperature for 5 days or longer 2. at least 1 other key symptom (listed below) These symptoms include: - bilateral conjunctival infection with or without tearing - mucosal involvement or changes (includes lips and oral cavity) – i.e. dry, red, cracked lips, a erythematous, edematous tongue, or perioral and intraoral erythema - changes to the hands and feet – such as swollen or painful hands or feet, or red or peeling skin on the palms of the hands or the soles of the feet - a polymorphous, non-vesicular rash - acute cervical lymphadenopathy
KD is a multisystem disease. Initial symptoms include a high fever that lasts for greater than 5 days, a non-pruritic macular rash over the trunk and extremities, conjunctivitis, and potentially myocarditis. Later in the disease course, patients experience desquamation of the hands, thrombocytosis, and the development of coronary artery aneurysms.
Less common manifestations include abdominal pain, vomiting or diarrhea, parotitis, intussusception, pain of larger weight-bearing joints, headache, rhinorrhea and cough. Testicular pain including epididymitis, orchitis or urethritis, is highly suggestive of KD (4).
Physical Examination: - Bilateral painless bulbar conjunctival injection without exudate - Erythematous mouth and pharynx, strawberry tongue or red, cracked lips - Polymorphous exanthem (morbilliform, maculopapular, or scarlatiniform) - Peeling of skin in periungual area 2-3 weeks after fever onset - Swelling of hands and feet with erythema of the palms and soles - Cervical lymphadenopathy (over 1.5 cm in diameter) - Transverse depressions (Beau’s lines) in the nails
Ocular features are a principal presenting feature of KD. Ocular manifestations in KD are commonly limited to the anterior segment and are characterized by bilateral bulbar conjunctivitis without exudate, superficial punctate keratitis, uveitis, or vitreous opacities (8).
Posterior segment lesions are rarely reported, with only 7 documented cases. In only one case did symptoms of severe enophthalmos and retinitis progress to retinal and choroidal detachment (9). The severity of the disease was hypothesized to be due to the patient’s older age, atypical presentation, and prolonged systemic inflammation. Tobramycin dexamethasone eye drops was effective in treating her ocular disease.
KD is a clinical diagnosis. If it is on the differential, an echocardiogram must be performed immediately. Additionally, a complete blood count (CBC), metabolic panel, ESR, CRP, and urinalysis can be used to support the diagnosis, but are not necessary.
Although there is no set laboratory testing for KD, the American Heart Association has established an algorithm to assist in diagnosing. According to their guidelines, patients with fever lasting longer than five days with two or three of the diagnostic signs of KD should continuously evaluated for systemic inflammation daily. Initially CRP (>3 mg/dL) and ESR (>40 mm/h) levels and complementary laboratory findings including albumin <3.0 g/dL, anemia for age, elevation of ALT, platelets after 7 days >450000/mm3, WBC count >15000/mm3, and urine >10 WBC/high-power field, should be reviewed. Patients who fulfill more more than two should also undergo echocardiography and ECG. (1)
Various infections can mimic Kawasaki Disease including: Cervical lymphadenitis Adenovirus, Enterovirus, Parvovirus B19 Measles Mononucleosis (Epstein-Barr virus) Scarlet Fever Rheumatic fever Toxic Shock Syndrome (TSS) Rocky Mountain Spotted Fever Staphylococcal scalded skin syndrome (SSSS) Toxic epidermal necrolysis (TEN) Ocular findings are critical in supporting a diagnosis of, or ruling out KD. Both KD and adenovirus present with conjunctival injection, however, the important differentiation is that adenovirus causes conjunctival exudates and KD does not (3). In addition, TSS and scarlet fever lack the ocular and joint involvement that KD has (10). Purulent conjunctivitis or exudative pharyngitis findings would each suggest a diagnosis other than KD.
The goal of treatment of KD is the prevention of cardiac complications and mitigation of long term sequalae. This is accomplished by decreasing the inflammation of the coronary arteries. Therefore, all patients diagnosed with Kawasaki disease should receive high dose IVIG and aspirin. It is important to note that children are at high risk of developing Reye syndrome if they contract influenza or varicella infections while taking aspirin. Accordingly, children should be vaccinated against both.
This treatment regimen should be adequate to treat most patients. However, the select few patients who develop severe perfusion deficits from an aneurysm may require coronary artery bypass graft surgery (4).
Long-term management starts after the acute illness has passed, typically 5-6 weeks after the initial onset of the fever. This is determined on a case by case basis, but includes follow up appointments, routine cardiac stress testing, and repeat echocardiograms.
Prognosis depends on the severity of cardiac disease. Recurrence is uncommon but is most likely to occur in younger children who had cardiac complications from the disease during the initial episode. All KD related deaths are essentially the result of cardiac complications and typically occur 15-45 days from the onset of fever (2).
KD can lead to serious consequences which in severe, untreated cases can include death. Most children that suffer from KD improve within three weeks, however serious complications may occur. Specifically, cardiology related complications include: - Lifetime risk of coronary artery disease - heart attack - myocarditis, endocarditis, or pericarditis - heart failure
Ophthalmic KD are not common and less severe, they include anterior surface disease changes such as keratoconjunctivitis sicca & blepharitis. Other less common complications from KD may occur within the nervous, immune, gastrointestinal, and urinary body systems.
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