SAMIR S. SHAH
HISTORY OF PRESENT ILLNESS
An 11-year-old boy was brought to the emergency department after having a syncopal episode at school. He was feeling “short of breath” and was being escorted to the school nurse when he “blacked out.” The event occurred suddenly and without a prodromal phase. A teacher who witnessed the event reported a transient loss of consciousness. Further discussion with his parents revealed a 1-month history of fatigue, malaise, and progressive dyspnea with exertion. He had also complained of blurry vision and mild photophobia.
The child was born at term. He had not had any prior episodes of syncope.
T 37.6°C; HR 40 bpm; RR 26/min; BP 110/48 mmHg
Weight 25th percentile and Height 50th percentile
On examination he was tired-appearing. Pen light examination of the left eye revealed conjunctival injection and an irregularly shaped pupil (Figure 18-4). There was a I/VI systolic ejection murmur. The lungs were clear to auscultation. There was palpable, nontender axillary lymphadenopathy.
FIGURE 18-4. Photograph of the patient’s eye. Note the conjunctival injection and irregularly shaped pupil.
The electrocardiogram (ECG) revealed second degree AV block (2:1) with a prolonged PR interval and right ventricular hypertrophy. The complete blood count revealed a WBC count of 4200/mm3 with 65% neutrophils, 30% lymphocytes, and 5% monocytes. The hemoglobin was 12.6 g/dL and the platelet count was 256 000/mm3. Hepatic transaminases were mildly elevated with an alanine aminotransaminase (ALT) of 250 U/L and an aspartate aminotransferase (AST) of 200 U/L. Serum electrolytes, including calcium, and uric acid levels were normal. Chest radiograph revealed mild cardio-megaly and bilateral hilar lymphadenopathy.
COURSE OF ILLNESS
Tuberculin skin test, histoplasma urinary antigen, and human immunodeficiency virus tests were all negative. The findings on eye examination, combined with the clinical presentation and abnormalities on ECG and chest radiograph, suggested a narrow range of possible diagnoses. The diagnosis was confirmed on lymph node biopsy.
DISCUSSION CASE 18-5
In Figure 18-4, the iris at the pupillary margin appeared scarred to the anterior capsule of the lens, which sits directly posterior to the iris. These adhesions are known as posterior synechiae and are a sign of uveitis or intraocular inflammation. The inflamed iris scars down to the surface of the lens. The pupil then appears misshapen with dilation in dim light because the scarred areas of the pupil do not dilate, while the unscarred areas do. If the synechiae are extensive, the result could be poor dilation altogether. Synechiae are an important sign for the pediatrician because the irregular pupil is visible to the naked eye. Therefore, whenever a red eye is being examined, the shape of the pupil should be assessed. Synechiae persist even after resolution of the acute episode of uveitis.
The finding of uveitis helps to narrow the differential diagnosis of the nonocular findings. Potential causes of uveitis include infection, systemic inflammation, neoplasia, trauma, and idiopathic disease (Table 18-5). A systemic laboratory and radiologic workup is indicated for bilateral, recurrent unilateral, or severe unilateral cases; posterior ocular involvement; or suspicion of systemic disease based on a detailed review of systems, medical history, and physical examination.
TABLE 18-5. Differential diagnosis of uveitis.
While many lung infections can cause hilar adenopathy, some infections and other conditions can cause hilar lymphadenopathy with minimal parenchymal disease (Table 18-6).
TABLE 18-6. Causes of hilar lymphadenopathy often with minimal lung parenchymal disease.
The serum angiotensin-converting enzyme (ACE) level was elevated with a value of 75 U/mL. Biopsy of the axillary lymph node revealed noncaseating granulomas which confirmed the diagnosis of sarcoidosis.
INCIDENCE AND EPIDEMIOLOGY
Sarcoidosis, a systemic disease of unknown cause, is characterized by noncaseating granulomas; the term noncaseating refers to the absence of necrosis within the granuloma. The disease occurs more commonly in blacks (approximately 35 per 100 000 per year) compared with whites (approximately 10 per 100 000 per year). Sarcoid is less common in children than in adults. Most pediatric cases occur in adolescents, though toddlers are occasionally diagnosed with the disease.
The clinical presentation of sarcoid varies considerably because extrapulmonary symptoms often cause the most prominent symptoms of the disease. Common sites of involvement in children include the lungs, eyes, skin, and lymph nodes. The heart, liver, and spleen are occasionally involved. Initial symptoms are usually nonspecific with children complaining of fever, malaise, fatigue, and weight loss. Older children will typically present with multisystem disease, while younger children present with the early-onset form with a triad of uveitis, rash, and arthritis.
Pulmonary. Symptoms of pulmonary sarcoidosis may include cough, dyspnea, wheezing, and, occasionally, chest pain. However, up to one-half of patients with pulmonary sarcoidosis are asymptomatic; in these instances, the disease is detected incidentally on chest radiograph. Lung auscultation is usually normal; crackles are infrequently present.
Ocular. Uveitis refers to inflammation of the uveal tract, which consists of iris, ciliary body, and choroid. Anterior uveitis, or iritis, is one subtype and remains the most common ocular manifestation of sarcoidosis. Clinical symptoms of uveitis include eye redness, pain, photophobia, and sometimes decrease in vision, all of which may be absent in some children. Most patients with anterior uveitis have concomitant systemic symptoms. Up to one-third of patients with posterior uveitis may have no signs of anterior segment inflammation. Sarcoid may also manifest as conjunctival nodules which are visible in the inferior fornix by pulling down the lower eyelid.
Lymph nodes. One-half to two-thirds of affected children have peripheral or hilar lymphadenopathy. The peripheral lymph nodes are usually firm, nontender, and moveable.
Cutaneous. Skin lesions on the face are papular and red or brown in color. Skin lesions on the trunk and extremities are usually violaceous and plaque-like. Erythema nodosum may also occur; these nodules are erythematous and tender and appear on the anterior legs. Sarcoid granulomas, though more common in adults, occasionally manifest in children; these granulomas typically infiltrate sites of scarring (i.e., “scar sarcoidosis”).
Other sites. As occurred in the current case, cardiac sarcoidosis can cause left ventricular dysfunction and arrhythmias. Cardiac involvement is far more common in adults than in children with sarcoidosis. Hepatomegaly and splenomegaly may be present, but severe liver or spleen dysfunction is uncommon. Renal involvement is relatively uncommon in children with sarcoidosis. Joint involvement may lead to joint pain or effusions. Bone lesions are relatively uncommon but when present tend to involve the hands and feet. Neurosarcoid in children manifests with seizures in one-third of affected children; in contrast to adults with neurosarcoid, cranial nerve palsies are uncommon.
Slit lamp examination of the eye. Uveitis is diagnosed by examination of the eye with a slit lamp biomicroscope, which permits direct visualization of inflammatory cells floating in the anterior chamber, and a fundus examination. Synechiae with a resultant irregular pupil are not common, but when present are visible without a slit lamp. Severe inflammation may also cause a grossly visible, white crescent of aggregated cells in front of the inferior iris, termed a “hypopyon.” The red reflex may be dull or absent with anterior or posterior uveitis. All patients with suspected uveitis require a dilated fundus examination to check for findings such as optic disc swelling, chorioretinitis, or vasculitis, as well as to rule out a life-threatening malignancy, such as retinoblastoma. The finding of uveitis should prompt consideration of underlying systemic causes, including sarcoid.
Angiotensin-converting enzyme (ACE) level. ACE is produced in the epithelioid cells of granulomas; ACE levels are elevated in more than 75% of children with sarcoidosis. Epithelioid cells within the granulomas are thought to be the source of ACE. While ACE levels may decrease with corticosteroid therapy, ACE levels do not necessarily correlate with symptoms. Other conditions that may produce elevated ACE levels include leprosy, Gaucher disease, hyperthyroidism, and disseminated granulomatous infections such as miliary tuberculosis.
Biopsy. Biopsy is performed to confirm the diagnosis of sarcoidosis. While enlarged peripheral lymph nodes are the preferred source given their accessibility, biopsy of skin lesions, central lymph nodes (e.g., mediastinal), lung, liver, or bone marrow may be required if peripheral lymph nodes are not enlarged. Microscopic examination classically reveals non-caseating granulomas; noncaseating refers to the absence of necrosis within the granuloma. Biopsy should be performed on the most readily accessible site. In children, the yield from palpable peripheral lymph nodes is typically high. Microscopic examination should also be performed to exclude infectious causes (e.g., tuberculosis, histoplasmosis, blastomycosis). Conjunctiva may offer a less invasive biopsy option than other body sites if the child is old enough to undergo the procedure without the need for general anesthesia; the biopsy site heals quickly and there is minimal discomfort to the child. Some experts recommend a “blind” biopsy (i.e., no conjunctival nodules or follicles) which has a sensitivity of approximately 50% before pursuing more invasive procedures (e.g., biopsy of mediastinal lymph nodes).
Chest radiograph. Chest radiographs should be obtained in all children in whom sarcoidosis is a diagnostic consideration. The chest radiograph often reveals bilateral hilar lymphadenopathy and interstitial pulmonary infiltrates; nodular infiltrates have also been described. Serial chest radiographs are sometimes used to follow the course of lung involvement.
Pulmonary function testing. Approximately half of all affected children have evidence of restrictive lung disease.
Complete blood count. Anemia and leukopenia with eosinophilia may occur.
Other studies. Serum chemistries may reveal elevated blood urea nitrogen (BUN) and creatinine values as well as hypercalcemia. Urinalysis may reveal proteinuria and hematuria. Hypercalciuria may also be present. C-reactive protein and other inflammatory markers are usually elevated, though this is a nonspecific finding.
Uveitis is a sight-threatening condition, which requires prompt management by an ophthalmologist. Management of uveitis includes treating the underlying cause as well as the use of topical steroids, topical cycloplegic (dilating) drops, and systemic steroids; immunosuppressive, steroid-sparing agents may be required for recalcitrant cases. Collaborative management by pediatric ophthalmologists and rheumatologists is common and beneficial. Pediatricians should refer any child with a red eye and a history of uveitis for ophthalmologic evaluation to rule out recurrent disease. Vision-threatening complications include cataract, glaucoma, and macular edema.
Treatment of sarcoid with multisystem involvement typically includes systemic corticosteroids. Corticosteroid therapy (typically prednisone) continues until clinical manifestations improve; the corticosteroids are then tampered over a period of several months to the lowest dose that controls disease activity. Immunosuppressive agents such as methotrexate are used for steroid nonresponsive cases and when side effects of corticosteroids are not tolerated. Other immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, and antitumor necrosis factor alpha are less well studied in the treatment of pediatric sarcoidosis.
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