Index of Suspicion

[Alon]

Although IBD typically presents with gastrointestinal complaints, mucocutaneous lesions have been reported to occur in 15% to 44% of cases and, when present, can precede gastrointestinal symptoms.1,2,3,4 Gregory and Ho5 reviewed the mucocutaneous lesions of IBD and divided them into specific, reactive, and miscellaneous categories (Table 2).

Although uncommon in children, pyoderma gangrenosum is a common mucocutaneous feature of IBD. Typically, the early papulopustules or hemorrhagic bullae rapidly enlarge, become necrotic, and ulcerate. The ulcerations have a characteristic violaceous, undermined border (Fig 4). Lesions can occur on any part of the body but are most frequently located on the lower extremities. Pyoderma gangrenosum is characterized by pathergy (predilection for lesions in areas of trauma); thus, aggressive debridement must be avoided. Twenty percent of adult patients with pyoderma gangrenosum will have associated IBD.6 It is associated more commonly with ulcerative colitis than Crohn's disease, occurring in 5% to 12% and 1% to 2% of patients, respectively.3,5,7 Pyoderma gangrenosum is uncommon in children, with 4% of cases reported in children <15 years old.8 Although IBD is the most common underlying cause of pyoderma gangrenosum in children, pyoderma gangrenosum in children can be associated with several other systemic disorders including immunodeficiencies (primary and HIV related), leukemia, hepatitis, and arthritis.9,10 The occurrence of pyoderma gangrenosum preceding gastrointestinal symptoms in IBD has only been described in a few patients.6,8,11

Perianal lesions including skin tags, fistulas, fissures, and abscesses are characteristic of Crohn's disease and occur during the course of IBD in 60% to 82% of patients; however, 25% to 30% of patients show perianal lesions before gastrointestinal complaints.12,13 The majority of our patients with Crohn's disease (6 of 8), as well as our 1 patient with ulcerative colitis, were noted to have perianal lesions before gastrointestinal symptoms. It is interesting to note that the 2 patients with Crohn's disease who did not have perianal lesions had pyoderma gangrenosum as their initial finding. Of the patients with perianal lesions, in only 2 (patients 8 and 9) was the perianal lesion the presenting complaint. This suggests that perianal lesions may often be present before gastrointestinal complaints but are less often brought to the attention of the physician, especially in adolescent boys.

Although not as well documented, oral lesions associated with IBD are relatively common, occurring in 6% to 20% of patients.14 When present, they are the presenting sign/symptom in approximately one half of cases.1,4,15–1617 In addition, more recent reviews have found an increased prevalence of various oral lesions in IBD, particularly in children. Barnard and Walker-Smith found that 80% of pediatric patients with Crohn's disease and 41% of children with ulcerative colitis had oral lesions in their series of patients.18 In reviews by Pittock et al19 and Plauth et al,4 48% and 66% of patients with Crohn's disease, respectively, were found to have oral manifestations, with an increased prevalence in children.

A variety of specific and nonspecific oral lesions can occur (Table 3). Differences in the percentage of patients with IBD described with oral lesions may relate to specific versus nonspecific oral findings reported. Aphthous ulcers are considered by many to be nonspecific, as they can be seen in up to 20% of the general population; however, aphthae are usually more extensive and persistent when associated with IBD.15 The descriptive term "orofacial granulomatosis" has been used for any granulomatous process of unknown etiology involving the oral cavity,16 which includes disorders previously described as granulomatous cheilitis and partial Melkersson-Rosenthal syndrome. Orofacial granulomatosis is a common manifestation in children with IBD and is typified by recurrent or persistent swelling of the lips, cheeks, gingiva, or oral mucosa with characteristic noncaseating granulomas on histologic examination. Many patients with orofacial granulomatosis do eventually develop gastrointestinal disease consistent with Crohn's disease.20,21 "Cobblestoning" refers to nodular granulomatous swellings that result in a cobblestone appearance of the oral mucosa, particularly on the labial and buccal mucosa. Along with mucosal tags, cobblestoning is highly suggestive of Crohn's disease. Pyostomatitis vegetans, on the other hand, is more characteristic of ulcerative colitis. It is characterized by multiple pustules, erosions, and ulcers on a diffuse erythematous background with vegetations or folding of the gingival and buccal mucosa. Deep, linear ulcers surmounted by hyperplastic folds occur in the gingival sulci and are also specific for IBD.

Genital findings associated with IBD are also more common in Crohn's disease and in children.1 Genital involvement includes vulvar swelling, skin tags, pustules, abscesses, fistulas, fissures, ulcerations, and vaginal discharge.22 Penile and scrotal lesions are less common and include subcoronal ulcers as well as penile and scrotal edema.23 Twenty-five percent of genital Crohn's disease presents before gastrointestinal complaints.1

Although there are few cases reported in the pediatric literature, mucocutaneous lesions presenting as the initial sign of IBD is relatively common and can be an important clue in making the diagnosis of IBD before the development of gastrointestinal symptoms. We have identified 9 pediatric patients with asymptomatic IBD presenting with mucocutaneous lesions. The majority of these patients had oral and/or perianal lesions. Because oral disease, in general, is uncommon in children, we believe that IBD is a common etiology for persistent oral lesions in the pediatric population. Children and adolescents with unexplained oral mucous membrane lesions such as lip/mucosal swelling, gingival hyperplasia, cobblestoning of the oral mucosa, or deep linear ulcerations should have a good history taken regarding gastrointestinal symptoms, fever, and weight loss as well as an examination of the rectal and genital mucosa to seek other mucocutaneous clues of IBD that may not be mentioned to the physician. We would also recommend additional work-up including complete blood count, iron levels, ESR, albumin, occult blood in the stool, and serial endoscopies with biopsies to aid in the diagnosis if suspicions are high.
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К сожалению, для таблиц и фотографии нет места.

[Alon]

"The time is out of joint": Pain, paresthesias, and weakness in a preadolescent

Your patient is a 10-year-old Latino girl brought to the clinic by her very concerned mother. The complaint is leg and joint pain—severe enough to make walking difficult. The visit comes after your colleague at the clinic saw the girl about a month ago for an unusual rash described in the record as a brownish, linear, papular eruption, possibly urticaria pigmentosa. He prescribed hydroxyzine.

Three weeks later, you read, your colleague saw the girl again, this time for a complaint of pain in the left wrist, symptoms of a common cold, and a barky cough of approximately two weeks' duration. She complained that she was feeling generally tired. He prescribed azithromycin for suspected Mycoplasma infection. Examination of the hands and arms was unremarkable. He instructed the mother to watch for joint swelling.

QD: Pain and a long nap

Now, five days after that last visit, the patient has returned with pain in the back, legs, and small joints of the fingers. Walking is difficult, she tells you. There is still a slight cough. She does not have a fever and does not complain of a sore throat or ocular or urinary symptoms. There is no nausea, vomiting, diarrhea, or constipation.

The girl denies weight loss or diminished appetite. She does complain of generalized fatigue and increased sleepiness: She takes a three-hour nap every day after school! You begin by taking the history.

Your patient is in the fourth grade and, her mother reports, is a good student. She lives with her mother and a younger, school-age brother. Her parents have been separated for about nine months; the father is involved in his children's life on an almost daily basis, the mother reports. She denies a history of domestic violence in the family.

The medical history is noncontributory. The girl was delivered at term. She has no history of hospitalization, surgery, or serious illness; has been fully immunized; and does not have known drug allergies. Hydroxyzine and azithromycin are her only medications over the past several months. She has had no recent exposure to ticks, has not been camping, and has not traveled recently. She has had no recent illnesses other than "colds" and "coughs" and no gastrointestinal problems.

The family history is positive for osteoarthritis on the maternal side, and a maternal grandmother who has rheumatoid arthritis.

On physical examination, your general impression is of a well-nourished, well-developed, slightly obese girl who is not in acute distress. The earlier rash over the left forearm is barely noticeable.

Height is at the 50th percentile for age; weight, between the 75th and 90th percentiles. Vital signs are unremarkable: Blood pressure, 107/59 mm Hg; pulse, 69/min; temperature, 97.3°F; and respiratory rate, 22/min. The ear, nose, and throat exam is benign. Oral mucosa is moist and without lesions. There is no conjunctival injection. Bilateral red reflexes are clear. Heart sounds are normal; no heart murmur is heard. Breath sounds are clear. The abdomen is soft and nontender; bowel sounds are present; and you do not palpate any masses or hepatosplenomegaly.

The genitalia are normal and Tanner Stage I. You note no cervical, axillary, or inguinal lymphadenopathy. The neck is supple without thyromegaly.

The patient expresses pain in the metacarpophalangeal and interphalangeal joints of both hands and describes pain in almost all other joints—neck, spine, and large and small joints of the extremities, including shoulders, hips, elbows, and knees. On thorough examination of those joints, you cannot detect swelling, erythema, effusion, or increased warmth over the skin—the tenderness she expresses over the metacarpophalangeal and interphalangeal joints by palpation notwithstanding. The pain is elicited in all small finger joints by passive motion, by wrist movements, and by examination of the large joints of the lower extremities, including knees and hips. She appears to have hyperflexible finger joints. Gait is guarded but there is full range of motion in all joints.

Much pain, no findings

You know that joint complaints are common in children and, in most cases, transient. Arthritis, defined as swelling of a joint or limitation of motion accompanied by heat, pain and tenderness, is much less common than arthralgia (simple joint pain). Disorders of periarticular inflammation may mimic arthritis.


Causes of arthritis and periarticular disorders

A number of thoughts come to mind about the differential diagnosis (see the table - не включена, Алон) in this patient—thoughts that are confounded by the constellation of symptoms. Could this be juvenile rheumatoid arthritis? Should you consider connective tissue disease, such as systemic lupus erythematosus (SLE)? Lack of a true arthritis or systemic or constitutional symptoms (other than the fatigue), plus the absence of fever, however, cast doubt on these possibilities.

What about inflammatory bowel disease, which can present with arthritis? Even if swelling of a joint were documented, it would likely affect only a few large joints—not all joints of the body.

Chronic active hepatitis can present with arthralgia, confined to single joints, but often several joints are involved, usually the large ones.

A migratory polyarthritis may be seen in mycoplasmal infection; this is an interesting possibility, considering that the girl has had a cough and a urticarial rash, although an atypical one.

What about Sch?nlein-Henoch purpura? The rash associated with this vasculitis of unknown cause—purpuric, petechial, or, occasionally, urticarial—is characteristic and most prominent on the lower extremities, although it sometimes occurs on the arms and face, and rarely, on the trunk. Arthralgias, with periarticular swelling involving a few joints, occur in approximately 40% of cases. Abdominal pain, nephritis, hypertension, and unusual areas of edema are common. Your patient's mother insists that she has noted intermittent swelling of her daughter's hands and feet, but you cannot appreciate this or other symptoms of Sch?nlein-Henoch purpura.

Hypermobility syndrome? Alone, this is not likely to affect all joints of the body at the same time.

Hypersensitivity arthritis—so-called serum sickness—caused by a drug or virus and accompanied by joint swelling, is a possibility. The condition can also be associated with edema of the hands and feet and urticarial rash.

Reactive arthritis after pharyngitis or gastrointestinal infection crosses your mind. This can involve single or multiple joints, and can be migratory. Other than the cold that the mother reported early this month, the girl has not had a sore throat or any GI problems.

Your diagnosis, for now, is generalized arthralgia, possibly postviral or of other infectious cause. You turn to basic laboratory work: complete blood count, erythrocyte sedimentation rate, C-reactive protein, comprehensive metabolic profile, urinalysis, antinuclear antibody titers, rheumatoid factor, anti-streptolysin O titer, and parvovirus titers. You also order radiographs of the hands and both hips.

You advise ibuprofen for pain and recommend follow-up in one week.

Most of the lab results arrive on a Friday afternoon. Other than an elevated anti-streptolysin O (ASO) titer of 718 and a positive antinuclear antibody (ANA) titer of 1:160 in a speckled pattern, the tests are normal, including an ESR of 12 mm/hr and C-reactive protein <0.4 mg/L. Some nitrates are noted on urinalysis. The metabolic profile shows that liver function is normal; only the CO2 is slightly low at 18.6 mEq/L. All films are read as normal by the radiologist.

In light of the elevated ASO titer, you elect to treat the girl with a 10-day course of amoxicillin—lack of evidence of poststreptococcal arthritis notwithstanding. When you call the mother with results, she reports that the girl's pain is intensifying, and you also prescribe acetaminophen with codeine for relief over the weekend.

"Born to set it right"?

Your patient returns to the clinic on Monday. She is now unable to walk well without assistance and is brought into your office in a wheelchair! She complains of dizziness, and tells you that she has had "a hard time breathing" and that "it hurts to cough."

Such an abrupt change in mobility is of major concern. You consider other explanations. Is the pain of muscular origin—myalgias or myositis? Perhaps this is dermatomyositis or scleroderma—given the history of an unusual linear-looking rash and pain on palpation over the extremities.

[Alon]

As for the cough and, now, shortness of breath, and the increasing weakness of the extremities and truncal musculature, you wonder: Is this true weakness or pain-induced? The mother reports that the patient is unable to sleep supine and has to be propped up in bed. You do not elicit any new findings on the physical exam—no joint swelling or erythema of the skin—but she is complaining of pain in all joints upon even minimal movement, to the point that it is difficult to examine passive range of motion without causing excruciating pain. She can move her legs but minimally; arm movements are limited. She expresses numbness and tingling of the hands. She now complains of intermittent swelling of the hands and feet.

The patient does not complain of dry mouth or difficulty swallowing; likewise, no dry eye or any other ocular symptoms. She does have episodes of shortness of breath and chest pain, particularly at night but also at school today. The school nurse notified the mother about this development, which was the occasion for today's visit. There is no abdominal pain or burning upon urination. No genital ulcers. Mother reports no depression, anxiety, or sleep disturbance.

As for the skin, the patient denies tightness, hair loss, or nodules. She does complain that her skin is pale, cold, and sweaty, and that her hands and feet at times become reddish or livid. Raynaud disorder comes to mind, but she has good peripheral pulses, distal extremities are pink, and skin is warm to the touch. You note two long, narrow, parallel track-like lesions along the lateral aspect of the left forearm, about one centimeter apart and reaching above the left elbow. They are barely palpable and have turned whitish.

Overall, you observe few objective findings. The lungs are clear to auscultation, and she is not in respiratory distress. Breath sounds are equal bilaterally. Heart sounds are not distant; no murmur or friction rub is noted. You have no reason to suspect pleuritis or pericarditis, which might explain the shortness of breath and chest pain. Oxygen saturation is 96% at room air; respiratory rate, 20/min.

You are puzzled—very much so. Because of her pain, you have a difficult time performing the neurologic exam, and find it impossible to assess deep-tendon reflexes. The Babinski sign is absent. Cranial nerves are grossly intact.

Confusion compounded

You order tests of anti-double stranded (DS) DNA, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH); repeat urinalysis and urine culture; and a chest radiograph and electrocardiogram. The chest radiograph shows mild peribronchial thickening. The ECG is normal for age. The CPK level is normal at 55 U/L; LDH is normal at 152 U/L; and the anti-DS DNA is 227 U/mL (positive, >120 U/mL). Urine culture of a clean-catch specimen grows >100,000 gram-negative bacilli. Parvovirus B19 titers come back with no significant level of detectable IgG or IgM antibodies. You suspect SLE now, but can't confine yourself to that diagnosis because of the normal ESR and acute-phase reactant levels.

You decide to refer your patient to a rheumatologist within the larger network of a children's hospital. There, your patient spends four days as an inpatient in a general pediatric ward. Lab tests are repeated; the ANA and anti-DS DNA tests are normal. That's somewhat of a surprise: The specificity of the ANA test is low enough to be elevated even in a healthy person or by transient causes. Considering the initial titer of the anti DS-DNA and the context of the case overall, you conclude that the ANA result is most likely laboratory error.

Other lab results arrive: The ASO titer is 800 IU/mL (normal, <200 IU/mL), and the LDH is 504 U/L—both elevated for age. Urine culture grows Escherichia coli, and the patient is treated accordingly.

A purified protein derivative test is placed and recorded as 9 mm in diameter—considered positive given that, by the history, there are several possible exposures to tuberculosis, including her great-grandfather, who had been given a diagnosis of drug-resistant tuberculosis earlier in the year. But this is later judged to be a nonsignificant contact because your patient had not been in direct contact with him. A repeat chest radiograph is normal. The girl is referred to the health department of her county of residence for treatment of latent tuberculosis infection with INH prophylaxis.

The rheumatologist's general impression is that the arthralgia is likely viral or postinfectious. She cannot rule out a later-manifesting malignancy, such as leukemia.

During the hospitalization, the patient experiences significant paresthesias and pain—at times so extreme that she cannot tolerate the weight of a bedsheet. An opiate analgesic is prescribed, from which she is weaned before discharge. The judgment of the team is that, throughout her stay and in contrast to her pain, she appears comfortable and happy—raising the question of a somatization disorder. She is able to walk a few steps, with support, during hospitalization but requires a wheelchair at discharge.

Symptoms waxing and waning and still unable to walk more than a few steps, your patient shows up at your office for post-discharge follow-up. No more complaints of difficulty breathing. No pain any longer in the arms. No swelling of joints or rash noted, and no fever. She seems stable and tells you that she doesn't need the anti-inflammatory medications at the moment.

You take a deep breath yourself—a pain-free one.

"O cursed spite!"

To your surprise, the girl returns to see you only five days later, complaining that she "feels worse." Pain has intensified in her arms, hips, and back. She complains of numbness of the legs although there is no loss of bladder or bowel control. She denies headache or blurred or double vision. She cannot walk.

You perform a neurologic exam, but you cannot elicit any clear corresponding objective findings and are at a loss to explain the waxing and waning of symptoms. You begin to think of possible psychosomatic or psychiatric disorders: Neurasthenia? Fibromyalgia? Psychogenic pain as a part of a conversion reaction? You cannot identify stressors in the history other than her parents' separation nine months ago; when questioned, mother and patient deny, for a second time, any domestic violence or significant psychogenic trauma. Could this be a case of atypical Guillain-Barr? syndrome, with paresthesias and hyperesthesias predominant, or a course of the syndrome with a pseudomyopathic picture, with waxing and waning symptoms in this chronic inflammatory neuropathic disorder?

That's not your gut feeling so far into the case, however; something among the pieces just does not fit. You call a colleague who is a neurologist and request consultation. He reviews the case and is most inclined to entertain Guillain-Barr? syndrome rather than vasculitis—especially in light of progressive ascending paresthesias and neuropathic pain. Upon examination, lower-extremity strength is 3/4 of 5. Deep-tendon reflexes are absent and toes are down-going. His plan is to obtain a magnetic resonance imaging scan of the brain and complete spine. He'll also perform electromyography (EMG) and nerve conduction-velocity studies. He decides to start the patient on gabapentin (Neurontin).

Needle EMG cannot be performed because the patient cannot tolerate the test. Nerve conduction-velocity studies are normal, as are all neuroimaging findings. Lumbar puncture is deferred.

The neurologist prescribes water physiotherapy twice a week, which, over the next two weeks, seems to improve the patient's mobility and relieve her pain. She still requires the use of a wheelchair but can move her legs somewhat, and can readily use her arms to push herself around.

Meanwhile, repeat tests of inflammatory markers all return normal. As for cytomegalovirus and Epstein-Barr virus titers, IgG antibodies are detected in low titers for both viruses and IgM antibodies are absent—a combination that makes recent infection unlikely. CMV and EBV titers are not retested.

Can it get worse?

Approximately eight weeks after the onset of her illness, your patient returns to see you. She complains of feeling poorly again. The pain in her arms, legs, and back is worse. She cannot move her right arm and must eat and write with her left hand. She again has experienced difficulty breathing at night. She had been to the neurologist two days earlier for follow-up; he prescribed a course of high-dose steroids for possible vasculitis. However, you recommend to the mother to hold off steroids because there is insufficient diagnostic evidence for vasculitis. Your rheumatology colleague at the children's hospital network agrees with your action. You express suspicion that the team could be dealing with a conversion reaction because no consistent evidence of physical illness has manifested during eight weeks of follow-up. You agree to admit the patient to the hospital again but under the rheumatology service, with neurology and psychiatry services in consultation.

Faced with a two-week wait for inpatient placement for the girl, you conclude that skin biopsy from the chronic rash might be helpful to rule in or out possible vasculitic changes. The biopsy is interpreted as chronic folliculitis with negative immunofluorescence.

You approach the mother about the possibility that her daughter's symptoms are psychological. She finds that difficult to accept, however, and prefers a somatic explanation for her daughter's illness.

[Alon]

Mind, not matter

At the girl's second hospitalization, opinion coalesces that her illness is not rheumatologic, and she is admitted under the neurology service. Investigation reveals total anesthesia below L5, although the balance of the sensory and motor exam is inconsistent with that finding and does not fit any neurologic distribution. Although some features suggest a psychosomatic disorder, chronic inflammatory neuropathy cannot be excluded.1,2

The patient does not appear in distress or concerned during the investigation, and again seems content and calm. She is easily suggestible. Once provided with stepwise recommendations for regaining her health, and sensation and mobility in her extremities, she improves in a short time and is discharged after six days, having made a full recovery.3

The neurology and psychiatry services' conclusion is that her parents' separation has been a significant stressor for the girl—especially because she has a close relationship with her father.4 Notably, approximately one year before the patient exhibited symptoms, her maternal uncle was paralyzed from the neck down in a car crash and is in a wheelchair. How much, you are left to wonder, might this event have unconsciously influenced her symptom "selection"?

Things are set right again

Your patient does well, without relapse, after psychological counseling and pediatric follow-up. At the beginning of a new school year, she is eager to return to the classroom.

This case illustrates the need to suspect a conversion disorder in children when the neurologic or somatic outline is difficult to clarify and all instrumental and clinical laboratory tests do not support a precise pathologic pattern or disease entity. Further exploration of behavioral or emotional problems and other stressors can be the missing key to the diagnosis.
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DR. ESTEP is an assistant professor of pediatrics at Texas Tech University Health Science Center

[Alon]

A 10-month-old boy presents to the ED with a 1-day history of poor feeding and a fluctuating level of consciousness. There has been no fever, vomiting, diarrhea, or cough.

On physical examination, the child looks ill and mottled. His temperature is 101.5°F (38.6°C), heart rate is 180 beats/min, respiratory rate is 60 breaths/min, blood pressure is 70/40 mm Hg, and oxygen saturation is 86% in room air. He requires 10 L of oxygen to maintain his oxygen saturation above 95%. His heart sounds are normal, capillary refill is 3 seconds, and femoral pulses are weak. Both lungs are clear, and the liver is palpable 5 cm below the right costal margin. The remainder of the physical findings are normal.

The patient is given a 20-mL/kg bolus of normal saline intravenously as well as ceftriaxone. The hypotension does not improve. Initial laboratory findings are: WBC count, 66.4x103/mcL (66.4x109/L) (polymorphs 64%, bands 15%, lymphocytes 10%); Hgb, 1.06 g/dL (106 g/L); and platelets, 848x103/mcL (848x109/L). The bedside glucose value is normal. Venous gas measurements include: pH, 7.23; PCO2, 42 mm Hg; bicarbonate, 17 mEq/L (17 mmol/L); and base excess, –9 mmol/L. Serum lactate is 72.1 mg/dL (8.0 mmol/L). A chest radiograph reveals a small left-sided infiltrate, a small pleural effusion, and a normal heart size. ECG shows small voltages, ST segment elevation in leads V2 through V5, and electrical alternans. A diagnostic test is performed.
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Cardiac involvement was suspected on initial assessment when the liver was noted to be enlarged. Furthermore, the child did not respond clinically to the fluid bolus, as would be expected in hypovolemic shock or septic shock without cardiac involvement. The electrocardiographic findings were highly suspicious for cardiac tamponade, and a bedside echocardiogram revealed a large pericardial effusion measuring 3 cm in diameter. Pericardiocentesis yielded 60 mL of purulent pericardial fluid, after which the patient’s blood pressure and perfusion improved almost instantaneously. Subsequent blood and pleural fluid cultures grew Streptococcus pneumoniae.

Differential Diagnosis
This child presented with a fluctuating level of consciousness and was found to be in shock on initial assessment. The differential diagnosis of his clinical picture is broad and includes septic shock, hypovolemic shock, hemorrhagic shock, cardiogenic shock, neurogenic shock, toxic ingestion, and nonaccidental injury. Echocardiography demonstrated the cause of this child’s shock to be cardiac tamponade from a large pericardial effusion.

Acute pericarditis with pericardial effusion in children can be caused by bacterial infection, viral infection, collagen vascular disease (systemic lupus erythematosus), malignancy, metabolic disease, or postpericardiotomy syndrome. In some cases, no cause can be found. Bacterial (purulent) pericarditis in childhood is caused most commonly by Staphylococcus aureus. The next most common pathogens are Neisseria meningitidis, Haemophilus influenzae, and S pneumoniae.

Pathogenesis
Patients who develop bacterial pericarditis are found frequently to have preceding or concurrent infections, including pneumonia, osteomyelitis, meningitis, septic arthritis, pyomyositis, and pyelonephritis. This child had radiographic evidence of pneumonia with a small pleural effusion. Bacteria are believed to invade the pericardium by direct extension from the neighboring pleura or lung or from transmission through the blood from another infected site. In some cases of meningococcal meningitis, an immunologically induced antibody response to the bacterial infection causes inflammation and fluid accumulation within the pericardial space. The discovery of pericarditis several days after the onset of infection and the absence of bacteria in the pleural fluid supports this mechanism.

Clinical Presentation and Diagnosis
Pericardial effusion with tamponade is diagnosed clinically by signs such as tachycardia, hypotension, elevated jugular venous pressure, muffled heart sounds, hepatomegaly, narrow pulse pressure, and pulsus paradoxus (systolic blood pressure during inspiration is lowered markedly). A pericardial friction rub may be present as well, but is less common in larger effusions where the large amount of fluid prevents friction. The presence of an enlarged cardiac shadow on chest radiography is supportive, as are the ECG findings of low voltages, raised ST segments, and when cardiac tamponade is present, electrical alternans. Electrical alternans, defined by the QRS amplitude increasing and decreasing on alternate beats, is caused by the beat-to-beat swinging motion of the heart with large pericardial effusions (Figure). Definitive diagnosis is made by echocardiography, which is safe, rapid, and noninvasive and has a high degree of sensitivity for the detection of pericardial effusion. The hallmark of the echocardiographic diagnosis of pericardial tamponade is diastolic collapse of the atrial and ventricular walls.

Treatment
Bacterial pericarditis is treated with specific antibiotics, which should be selected to target the suspected organism. Associated infection or illness can provide guidance in the selection. Pericardiocentesis is indicated to relieve the symptoms of cardiac tamponade. Rapidly accumulating effusions are more likely to present with symptoms. Pericardiocentesis also is useful for diagnostic purposes; pleural fluid can be sent for cytologic and biochemical analysis as well as culture for bacteria, fungi, and viruses. Except in emergencies, this procedure should be performed by a cardiologist, cardiovascular surgeon, or thoracic surgeon under echocardiographic guidance. Diuretics are contraindicated in the setting of symptomatic cardiac tamponade because the cardiac output is highly dependent on ventricular filling. By the same token, endotracheal intubation and mechanical ventilation can cause an acute decrease in ventricular filling that may lead to sudden cardiac arrest.

Conscious sedation and analgesia are recommended when performing pericardiocentesis. Under aseptic conditions, an 18-gauge needle is attached to a three-way stopcock and a 50-mL syringe. The needle is inserted just under the xiphoid process, directed toward the left shoulder tip, and advanced with constant suction. The heart should be monitored during the procedure, enabling the detection of arrhythmias that may occur when the myocardium is touched. Other techniques have been described in the literature, including subxiphoidal tube drainage and irrigation with thrombolytics, as well as pericardiectomy. Pericardiectomy usually is reserved for patients who have loculated effusions or recurrent pericarditis and are at higher risk for constrictive pericarditis.

Lessons for the Clinician
When a patient presents with clinical signs of shock, the clinician should examine the patient carefully for signs of cardiac tamponade. If clinical signs are present, immediate chest radiography should be performed to determine heart size and an ECG obtained to assess for small voltages, ST segment changes, and electrical alternans. Echocardiography is essential for definitive diagnosis and for facilitating guided pericardiocentesis to relieve cardiac tamponade.


Adam Cheng, MD
Jennifer Russell, MD
The Hospital for Sick Children, Toronto, Ontario, Canada

[Alon]

A 19-month-old girl is brought to the ED because of abdominal pain for the last week, fever for 5 days, and crying on urination together with constipation for 2 days. She had passed several watery stools without mucus or blood prior to the last bowel movement.

On physical examination, the girl appears uncomfortable and mildly dehydrated. Her temperature is 103.1°F (39.5°C), pulse is 148 beats/min, blood pressure is 121/78 mm Hg, and respiratory rate is 28 breaths/min. She has diffuse abdominal tenderness and mild distention without guarding or rebound. Her bowel sounds are normal, and no hepatomegaly or splenomegaly is noted.

The WBC count is 26.8x103/mcL (26.8x109/L), with 77% neutrophils, 5% bands, 13% lymphocytes, and 5% mononuclear cells. Her Hgb is 10.6 g/dL (106 g/L), Hct is 31.3% (0.31), and platelet count is 666x103/mcL (666x109/L). The child has normal serum concentrations of sodium, potassium, chloride, urea nitrogen, creatinine, and glucose. Findings on urinalysis are normal. A radiograph of her abdomen shows dilated loops and fecal material throughout the colon. An imaging test leads to the correct diagnosis.
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Abdominal CT revealed a complex cystic mass involving much of the pelvis. The mass was predominant on the left side but also contiguous with the cecum. This mass represented an abscess that had formed from a ruptured appendix. Evidence of mild hydronephrosis and hydroureter on the left, probably due to the pelvic mass, also was seen. Triple antimicrobial therapy with gentamicin, metronidazole, and ampicillin was initiated and continued for 5 days. Repeat abdominal CT showed a persistent pelvic abscess compressing the rectum. The child underwent transanal drainage of the abscess and was scheduled for elective appendectomy.

Differential Diagnosis
Acute abdominal pain is a common complaint in children. Children, especially young children, are poor at localizing pain to an abdominal quadrant. Therefore, a wide range of possible disorders needs to be considered. The causes of abdominal pain are age-related.

Intussusception occurs typically in infants between approximately 6 months and 2 years of age. The clinical presentation is characterized by attacks of colicky abdominal pain, during which the child draws up the legs, followed by periods of relaxation and sometimes profound somnolence. During the colicky episodes, the child appears pale and returns to having normal color when the pain passes. Currant jelly stools are passed by about 33% of patients and represent mucosal injury. Failure to pass a bowel movement at the usual interval also can occur. On abdominal radiographs, a mass lesion can be seen indenting the colon, with or without signs of bowel obstruction. Plain radiographs also may appear normal in this disorder.

Acute gastroenteritis is the most common diagnosis recorded when appendicitis is missed. The child presents with vomiting, diarrhea, and abdominal pain. The diarrhea may be preceded by severe abdominal pain and abdominal wall rigidity, mimicking acute abdominal inflammation. Bloody stools may cause further confusion because this picture mimics intussusception. Although enteritis due to Yersinia enterocolitica or Y pseudotuberculosis has been named "the great imitator" of appendicitis, affected patients usually have substantial diarrhea.

The symptoms of bowel obstruction include bile-stained vomiting, pain, and abdominal distention, with a paucity or absence of bowel gas distal to the level of the obstruction. In children, the site of the obstruction almost always is in the small bowel. Causes of obstruction include incarceration of a hernia, postoperative adhesive obstruction, malrotation, volvulus, and a Meckel diverticulum causing volvulus or intussusception. Radiologically, the typical pattern of a bowel obstruction is distended loops of bowel proximal to the obstruction, absence of gas distally, and multiple short air-fluid levels, often referred to as a "ladder" pattern.

Appendicitis also can mimic urinary tract infection. Caution must be exercised in interpreting findings on urinalysis because mild pyuria, hematuria, and bacteriuria can be present if an inflamed appendix is located adjacent to a ureter or to the bladder.

Pain may be associated with abdominal masses, with constipation, or less often, with anuria if the mass obstructs the bladder outlet. Imaging is required to identify the originating organ of the mass, to determine its nature (solid or cystic), and in the case of malignant lesions, to aid tumor staging. Ultrasonography usually can identify the organ of origin.

Children who have mesenteric adenitis present with abdominal pain that may be severe, which raises concern about a disorder requiring surgery, especially appendicitis. Often, there is a preceding history of upper respiratory tract infection. There may be recurrent attacks. Abdominal radiographs show normal results. Ultrasonography reveals enlarged (>1 cm) nodes around the root of the mesentery, occasionally with edema of the mesentery.

Signs and symptoms of inflammatory bowel disease include abdominal pain, weight loss, diarrhea, and the passage of bloody stools. Although adolescents and young adults between 15 and 35 years of age are affected most often, the disease has been diagnosed in infants as young as 18 months of age.

Henoch-Sch?nlein purpura (HSP), a common vasculitic disease affecting children between 2 and 8 years old, results in a constellation of findings, including a purpuric rash occurring on the lower extremities, abdominal pain, renal involvement, and arthritis. However, any of the components may be absent, which often leads to confusion in diagnosing the condition. The second most frequent element of HSP is colicky abdominal pain, which occurs in up to 65% of cases and may be severe and associated with vomiting. The pain may mimic that of acute intraperitoneal inflammatory disease.

Incarcerated hernias usually present with irritability from abdominal pain. Otitis, pharyngitis, and upper respiratory tract infections may present with abdominal pain. Right basal pulmonic consolidation can refer pain to the abdomen. Food poisoning and sickle cell pain crisis commonly present with abdominal pain; in these cases, however, a previous history can narrow the search.
The Condition
Appendicitis is the most common abdominal surgical emergency in infants and young children, but rarely is it considered in children younger than 3 years of age.
In young children, the typical history seldom is obtained. Because the disease can progress rapidly and escape detection, the child often presents with pyrexia and poorly localized abdominal pain, frequently with signs of septicemia, peritonitis, and bowel obstruction. If a pelvic abscess already has developed, diarrhea may be the presenting complaint. Children younger than 2 years of age usually have diarrhea as a primary symptom. Children who have a retrocecal appendix may present with right upper quadrant or flank pain. Due to the difficulty in evaluating these young patients who have abdominal pain, the perforation rate is higher (30% to 65%) than in adults. Because the omentum is less developed in children, perforations are less likely to be "walled-off" or localized, leading to generalized peritonitis.
Laboratory Findings
Leukocytosis and an increased concentration of C-reactive protein usually are present. WBCs may be present in the urine and cause confusion by suggesting urinary tract infection. If the clinical and hematologic findings are sufficiently typical, no radiologic investigation need be undertaken
Radiologic Assessment
Positive radiographic findings include the presence of a fecalith in the RIF (in approximately 30% of cases) and a localized ileus with mildly dilated loops of bowel. As sepsis advances, the properitoneal fat line blurs. Free air in the abdomen (pneumoperitoneum) is not a typical feature of a perforated appendix because the inflammatory mass prevents release of the luminal gas. A subphrenic abscess may occur if the sepsis is untreated and is seen as an air-fluid level in the subdiaphragmatic region.
CT of the pelvis and RIF, especially an intravenous contrast-enhanced procedure, with or without colonic contrast, is a useful and sensitive technique for identifying an inflamed appendix. A calcified appendicolith is well demonstrated by CT, as are postoperative fluid or pus collections.
On ultrasonography, the normal appendix appears as a tubular structure with a maximum transverse diameter of 6 mm located in the RIF, with good visualization of all layers of the bowel. The appearance of an abscess depends on the stage of evolution, but an abscess usually appears as an area of mixed solid and fluid echoes in the RIF. When there is rupture and peritonitis, abscess collections may be found in the pelvis or the subhepatic or subphrenic region.
Management
When perforated appendicitis is suspected, preoperative broad-spectrum antibiotic therapy is indicated because of the high morbidity that results from intra-abdominal abscess, peritonitis, and wound infection. Appendectomy is performed with or without drainage of the peritoneal cavity, and antibiotics are continued for 7 to 10 days. Occasionally, a localized abscess is treated with antibiotics with or without open or percutaneous drainage, with appendectomy scheduled as an elective procedure in 4 to 6 weeks. Children who have nonperforated appendicitis require minimal preoperative preparation with intravenous fluids and antibiotics. Although the use of antibiotics in uncomplicated appendicitis is controversial, it has decreased the incidence of postoperative wound infections.

MD
John H. Stroger, Jr
Hospital of Cook County, Chicago, Ill

[Alon]

A 17-year-old Caucasian girl is admitted to the hospital because of pain, swelling, and redness of her left leg for 6 months, with occasional low-grade fevers.

Previously, cellulitis had been diagnosed and antistaphylococcal antibiotics prescribed on more than one occasion, with temporary improvement. Cultures of the cellulitis had yielded Staphylococcus aureus sensitive to all antistaphylococcal antibiotics. CBC, ESR, liver and renal function tests, calcium, phosphorous, antinuclear antibody (ANA), rheumatoid factor (RF), and blood cultures resulted in normal or negative findings. Radiographs of the pelvis, hip, femur, knee, tibia, fibula, ankle, and lumbosacral spine, as well as a venogram and bone scan, were interpreted as normal. Arthrocentesis yielded normal results. Additionally, she had been admitted repeatedly for strict bed rest, elevation of the extremity, and intravenous antibiotics, with no sustained resolution of swelling, redness, or pain.

She had been traveling to various islands of the western Pacific as a member of a soccer team prior to the onset of her symptoms.

Physical findings today are normal, with the exception of redness, pain, and warmth over the left calf and anterior portion of the lower left leg, with pitting edema involving the calf, pretibial region, ankle, foot, and knee area, although results of the knee examination are normal. Pulses and strength are normal.
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This patient had experienced numerous episodes of disease in her left lower leg that involved variable degrees of swelling, erythema, warmth, and pain. Her clinical picture suggested both inflammation of unknown cause and secondary infection. To complicate the picture, she demonstrated features of chondromalacia of the left patella, which the clinicians thought might be related to the lower extremity disease, perhaps through infection. The differential diagnosis included cellulitis, septic arthritis, osteomyelitis, thrombophlebitis, collagen vascular disease, necrotizing fasciitis, pyomyositis, compartment syndrome, immunodeficiency, venomous insect or snake bite, and lymphedema.

By the time of admission to this hospital, an extensive evaluation had been completed, eliminating many of the diagnoses on the list, including septic arthritis (negative arthrocentesis), chronic osteomyelitis (negative radiograph, bone scan, and blood culture), thrombophlebitis (negative venogram), and collagen vascular disease (negative RF and ANA and normal ESR).

With necrotizing fasciitis, progression should be more acute. Signs and symptoms of pyomyositis should progress and by 6 months would require surgical management for resolution. With compartment syndrome, there should be a history of pain on exercising. Immunodeficiency is unlikely given the onset of symptoms at age 17 years and absence of risk factors for human immunodeficiency virus. There was no history of snake or insect bite.

One other important diagnostic consideration is lymphedema. This finding can occur in lymphedema praecox (Meige disease), which is a primary lymphedema with onset in adolescence and usually is a diagnosis of exclusion. In addition, several secondary causes of lymphedema include tumors; postradiation fibrosis; retroperitoneal fibrosis; infection (including filariasis); and postinflammatory scarring from trauma, surgery, or burns. Lymphoscintigraphy can be used to differentiate primary from secondary lymphedema.

In this patient, filariasis was an intriguing possibility given her travel history. Filariasis is a roundworm infestation that can lead to massive lymphedema of the legs and genitalia. Diagnosis is made by reviewing blood smears for microfilariae or by antigen immunoassay. In this case, blood smears were negative.

The Condition
This patient’s diagnostic dilemma was solved dramatically one day on rounds when she was discovered to be applying a constrictive tourniquet around her leg just above the knee. When she was confronted, she became withdrawn and denied she was doing anything. With one-to-one nursing supervision to ensure no further placement of the tourniquet, the redness and swelling resolved rapidly. A psychiatrist was consulted, and factitious illness was diagnosed.

This unusual presentation is a striking example of how physicians can be deceived by patients who have factitious disorders and can be compelled into performing extensive and invasive diagnostic procedures. In retrospect, one diagnostic clue could have been a zone of demarcation between the normal and edematous areas caused by the tourniquet. Careful re-examination after the true cause had been revealed did show that finding, which had not been evident on previous examinations.

Psychosomatic illnesses have a wide spectrum of presentations and are common in adolescents. Frequently, they are manifestations of underlying psychological disease, but they also can be seen in healthy adolescents during stressful situations. Examples include adjustment disorders, somatization disorders, conversion disorders, hypochondriasis, malingering, and factitious disorder.

According to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Edition 4 (DSM IV), adjustment disorders relate to a difficult adjustment to a situation that is out of proportion to the circumstances. In these disorders, stress can lead to physical symptoms. Examples include tension headaches, palpitations, neurodermatitis, and tremor.

In somatization disorders such as conversion disorder and hypochondriasis, a variety of symptoms can present vaguely and imprecisely over a period of several years. There must be a significant impairment in functioning or a history of no explanation of symptoms after an appropriate assessment. The patient often goes to many different physicians and frequently has underlying anxiety and depression.

Conversion disorder is characterized by neurologic or other somatic symptoms that do not fit biologic explanations. The patient benefits from these symptoms by avoiding stressful conflict (primary gain) and evokes attention and sympathy for being stricken with often dramatic symptoms (secondary gain). For patients who have hypochondriasis, there is an exaggerated preoccupation or belief that they have a serious disease.

There are three mental health disorders in which an individual intentionally produces symptoms: malingering, factitious illness, and factitious illness by proxy. In malingering, the patient voluntarily, deliberately, and purposefully produces his or her symptoms to achieve some goal, such as gaining insurance money, avoiding military service, obtaining drugs, or avoiding work.

In factitious illness, or M?nchhausen syndrome, the patient produces signs or symptoms to assume the sick role. Examples of clinical presentations include factitious fever, induced infections, and hypoglycemia caused by exogenous insulin injections. There was one reported case of a tourniquet placed around the wrist, which mimicked reflex sympathetic dystrophy. "M?nchhausen syndrome by proxy" is a term used when a caregiver induces signs or symptoms in a child.

Patients who have factitious illness often have a vague and inconsistent history. When questioned in detail, they frequently have an extensive knowledge of diseases and may have a medical background. Patients commonly become hostile about not being diagnosed correctly and demand and request medications and procedures that are medically unnecessary. The cause of factitious illness is unknown. The diagnosis requires a high degree of suspicion and often is difficult to prove. The patient frequently uses the symptoms to gain attention and recognition. Prolonged psychotherapy is recommended.

Lessons for the Clinician
This case reminds clinicians always to consider the possibility of factitious illness in patients who present with atypical clinical manifestations. Careful observation of the patient in the hospital, including video surveillance, may be necessary to confirm the diagnosis, although clinicians contemplating video surveillance should consult the hospital attorney and risk management office to be sure they are acting legally. Once the diagnosis is considered, clinicians should avoid harmful invasive procedures or treatment with potentially toxic medications.


James J. Burns, MD
Baystate Medical Center, Springfield, Mass

[Alon]

A12-month-old girl is brought to the ED after a seizurelike episode. On awakening from a nap, she screamed and then became stiff. Her eyes rolled back, and she began to shake. Both arms and legs were involved symmetrically. The episode lasted 2 minutes, after which she appeared tired. She has been well recently, with no fever or respiratory symptoms.

Her mother reports a history of similar episodes over the last 3 months, with increasing frequency in the last week (up to 10/d), but no medical attention has been sought until now. The child has had no serious illnesses, is receiving no medications, has no allergies, and has not been immunized (by parental choice). She walked at 10 months of age, but in the last week has become unsteady, stumbling when walking. The family history is noncontributory.

The physical examination reveals an alert child who has normal tone, strength, reflexes, and vital signs. All other physical findings also are normal; specifically, no focus of infection is evident.

Blood chemistry levels include: sodium, 137 mEq/L (137 mmol/L); potassium, 5.4 mEq/L (5.4 mmol/L); calcium, 10.4 mg/dL (2.60 mmol/L); and magnesium, 2.43 mg/dL (1.00 mmol/L). The blood glucose level is 37.8 mg/dL (2.1 mmol/L), and liver function test results are normal. The WBC count is 11.5x103/mcL (11.5x109/L), Hgb level is 12.2 g/dL (122 g/L), and platelet count is 347x103/mcL (347 x109/L). A full evaluation for sepsis is negative. CT of the head shows normal findings. Additional testing confirms the diagnosis.
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The girl was admitted to the hospital and started on an intravenous dextrose solution to stabilize her blood glucose. The infusion was interrupted, and repeated blood glucose testing and symptom monitoring were instituted. When hypoglycemia (glucose <50 mg/dL [2.7 mmol/L]) was reached, metabolic studies consisting of measuring serum carnitine, urine organic acids, and plasma amino acids and free fatty acids were carried out to rule out an inborn error of metabolism. All results were normal.

In addition, a critical sample (a measure of various metabolic precursors and hormones involved in glucose regulation taken during an episode of hypoglycemia) was drawn and revealed a glucose value of 1.4 mg/dL (0.8 mmol/L) (asymptomatic). The cortisol concentration was 24.4 mcg/dL (673 nmol/L). The reference range for a morning level is 4.3 to 22.4 mcg/dL (119 to 618 nmol/L); a high value represents a normal response to hypoglycemia. The growth hormone concentration was 12.35 ng/mL (543.4 pmol/L). The reference range for a normal growth hormone value during an episode of hypoglycemia is greater than 8.0 ng/mL (352 pmol/L). The insulin level was 11.4 mcU/mL (82 pmol/L), which was in the normal range (6.0 to 27.0 mcU/mL [43.1 to 193.7 pmol/L]), but during hypoglycemia, insulin should be suppressed (<5.0 mcU/mL [35.9 pmol/L]). Therefore, her value was inappropriately high, given her physiologic state.

MRI of the head and EEG to rule out CNS abnormalities gave normal results. Repeated episodes of asymptomatic hypoglycemia occurred during the first few days in the hospital, then stabilized with initial intravenous dextrose therapy followed by treatment with diazoxide, an inhibitor of insulin release. No additional seizures occurred. The patient was discharged from the hospital on diazoxide (10 mg/kg in three daily doses) and with a glucagon kit and instructions on treating hypoglycemia.

An MRI of the abdomen obtained as an outpatient revealed a discrete mass in the tail of the pancreas, amenable to resection, suggesting the presence of an insulinoma that explained the patient’s hypoglycemia. She underwent a partial pancreatectomy to remove the tumor. Since the surgery, she has been weaned from diazoxide and has had stable blood glucose concentrations.

The Disorder
Insulinomas are extremely rare in children. Although most present as isolated tumors, they may be associated in younger children with the condition known as multiple endocrine neoplasia type I, which is characterized by hyperparathyroidism, pituitary adenomas, and pancreatic adenomas. Symptoms and signs are due primarily to the effects of hypoglycemia on the CNS (tremulousness, poor feeding, irritability, anxiety, dizziness, seizure, coma), may be present for days to years, and may be misdiagnosed as neurologic or psychiatric disease. In 30% to 40% of patients, the hyperinsulinism is caused by a discrete region of adenomatous hyperplasia, but all pancreatic beta cells can be involved (both hyperplasia and hypersecretion), and this determination can affect the treatment plan.

Diagnosis
In general, persistent or recurrent hypoglycemia can result from three mechanisms. Lack of substrate can be due to prolonged fasting, inborn errors of energy metabolism (affecting gluconeogenesis, glycogenolysis, or fatty acid oxidation), and ketotic hypoglycemia. Increased utilization of glucose can result from hyperinsulinemia, either endogenous (infant of a diabetic mother, diffuse or focal hyperinsulinism) or exogenous. The third mechanism involves an inadequate response or deficiency of counterregulatory mechanisms designed to raise blood glucose, causes of which can be endocrinologic (cortisol deficiency, growth hormone deficiency, panhypopituitarism) or toxin-mediated (ethanol, salicylates, propranolol). In a 12-month-old child, the most likely causes are hyperinsulinism, hypopituitarism, adrenal insufficiency, or ketotic hypoglycemia. The critical sample helps to differentiate these diagnoses.

The diagnosis of hyperinsulinemia should be considered in any case of hypoglycemia, particularly if episodes are persistent or recurrent and when other mechanisms have been ruled out. Endogenous hyperinsulinemia is diagnosed by demonstrating inappropriately high insulin and C-peptide levels in the face of hypoglycemia (exogenous administration of insulin causes high insulin, but low C-peptide levels). Indirect measures of hyperinsulinism include lack of ketones in the face of hypoglycemia, an increased glycemic response to glucagon, and an increased glucose requirement (>15 mg/kg per min).

In this case, interpretation of the critical sample showed a normal response of the counterregulatory hormones. The insulin level, although reported as within the normal range, was inappropriately high for the circumstance; insulin should be suppressed completely by hypoglycemia. Additional evidence of hyperinsulinemia was provided by the absence of plasma ketones. Again, although reported as normal, this finding is inappropriate for the circumstance; hypoglycemia should trigger fat oxidation and ketogenesis, but in this case, the presence of insulin inhibited ketogenesis.

Treatment
Once hyperinsulinemia is diagnosed, differentiating between focal (discrete insulinoma) and diffuse disease (infant of a diabetic mother, persistent hyperinsulinemic hypoglycemia of infancy, diffuse hyperinsulinism) has important implications for treatment. Focal disease can be treated pharmacologically, but also may be amenable to partial surgical resection; diffuse disease is less amenable to partial resection. There are two primary pharmacologic options, the first being diazoxide (10 mg/kg per day orally divided into three doses), an inhibitor of insulin release. Major adverse effects include hirsutism, fluid retention, and neutropenia. Octreotide (5 to 20 mcg/kg per day by subcutaneous injection every 6 to 8 h), a somatostatin analogue that inhibits insulin secretion (as well as glucagon and growth hormone), also can be used. Adverse effects include abdominal discomfort, cholelithiasis, and transient growth impairment.

Many approaches have been attempted to localize focal disease. Radiologic studies have not been as successful as hoped, with MRI being the best, correctly localizing up to 45% of insulinomas. A newer, more invasive approach, consisting of selective sampling of pancreatic veins for insulin levels following stimulation with calcium gluconate, has an overall accuracy of up to 94%, but is not yet widely available. Isolated insulinomas localized to the tail of the pancreas are potentially curable with partial resection; diffuse disease, particularly if resistant to pharmacologic treatment, may require subtotal pancreatic resection. Although this procedure cures the hyperinsulinemia, the child ultimately may develop diabetes mellitus from the resulting relative insulin deficiency, once growth exceeds pancreatic function. Unfortunately, the timing of this complication is unpredictable, requiring ongoing monitoring.

Lessons for the Clinician
Investigation of any child presenting with a seizure must include a blood glucose measurement. Hypoglycemia is treated easily, and hypoglycemic seizures may be refractory to anticonvulsant therapy. Hyperinsulinemia, specifically as caused by insulinoma, is a rare condition but one important to diagnose. Obtaining a true hypoglycemic blood sample is vital in making the diagnosis. It is important to remember that results of critical samples must be considered in context. Although the laboratory may report a result as being normal, that level may not be appropriate for the physiologic state. Accurate localization of insulinomas can affect the treatment, allowing the possibility of a cure without sequelae in focal disease.


Marielena DiBartolo, MD
Robert I. Stein, MD
Children’s Hospital of Western Ontario, University of Western Ontario, London, Ontario, Canada
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Хочется подчеркнуть, что у таких больных важно определять КЩС во время эпизода гирогликемии . При отсутствии ацидоза круг диф.диагностики существенно сужается
(практически - до гиперинсулинизма и проблем с обменом жиров).
Кстати, а если бы сахар был нормален, то о каком заболевании при подобной клинике важно было бы подумать?

[dr.Ira]

Первое, о чем я бы подумала при НЕ фебрильных судорогах, это, конечно, эпилепсия. Второе - эпилептические приступы, вторичные к процессу в голове. Но, поскольку, первичное обследование включает глюкозу крови, а результаты EEG, CT И MRI -отрицательные, то надо искать другую причину гипогликемии (факт - нашли.) У маленьких детей презентация диабета часто именно в форме гипогликемии, которая может сопровождаться судорогами. Но, слава Б-гу, поставить диагноз сахарного диабета сегодня - это не самое сложное.

[Alon]

Hepatosplenomegaly, pancytopenia, coagulopathy: Big words about a feverish infant
Oct 1, 2005
By: Fasika Woreta et al.
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You meet your new patient late one afternoon on the general pediatric service of your tertiary care hospital. He is a 2-month-old boy of Native American and Puerto Rican descent who has been undergoing evaluation of fever, hepatomegaly, and pancytopenia of uncertain cause.

You familiarize yourself with what has become a rocky infancy for this baby. He was in generally good health until two weeks ago when, you learn, he developed a rotavirus infection. The diarrhea was improving, but had not resolved, when, one week before admission, he developed a fever as high as 104° F and had a generalized tonic-clonic seizure. He was transported to a nearby community hospital and found to be anemic (hematocrit, 20%). There, he was given a transfusion of packed red blood cells. Multiple cultures (blood, urine, and CSF) were obtained and were ultimately negative. Empiric antibiotics were started for possible sepsis.

Over the next five days, the boy developed pancytopenia, ascites, hepatomegaly, direct hyperbilirubinemia, and coagulopathy, requiring transfusions of platelets, fresh frozen plasma, vitamin K, and additional packed RBCs. Bone marrow aspiration and biopsy showed normal cellularity, trilineage hematopoiesis, and no abnormal cells.

He was transferred to the pediatric intensive care unit (PICU) of your hospital for further evaluation and management of the coagulopathy and pancytopenia. There, these problems persisted and were managed with frequent blood product support (fresh frozen plasma, platelets, cryoprecipitate). Transjugular liver biopsy showed cholestasis with normal architecture and no evidence of intrahepatic disease. Biopsy specimens were sent for fungal, viral, and bacterial cultures and were ultimately negative.

Infectious disease, gastroenterology, and immunology specialists were consulted. Today, after three days in the PICU, the patient's transfusion-dependence had apparently resolved, he was no longer febrile and, after narrowing antibiotic coverage to cefotaxime, he was transferred to your care.

Arriving jaundiced and swollen

The brief history is significant for two infections. The infant was hospitalized at 11 days of age for respiratory syncytial virus bronchiolitis, which resolved without apparent complication. He then developed rotavirus infection. Neither is unusual, you consider, for a newborn in a late winter month.

The boy is the product of a full-term pregnancy; the mother is 29 years old, gravida 3, para 3. She confides that she is a recovering heroin addict who used heroin through the first trimester of this pregnancy. She received prenatal care, and routine prenatal testing was negative, including an HIV antibody test. The baby received hepatitis B vaccination at birth but has not yet received the 2-month-old vaccination. Medications include ranitidine (Zantac), which he has taken since he was 1 month old for gastroesophageal reflux disease.

The family history is significant for epilepsy in his mother and paternal grandfather. He has a 2-year-old brother and an 8-year-old half-sister, both in good health. He lives with his mother in a group home for previously incarcerated mothers who are recovering from heroin addiction.

On physical examination, you observe a baby who is alert and does not appear toxic but is diffusely jaundiced. He is now afebrile, with a pulse of 130/min and a respiratory rate of 48/min. Blood pressure is 102/57 mm Hg; O2 saturation, 98% on room air. Weight is 4.8 kg (at the 25th percentile, weight-for-age).

Physical examination is notable in several regards. Sclerae are icteric. The neck is supple without lymphadenopathy. Abdominal examination is remarkable for prominent distension, with a positive fluid wave and a liver palpable 4 cm below the right costal margin. There is splenomegaly, which had not been noted earlier; the spleen is palpable 3 cm below the costal margin. Extremities are well perfused, with a capillary refill of less than two seconds. There is a right femoral line in place, without erythema of surrounding skin. There is nonpitting trace edema of the lower extremities and marked scrotal edema. The rest of the examination is unremarkable.

Laboratory tests obtained in the PICU on the day of transfer show a white blood cell count of 2.2 X 103/μL, with 16% neutrophils, 71% lymphocytes, 12% monocytes, and 1% eosinophils. He is neutropenic, with an absolute neutrophil count of 0.34 X 103/μL. Hemoglobin (8.3 g/dL) and hematocrit (24.2%) are decreased; the platelet count is extremely low at 29 X 103/μL. Total bilirubin (8.9 mg/dL) and direct bilirubin (6.1 mg/dL) are significantly elevated. Aspartate aminotransferase (81 U/L [normal, 0-37 U/L]) and gamma glutamyl transferase (550 IU/L [normal, 12-55 IU/L]) are elevated, but alanine aminotransferase and alkaline phosphatase levels are within normal limits. Fibrinogen is low at 55 mg/dL (normal, 150-450 mg/dL); a d-dimer test is elevated at 6.62 mg/L (normal, 0.43-2.24 mg/L); prothrombin time is slightly elevated at 15.8 seconds; and the activated partial thromboplastin time is normal for age at 40 seconds. Albumin is 2.9 g/dL. Serum electrolytes and creatinine are normal.

The differential is broad

You consider how extensive the differential diagnosis is in an acutely ill 2-month-old with pancytopenia. Ingestion of a toxic substance (including prescription and over-the-counter medications), an infectious process, immune disorders, metabolic disorders, and hematologic processes such as leukemia, lymphoma, or a hemophagocytic syndrome—all could result in pancytopenia and prompt your patient's clinical picture. The boy is being given ranitidine, which can cause hepatotoxicity. Could the recent rotavirus infection explain the clinical picture? You've read case reports of viremia from rotavirus, with systemic manifestations. Notably, the extensive infectious disease workup has been unrevealing: serologic tests for enteroviruses, Histoplasma, Cryptococcus, HIV, hepatitis A and C antibody, cytomegalovirus and Epstein-Barr virus (EBV) antibody, Toxoplasma antibody, parainfluenza, influenza, adenovirus, respiratory syncytial virus, parvovirus, and Haemophilus influenzae type b antigen all return negative. Stool cultures for Salmonella, Shigella, Yersinia, and Campylobacter and a test for rotavirus antigen are also negative. So is a purified protein derivative skin test for Mycobacterium tuberculosis (none was placed on the mother or siblings).

More tests are needed

You decide to order abdominal computed tomography with intravenous contrast. The scan reveals hepatomegaly and an enlarged spleen with an irregular appearance, possibly indicating small implants, abscesses, or infarcts. A doppler ultrasound scan to further evaluate the splenic lesions shows splenomegaly but no areas of abnormal signal.

On the fourth day after transfer, the infant again begins spiking a fever, to a maximum axillary temperature of 104° F. The femoral line is removed and antibiotic coverage is broadened, although cultures of cerebrospinal fluid, blood, urine, and stool continue to show no growth. Persistent pancytopenia is managed with multiple blood and platelet transfusions. On the fifth day, blood cultures return positive for presumptive Enterococcus and the antibiotic coverage is appropriately broadened.

Given the boy's deterioration, you ask the hospital's pediatric hematologists to review the initial bone marrow biopsy and aspirate from the other hospital and to comment on the slightly increased number of histiocytes in the background. They also note one phagocytic histiocyte, which may be normal. Despite an unimpressive bone marrow, the team is concerned that your patient's clinical picture is highly suspicious for hemophagocytic lymphohistiocytosis; repeat bone marrow aspiration and biopsy, along with a lumbar puncture, are performed. Additional laboratory tests are ordered, and you take note of an elevated ferritin level (1,098 ng/mL [normal, 10-300 ng/mL]) and elevated serum triglycerides (237 mg/dL [normal, <150 mg/dL]).

.

[Alon]

An unfortunate answer

A few hours after the procedures, you receive an urgent call from the hematologist to come view the slides. The aspirate reveals numerous histiocytes in the process of hemophagocytosis. Vacuolized histiocytes are also visible in the CSF. The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is made and the patient is evaluated emergently by the oncology consultants for chemotherapy.

That night, your patient has an acute decompensation, with increased work of breathing, decreased O2 saturation, and hypotension. He is intubated and transferred to the PICU. The following day, chemotherapy with the HLH-2004 protocol—cyclosporine, etoposide, and dexamethasone is initiated.

Over the next week, the boy develops renal failure, fulminant hepatic failure, worsening coagulopathy, an inability to maintain serum glucose hemostasis, and persistent seizures. Eight days after the diagnosis was established, and one day short of being 3 months old, support is withdrawn and he is pronounced dead.

The challenge: A nonspecific presentation

Hemophagocytic lymphohistiocytosis, also known as hemophagocytic syndrome, encompasses a heterogeneous group of disorders that share a nonspecific clinical picture comprising fever, hepatosplenomegaly, and cytopenia resulting from uncontrolled macrophage activation and subsequent phagocytosis of blood cells.

Two distinct forms of the disease have been described: a primary, or familial, form, inherited as an autosomal-recessive disorder, and a secondary, or sporadic, form that has been associated with a variety of infections, autoimmune diseases, and malignancies, and with several genetic immunodeficiency syndromes.

A retrospective Swedish study estimated the annual incidence of familial HLH to be 1.2 cases for every 100,000 children.3 Peak age of diagnosis is between 1 and 6 months, with 70% to 80% of cases presenting before 1 year. Gender distribution is thought to be even.

Pathophysiology Although the pathophysiology of HLH is poorly understood, it is hypothesized to be a disorder of immune regulation, with a failure of cytolytic lymphocyte function resulting in hypersecretion of cytokines and subsequent uncontrolled activation of lymphocytes and macrophages. The sera of patients who have HLH have been found to have a strikingly high level of numerous cytokines, including interferon gamma, TNF alpha. Several studies have demonstrated markedly reduced or complete absence of cytotoxic T cell and natural killer activity in patients with HLH. The cytotoxic T lymphocytes and natural killer cells are effector lymphocytes that share a common cytotoxic pathway required for defense against viral infections. This cytotoxic pathway is disrupted in HLH; when the disruption occurs with intercurrent infection, it induces lethal immune deregulation (in some forms of HLH).

Two genetic mutations have been identified in patients with familial HLH. One gene is on chromosome 10 and encodes a protein called perforin, an important mediator of cytotoxic T cells and natural killer cell cytotoxicity. Cytotoxic cells kill their targets primarily through a localized secretion of toxic granules, and perforin is thought to be essential for this process. This mutation is estimated to account for 20% to 40% of cases of familial HLH. More recently, mutations in the hMunc13-4 gene, on chromosome 17, have been identified in a subset of patients with familial HLH. Like perforin, hMunc13-4 also participates in cytotoxic granule release. Without proper cytotoxic granule release, the activity of activated macrophages goes unchecked and leads to cytokine release and phagocytosis.

A variety of infectious agents can provoke secondary HLH and can trigger the familial form of the disorder. Viruses are most often implicated, with EBV reported to be the most common cause. Other viruses reported to trigger HLH include CMV, human herpesvirus, varicella-zoster virus, herpes simplex virus, adenoviruses, and parvovirus B19. EBV-associated HLH is important to diagnose because it is associated with a more fulminant course and higher mortality rate.

Diagnosis Signs and symptoms of HLH vary widely. The principal clinical features are fever and hepatosplenomegaly. Other common clinical findings include rash, lymphadenopathy, and neurologic symptoms. The latter are seen in as many as 75% of cases, may be the presenting sign, are highly variable, and include seizures, lethargy, cranial nerve findings, abnormal tone, and ataxia.

Common laboratory findings include pancytopenia, direct hyperbilirubinemia, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia. Hyponatremia, hypoalbuminemia, elevated LDH, coagulopathy, transaminitis, and CSF pleocytosis with mononuclear cells and an elevated protein level have also been reported.

The pathognomonic histopathologic finding is numerous histiocytes actively phagocytosing blood cells—erythrocytes, mostly, but also leukocytes and platelets. The most frequently involved organs are bone marrow, lymph nodes, the CNS, liver, and spleen. An initial bone marrow specimen may not demonstrate phagocytosis; repeat aspiration may be necessary to establish the diagnosis. A key learning point, therefore, is that an initially negative bone marrow specimen should not rule out HLH or delay immediate treatment if other diagnostic criteria are met.

The familial and the infectious forms of HLH are often indistinguishable clinically. Diagnosis of the familial form can be made by an established positive family history or demonstration of mutations in the perforin or hMunc13-4 genes. Also suspect familial HLH in the presence of parental consanguinity or age of onset earlier than 1 or 2 years. Measurement of perforin expression in natural killer cells and CD8+ lymphocytes and mutational analysis of the perforin and hMunc13-4 genes can be performed in patients with HLH.

Prognosis and therapy Without bone marrow transplantation, familial HLH is uniformly fatal soon after birth; median survival is two to three months. The prognosis is better in the majority of secondary forms, with recovery reported in 60% to 70% of cases. The exception is EBV-associated HLH, in which recovery is thought to be much less likely. In a 1996 study of 122 patients with HLH, overall estimated five-year survival was 22%. Among patients who underwent bone marrow transplantation, five-year survival was 66%; for those receiving chemotherapy with etoposide or another single chemotherapeutic agent, five-year survival was 10.1%.

In 1994, the Histiocyte Society initiated a prospective collaborative therapeutic study of the disorder (HLH-94) with the aim of improving survival. The protocol comprised an initial eight weeks of treatment with etoposide and dexamethasone. Following that, children with familial or recurring HLH, or both, continued with etoposide and dexamethasone in combination with cyclosporine for as long as one year. Subsequently, bone marrow transplantation (the only curative treatment for primary HLH) was performed if a donor became available. Intrathecal methotrexate was also used in cases of CNS involvement. This protocol resulted in an overall survival of 55% at median follow-up of 3.1 years and a three-year probability of survival of 62% after marrow transplantation. Although survival of children with HLH is still poor, therefore, it has greatly improved over the past decade. In the most recent revision of this protocol (HLH-2004), cyclosporine is administered at the start of therapy.

Although it can be difficult to distinguish the primary form of HLH from secondary forms, the distinction is important: Familial HLH is uniformly lethal without bone marrow transplantation. A child who has presumed secondary HLH and who has experienced complete resolution following immunochemotherapy should be monitored carefully for relapse.

Early treatment is thought to be beneficial when feasible because a response to treatment is less likely subsequent to CNS involvement and bone marrow failure.

The diagnosis of HLH is challenging—and often delayed for several reasons, including this rare disorder's variable, nonspecific manifestations and clinicians' lack of awareness of it. Because of the aggressive nature of HLH and the likely need for early treatment, early diagnosis is crucial. Consider HLH, therefore, in any child in whom fever, hepatosplenomegaly, and cytopenia go unexplained, because early treatment may be life-saving

[dr.Ira]

18-летний юноша осмотрен в приемном отделении по поводу 2-х недельной истории диарреи и слабости. Лечащий врач поставил д-з "Вирусный гастроэнтерит". За 4 дня до осмотра в п/о его диаррея стала более частой, появилась рвота без примеси крови и желчи, усилилась слабость. Он отрицает позывы наличие дефекаций по ночам, но отмечает, что был один эпизод недержания кала. Отрицает боли в животе, ночные поты, потерю веса, желтуху сыпь, частые немотивированные синяки или кровотечения.Нет истории о путешествиях или каких либо других нерутинных особенностей жизни. В медицинском анамнезе - псориаз. В семейном анамнезе нет указаний на Inflamattory Bowel Disease или Celiac dis., но у дедушки со стороны матери был " разрыв кишки". Нет истории кровотечений или нарушения свертываемости.
При осмотре :бледный, хорошо развитый юноша без признаков какой-либо недостаточности (in no distress). Без температуры, ч.с.с. 119/мин. , АД 148/72 , ч.д.д. в норме. Вес 90 персентиль, рост 75 персентиль. При осмотре головы, ушей, носа и глотки - нет иктеричности, но отмечается язва на левой миндалине. При аускультации сердца - систолический шум 1/6 по левой стернальной линии. Живот мягкий, б/б, печень не пальпируется, палпируется край селезенки. При ректальном осмотре - кровь. Фиссуры нет. На коже нет петехий , расчесов, сыпи...
Пациент госпитализирован для обследования. Диаррея остается, в кале большое кол-во крови и слизи.
Лаборатория:
- WBC 22,300 cells/mm (мм куб)
Neut -44%
Lymph-9%
Mono-7%
Bands-36%
eos-1%
metamyelocytes-1%
myelocytes-2%
-Hb -8,3 g/dl
-MCV -63
-RSW -19,4%
-PLT -38000/mm (мм куб)
-ESR (CОЭ)- 24 mm/h
Ретикулоцитов 4,5%, в периферическом мазке - фрагменты эритроцитов, овалоциты, слезовидные клетки (teardrops) и гипохромия.
-BUN -13mg/dL, creatinin - 1,5 mg/dL
-ALT -1030 IU/L
-AST -746 IU/L
-GGT -73 IU/L
-Alk Phos -133 IU/ L
-Bil total -0,4 mg/dL
-Albumin - 2,9g/ dL
-PT -19,8 sec.
-PTT -29,4 sec.
-INR -1,8
-LDD - 1118 IU/L
-Uric acid - 8,8 mg/dL
В моче 2 эритроцита, следы кетона, небольшое кол-во белка и 26 гиалиновых цилиндров.
Посев кала, а также анализ на глистов и паразитов, а также на токсин клостридии - отрицательно.
Посев крови - отрицательно.
Тест на гепатиты и ЦМВ -отрицательный, тест на ЕБВ - нет речи об острой инфекции (prior infection). Повторные анализы крови и печеночных проб показали возвращение к норме. Почечные пробы вернулись к норме. Осмотрен окулистом на предмет выявления колец Kayser-Fleischer - не найдено, церулоплазмин сыворотки и уровень меди - в норме и в крови , и в моче.

Что делать дальше, по Вашему мнению? (Я-то ответ знаю, выложу через пару дней в ординаторской... )
P.S. Прошу прощения за некую корявость перевода.

[Alon]

Не забывая о других возможностях (например, IBD и пр.), я бы на первое место в списке диф.диагнозов поставил Hemolytic-uremic syndrome.

[DrOleg]

Сообщение от dr.Ira

Что делать дальше, по Вашему мнению? (Я-то ответ знаю, выложу через пару дней в ординаторской... )

Пришлите также ответ мне на личку.
Не описаны лимфоузлы пациента, не описано наличие или отсутствие температуры
Кроме всего прочего я бы обследовал на HIV и сделал стернальную пункцию

[dr.Ira]

"Не описаны лимфоузлы пациента, не описано наличие или отсутствие температуры"

Олег, читайте внимательно! Что же я зря старалась, переводила