Index of Suspicion

A 9-year-old boy presents to the ED with a 1-day history of increased work of breathing and cough. Over the past few days, he also has experienced increasing lethargy and fatigue. His past history is significant for situs inversus and asplenia. He has had multiple prior admissions for pneumonia and had a gastric volvulus at age 3 years, which was treated with an esophagojejunal anastomosis. He had been fed by a jejunal tube, but this was removed. The patient subsequently was lost to follow-up until recently. Current medications include fluticasone 125 mcg, 1 puff twice daily via spacer, and amoxicillin 125 mg by mouth daily; his compliance is questionable.The physical examination reveals a pale child who does not appear toxic. His temperature is 98.6°F (37°C), heart rate is 110 beats/min, respiratory rate is 32 breaths/min, blood pressure is 104/54 mm Hg, and oxygen saturation is 92% on 6 L of oxygen/min. His height and weight are at the 40th and 25th percentiles, respectively. He has diffuse wheezing and crackles in the left base. The rest of the examination findings are unremarkable.A chest radiograph demonstrates a left lower lobe infiltrate. Blood cultures are ordered and broad-spectrum antibiotics begun. A complete blood count demonstrates a Hgb of 5.8 g/dL (58 g/L), mean corpuscular volume (MCV) of 133.8 fL, mean corpuscular hemoglobin concentration (MCH) of 45.4 pg, WBC count of 3.16×103/mcL (3.16×109/L) (1.55×103/mcL neutrophils, 1.51×103/mcL lymphocytes, 0.1 ×103/mcL basophils), and platelets of 70×103/mcL (70×109/L). The peripheral smear shows Howell-Jolly bodies, multilobulated neutrophils, large platelets, macro-ovalocytes, and nucleated red blood cells. Values for serum electrolytes, alkaline phosphatase, AST, and ALT are normal. The lactate dehydrogenase concentration is 1,670 U/L, and the bilirubin is 1.3 mg/dL (22.0 mcmol/L). An additional investigation reveals the cause of his anemia.A 6-year-old girl presents with excessive daytime sleepiness and school difficulties. She had enjoyed normal health during infancy and the preschool years. Over the past 2 years, however, the mother reports that her daughter has experienced excessive daytime sleepiness to the extent that she frequently falls asleep on the drive to school. She seems to tire more easily than her peers and has difficulty keeping up when playing team sports. The mother also describes several “drop attacks,” when her daughter suddenly loses muscle tone and collapses to the floor. She does not lose consciousness with these episodes and does not have seizure activity. The school reports that the girl is inattentive and immature and recommends that she repeat first grade. Her past medical history is otherwise unremarkable, and her development is normal. Findings on physical examination, including neurologic assessment, are within normal limits. Normal results are documented on MRI; EEG (nonsleep-deprived); CBC; and measurement of serum electrolytes, creatinine, BUN, ESR, and C-reactive protein.A 17-year-old boy presents with a 3-day history of worsening sore throat and dysphagia. He was seen in the ED yesterday, had a negative rapid strep test result, and was prescribed azithromycin and told to follow-up in the clinic today. He has to sit up continuously and catch his saliva because he cannot swallow it, and he cannot lie down because he has difficulty breathing when he is recumbent. He has no fever.The boy is fully immunized, including vaccination against Haemophilus influenzae type B (Hib) and Neisseria meningitidis. One week ago, he had oral and vaginal intercourse. His 15-year-old sister was admitted to the hospital yesterday with a nonhealing axillary abscess infected with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).Physical examination reveals a distressed young man who is crying and leaning against his mother for support. His temperature is 100.0°F (37.8°C), respiratory rate is 16 breaths/min, and pulse oximetry is 100% on room air. His tonsils are slightly swollen bilaterally and erythematous without discharge. The uvula is in the midline. He is unable to open his mouth fully because of increased right-sided ear and neck pain. His neck is supple, with 1-cm tender anterior cervical lymph nodes bilaterally. He has normal range of motion at the neck without any stiffness, but he complains of pain when looking upward with cervical extension. The rest of his examination findings are unremarkable. A radiologic study reveals the diagnosis.The boy's serum vitamin B12 value was less than 60 pg/mL (44 pmol/L) (normal, 187 to 1,059 pg/mL [138 to 781 pmol/L]), confirming a diagnosis of megaloblastic anemia caused by vitamin B12 deficiency. His red blood cell folate concentration was 256 ng/mL (579 nmol/L) (normal, 160 to 714 ng/mL [362 to 1,617 nmol/L]). Additional questioning revealed that he had not received prophylactic vitamin B12 since his gastrectomy 6 years ago.Macrocytic anemias, defined as an MCV greater than 100 fL, are rare. Megaloblastic anemia is defined as a macrocytic anemia associated with macro-ovalocytosis and hypersegmented neutrophils. Importantly, not all macrocytic anemias are megaloblastic. Macrocytosis without macro-ovalocytes and hypersegmented neutrophils defines a normoblastic anemia, causes of which include increased immature cells (identified by an increased reticulocyte count) and Diamond-Blackfan anemia.The differential diagnosis of megaloblastic anemia includes vitamin B12 and folate deficiency. Both vitamins are involved in DNA synthesis, and their absence leads to ineffective erythropoiesis. There is marrow erythroid hyperplasia but also reticulocytopenia because the precursors die in the marrow. Granulocytes and megakaryocytes also may be involved, leading to neutropenia and thrombocytopenia. Various drugs, including zidovudine, 6-mercaptopurine, cytosine arabinoside, azathioprine, and hydroxyurea, also can cause megaloblastic anemia. Rarely, orotic aciduria, Lesch-Nyhan syndrome, and thiamine-responsive megaloblastic anemia present in infancy with normal vitamin B12 and folate values.Folate is absorbed rapidly in the jejunum. Deficiencies can result from dietary inadequacy. Sources of folate include fruit and green leafy vegetables, liver, and fortified flour. Human milk is adequate, although raw goat milk is deficient. Other causes of folate deficiency include disorders leading to impaired absorption, such as inflammatory bowel disease. Folate antagonists, such as methotrexate and trimethoprim, can cause deficiency, as can several rare genetic enzyme or receptor deficiencies. Phenobarbitol and phenytoin generally do not cause clinical deficiency, although increased folate supplementation is recommended for pregnant women receiving anticonvulsants to reduce the risk of neural tube defects.Rare causes of folate deficiency include severe eczema, exfoliative dermatitis, and chronic hemolysis because of increased cellular turnover and DNA synthesis in these conditions. Diagnosis is made by measuring erythrocyte folate because serum concentrations are variable. Folate storage is limited, and deficiency develops within 2 to 3 months of a dietary deficit.Dietary vitamin B12 is complexed with binding proteins in saliva and gastric juices, then liberated in the duodenum by pancreatic proteases, where it binds with intrinsic factor (IF), which is derived from gastric parietal cells. This complex is absorbed in the ileum, is bound to a plasma carrier (transcobalamin II [TCII]), enters the cells, and is converted to active forms.Because vitamin B12 is widely available in animal food sources, dietary deficiency usually occurs only in individuals consuming a vegan diet. Because of relatively large hepatic stores, it can take years for clinical deficiency to manifest, as demonstrated in this patient.Other causes of vitamin B12 deficiency include any abnormalities of the previously mentioned pathway. Congenital pernicious anemia is an autosomal recessive disorder resulting from abnormal or deficient IF, with symptoms beginning near the end of the first postnatal year. This condition differs from juvenile pernicious anemia, which includes gastric atrophy and achlorhydria and is believed to be an autoimmune disorder resulting from antiparietal cell and anti-IF autoantibodies, similar to the adult form. There may be associated immunologically mediated endocrine deficiencies. Both forms of pernicious anemia are relatively uncommon in childhood.Gastric disorders (gastrectomy, gastritis) also may result in absent IF and clinical vitamin B12 deficiency. Pancreatic insufficiency can cause vitamin B12 deficiency by impairing cleavage and IF complex formation. Disorders of the distal small intestine can impair absorption of the vitamin B12-IF complex and include inflammatory bowel disease, celiac disease, ileal resection, and bacterial overgrowth. Rare cases of abnormalities of the vitamin B12-IF receptor in the terminal ileum have been described, and affected individuals also may have proteinuria. In endemic areas, infection with the fish tapeworm Diphyllobothrium latum can result in a deficiency.When vitamin B12 absorption is normal, deficiencies of the TCII transport protein can occur. These conditions usually are inherited in an autosomal recessive pattern and present in early infancy. Serum vitamin B12 concentrations typically are normal, and diagnosis is made by demonstrating reduced TCII values. Other causes of vitamin B12 deficiency that should be apparent from the history include medications such as proton pump inhibitors, neomycin, and metformin.Symptoms of vitamin B12 deficiency relate to the anemia and include pallor, fatigue, decreased appetite, and irritability. Glossitis, a smooth painful tongue, is characteristic. There may be coexisting neurologic symptoms (absent in folate deficiency) as a result of posterior and lateral spinal column degeneration. These effects include ataxia, paresthesias, and difficulty walking. Decreased reflexes, vibration, and position sense may be found. Late stages may be characterized by altered mental status. Neurologic changes may coexist with anemia or occur in its absence.Vitamin B12 deficiency anemia is diagnosed by recognizing the classic findings of megaloblastic anemia (macrocytosis with hypersegmented neutrophils) and is confirmed by low serum vitamin B12 values. Increased serum lactate dehydrogenase and bilirubin concentrations are usual findings, reflecting ineffective erythropoiesis. Methylmalonic acid is elevated in the urine, but is low in folate deficiency. Homocysteine is elevated, and the reticulocyte count is low (for the degree of anemia). Thrombocytopenia and neutropenia frequently are associated, although such findings indicate the need to scrutinize the peripheral smear to rule out other conditions. A bone marrow examination may be indicated to exclude disorders such as acute myeloid leukemia or aplastic anemia.The specific cause can be determined by considering the differential diagnosis in the individual patient. Pernicious anemia can be tested for by examining for antibody to IF. The classic Schilling test no longer is regarded as the diagnostic test.Treatment of this deficiency is via parenteral administration of vitamin B12, unless the cause is dietary deficiency. Clinical response usually follows the administration of 100 to 1,000 mcg intramuscularly daily for 1 to 2 weeks, followed by 50 to 1,000 mcg monthly. For an individual undergoing complete gastric or ileal resection, vitamin B12 should be started prophylactically. Where there is uncertainty, close follow-up is mandated. Surveillance must continue long-term because typical hepatic storage allows for a delay in clinical presentation of up to 5 years in cases of malabsorption and up to 20 years in dietary deficiency.Following treatment, reticulocytosis should occur within 72 hours, followed by an increase in Hgb within 7 to 10 days and a subsequent decreased MCV. Potassium concentrations should be monitored in cases of severe anemia because significant hypokalemia may develop as a result of potassium incorporation into new cells. Neurologic symptoms resolve much more slowly, over the next 6 months, but can be irreversible. Therefore, prevention in a susceptible child, as described here, is warranted.This case emphasizes the importance of a careful history, which immediately led to the suspected diagnosis. Any child undergoing gastric or distal ileal resection should receive vitamin B12 prophylactically. Examination of the red blood cell indices, including MCV and MCH, and a peripheral smear can give valuable clues as to the cause of the anemia. (Susanna Martin, MDCM, FRCP(C), Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada)Because of the history of daytime sleepiness, the girl was referred to a sleep specialist. She underwent overnight polysomnography (PSG) and a multiple sleep latency test (MSLT), which demonstrated a pattern diagnostic of narcolepsy.PSG records a number of physiologic measures during sleep, including EEG activity; eye, chest wall, and leg movements; oxygen saturation; and electrocardiographic activity. In narcolepsy, overnight PSG documents that the patient had enough sleep time before the MSLT and rules out other sleep disorders that may interfere with sleep quality. Specifically, no findings should suggest obstructive or central apnea events that could interfere with the patient's quality of sleep and induce daytime sleepiness. Other abnormalities that should be ruled out on PSG include seizures and periodic limb movements.The MSLT should demonstrate objectively the degree of daytime sleepiness in the child by providing four or five regularly scheduled nap opportunities, each separated by approximately 2 hours. EEG demonstrating sleep-onset rapid eye movement (REM) periods (SOREMPs) in two or more naps is considered suggestive for narcolepsy. SOREMPs are diagnosed when REM sleep occurs within 15 minutes of sleep onset. MSLTs are not validated in children younger than age 8 years.Narcolepsy is defined as a disorder of daytime sleepiness combined with cataplexy, hypnagogic hallucinations, and sleep paralysis. The condition affects 1 in 2,000 people (equally across sexes) and is diagnosed most commonly in the teens or early 20s. The condition has been diagnosed in children as young as 5 years of age. Many people who have narcolepsy demonstrate only two or three of the characteristic symptoms: The differential diagnosis for narcolepsy should include other causes of excessive daytime sleepiness. Social stresses and recent changes (eg, divorce, new baby, foster care) that may interfere with sleep quantity or quality should be explored. Similarly, obstructive sleep apnea syndrome and circadian rhythm disorders may present with poor nighttime sleep and daytime sleepiness. Many medications, such as those used for epilepsy and behavior disorders, may cause drowsiness. Daytime sleepiness can be confused with attention-deficit/hyperactivity disorder, epilepsy (especially absence seizures), depression, or learning disability. The drop attacks of cataplexy may look very similar to atonic seizures.Narcolepsy ideally is diagnosed by combining overnight PSG with an MSLT the following day. The PSG should rule out sleep apnea and many other causes of daytime sleepiness. It also may show an earlier-than-normal entry into REM sleep. The MSLT assesses the severity of excessive daytime sleepiness and whether the patient's naps involve REM sleep. The appearance of REM sleep in at least two naps is highly suggestive of narcolepsy.The treatment of narcolepsy involves lifestyle modifications as well as medications. Affected children are encouraged to adhere to regular sleep and wake times. In addition, allowance must be made for them to take one or two planned 30-minute naps during the day. This adjustment may require modifications to the school schedule. The naps should occur in a quiet, dark room that feels comfortable to the child.Medications are used in conjunction with these lifestyle changes to increase daytime alertness. The mainstay of pharmacologic treatment for daytime sleepiness for affected patients is stimulant therapy. Methylphenidate and have been used with to excessive daytime sleepiness that is associated with narcolepsy. have made these medications more to is an new because of its and its an it is a very and has not been by the and for in Other medications, including and have been used in cataplexy in with in child who has excessive daytime sleepiness can as or should be for a sleep The history and physical examination should rule out the causes such as sleep syndrome, circadian rhythm disorder, and other conditions. narcolepsy is in and a significant of patients diagnosed in have had symptoms in Any child suspected of narcolepsy should be referred to a sleep for additional is a condition with that can be although not with and lifestyle Hospital, to or bacterial A Neisseria and considered in the differential diagnosis. 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