DEFINITION OF THE COMPLAINT
The term decreased activity level describes a wide spectrum of existence ranging from boredom to coma. The diagnostic evaluation focuses on encouraging parents to provide a detailed account, particularly with regard to the magnitude and time course of the changes. Clearly, the differential diagnosis of subtle behavioral changes developing during a period of several months differs from that of changes occurring during several hours.
COMPLAINT BY CAUSE AND FREQUENCY
The causes of decreased level of activity in children vary according to age (Table 2-1), and can be placed into several broad categories (Table 2-2). Additional issues to consider include whether there is depressed sensorium indicating an underlying central nervous system (CNS) disorder, weakness indicating a muscular disorder, or endurance problems suggesting a cardiac or pulmonary issue. Systemic illness may manifest with somnolence or lethargy.
The patient who presents for evaluation of decreased level of activity represents a broad differential. Several important historical questions can help classify the underlying etiology:
• What is the time course of decreased level of activity?
—Infectious etiologies typically present during a shorter time course than do other etiologies, such as iron deficiency anemia or certain types of CNS malignancies.
• Is the patient febrile?
—Fever, from an infectious etiology, can cause a decreased level of activity in children. However, hypothermia, particularly in neonates, can also result in decreased level of activity. In the neonate, hypothermia is a common manifestation of perinatally acquired herpes simplex virus infection and sepsis.
• Have the activities of daily living been impacted?
—Cardiac or pulmonary disease may be reflected in decreased activity levels. In older children, this would be evidenced by poor physical play, whereas in infants, poor feeding. Secondary gain in an older child may play a role if school avoidance appears to be an issue.
• Is there a history of decreased oral intake or increased output?
—Younger children are particularly sensitive to the metabolic demands of glucose utilization. Hypoglycemia can occur from increased losses from diarrhea and/or vomiting, and hyperglycemia from diabetes mellitus. In both instances, behavior changes can occur due to abnormal glucose levels.
• Has there been a change in behavior with friends or with school performance in the older child or adolescent?
—Mental health causes, in particular depression, should always be investigated as potential culprit when behavior change impacts relationships and school. Drug and alcohol abuse should also be considered in adolescents.
• Is there any history of trauma?
—In the acute setting, head injury from mild traumatic brain injury to concussion to intracranial bleeds can result in abnormal level of activity.
• Is there any reason to suspect nonaccidental trauma?
—Child abuse should always be taken into consideration in any child presenting with decreased level of activity. Physical, sexual, and neglect could all be demonstrated through a decreased level of activity. Any unusual injuries not consistent with the child’s age and mechanism of injury should also raise the clinician’s concern for child abuse.
• Is there a history of ingestion?
—Toxins frequently alter mental status in children. The mechanism may be through sedation (hypnotic agents, opiates, alcohols) or hypoglycemia (oral hypoglycemic agents or beta-blockers).
• Is there any history of abdominal pain or vomiting?
—Intussusception can present with depressed mental status in a child between 6 months and 5 years of age.
HISTORY OF PRESENT ILLNESS
A 15-year-old girl presented to the emergency department with a 3-month history of increasing fatigue. She gradually stopped participating in sports because of dizziness and palpitations. Her decreased level of activity has worsened to the point that as soon as she returns home from school in the afternoon she sleeps the rest of the day. She has had an 18-pound weight loss during this time period. Furthermore, for the past 5 days she has had a headache and occasional nonbloody, nonbilious
She was the product of a full-term delivery and has had no major medical illnesses. She has not required any surgeries. emesis. For the past 4 days she has also had mild upper abdominal pain. The remainder of her history and review of systems were noncontributory.
T 37.2°C; HR 110 bpm; RR 16/min; BP 100/60 mmHg
Weight and Height 25th percentile
On examination she appeared pale and tired, but was nontoxic appearing. She answered questions appropriately. Her head and neck examination revealed pale conjunctiva. She did not have any papilledema. Her lungs were clear to auscultation. Cardiac examination revealed tachycardia, but there were no murmurs or other abnormal heart sounds. Her abdomen was soft with normal bowel sounds. There was no hepatosplenomegaly. Capillary refill was delayed at 3 seconds. Her neurologic examination was normal. Of particular interest is the fact that her cranial nerve examination and motor strength were also normal.
A complete blood count revealed a white blood cell count of 2100 cells/mm3 (3% bands, 45% segmented neutrophils, 51% lymphocytes), hemoglobin of 5.4 g/dL, and a platelet count of 173 000/mm3. The mean corpuscular volume (MCV) was elevated at 98.7 fL.
COURSE OF ILLNESS
The patient was hospitalized for evaluation of her severe anemia. The peripheral blood smear provided a clue to the diagnosis (Figure 2-1).
FIGURE 2-1 Peripheral blood smear. (Photo courtesy of Marybeth Helfrich, MT, ASCP).
DISCUSSION CASE 2-1
The patient has a significant anemia. Anemia can be categorized on the basis of several etiologies. It could be because of nutritional deficiencies such as iron, folic acid, or vitamin B12. It could also be because of hemoglobinopathy, such as sickle cell anemia or thalassemia. The anemia could be from a hemolytic process such as hereditary spherocytosis or glucose-6-phosphatedehydrogenase deficiency. Finally, anemia could be from a hypoplastic or aplastic crisis.
When evaluating anemia, it is easiest to arrive at the correct diagnosis by assessing the hematologic indices, specifically the MCV. If the MCV is low, anemia is a microcytic anemia and causes iron deficiency anemia, lead poisoning, anemia of chronic disease, and thalassemias should be considered. If the MCV is normal, chronic disease, hypoplastic or aplastic crisis, malignancy, renal failure, acute hemorrhage, and hemolytic processes should be considered. Finally, if the MCV is high, the megaloblastic anemias should be evaluated, specifically folate deficiency, vitamin B12 deficiency, as well as some of the aplastic anemias.
Returning to our patient, we see that she had a macrocytic anemia as indicated by an elevated MCV of 98.7 fL. A hypersegmented neutrophil is located in the center of the peripheral blood smear (Figure 2-1). In the lower portion of the figure are several megaloblasts with a loose-appearing nuclear chromatin. Also noted are numerous misshapen mature erythrocytes, reflecting the mechanical fragility associated with megaloblastic anemias (Figure 2-1). The appropriate next step would be to measure the folate levels and vitamin B12 levels in her serum. Her folate levels returned at 8.2 ng/mL with normal in the range of 2-20 ng/mL. Her vitamin B12 level was less than 100 pg/mL with normal levels ranging from 200 to 1100 pg/mL. On further questioning, the patient stated that she has been a strict vegan for the past two years and has had no meat or animal-based products. Additionally, she did not take vitamin supplements and did not attempt to eat nonmeat-based foods containing vitamin B12, such as fortified cereal and fortified meat analogues (e.g., wheat gluten, soy-products). The diagnosis is dietary vitamin B12 deficiency.
INCIDENCE AND EPIDEMIOLOGY
Dietary vitamin B12 must combine with a glyco-protein (intrinsic factor) that is secreted from the gastric fundus. The vitamin B12-intrinsic factor complex is then absorbed at the terminal ileum via specific receptor mechanisms. Vitamin B12 is present in many foods and a pure dietary deficiency is rare. However, it may be seen in patients who do not drink any milk or eat eggs or animal products (vegans). Vitamin B12 deficiency can also result from lack of secretion of intrinsic factor in the stomach. When the cause of the lack of intrinsic factor is chronic atrophic gastritis, this condition is referred to as pernicious anemia. Other causes of vitamin B12 deficiency include surgical resection of the terminal ileum, regional enteritis of the terminal ileum, overgrowth of intestinal bacteria, disruption of the B12-intrinsic factor complex, abnormalities/absence of the receptor site in the terminal ileum, or inborn errors of the metabolism of vitamin B12.
Vitamin B12 plays an important role as a cofactor for two metabolic reactions, methylation of homocysteine to methionine and conversion of methylmalonyl coenzyme A to succinyl CoA. Vitamin B12 deficiency leads to accumulation of these precursors. Methionine is an important step in the synthesis of DNA. RNA production and cytoplasmic components are produced normally and the red blood cell production in the bone marrow yields large cells and hence a macrocytic anemia. Methionine is also converted to S-adenosylmethionine, which is used in methylation reactions in the central nervous system and hence CNS effects are seen with vitamin B12 deficiency. Neurologic manifestations in children include abnormalities, such as paresthesias, loss of developmental milestones, hypotonia, seizures, dementia, and depression. The neurologic changes are not always reversible.
Complete blood count and folic acid and vitamin B 12levels. The term megaloblastic anemia refers to a macrocytic anemia usually accompanied by a mild leukopenia or thrombocytopenia. The presence of a macrocytic anemia with normal folic acid levels and low vitamin B12 levels will diagnose most vitamin B12 deficiencies. However, reliance on abnormal hemoglobin may miss up to 30% of adult cases of vitamin B12 deficiency. On peripheral blood smear there are numerous schistocytes and misshapen mature red blood cells due to the increased mechanical red blood cell fragility associated with this condition. Erythroid precursors have loose appearing chromatin, giving them a characteristic appearance. Hypersegmented or multilobar neutrophils may also be noted. The appearance of at least one neutrophil with more than six lobes or more than five neutrophils with more than five lobes is considered significant. To assist in the diagnosis of vitamin B12 deficiency, serum levels of homocysteine and methylmalonyl coenzyme A may be elevated. Levels of methylmalonic acid (MMA), a precursor to methylmalonyl coenzyme A, may be elevated as well.
Other studies. After the diagnosis of vitamin B12 deficiency has been made, further studies can be performed to identify the cause. Specifically, a comprehensive dietary assessment, evaluation for parasitic infections, Schilling test (measures ability to absorb orally ingested vitamin B12), amino acid analysis, measurement of the unsaturated B12 binding capacity and transcobalamin II levels, genetic evaluation, and measurement of antibodies to parietal cells and intrinsic factor. Subspecialty consultation is often required to assist with the diagnosis.
Treatment of vitamin B12 deficiency depends on the cause. Frequently, vitamin B12 administration is necessary. If the anemia is severe, treatment should be instituted slowly and in a monitored environment. For malabsorptive causes, long-term treatment will be indicated. The recommended treatment is monthly injections of 100 μg/d of vitamin B12. Following the clinical response and laboratory values enables the clinician to titrate treatment to the patient’s response. It is not known whether folic acid therapy in patients who have vitamin B12 deficiency will worsen the neurologic symptoms of the vitamin B12 deficiency and may mask the hemato-logic symptoms of the megaloblastic anemia. In this case, the patient received a vitamin B12 injection and then began oral multivitamin and vitamin B12 supplementation. She also received nutritional counseling to help her create a nutritionally balanced vegan diet.
1. O’Grady LF. The megaloblastic anemias. In: Keopke JA, ed. Laboratory Hematology. New York: Churchill Livingstone; 1984:71-83.
2. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001;138:10-17.
4. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997;337:1441-1448.
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HISTORY OF PRESENT ILLNESS
A 16-day-old male presented to the emergency department with a 24-hour history of decreased level of activity and a choking episode with a feed. The infant has breastfed poorly since birth, worsening during the past several days. Two days prior to presentation, he was started on cow-milk-based formula supplementation; however, he continued to feed poorly. On the day of presentation, when the infant began to take a bottle, he gagged and choked and his eyes appeared to “roll into the back of his head” for approximately 2 seconds. Parents denied tonic-clonic, jerking activity, or color change, although he was less active after this episode. The infant has had decreased urine output, with only one wet diaper in the preceding 24 hours.
This was the fourth child born to a 28-year-old mother at 36 weeks gestation. The pregnancy was complicated by preterm labor and the mother received magnesium tocolysis. At 36 weeks gestation, the magnesium was stopped and labor was allowed to progress. Delivery was uncomplicated. Maternal prenatal labs and cultures were reportedly normal. The child was discharged from the hospital on the second day of life.
T 37.5°C; HR 142 bpm; RR 32/min; BP 95/65 mmHg
Weight and Height 5th percentile
On examination he was observed as being thin appearing and awake, but only cried with stimulation. His anterior fontanel was sunken; his lips and mucous membranes were dry. He had decreased tear production. His lungs were clear. The cardiac examination revealed a normal rate and rhythm without any murmur or abnormal heart sounds. His abdomen was soft without any organomegaly. His extremities were cool with a 2-second capillary refill. Both testicles were descended. His neurologic examination was significant for symmetric hypotonia without any focal abnormalities.
The white blood cell count was 16 300 cells/mm3 (38% segmented neutrophils, 54% lymphocytes, and 6% monocytes). Hemoglobin level was 18.2 g/dL and platelet count was 658 000/mm3. The results of the basic metabolic panel revealed sodium level to be 115 mEq/L; potassium, 7.7 mEq/L; chloride, 81 mEq/L; bicarbonate, 16 mEq/L; blood urea nitrogen, 31 mg/dL; creati-nine, 1.0 mg/dL; glucose, 89 mg/dL; and calcium, 10.7 mg/dL. A serum ammonia level was 39 μg/dL. Lumbar puncture revealed 1 white blood cell/mm3. The cerebrospinal fluid glucose and protein were normal. Cultures of cerebrospinal fluid, blood, and urine were obtained.
COURSE OF ILLNESS
Acutely, the infant received IV normal saline boluses for fluid resuscitation, as well as management to correct his hyperkalemia. He was empirically treated with intravenous hydrocortisone as well as ampicillin and cefotaxime owing to his ill appearance. He was admitted to the neonatal intensive care unit for further evaluation. Careful consideration of the laboratory studies suggested a diagnosis.
DISCUSSION CASE 2-2
Hyponatremia with hyperkalemia in a 2-week-old infant is most concerning for adrenal crisis due to congenital adrenal hyperplasia (CAH). Less common causes for adrenal crisis include adrenal hypoplasia congenita and bilateral adrenal hemorrhage. Other causes of electrolyte abnormalities in a young infant include water intoxication, inappropriate formula preparation, and gastroenteritis. Acute renal failure is uncommon in this age group, but can cause significant electrolyte disturbance. If an ill-appearing infant presents primarily with vomiting, pyloric stenosis and malrotation should be included in the differential diagnosis.
Additional laboratory evaluation revealed markedly elevated levels of 17-hydroxyprogesterone (>120 000 ng/dL; normal 4-200 ng/dL), a precursor for 21-hydroxylase enzyme. Additionally, the ACTH level was markedly elevated at 541 pg/mL (reference range, 9-52 pg/mL). The laboratory pattern was consistent with a salt wasting form of congenital adrenal hyperplasia. The diagnosis is 21-hydroxylase deficiency.
INCIDENCE AND EPIDEMIOLOGY
The adrenal gland is responsible for the production of three categories of steroids; mineralcorticoids, glucocorticoids (cortisol), and androgens (dehydroepiandrosterone, androstenedione, 11-β-hydroxyandrostenedione, and testosterone). Congenital adrenal hyperplasia is a category of autosomal recessive enzyme disorders that result in a deficiency of cortisol synthesis. Cortisol deficiency results in hypersecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and subsequent hyperplasia of the adrenal cortex. Depending on the location of the blockade, excesses or deficiencies of the mineralcorticoids and androgens can occur. The biochemical pathways of steroid synthesis are shown in Figure 2-2.
FIGURE 2-2. Adrenal steroid biosynthesis pathway.
The incidence of CAH ranges from 1 in 5000 to 1 in 15 000. Severity of illness depends on the severity of the genetic mutation. Although several enzyme deficiencies can result in CAH, 90%-95% are due to lack of 21-hydroxylase and 4% are due to 11β-hydroxylase deficiency. Other rare enzyme defects that have been described include 3β-hydroxysteroid dehydrogenase deficiency, 17a-hydroxylase deficiency, and cholesterol side chain cleavage enzyme deficiency, or lipoid CAH.
Clinical presentation of CAH depends on the gender of the patient as well as the enzyme deficiency. The key feature of classic 21-hydroxylase deficiency is androgen excess. Patients have inadequate production of glucocorticoids and miner-alocorticoids and subsequent ACTH stimulation. Excess precursors are shunted to the androgen pathway, leading to androgen excess and virilization. In the female, there is usually some degree of clitoromegaly and labial fusion. CAH is the most common cause of ambiguous genitalia in genetic females. The female internal genital organs are normal. Androgen excess in male infants is often limited to subtle penile enlargement.
While 25% of patients with 21-hydroxylase deficiency present with virilization alone, approximately 75% of patients will also present with salt wasting. Mineralocorticoid deficiency results in an inability to exchange potassium for sodium in the distal tubule of the nephron and hence there is sodium loss in the urine and an inability to secrete potassium. This electrolyte abnormality is referred to as salt wasting. Patients with the salt wasting type of CAH become symptomatic shortly after birth. They have progressive weight loss, dehydration, and vomiting. If the condition is not recognized, adrenal crisis and death occur.
Virilized females are often diagnosed at birth due to the ambiguous genitalia, whereas male patients may be diagnosed at one to two weeks of birth with a salt wasting CAH or in early childhood when they present with premature development of secondary sexual characteristics. Newborn screening for 21-hydroxylase deficiency is performed in most states in the United States of America.
The deficiency of 11β-hydroxylase results in both androgen and mineralocorticoid excess and therefore presents with virilization alone without salt wasting. Patients may have hypertension because of salt retention.
Other forms of CAH are extremely rare and may cause ambiguous genitalia in males. The 3β-hydroxysteroid dehydrogenase defect presents with salt wasting and virilization or ambiguous genitalia. The deficiency of 17a-hydroxylase may also cause hypertension and ambiguous genitalia. Lipoid CAH, while very rare, is often the most severe form, patients present with salt wasting and female phenotype.
There are several tests to assess for CAH.
Serum electrolytes. Hyponatremia, hyperkalemia, and hypoglycemia, while not adiagnostic, are often the laboratory abnormalities that prompt further investigation.
Other studies. In classic 21-hydroxylase deficiency, serum levels of 17-hydroxyprogesterone are markedly elevated. Interpretation of 17-hydroxyprogesterone levels in neonates is difficult because this level may be elevated in sick or premature infants and in healthy infants during the first two days of life. Cortisol levels are typically low in patients with salt wasting variety and normal in patients with virilization.
In 11-hydroxylase deficiency, the levels of 11-deoxycorticosterone and 11-deoxycortisol are elevated. The 3β-hydroxysteroid dehydrogenase defect will cause levels of 17-hydroxypregneno-lone to be elevated as well as 17-hydroxyprogesterone and hence may be confused with 21-hydroxylase deficiency.
Acutely, identification and management of adrenal crisis is critical. Aggressive fluid resuscitation and management of abnormal serum electrolytes as well as administration of stress dose IV hydro-cortisone are paramount.
Long-term management of CAH includes administration of glucocorticoids to inhibit excessive production of androgens. The most frequently recommended glucocorticoid is hydrocortisone administered orally. Dosages should be individualized based on growth and hormone levels. The administration of exogenous glucocorticoids continues indefinitely. Children with CAH require higher doses of glucocorticoids during periods of stress, such as illness, infection, and surgery. In the long term, patients with 21-hydroxylase deficiency reach an adult height below their predicted height based on mid-parental target height; treatment with growth hormone alone or in combination with a luteinizing hormone releasing hormone analog.
If the patient also has salt wasting, then mineralocorticoid replacement and sodium supplementation are also required. Fludrocortisone (florinef) is the currently recommended mineralocorticoid.
In the neonate with ambiguous genitalia, determining the sex is important. Consultation with a pediatric urologist can assist in achieving a more normal appearance. Because CAH is autosomal recessive, it is important to test siblings of affected patients.
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2. Lim YJ, Batch JA, Warne GL. Adrenal 21-hydroxylase deficiency in childhood: 25 years’ experience. J Paediatr Child Health. 1995;31:222-227.
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HISTORY OF PRESENT ILLNESS
A 3-month-old female presented to the emergency department with several days of increasing fussiness and poor feeding. The infant has always breastfed well; however, three days prior to admission the infant developed a weak suck and difficulty breastfeeding. Although the number of wet diapers had not changed, they have been less saturated, and the baby has had no bowel movement during the previous four days. The parents related that the child’s cry was not as loud as usual. The infant was evaluated by his pediatrician and referred to the emergency department. There has been no history of fever, vomiting, or diarrhea. There have been no ill contacts.
T 37.4°C; HR 156 bpm; RR 30/min; BP 100/80 mmHg
Weight and Height 50th percentile
On examination she was alert, but had a weak cry. Her head and neck examination was remarkable for bilateral ptosis and decreased facial expression. Cardiac and pulmonary examinations were normal. Her abdomen was distended but soft. On neurologic examination, she had a weak gag and poor tone. Her deep tendon reflexes were intact.
Laboratory testing revealed a white blood cell count of 10 100 cells/mm3 (33% segmented neutrophils, 56% lymphocytes, 8% monocytes); hemoglobin, 11.7 g/dL; platelets, 490 000/mm3; sodium, 139 mmol/L; potassium, 4.9 mmol/L; chloride, 106 mmol/L; carbon dioxide, 18 mmol/L; blood urea nitrogen, 12 mg/dL; creatinine, 0.3 mg/dL; and glucose, 58 mg/dL. A negative inspiratory force was measured at 20 cmH2O.
COURSE OF ILLNESS
Intravenous glucose and normal saline were administered in the emergency department. The patient ultimately required endotracheal intubation due to inability to protect her airway. Her appearance combined with historical features suggested a diagnosis that was confirmed by additional testing.
DISCUSSION CASE 2-3
The diagnostic possibilities in this child with decreased activity and hypotonia include neurologic conditions that involve either the upper motor neuron (cerebral cortex and spinal cord) or lower motor neuron (anterior horn cell, peripheral nerve, neuromuscular junction, or the muscle) (Table 2-3). Upper motor diseases, such as stroke, hemorrhage, and transverse myelitis, are possibilities. Lower motor diseases include poliomyelitis, spinal muscular atrophy, Guillain-Barré syndrome, congenital myasthenia gravis, botulism, and muscular dystrophies. Infectious etiologies such as overwhelming sepsis should be considered; however, lack of a fever makes these less likely. Ingestions can cause weakness, particularly barbiturates. Inborn errors of metabolism should be considered as well. Chromosomal disorders such as Down syndrome, Prader-Willi syndrome, achondroplasia, familial dysautonomia, and trisomy 13 may present with hypotonia as an early clinical feature; however, the acute onset in this case makes these diagnoses unlikely. The history of weakness, decreased feeding, weak cry, and constipation is a classic presentation of infant botulism.
TABLE 2-3. Causes of hypotonia in an infant.