Index of Suspicion

A 15-year-old boy is admitted to the hospital because of a prolonged generalized seizure after having become progressively lethargic over the past 24 hours. He has a 1-week history of malaise, anorexia, and headaches. His Glasgow Coma Scale (GCS) score is 8/15. Despite termination of abnormal movements following administration of intravenous anticonvulsants, his level of consciousness remains depressed, and endotracheal intubation is performed. He is admitted to the intensive care unit. CT scan of his head shows no focal abnormalities.He has a mild global developmental delay of unknown cause. He had three febrile convulsions at age 3 years and one generalized seizure when 9 years old. He takes no medication, is fully immunized, and has no family history of similar illness.The boy fails to waken after sedative medications are stopped. On physical examination, he remains comatose and has a GCS score of 4/15. His temperature is 100.76°F (38.2°C), pulse is 98 beats/min, and blood pressure is 127/68 mm Hg. Abnormal muscle tone and intermittent extensor posturing are noted. Pupils are equal in size and reactive. No neck stiffness or rash is noted. All other physical findings are normal.His hemoglobin concentration is 12.3 g/dL (123.0 g/L), WBC count is 8.0×103/mcL (8.0×109/L), and platelet count is 257.0×103/mcL (257.0×109/L). Serum electrolytes, C-reactive protein, BUN concentration, creatinine concentration, and coagulation studies are within normal limits. All cultures remain negative. An EEG shows diffuse, severe, nonspecific encephalopathy, but no epileptiform discharges. An additional test result reveals the underlying cause of his illness.A 14-year-old boy who has a past history of asthma, allergic rhinitis, sinusitis, and two previous hospitalizations for pneumonia presents to the ED with fewer than 24 hours of severe, worsening respiratory distress and temperature to 103.0°F (39.5°C). His asthma symptoms have been worsening, and he is scheduled to see a pulmonologist soon because bronchodilators and inhaled steroids have not improved his disease. Two maternal cousins also have asthma and recurrent pneumonias.Physical examination reveals a small, thin boy (weight and height below the 5th percentile for age) who breathes with severe subcostal and suprasternal retractions and tachypnea. Breath sounds are equal on both sides, with crackles audible bilaterally. No wheezing is present. Heart sounds are more prominent on the right, but normal first and second heart sounds are audible, and no murmurs are present. The boy has significant digital clubbing. The patient is placed on bilevel positive airway pressure, with resultant improvement in his distress. A chest radiograph elucidates the underlying diagnosis.A 9-year-old Amish boy presents with a 3-day history of a sore and stiff neck, jaw pain, drooling, difficulty swallowing, and stiffness of his right leg. Three days ago, he began to complain of jaw stiffness and a sore neck. Yesterday, his neck was canted to the right and his right leg felt sore. Today, he is unable to walk and is brought to the ED. He has received no immunizations.On physical examination, the boy has severe right torticollis and trismus and is drooling. There is no evidence of respiratory compromise. He has painful muscle spasms triggered by movement as well as generalized increased muscle tone and brisk-to-hyperactive deep tendon reflexes. His abdomen is tense and firm to palpation. His cognitive abilities are intact. He has a 6.0×1.0-cm gaping wound in the left parietal region of his scalp that extends to the galea aponeurotica. The wound bed is moist and red, and there is serous drainage.Laboratory results reveal a total WBC count of 11.0×103/mcL (11.0×109/L) with 82% neutrophils and 7% lymphocytes, Hgb of 14.3 g/dL (143.0 g/L), and platelet count of 327.0×103/mcl (327.0×109/L). His creatine kinase concentration is 228 units/L. His electrolyte and liver enzyme values are within normal limits. A clinical diagnosis is made that is confirmed later by a laboratory result.A metabolic screen was performed and revealed severe hyperammonemia (serum ammonia concentration of 456 mcmol/L; normal is <40 mcmol/L). A urea cycle disorder (UCD) was suspected, and additional laboratory investigations were ordered to confirm the diagnosis and identify the specific enzyme deficiency. Concentrations of citrulline and argininosuccinic acid were elevated, which suggested the condition argininosuccinate lyase deficiency, a diagnosis confirmed on erythrocyte enzyme analysis.Continuous high-flow venovenous hemofiltration was performed, and within 4 hours, the boy's serum ammonia concentration fell to the normal range. Concurrent therapy consisted of suspending protein intake, providing calories by intravenous administration of lipids and glucose, administering the nitrogen scavengers sodium benzoate and sodium phenylbutyrate, and providing supplemental arginine. Neurologically, the patient improved to a preadmission mental state within 7 days.Two months after admission, his ammonia values remain within the normal range on a low-protein diet (approximately 1 g/kg per day) with sodium phenylbutyrate and arginine supplementation. He is back in mainstream school with special educational support.Acute encephalopathy has a broad differential diagnosis that includes primary structural brain disease (eg, tumor, hemorrhage), trauma, infection (eg, meningoencephalitis), seizures, intoxication, and metabolic disorders. The differential diagnosis can be narrowed by considering age, presentation, relevant history, and physical findings. Cranial ultrasonography in newborns or CT scans in older patients should be performed to rule out structural causes of encephalopathy. The EEG can both confirm global cerebral dysfunction and exclude subclinical seizures, as demonstrated in this patient.No lumbar puncture was performed in this child due to the possibility of raised intracranial pressure, but he was given antimicrobial therapy because of the potential for meningoencephalitis.Intoxication is an important diagnostic consideration, and toxicologic screening is mandatory in all patients presenting with acute encephalopathy.Metabolic disorders must be considered in the patient who has encephalopathy. In addition to encephalopathy, other manifestations of inborn errors of metabolism (IEM) include chronic vomiting, developmental delay, psychomotor abnormalities, seizures, failure to thrive, and psychiatric illness. Patients tend to prefer low-protein vegetarian diets. Metabolic disorders also may present as a pattern of episodic acute decompensation triggered by changes in dietary intake, fasting, intercurrent illness, trauma, or childbirth. The specific signs and symptoms depend on the condition and its severity.Newborns who have an IEM typically appear well after birth and may become symptomatic after feeding has started because milk provides protein and carbohydrate loading. In the neonate, typical presentations include poor feeding, vomiting, lethargy, seizures, and shock. Sepsis usually is suspected initially in a baby who shows these signs, but a metabolic disorder always should be considered if results of the septic evaluation remain negative. Other conditions that can cause a newborn to become acutely ill after a period of stability include duct-dependent heart disease, drug withdrawal, congenital viral infection, and congenital adrenal hyperplasia. Basic laboratory findings suggestive of IEM include hyperammonemia, hypoglycemia, and unexplained acid-base disorders.Detecting IEM requires a high degree of suspicion, and these disorders can present at any time, even in adulthood. An understanding of the broad clinical manifestations of IEM provides the basis for knowing when to screen for these diseases.A history and physical examination are essential and should be tailored to the age of presentation. Specific laboratory studies should be undertaken in all patients who have a suggestive history, physical findings, or initial laboratory results. Metabolic samples should be obtained while the patient is symptomatic because values can be normal when the patient is well.Initial evaluation of suspected IEM includes the tests listed in Table 1. Specimens for specialized testing, as listed in Table 2, should be collected and stored in the acute phase and processed when indicated by the initial results and after metabolic specialist input is obtained.The urea cycle is a metabolic pathway that transforms nitrogen derived from protein metabolism to water-soluble urea, which is excreted in the urine. UCDs are IEM characterized by episodic, life-threatening hyperammonemia resulting from partial or complete inactivity of enzymes responsible for eliminating nitrogen waste.Deficiencies in the first four enzymes of the urea cycle (carbamyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, or argininosuccinate lyase) result in accumulation of ammonia and the precursor metabolites (Fig. 1). Metabolic decompensation resulting in hyperammonemia causes neurologic injury because free ammonia is highly toxic to the CNS.Plasma quantitative amino acid analysis identifies which precursor metabolites are elevated and can be used to differentiate among the UCDs. The specific UCD, however, must be confirmed by enzyme analysis of tissue samples.Argininosuccinic aciduria is an autosomal recessive deficiency of the enzyme argininosuccinate lyase. This enzyme catalyzes the conversion of argininosuccinic acid to arginine and fumaric acid (Fig. 1). A deficiency in this enzyme leads to accumulation of argininosuccinic acid and the precursor metabolites citrulline and ammonia as well as a deficiency in arginine, as demonstrated in this case.The clinical phenotype of UCDs is extremely variable and depends, in part, on the amount of protein intake. The classic presentation in newborns is similar to that of other IEM and includes poor feeding, vomiting, lethargy, and coma due to hyperammonemia.Patients who have partial enzyme deficiencies may present outside the newborn period. Recurrent vomiting, developmental delay, learning difficulties, seizures, brittle hair in infancy (trichorrhexis nodosa), and protein intolerance are common manifestations, and all were present in this patient on additional inquiry. Failure to thrive and psychomotor delay may warrant suspicion of a UCD. It is of interest that this boy had poor growth as a toddler but now is growing in the normal range, although he is slim. Less severe forms of enzyme deficiency may present in older patients with subtle neurologic abnormalities or psychiatric abnormalities.Precipitants of acute hyperammonemic encephalopathy include catabolic states due to infection, trauma, or fasting. Medications affecting protein catabolism such as glucocorticoids can induce a metabolic decompensation and should be avoided in patients known to have UCD.On further questioning, this patient's mother reported that her son had a “dairy and egg allergy” diagnosed at 2 years of age. Interestingly, the patient had self-selected a low-protein diet; he had refused to eat any meat from a young age and avoided any high-protein food. When he was less able to control his protein intake, as when eating out, he suffered recurrent episodes of vomiting. Furthermore, he has had brittle hair from infancy and failure to thrive, both typical features of a UCD.General principles for managing hyperammonemic encephalopathy due to decompensation in patients who have UCDs include removing ammonia with hemodialysis or hemofiltration and nitrogen scavengers, decreasing the protein load, minimizing catabolism, and supplementing essential amino acids.A metabolic disorder should be included in the differential diagnosis of every patient who has encephalopathy of unknown cause regardless of the patient's age. Inherited metabolic disease can present at any age and requires a high degree of suspicion. This case illustrates the importance of obtaining a past medical history; this patient's history showed multiple clues of metabolic disease. Early recognition and treatment might have prevented some of his neurologic handicap.This child's refusal to eat protein is an example of the unconscious decision-making that can occur without understanding how or why the choice was made. Patients may make such instinctive and effective adjustments to compensate for their own vulnerabilities and, in turn, minimize the manifestations of their diseases. (Nicole L. Mettauer, MD, Christine M. Pierce, MB, Mark J. Peters, MB, PhD, Great Ormond Street Hospital, London, United Kingdom)The chest radiograph demonstrated situs inversus, with extensive bilateral airspace disease and cystic changes (Fig. 2). A Gram stain of sputum showed many nucleated cells and gram-negative rods (later identified as Haemophilus influenzae). Viral direct antigen testing was positive for influenza A.This clinical spectrum is consistent with the diagnosis of Kartagener syndrome. Although bronchiectasis, multiple pneumonias, and failure to thrive also occur in patients who have cystic fibrosis, the presence of situs inversus is classic for Kartagener syndrome.Kartagener syndrome consists of a clinical triad of situs inversus, chronic sinus disease, and bronchiectasis, initially described in 1904 but first published by Manes Kartagener in 1933. This syndrome is part of a larger disease spectrum known as primary ciliary dyskinesia (PCD). Infertility in male patients was noted as an additional manifestation in the 1970s.PCD is an autosomal recessive condition that has no racial predilection and has a reported incidence of 1 per 15,000, although the disorder is believed to be underreported. As the name implies, the principal defect is one of ciliary motility, ranging from mild impairment and abnormal motion to complete absence of motion. The severity of the condition varies greatly, based on the gene mutations and subsequent degree of dysmotility. Interestingly, 50% of patients who have PCD have situs inversus. During embryonic stages of development, cilia are responsible for the normal rotational pattern and laterality of organs. When this function is not intact, laterality becomes random. Thus, probability dictates that only 50% of affected patients develop situs inversus.Clinical manifestations vary, depending on the age when the disease presents. Descriptions have been published of neonates who have situs inversus, rhinorrhea, and radiographic findings consistent with pneumonia or retained lung fluid. Infants present with chronic otitis, chronic cough, and frequent episodes of bronchiolitis. Older children have the more classic presentation of cough, recurrent sinus disease, and frequent pneumonias.Decline in pulmonary function and the presence of bronchiectasis tend not to appear until late childhood or early adulthood. Digital clubbing (Fig. 3) is a late finding and indicates severe disease. A misdiagnosis of asthma is common, and many patients are diagnosed as having allergic rhinitis or sinusitis. Occasionally, infertility is the primary presenting complaint, with subsequent elucidation of a history of sinus disease or recurrent pneumonias. Males afflicted with the syndrome have immotile sperm, and females are subfertile but can conceive. Congenital heart lesions are present in approximately 5% to 10% of cases. Various diagnostic tests have been used over the years, but electron micrography of the cilia is the most definitive.Although the presence of situs inversus is helpful for diagnosis and PCD should be sought in all patients who have situs inversus, it is important to remember that only 50% of patients who have PCD have situs inversus. The presence of situs inversus often leads clinicians to a suspicion of cardiac defects. In reality, very few patients born with true situs inversus have this association.However, 20% of children born with situs inversus have Kartagener syndrome. Therefore, a patient who has the incidental finding of situs inversus in the absence of a murmur or other cardiac symptoms would be served better by a referral to a pulmonologist than a cardiologist.Disease progression bears a remarkable similarity to cystic fibrosis, although there is no significant decrease in the lifespan of patients who have PCD if appropriate therapy is obtained. Patients do, however, occasionally require lobectomies, and lung transplantation has been documented. Patients who have PCD tend to follow infectious patterns similar to patients who have cystic fibrosis, with early colonization with H influenzae or Staphylococcus, and in later life, Pseudomonas colonization. Sputum cultures from two previous hospitalizations for this patient were positive for H influenzae.Patients suspected of having PCD should be referred to a pulmonologist, otolaryngologist, and a and to a to for of PCD pulmonary to control and pneumonias, and of sinus and airway disease. is for has not been to the clinical and many patients develop remains a disease although is Early diagnosis is to in pulmonary although most patients are of school age or at the of PCD should be considered in any patient afflicted with bronchiectasis, in patients suspected of having cystic but who have test or and in children multiple or chronic to The presence of clubbing in any patient should referral to a pulmonologist if symptoms of heart disease are MD, MD, of at further questioning, the boy's that days he was on his head by a part of a The wound was at with and a a of was A clinical diagnosis of generalized was made. The boy received of one of and The head wound was and, muscle spasms to and were with intravenous with to every 3 hours. He was placed on and the was to He later was placed on every hours. His spasms on the and the for frequent was at a of every cultures were for growth of and there was growth of and days after admission, the boy began to improvement in his muscle On of admission, he a evaluation by the and a diet was after admission, his muscle stiffness was and physical therapy was He was 9 days after on and analysis performed after revealed in the used to the scalp in the United is an but disease that among or is a infection, by an by the the muscle and the to cause muscle is in and and its are in the The in The period of can range from days to most occur within days of by is by tissue that has a Thus, due to (eg, and a have been known to develop with or infection more by of deep with tissue with or from and are to infection by that not tissue such as are less to develop to of who have not evidence of a clinical varies with the forms of the disease. In muscle spasms usually in to the In generalized the spasms often with which can to The muscle spasms to the and are triggered by also can is with head and neck is characterized by and may to generalized in is with and with poor and for in that include of birth in an and the of or of or with or to the differential diagnosis of includes infection, drug seizures, and The diagnosis of remains studies are of in with a of positive findings from wound of includes of treatment of infection, and A of in a of to is to although some a of and intravenous can be used if is or intravenous is the of is an treatment for to days is should be and of tissue may be such as anticonvulsants, and have been used for muscle and In and are case for from 10% to are with a poor in most of is to be with to normal function in most cases. there are reported of physical or may result in developmental is with or should of of at 2, and to months and 4 to or years of age, a of is This also can be given in of one in older and from to and effective is in most children after three have been are to to include on the of and on and of a is with treatment of deep and of or depending on the of the wound and the history infection not and an should be after clinical is very even in may include pain, and following administration are with a high degree of suspicion must be is a clinical and the diagnosis is treatment is without for laboratory results. by remains the of this disease. MD, of J. MD, PhD,