BOARD REVIEW ANSWERS 2/18 Question 22 A Headache is a frequent primary or secondary complaint in pediatric practice. The clinician must be able to distinguish primary, benign headaches (ie, migraines or tension headaches) from secondary, pathologic headaches, which can stem from a tumor, abscess, or other causes of increased intracranial pressure. Secondary or ominous headaches are characterized by occipital or frontal pain. The headache frequently is worse in the morning, after the child has been recumbent at night and intracranial pressure rises with less effect from gravity. The child may wake in the early morning with a complaint of head pain. Vomiting may occur at that time, too. Headaches that are associated with persistent vomiting are worrisome, especially when diarrhea is absent. Secondary headache also may be precipitated by the Valsalva maneuver. New-onset neurologic findings in the first 2 to 6 months after onset of pain are especially concerning for a secondary headache. Specifically, the finding of papilledema, strabismus, unilateral weakness, or ataxia should alert the practitioner to the likelihood of a structural lesion. Neurologic deficits such as weakness, strabismus, or ataxia also can be seen rarely with migraine variants, such as hemiplegic migraine, ophthalmoplegic migraine, or basilar migraine, respectively, but such atypical headache syndromes are diagnoses of exclusion. Urgent neuroimaging should be obtained for children who have headache and neurologic deficits. Computed tomography scan of the head without contrast can be obtained quickly without sedation to identify a structual lesion causing headache from mass effect. Alernatively, magnetic resonance imaging of the head can be obtained if the child is stable and monitored closely during any sedation that may be required. The headaches exibited by the 17-year-old girl in the vignette, combined with her ataxia, left hemisensory loss, right dyscoordination, and neck pain, point to a posterior fossa mass. Head computed tomography scan is the most appropriate next step. Lumbar puncture is contraindicated when there is suspicion of a mass. Nerve conduction velocities are useful only to evaluate a peripheral neuropathy, and somatosensory evoked potentials are used to evaluate demyelination in the peripheral or central nervous system. A toxin would not produce this constellation of symptoms and signs. Question 211C Seizures in the neonatal period often are due to hypoxic-ischemic encephalopathy or intracranial pathology such as malformation or hemorrhage. Most are controlled readily with a single or, possibly, two anticonvulsant therapies. The patient described in the vignette has refractory seizures that have not responded to three anticonvulsants, and the infant's condition progresses to coma. This presentation is not uncommon in metabolic diseases, where seizures may be focal or multifocal clonic jerks or generalized and tonic. Such events typically occur after the first 48 postnatal hours. Because transient abnormalities in glucose and electrolytes are not present in this patient, inborn errors of metabolism need to be ruled out. A categorical approach to the laboratory evaluation of the comatose newborn or young infant is helpful. Toxins and drugs can be evaluated by history and blood, urine, or meconium toxicology screens. Intracranial pathology can be evaluated by ultrasonography or computed tomography scan. Hypoxia-ischemia mechanisms can be discerned by history, blood gas analysis, evidence of multiple organ system dysfunction, the neurologic examination, and the timing of the onset of seizures (generally in the first 24 hours of postnatal life). Infection may be systemic or focal (central nervous system) and can be evaluated by cultures, antigen testing, and use of specific viral polymerase chain reaction tests of the blood, urine, and cerebrospinal fluid. The diagnosis of inborn errors of metabolism requires consideration of broad categories of metabolism: problems with amino acid metabolism that produce elevated serum concentrations of certain amino acids (eg, phenylketonuria with excessive serum phenylalanine and urinary excretion of phenylalanine and its metabolites); carbohydrate metabolism that may result in hypoglycemia, organic acidemias, hyperammonemia, and acidurias; and problems in fatty acid metabolism that result in hypoglycemia with corresponding hypoketosis and often elevated serum transaminases and ammonia concentrations. For these reasons, the evaluation should include measurement of serum electrolytes, glucose, lactic acid, ammonia, and amino acids as well as organic acids from the serum and urine. Lead toxicity is a consideration for coma in the older infant, toddler, or child exposed to environmental lead. Measurement of urinary reducing substances may be helpful in galactosemia, but is insufficient when evaluating encephalopathy and coma in the newborn or young infant in whom an inborn error of metabolism is being ruled out. Serum cortisol, thyroxine, and thyroid-stimulating hormone may be important in evaluating congenital hypotonia, persistent hypoglycemia, or suspected panhypopituitarism. Total and free carnitine and acylcarnitine profile results are abnormal in infants who have fatty acid oxidation defects. Affected infants present with hypoglycemia, cardiomyopathy, and urinary hypoketosis. Question 54 E Ataxia is a broad term implying simply dyscoordination. Although acute ataxia often is associated with cerebellar pathology, this disturbance also can arise from defects in proprioception, vestibular function, vision, or even weakness. When evaluating the child who has acute ataxia, the clinician should consider categories of disease, including toxic ingestion (eg, alcohol, thallium used as a pesticide, and anticonvulsants such as phenytoin), neoplasm (eg, brainstem glioma, medulloblastoma), infection (labyrinthitis, postinfectious encephalomyelitis [also known as acute cerebellar ataxia], Guillain-Barré syndrome), vasculopathy (cerebellar hemorrhage), trauma, metabolic conditions (eg, Hartnup disease and abetalipoproteinemia), and conversion disorder. Specific clues from the history and physical examination may point to a diagnosis. For example, fever suggests meningoencephalitis, and acute cerebellar ataxia follows a viral infection, such as varicella or influenza. Deep tendon reflexes are depressed or absent in Guillain-Barré syndrome. Horizontal nystagmus is common with peripheral processes such as labyrinthitis or even cerebellar hemisphere lesions or sedative-hypnotic ingestion. Vertical nystagmus can be seen with central processes such as hemorrhage or Chiari malformation, but also is suggestive of phencyclidine, phenytoin, and lithium poisoning. The development of clumsiness, dysarthria, and nystagmus over only hours described for the child in the vignette suggests a very rapid process. The vertical plus horizontal nystagmus is typical of phenytoin ingestion. The lack of fever makes an infectious process unlikely. Some degree of obtundation would be expected with cerebellar hemorrhage. The normal reflexes are inconsistent with Guillain-Barré syndrome. Ataxia with a brain tumor develops over days or weeks. Question 70 B The sudden and self-limited ataxia with nystagmus, but without vomiting or loss of consciousness, followed by some residual horizontal nystagmus described for the girl in the vignette is typical of benign paroxysmal vertigo. Benign paroxysmal vertigo is characterized by abrupt, brief episodes of vertigo with ataxia in children ages 1 to 3 years. The child may appear frightened, have pallor, and may indicate feeling dizzy. Rapid eye movements or nystagmus may be observed if the eyes are open. Benign paroxysmal vertigo is believed to be a migraine variant. Vertigo is defined as an illusion of movement, most often a sensation of rotation. The simplest approach to evaluating this complaint is to consider its temporal pattern and whether hearing is affected. Acute vertigo without hearing loss may stem from benign paroxysmal vertigo in toddlers, vestibular neuronitis in adolescents, labyrinthine concussion, migraine, seizures (rarely), and benign paroxysmal positionalvertigo (BPPV). Most of these disorders last minutes to sometimes hours, although BPPV lasts only 5 to 20 seconds and occurs with changes in head position. BPPV can be elicited by the Hallpike-Dix maneuver. The child is moved abruptly from a sitting to lying posture, with the head hanging 45 degrees below the horizontal and rotated 45 degrees to one side, evoking vertigo and nystagmus. Acute vertigo lasting hours to days accompanied by hearing loss may be due to labyrinthitis, otitis media, perilymphatic fistula, temporal bone fracture, and Ménière disease. Ménière disease is a recurrent disorder that involves tinnitus and progressive hearing loss. Continuous vertigo over days to weeks may indicate a cholesteatoma; posterior fossa tumor; vestibular schwannoma (associated with neurofibromatosis II); demyelinating disease; or drug toxicity from aminoglycosides, isoniazid, furosemide, or phenytoin. The 2-year-old child in the vignette has not displayed headache or cranial neuropathies, making basilar migraine unlikely. The spontaneous and rapid resolution of her symptoms excludes cerebellar hemorrhage and phenytoin intoxication. No loss of consciousness has been observed, making seizure unlikely. Question 246 D Metabolic disorders, degenerative diseases, and infections can produce movement disorders, but drug exposures also should be considered as causes of ataxia, tremor, and dystonia. Ataxia can be triggered by anticonvulsant toxicity from phenytoin, phenobarbital, and even carbamazepine. Alcohol and thallium also can lead to ataxia. Drugs that can cause tremor include amphetamines, valproic acid, neuroleptics such as phenothiazines, tricyclic antidepressants, caffeine, and theophylline. Stimulant medications can unmask Tourette syndrome, but by themselves do not produce tics. Certain drugs are capable of producing an acute dystonic reaction in children. Therapeutic doses of phenytoin or carbamazepine rarely cause progressive dystonia in children who have epilepsy and an underlying structural abnormality of the brain. Children may have an idiosyncratic reaction to neuroleptic drugs, characterized by acute dystonic posturing that may be confused with encephalopathy. Intravenous diphenhydramine, 1 to 2 mg/kg per dose, may reverse the drug-related dystonia rapidly. Severe rigidity combined with high fever and delirium also may occur as part of the neuroleptic malignant syndrome a few days after the initiation of neuroleptic drugs. The 9-year-old girl described in the vignette is experiencing a classic acute dystonic reaction, with posturing and even oculogyric crisis. Metoclopramide is in the family of neuroleptic drugs, although used most often for nausea or gastrointestinal motility and most likely is the cause of the dystonic reaction. The antiemetics lorazepam and ondansetron do not induce movement disorders, and diphenhydramine is used to reverse dystonia from metoclopramide. Aprepitant is a new substance P/neurokinin-1 antagonist used for chemotherapy-induced nausea and vomiting. It can cause weakness or dizziness, but does not cause movement disorders. Question 102 C Weakness can be a broad complaint in a child, but identifying the neurologic origin of the weakness, its temporal pattern, and associated findings can point to appropriate neurodiagnostic tests and help establish the diagnosis. In general, muscular weakness tends to be greater proximally than distally, affecting most the hips and shoulders. Creatine kinase is often elevated in myopathy. Neuropathy also produces symmetric weakness, but the deficit is greater distally than proximally and associated with hyporeflexia and sometimes, sensory loss. Nerve conduction velocities in neuropathy demonstrate diminished velocity or amplitude. Neuromuscular junction problems tend to worsen throughout the day, and in children are more notable rostrally than caudally. Myelopathy produces weakness inferior to a spinal lesion, often with a sensory deficit inferior to a specific dermatome. Weakness associated with brainstem processes often is asymmetric and characterized by cranial neuropathies. Cerebral processes with weakness produce hemiparesis and unilateral hyperreflexia and may cause visual field loss or speech problems. Acute causes of weakness include stroke (cerebrum or brainstem); acute intermittent porphyria, diphtheria, poliomyelitis, West Nile virus infection, or tick paralysis (neuropathy); organophosphate poisoning or botulism (neuromuscular junction); and periodic paralysis and acute infectious myositis (muscle). Subacute processes include tumor or abscess (cerebrum or spine), transverse myelitis (spine), myasthenia gravis (neuromuscular junction), Guillain-Barré syndrome (nerve), and polymyositis and dermatomyositis (muscle). Muscular dystrophies tend to present chronically. The 7-year-old girl described in the vignette displays weakness that is proximal more than distal, as well as elevated creatine kinase concentrations, suggesting a myopathy. The 4-week duration plus the erythematous malar rash raise suspicion about dermatomyositis. Muscle biopsy can demonstrate the fiber type variability, central nuclei that are vesicular, infiltration with inflammatory cells, and necrosis that characterize condition. The erythrocyte sedimentation rate is a nonspecific test; it is elevated in myopathy, infections, and multiple other disorders. This child does not have the chronic course of the three most common dystrophies (Duchenne, Becker, and fascioscapulohumeral). Therefore, polymerase chain reaction testing for dystrophin or genetic testing for fascioscapulohumeral dystrophy is not warranted. Serum antinuclear antibody may be positive in patients who have dermatomyositis, but it is a nonspecific finding. It is most useful in the evaluation of patients who may have systemic lupus erythematosus, but lupus will not produce the myopathic weakness reported for this girl. Question 118 C The limpness or floppiness reported for the infant in the vignette points to hypotonia, which often is disproportionate to weakness. The trunk and extremities of the infant who has hypotonia hang limply when the child is suspended horizontally. When the clinician suspends the child vertically by holding the infant's axillae, the baby will "slip through" the examiner's hands, rather than adducting his or her shoulders. Hypotonia is found in a wide variety of pathophysiologic processes arising throughout the motor system. Cerebral, or central, causes of hypotonia include chromosomal abnormalities (Down syndrome, Turner syndrome, Prader- Willi syndrome), metabolic abnormalities (hypothyroidism, leukodystrophies), sepsis, and perinatal trauma (hypoxia-ischemia or intracranial hemorrhage). The most worrisome cause of hypotonia localizing to the brainstem and spine is spinal muscular atrophy. Neuropathy is rarely a cause of infant hypotonia (congenital polyneuropathy, familial dysautonomia), but peripheral hypotonia commonly stems from the neuromuscular junction (botulism, myasthenia gravis, or myasthenic syndrome) or muscle (muscular dystrophy and congenital myopathies). Clues on physical examination often help lead to the diagnosis. Depressed or absent deep tendon reflexes are seen with spinal muscular atrophy, neuropathies, and even botulism. Tongue fasciculations are common with spinal muscular atrophy. Botulism produces rostral greater than caudal weakness. Low birthweight, almond-shaped palpebral fissures, and hypogonadism are typical of Prader-Willi syndrome. Laboratory investigations are targeted toward the disorders suggested by physical examination findings. The child in the vignette has physical findings typical for Prader-Willi syndrome; fluorescent in situ hybridization testing for the gene locus at the 15q11-13 chromosomal region is indicated. Arylsulfatase A testing assesses for metachromatic leukodystrophy, which develops later in the first postnatal year. Measuring thyroid-stimulating hormone is not likely to be useful because the boy lacks signs of hypothyroidism. Electromyography and nerve conduction studies are used to assess a congenital myopathy or spinal muscular atrophy. Magnetic resonance imaging of the brain would be useful if there were a history of perinatal trauma or concern about cerebral dysgenesis. Question 11 D The developmental regression, acquired microcephaly, and hand-wringing movements described for the girl in the vignette are typical findings in the X-linked condition Rett syndrome. Rett syndrome is a neurodegenerative disorder that is associated with developmental regression as well as generalized tonic-clonic seizures, poor feeding, constipation, sleep disorder, breath-holding spells, scoliosis, muscle wasting, cardiac arrhythmias, and death in late adolescence. The diagnosis can be made by testing for the MECP2 gene (chromosome X q28), a gene for a transcription factor that binds to methylated CpG island and silences transcription. Deficiency of arylsulfatase A causes the degenerative lysosomal disorder metachromatic leukodystrophy. Fragile X testing is performed primarily in boys who have cognitive impairment and dysmorphic features. Hexosaminidase A deficiency causes Tay-Sachs disease. Accumulation of N-acetyl-aspartic acid in the urine is associated with the leukodystrophy Canavan disease. Question 7 A Distinguishing ominous, or secondary (ie, underlying pathology), headaches from primary, benign (ie, migraine or tension) headaches is a challenge for pediatricians. Headaches from structural lesions, such as a brain tumor, have characteristic symptoms and signs. The pain is often occipital or frontal, and the headache is recent in onset or has been present for a short duration. The headache often is worse in the morning, after the child has been prone or supine at night and intracranial pressure has increased. The child may wake in the early morning with a complaint of head pain and vomiting. Headaches that are associated with vomiting, particularly when increasing in severity or frequency, can be worrisome, especially when diarrhea and non-neurologic symptoms are absent. Pain also may be precipitated by a Valsalva maneuver. Migraines tend to be familial. An absence of other family members who have headache might suggest a secondary headache, if other features are present. New-onset neurologic findings within the first 2 to 6 months of the onset of pain are especially worrisome for a secondary headache. Specifically, the finding of papilledema, strabismus, unilateral weakness, or ataxia should alert the practitioner to the likelihood of a structural lesion. Urgent neuroimaging should be obtained for children who have such findings. Computed tomograpy of the head without contrast can be obtained quickly without sedation to identify a structual lesion causing headache from a mass effect. Magnetic resonance imaging of the head is an alternative if the child is stable and monitored closely during sedation. The 8-year-old boy described in the vignette has new-onset occipital headaches in addition to a complaint of blurred vision. The esotropia, indicative of strabismus, likely arises from an abducens paresis, and ugent computed tomography of the head is warranted. Lumbar puncture is contraindicated until a mass lesion, and the attendant risk of cerebral herniation, has been excluded. The child's blurry vision stems from diplopia, not a retinal or optic nerve process. Thus, electroretinography and visual evoked responses, respectively, have no role. Radiographs of the skull and cervical spine only rarely are useful in the evaluation of headache, such as when platybasia or Klippel-Feil deformity are suspected. Question 39 C Ataxia is a nonspecific term referring to muscular incoordination from a neurologic process. Although this process most often arises in the cerebellum, ataxia also can stem from a proprioceptive deficit due to neuropathy; weakness due to a cerebral, brainstem, spine, or muscle process; an inner ear disturbance producing vertigo; or a conversion disorder (a diagnosis of exclusion). The key to evaluating the child who has ataxia is to identify the nervous system origin and cause of the process. A neurologic examination, including assessment of eye movements, strength, gait, deep tendon reflexes, and sensation, is the first step. Subsequent laboratory investigations might include urine toxicology screen or computed tomography (CT) of the head if a cerebellar mass is suspected. Lumbar puncture to examine cerebrospinal fluid is indicated if there is fever, absence of deep tendon reflexes as recognized in Guillain-Barré syndrome, or abrupt onset with encephalopathy or seizures that suggests acute disseminated encephalomyelitis. In general, lumbar puncture should be performed in the child who has ataxia only after head CT has excluded a mass lesion and the accompanying risk of cerebral herniation, unless there are signs such as absent reflexes that localize the process outside the brain. The ataxia plus areflexia reported for the girl in the vignette, paired with a facial palsy, are virtually pathognomonic for Guillain-Barré syndrome. The pain, loss of motor function, and altered sensation stem from demyelination of nerve roots. Lumbar puncture will reveal albuminocytologic dissociation, with an increase in protein and no pleocytosis. CT is unnecessary before the lumbar puncture in this case because the facial palsy and absent reflexes point to a peripheral nerve process. Electroencephalography would be useful for a child who has paroxysmal events suggestive of seizure, unlike this patient. The presentation also makes accidental ingestion unlikely, and there is no need for a urine toxicology screen. Magnetic resonance imaging of the spine would be useful if, instead of facial palsy, there was localizing back pain and loss of sensation or motor function inferior to that region of the cord. Question 55 A The 15-year-old boy described in the vignette has frontal headaches and papilledema, suggestive of increased intracranial pressure. Head computed tomography (CT) has excluded the possibility of a mass lesion causing the pain. Although magnetic resonance imaging with gadolinium rarely can provide helpful diagnostic information not demonstrated by noncontrast CT, a mass lesion that produces papilledema or headache would be large enough to be seen on CT by a display of mass effect or effacement of ventricles or cerebral sulci. Lumbar puncture should be the next test performed in the patient to determine opening pressure and exclude infection, aseptic meningitis, or pseudotumor cerebri. Consultation with an ophthalmologist or neurosurgeon is not necessary before performing this essential test. A urine toxicology screen will not detect any illicit substances that increase intracranial pressure. Indeed, because the child is receiving isotretinoin, a drug known to raise intracranial pressure, lumbar puncture should lead to the diagnosis of pseudotumor cerebri. Pseudotumor cerebri, sometimes referred to as benign intracranial hypertension, is an elevation of intracranial pressure, as measured by a lumbar cerebrospinal fluid opening pressure beyond 20 to 25 cm H2O in a decubitus position, without underlying neuropathology. The cerebrospinal fluid cell count is normal, as are the glucose and protein levels, although protein concentrations sometimes are low. Children present with headache and papilledema and sometimes diplopia or rarely other cranial neuropathies. The condition often is self-limited and resolves after a single lumbar puncture. If pseudotumor cerebri persists for weeks or longer, treatment with serial lumbar punctures or oral acetazolamide and furosemide is indicated to decrease pressure, so that optic nerve edema does not lead to permanent enlargement of the physiologic blind spot and persistent visual loss or even blindness. In rare instances, a lumboperitoneal shunt is placed to decrease pressure. In dire situations, optic nerve fenestration is performed to open the nerve sheath. Multiple causes of pseudotumor cerebri have been reported, and the clinician should exclude the possibility of these coexisting conditions. Metabolic disorders (hyper- or hypovitaminosis A, Addison disease, hypoparathyroidism, pseudohypoparathyroidism), hematologic disorders (iron deficiency, polycythemia), infections (otitis media and mastoiditis), systemic lupus erythematosus, and pregnancy all can lead to pseudotumor cerebri. More frequently in children, the disorder can be associated with obesity or drugs (isotretinoin and other retinoids, tetracycline, minocycline, corticosteroids, nalidixic acid, nitrofurantoin, oral contraceptives). This boy's isotretinoin should be discontinued to eliminate definitively his pseudotumor cerebri. Question 199 E Herpes simplex virus (HSV) infection of the central nervous system occurs primarily in two circumstances: 1) the newborn and 2) encephalitis of older children and adults. HSV infection should be considered in any baby who has signs consistent with encephalitis, including focal, multifocal, or generalized seizures; apnea; bradycardia; and cranial nerve abnormalities. HSV infection occurs most often in the second to third week after birth, and multiorgan disease (skin, liver, lungs) may be present. Cerebrospinal fluid (CSF) findings are nonspecific and include pleocytosis and increased protein. As in all cases of neonatal HSV infection, prompt initiation of therapy is critical and should commence whenever the diagnosis is suspected, while confirmatory diagnostic procedures are pursued. Even with treatment, most babies develop persistent and significant neurologic impairment. In older children, the hallmarks of HSV encephalitis are fever, altered mental status, and focal neurologic signs. However, as with the 3-year-old in the vignette, HSV can be difficult to diagnose clinically because presenting symptoms and signs are nonspecific and variable. Thus, acyclovir should be instituted while the diagnosis is being pursued. Laboratory and imaging studies may help. Electroencephalographic findings can include spike and slow wave activity localized to the temporal region, but their absence does not eliminate the possibility of HSV encephalitis. Computed tomography or magnetic resonance imaging may reveal a localized cerebral lesion with edema and hemorrhage (Item C199A), suggestive of HSV infection, but this occurs relatively late in the course of the illness. Similar to neonates, routine CSF findings in children are not diagnostic. There may be pleocytosis or increased protein concentrations; the presence of red blood cells is variable. HSV rarely is isolated by culture of the CSF. Given this relatively low yield, detection of the HSV DNA by polymerase chain reaction has become the "gold standard" for diagnosing HSV encephalitis. Because the toddler in the vignette continues to be febrile and lethargic 1 hour following his seizure, a febrile seizure is unlikely. In view of these findings and because the Gram stain is negative, serious consideration must be given to the possibility of HSV encephalitis. Acyclovir should be instituted intravenously along with intravenous broad-spectrum antibiotics. Administration of oral acyclovir is inappropriate. Intravenous dexamethasone is not indicated because there is no suspicion of Haemophilus influenzae type b meningitis or a brain tumor. Because the child is not presently seizing, there is no need for rectal diazepam or intramuscular fosphenytoin.