BRS – Pediatrics: Neurology
Source: BRS Pediatrics, 2019
I. The Hypotonic Infant
A. Definition. Hypotonia is a reduction in muscle tone in which there is decreased resistance of movement during passive stretching of muscles and a decrease in spontaneous activity. In contrast, weakness is the decreased or less than normal force generated by active contraction of muscles. Weakness is often manifested as an inability to move the limbs against gravity.
B. Classification of hypotonia
1. Central hypotonia is dysfunction of upper motor neurons (i.e., cortical pyramidal neurons and their descending corticospinal pathways).
2. Peripheral hypotonia is dysfunction of lower motor neurons (i.e., spinal motor neurons, peripheral nerves, and the neuromuscular junction).
C. Clinical features
1. History may reveal antenatal problems, such as decreased fetal movements in utero.
2. Physical examination findings in both central and peripheral hypotonia may include weak cry, poor suck, drooling, decreased spontaneous movements, delay of motor milestones, frog-leg positioning (hips are externally rotated and flexed), poor posture on horizontal and vertical suspension (infant slips through examiner’s hands when lifted up under the axillae), and head lag when pulled to the sitting position. Other findings may include flattened occiput, occipital hair loss, arthrogryposis (muscle contractures), congenital hip dislocation, and pectus excavatum.
a. Central nervous system (CNS) involvement is suggested by seizures, axial hypotonia, scissoring of the legs on vertical suspension, dysmorphic features, cortical thumbing/fisting (persistent adduction and infolding of the thumbs), and global developmental delay.
b. Peripheral nervous system involvement is suggested by atrophy, muscle fasciculation, and loss of deep tendon reflexes.
c. In addition to hypotonia, patients with congenital neuromuscular disorders may have additional findings such as bilateral ptosis, ophthalmoplegia, flat midface, high-arched palate, chest wall abnormalities (e.g., bell-shaped chest, pectus excavatum or carinatum), and bilateral cryptorchidism.
D. Differential diagnosis of hypotonia (Figure 12-1)
1. Systemic pathology: sepsis, meningitis, and both renal and hepatic encephalopathy
2. Nonprogressive encephalopathies: cerebral malformations, hypoxic–ischemic encephalopathy, intracranial hemorrhage, and trauma (e.g., spinal cord injury)
3. Chromosomal disorders: Prader–Willi and Down syndromes
4. Metabolic disorders: neonatal adrenoleukodystrophy, primary carnitine deficiency, acid maltase deficiency, urea cycle defects, and Zellweger syndrome
5. Muscle disorders: congenital myotonic dystrophy, congenital myopathy, and congenital muscular dystrophies
6. Neuromuscular junction disorders: congenital and neonatal myasthenia gravis
E. Evaluation
1. It is important to rule out acute life-threatening causes, such as sepsis, meningitis, or an acute metabolic disorder. Serum electrolytes, including calcium and magnesium, ammonia, lactate, and pyruvate levels should be drawn to evaluate for a metabolic disorder.
2. When central hypotonia is suspected, it is necessary to consider:
a. Head computed tomography (CT) scan to evaluate for acute CNS injury, such as hemorrhage or trauma. Magnetic resonance imaging (MRI) may be indicated to evaluate for structural abnormalities, neuronal migrational abnormalities (i.e., polymicrogyria, lissencephaly), basal ganglia signal abnormalities (seen in metabolic conditions), and deep white matter changes.
b. High-resolution chromosomal studies to evaluate for a suspected genetic disorder, which include chromosomal microarray and fluorescent in situ hybridization (FISH).
3. When peripheral hypotonia is suspected, it is necessary to consider the following:
a. Serum creatine kinase (CK) levels to screen for myopathy.
b. Electromyography (EMG). Nerve conduction studies are performed to identify myopathies (especially congenital) neuromuscular junction disorders and some neuropathies.
c. Muscle and nerve biopsy
d. Genetic testing for spinal muscular atrophy (SMA) or myotonic dystrophy
F. Specific peripheral hypotonic disorders are described in more detail in the following discussion.
1. Spinal muscular atrophy (SMA)
a. Definition. Degeneration of anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. Lower motor neurons control movement in the arms, legs, chest, face, throat and tongue. SMA therefore presents with hypotonia, difficulty feeding, and tongue fasciculations.
b. Epidemiology. Incidence is 4–10 in 100,000 live births. SMA is the second most common hereditary neuromuscular disorder, after Duchenne muscular dystrophy.
c. Classification
1. SMA type 1 is also called infantile-onset SMA or Werdnig–Hoffman disease. Onset <6 months of age. These children never attain sitting or walking milestones.
2. Type 2 or intermediate form. Onset at 6–18 months of age. These children sit but never walk.
3. Type 3. Onset >18 months of age. These children are able to sit and walk.
4. Type 4 adult onset
d. Etiology
1. Autosomal recessive inheritance
2. All four forms of SMA are caused by mutations in the survival motor neuron gene (SMN1) on chromosome 5. Loss of SMN1 protein is partially compensated by SMN2 protein synthesis. Presence of more copies of SMN2 usually presents with a milder phenotype.
3. Pathology of the spinal cord shows degeneration and loss of anterior horn motor neurons and infiltration of microglia and astrocytes.
e. Clinical features
1. Weak cry, tongue fasciculations, and difficulty sucking and swallowing
2. Bell-shaped chest
3. Frog-leg posture when in the supine position, with generalized hypotonia, weakness, and areflexia
4. Normal extraocular movements and normal sensory examination
f. Diagnosis
1. DNA testing for the abnormal gene is diagnostic in >90% of cases.
2. Muscle biopsy shows a characteristic atrophy of groups of muscle fibers innervated by the damaged axons.
g. Management. Treatment is supportive. The mainstay of treatment is supportive care, including gastrostomy tube feeding to ensure adequate nutrition, overnight noninvasive ventilation to prevent sleep apnea, diligent surveillance and treatment of respiratory infections, and physical therapy to maintain range of motion and prevent contractures. In December 2016, the Food and Drug Administration (FDA) approved a new treatment (Nusinersen) to improve motor function in children with SMA. The drug is designed to increase the amount of functional survival motor neuron protein that is deficient in patients with SMA.
h. Prognosis. For SMA type 1, survival beyond the first year of life is unusual. Death occurs as a result of respiratory insufficiency or pneumonia. For SMA types 2 and 3, survival until adolescent and adult years, respectively, is common.
2. Infantile botulism
a. Definition. Infantile botulism is bulbar weakness and paralysis that develops in infants during the first year of life secondary to ingestion of Clostridium botulinum spores and absorption of botulinum toxin.
b. Etiology. The source of the botulinum toxin is infected foods, such as contaminated honey, or spores unearthed from the ground. The toxin prevents the presynaptic release of acetylcholine.
c. Clinical features
1. Onset of symptoms occurs 12–48 hours after ingestion of spores.
2. Constipation is the classic first symptom of botulism.
3. Neurologic symptoms follow, including weak cry and suck, loss of previously obtained motor milestones, ophthalmoplegia, and hyporeflexia.
4. Paralysis is symmetric and descending, and at times, diaphragmatic paralysis may also occur.
d. Diagnosis. Diagnosis is based on suggestive history, neurologic examination, and identification of the toxin or bacteria in the stool. EMG is sometimes performed and demonstrates brief, small-amplitude muscle potentials with an incremental response during high-frequency stimulation.
e. Management. Treatment is supportive, with nasogastric feeding and assisted ventilation as needed.
1. Botulism immune globulin improves the clinical course.
2. Antibiotics are contraindicated and may worsen the clinical course.
f. Prognosis. The outlook is excellent, and complete recovery is expected. However, recovery may take weeks or even months.
3. Congenital myotonic dystrophy
a. Definitions
1. Myotonia is the inability to relax contracted muscles.
2. Congenital myotonic dystrophy is an autosomal dominant muscle disorder that presents in the newborn period with weakness and hypotonia.
b. Epidemiology. Incidence is 1 in 30,000 live births.
c. Etiology. Myotonic dystrophy is a CTG trinucleotide repeat disorder with autosomal dominant inheritance, with symptoms becoming more severe with each successive generation (genetic anticipation). The gene has been identified on chromosome 19. Transmission to affected infants is through their affected mothers in more than 90% of cases. The earlier the onset of the disease in the mother, the more likely she will have affected offspring.
d. Clinical features
1. Antenatal history may reveal decreased fetal movements and polyhydramnios caused by poor swallowing in utero.
2. Neonatal history is often significant for feeding and respiratory problems.
3. Physical examination of the neonate is notable for facial diplegia (bilateral weakness), which results in characteristic “V” shape of the upper lip, hypotonia, areflexia, and arthrogryposis (multiple joint contractures).
4. Myotonia is not present in the newborn but develops later, almost always by 5 years of age.
5. In adulthood, typical myotonic features include myotonic facies (atrophy of masseter and temporalis muscles), ptosis, a stiff, straight smile, and an inability to release the grip after handshaking (myotonia).
6. Additional problems include intellectual disability, cataracts, cardiac arrhythmias, and infertility.
e. Diagnosis
1. This disorder should be suspected in all infants with hypotonia. The child’s mother should also be examined, as she will often have intellectual disability, as well as the typical physical exam features of myotonic dystrophy.
2. DNA testing to identify the gene can be performed to confirm the diagnosis. Because of the availability of DNA testing, EMG and muscle biopsy are no longer indicated.
f. Management. Treatment is supportive. Infants may require assisted ventilation and gastrostomy tube feedings.
g. Prognosis. The outlook is guarded. Infant mortality can be as high as 40% because of respiratory problems.
1. All survivors have intellectual disability (average intelligence quotient [IQ] of 50–65).
2. Feeding problems tend to subside with time.
FIGURE 12.1 Differential diagnosis of hypotonia.
II. Hydrocephalus
A. Definition. Hydrocephalus is an elevation in intracranial pressure (ICP) due to a disturbance in the flow of cerebral spinal fluid (CSF). This can be caused by increased production, blockage of flow, or decreased absorption of CSF. The normal production of CSF is between 400 and
500 mL daily.
B. Types of hydrocephalus
1. Noncommunicating (obstructive) hydrocephalus is due to an obstruction of CSF flow. As a result of this obstruction, the pathways of the ventricular system do not communicate correctly, and there is a buildup of CSF proximal to the blockage.
2. Communicating (nonobstructive) hydrocephalus is due to either an increase in production or a decrease in absorption of CSF. Therefore, all of the pathways of the ventricular system communicate normally, and the problem occurs at the beginning or end of the pathway.
3. Hydrocephalus ex vacuo is not true hydrocephalus, but rather a term used to describe ventricular enlargement caused by brain atrophy.
C. Etiology
1. Congenital causes of hydrocephalus
a. Chiari type II malformation is characterized by downward displacement of the cerebellum and medulla through the foramen magnum, blocking CSF flow. This malformation is often associated with a lumbosacral myelomeningocele.
b. Dandy–Walker malformation is a combination of an absent or hypoplastic cerebellar vermis and cystic enlargement of the fourth ventricle, which blocks the flow of CSF.
c. Congenital aqueductal stenosis is the most common cause of noncommunicating hydrocephalus. Some cases of aqueductal stenosis are inherited as an X-linked trait, and these patients may have thumb abnormalities and other CNS anomalies such as spina bifida (SB).
2. Acquired causes of hydrocephalus include intraventricular hemorrhage (most common in preterm infants), bacterial meningitis, and CSF-producing brain tumors.
D. Clinical features
1. Increasing head circumference that crosses percentile lines, or head circumference >97%
for age
2. Infants with open cranial sutures have the following clinical signs:
a. Large anterior and posterior fontanelles and split sutures
b. Setting-sun eyes, a tonic downward deviation of both eyes caused by pressure from the enlarged third ventricles on the upward gaze center in the midbrain
3. Older children with closed cranial sutures have the following symptoms and signs of
increased ICP:
a. Headache
b. Nausea and vomiting
c. Unilateral sixth nerve palsy
d. Papilledema
e. Brisk deep tendon refluxes (DTRs), but usually with a downward plantar response
E. Evaluation. Increasing head circumference and signs or symptoms of increased ICP mandate an urgent head ultrasound in infants or head CT scan in older children.
F. Management. Hydrocephalus requires the surgical placement of a ventriculoperitoneal shunt to divert the flow of CSF. Complications of ventriculoperitoneal shunts include shunt infection and shunt obstruction. In older children, acetazolamide may be used to decrease
ICP as well.
G. Prognosis. Outcome varies depending on the cause of the hydrocephalus and the success of the intervention.
1. Patients with aqueductal stenosis have the best cognitive outcome.
2. Patients with Chiari type II malformation may have low normal intelligence and language disorders.
3. Patients with X-linked hydrocephalus frequently have cognitive delays.
III. Spina Bifida
A. Definitions
1. Spina bifida (SB) is a general term that refers to any failure of bone fusion in the posterior midline of the vertebral column.
2. Neural tube defect is a broad term that includes all forms of failure of neural tube closure, from anencephaly to sacral meningocele.
B. Types of SB
1. SB occulta is an incomplete closure of vertebrae without herniation of tissue through the cleft.
2. Meningocele is the herniation of the meninges only through a bony cleft, most commonly in the lumbosacral region.
3. Myelomeningocele is the herniation of the meninges and spinal cord tissue through the bony cleft, most commonly in the lumbosacral region. Myelomeningocele is more common than meningocele.
C. Epidemiology. The incidence of neural tube defects varies with geographic location. In the United States, the prevalence is approximately 0.5 in 1000; however, in China and India, it is as high as 10 per 1000.
D. Etiology. The multifactorial etiology includes environmental, genetic, nutritional, and teratogenic factors.
1. Taking a prenatal multivitamin preparation that includes folic acid has decreased the incidence of SB in the newborn. The mechanism of action of folic acid is uncertain.
2. Risk factors include a history of previous affected pregnancy, inadequate folic acid intake, and maternal diabetes.
3. Teratogens causing SB include valproic acid, carbamazepine, phenytoin, colchicine, vincristine, azathioprine, and methotrexate.
E. Clinical features
1. SB occulta. The skin on the back (usually lumbosacral region) is epithelialized, and a hairy patch or dimple often covers the area. No neurologic deficits are present.
2. Meningocele. A fluctuant midline mass is present overlying the spine. The mass is filled with CSF but does not contain spinal cord tissue and can be transilluminated. Neurologic deficits are usually not present or are only very mild.
3. Myelomeningocele
a. A fluctuant midline mass is present anywhere along the spine, but most commonly in the lumbosacral region.
b. Neurologic defects are present and depend on the level of the lesion, varying from complete paraplegia (above L3) to preserved ambulation and variable bladder or bowel incontinence (S3 and below).
c. Associated anomalies and complications
1. Hydrocephalus. Ninety percent of lumbosacral myelomeningoceles are associated with Chiari type II malformation and hydrocephalus. Cervical and thoracic myelomeningoceles are not associated with hydrocephalus.
2. Cervical hydrosyringomyelia (accumulation of fluid within the central spinal cord canal and the cord itself)
3. Defects in neuronal migration (e.g., gyral anomalies, agenesis of the corpus callosum)
4. Orthopedic problems (e.g., rib anomalies, deformities of the lower extremities, and lower extremity fractures from loss of sensation)
5. Genitourinary neurologic deficits
F. Diagnosis
1. Prenatal diagnosis is common.
a. α-Fetoprotein (AFP), the main serum protein in fetal life, is elevated in amniotic fluid and maternal serum in open neural tube defects, and when measured in maternal serum at 16–18 weeks’ gestation, detects 80% of spinal defects.
b. Fetal sonography is highly sensitive in detecting spinal defects.
2. Diagnosis after birth
a. SB occulta is suggested by finding any skin abnormality overlying the spine and may be confirmed by spinal radiographs.
b. Meningocele is suggested by physical examination findings and is confirmed by MRI of the spinal cord and spine.
c. Myelomeningocele is a clinical diagnosis based on physical examination at birth.
G. Management
1. SB occulta does not require treatment.
2. Meningocele requires surgical repair.
3. Myelomeningocele requires urgent surgical repair within 24 hours of birth, or in some cases in utero, to reduce the morbidity and mortality from infection and to prevent further trauma to the exposed neural tissue.
H. Prognosis
1. SB occulta and meningocele have excellent prognoses as a result of the absence of neurologic deficits.
2. Myelomeningocele. Without treatment, around 85% die within the first year of life. With treatment, 90% of patients survive to adolescence, but many have functional disabilities. Associated problems include wheelchair dependency, bladder or bowel incontinence, seizures, precocious puberty, pressure sores, and fractures.
IV. Approach to the Comatose Patient
A. Definition. Coma is a state of unawareness of self and environment in which the patient lies with the eyes closed, without purposeful movement or sleep–wake cycles, and is unarousable by external stimuli.
B. Etiology (Table 12-1). In addition to traumatic brain injury, the most common non-traumatic cause of coma in children is infection.
C. Assessment. The goal of assessment of the comatose patient is to determine the depth of coma, to identify the neurologic signs that indicate the site and cause of the coma, and to monitor the patient’s recovery.
1. Glasgow Coma Scale provides a standard measure to monitor the level of consciousness (see Chapter 20, Table 20-1).
2. Head and neck exam. The patient should be assessed for scalp injuries, breath odors (for alcohol intoxication or ketosis caused by diabetic ketoacidosis), and nuchal rigidity (caused by meningitis). CSF or blood draining from the nose or external auditory canal may indicate a basilar skull fracture.
3. Abnormal motor responses to stimuli can indicate the location of brain damage.
a. Flaccidity or no movement may suggest severe spinal or brainstem injury.
b. Decerebrate posturing (extension of arms and legs) is seen in diffuse toxic/metabolic disorders or midbrain compression.
c. Decorticate posturing (flexion of arms and extension of legs) is seen in cortical and/or subcortical abnormalities with preservation of brainstem function.
d. Asymmetric responses suggest hemispheric injury.
4. Abnormal respiratory responses may indicate the location of brain injury or its cause.
a. Hypoventilation suggests opiate or sedative overdose.
b. Hyperventilation suggests metabolic acidosis (Kussmaul respirations or rapid, deep breathing may occur), neurogenic pulmonary edema, or midbrain injury.
c. Cheyne–Stokes breathing (alternating apnea and hyperpnea) suggests bilateral cortical injury and is associated with herniation, specifically displacement of the diencephalon (thalamus and hypothalamus).
d. Apneustic breathing (pausing at full inspiration) indicates pons or upper medulla damage.
e. Ataxic or agonal breathing (irregular respirations with no particular pattern) indicates medullary injury and impending brain death.
5. Pupillary size and reactivity may provide clues.
a. Unilateral dilated nonreactive pupil suggests uncal herniation.
b. Bilateral dilated nonreactive pupils suggest topical application of a dilating agent, a postictal state, or irreversible brainstem injury.
c. Bilateral constricted reactive pupils suggest opiate ingestion or pontine injury.
6. Other brainstem reflexes should be assessed to determine the extent of injury to the brainstem.
a. Oculocephalic maneuver (doll’s eyes). When turning the head of an unconscious patient, the eyes normally look straight ahead and then slowly drift back to midline position, because the intact vestibular apparatus senses a change in position. In an injured brainstem, movement of the head does not evoke any eye movement. This is termed a negative oculocephalic maneuver or negative doll’s eyes.
b. Caloric irrigation. When the oculocephalic response is negative or cannot be performed because of possible cervical cord injury, caloric testing should be performed. This involves angling the head at 30° and irrigating each auditory canal
with 10–30 mL of ice water. An intact (normal) cold caloric response is reflected by eye deviation to the ipsilateral side, with nystagmus to the contralateral ear. An abnormal response suggests pontine injury.
c. Abnormal corneal and gag reflexes indicate significant brainstem injury.
D. Evaluation. Once the airway, breathing, and circulation are stable, further diagnostic workup may begin.
1. Glucose should be checked immediately in any comatose patient.
2. Urine toxicology screen, serum electrolytes, and metabolic panel should also be evaluated.
3. Head CT scan should be performed to identify mass lesions or trauma.
4. Lumbar puncture (LP) to rule out meningoencephalitis should be considered if the CT scan is negative.
5. Urgent electroencephalography (EEG) should be considered, even in patients without a history of clinical seizures.
Table 12-1
Causes of Impaired Consciousness and Coma in Childhood and Adolescence
Infectious
Meningitis Encephalitis
Focal infection (abscess, cerebritis)
Inflammatory
Vasculitis
Demyelinating disorders (acute disseminated encephalomyelitis)
Traumatic
Concussion
Abusive head trauma Diffuse axonal injury
Cerebral hematoma or contusion
Vascular disease
Cerebral infarction Cerebral hemorrhage
Neoplasm
Hypoxia
Shock
Cardiac failure Nonfatal drowning
Carbon monoxide poisoning
Metabolic disorders
Fluid or electrolyte imbalance Hypoglycemia/hyperglycemia Hyponatremia
Diabetic ketoacidosis Organic acidemias Amino acidemias Hepatic encephalopathy Urea cycle disorders
Disorders of fatty acid metabolism Reye syndrome
Hyperammonemia
Hypothyroidism or hyperthyroidism
Nutritional
Thiamine deficiency Pyridoxine deficiency
Folate and vitamin B12 deficiency
Toxins/poisons
Alcohol
Prescription medications
Atropine, scopolamine, benzodiazepines, barbiturates, lithium, opiates, tricyclic antidepressants Over-the-counter medications
Heavy metal poisoning
Lead, mercury, arsenic Illicit drugs*
*Amphetamine, cocaine, and hallucinogens (lysergic acid diethylamide [LSD], mescaline, phencyclidine hydrochloride [PCP]) cause agitation, confusion, delirium, and hallucinations but not coma.
V. Seizure Disorders of Childhood
A. Definitions
1. A seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
2. Epilepsy is diagnosed if any of the following three scenarios occur:
a. The patient has at least two unprovoked seizures >24 hours apart
b. The patient has one unprovoked seizure and the probability of further seizures occurring over the next 10 years (i.e., the patient has another diagnosis that predisposes to an increased risk of seizures, such as a brain tumor)
c. The patient is diagnosed with an epilepsy syndrome (e.g., childhood absence epilepsy)
3. Status epilepticus is defined as 5 or more minutes of continuous seizure activity, or repetitive seizures without recovery of consciousness.
B. Epidemiology
1. One percent of children have a single unprovoked seizure before 16 years of age.
2. After a single unprovoked seizure, approximately 40% of children will have a second seizure.
3. Prevalence of epilepsy in children is 0.5–0.8%.
C. Etiology
1. The seizure discharge is caused by an imbalance between excitatory and inhibitory input within the brain, or abnormalities in the membrane properties of individual neurons.
2. In some children, the cause of seizures is known (Table 12-2); however, in many, the cause remains unknown.
D. Classification of seizures. Criteria for the classification of seizures include the presence or absence of fever, the extent of brain involvement, whether consciousness is impaired, and the nature of the movements (Figure 12-2).
1. Febrile seizures are a common but benign type of seizure associated with fever [see section V.K].
2. Afebrile seizures are either generalized (starting throughout the entire brain) or partial (starting from a single part or “focus” in the brain).
a. Generalized seizures are caused by the discharge from a group of neurons in both cerebral hemispheres and are associated with an alteration of consciousness. Two common types are tonic–clonic and absence seizures.
1. Tonic–clonic seizures are the most common type of generalized seizure. These seizures are characterized by increased thoracic and abdominal muscle tone, followed by clonic movements of the arms and legs, eyes rolling upward, incontinence, decreased consciousness, and a postictal state of variable duration.
2. Absence seizures are brief staring spells that occur without loss of posture and with only minor motor manifestations (e.g., eye blinking or mouthing movements). The seizure lasts <15 seconds, and there is no postictal state.
3. Other generalized seizures include tonic, clonic, myoclonic, and atonic.
b. Focal (partial) seizures are caused by the discharge from a group of neurons in one hemisphere. Seizure symptoms may have predominately motor, sensory, or psychomotor features. There are two types:
1. In focal seizures (prior term: simple partial seizure), consciousness is not
impaired.
2. In focal dyscognitive seizures (prior term: complex partial seizure),
consciousness is altered.
E. Classification of epilepsy. Classification may be based on either the predominant seizure type, the site of origin of the epileptic discharge or the genetic mutation.
F. Differential diagnosis of seizure-like events (Table 12-3)
G. Diagnosis. Epilepsy is diagnosed on the basis of history and physical examination, as well as testing for genetic mutations. Other studies (EEG, MRI) may be useful.
1. EEG is useful to evaluate the background rhythms as well as seizures, particularly in determining the location of onset of focal seizures. However, an abnormal EEG is not required for the diagnosis of epilepsy (in particular, focal seizures may have a normal EEG during the interictal period between seizures).
2. Video-EEG monitoring is a useful tool when clinical information is inadequate or incomplete (e.g., when patients are <3 years of age, when events concerning for seizures occur during sleep, or when the history is unclear). Video-EEG monitoring is also useful to capture and characterize focal seizures for possible surgical intervention.
3. Neuroimaging studies (primarily MRI) may be useful in children with epilepsy. Children diagnosed with absence seizures or benign rolandic epilepsy [see sections V.L.4 and V.L.5] do not require imaging.
H. Evaluation of an acute seizure
1. Initial treatment starts with assessment of the patient’s airway, breathing, and circulation.
2. For a first nonfebrile seizure, routine EEG is recommended; however, laboratory studies, LP, and neuroimaging are based on clinical circumstances and typically are unnecessary in a child with a normal neurologic exam.
3. For a simple febrile seizure evaluation should be focused on determining the cause of the child’s fever [see section V.K]. Meningitis should be considered, and LP should be performed if there are concerns for a CNS infection. Further evaluation, including lab studies, EEG, or neuroimaging, is usually not required.
I. Management
1. Treatment of status epilepticus requires intravenous anticonvulsants, such as a short- acting benzodiazepine (e.g., lorazepam or diazepam) followed by a loading dose of either phenobarbital or phenytoin.
2. Treatment of epilepsy
a. Pharmacotherapy. Once the type of seizure has been determined, single-drug therapy is started with the antiepileptic drug that has the best combination of high efficacy and low toxicity. Examples of commonly recommended drugs for the following seizure types:
1. Generalized epilepsy: valproic acid, lamotrigine, levetiracetam
2. Absence epilepsy: ethosuximide, valproic acid, lamotrigine
3. Focal epilepsy: carbamazepine, lamotrigine, levetiracetam
4. Lennox–Gastaut: felbamate, rufinamide, lamotrigine, topiramate
b. Surgery
1. For medically intractable epilepsy, surgery to remove epileptic tissue may be an option.
2. The best prognosis is for patients with temporal lobe lesions, >75% of whom have complete seizure control or remission after surgery.
c. Vagal nerve stimulator is a pacemaker-sized device that sends an electrical impulse to the vagus nerve. A common side effect is hoarseness.
d. Ketogenic diet (a high-fat, low-carbohydrate diet) is thought to suppress seizure activity by producing a state of ketosis.
J. Prognosis. Epilepsy is not necessarily a lifelong disorder. About 70% of epileptic children can
be weaned off their medications after a 2-year seizure-free period and normalization of the EEG.
K. Febrile seizures
1. Definition. Seizures that occur in children between 6 months and 6 years of age accompanied by a fever (temperature > 38°C), in whom CNS infection, metabolic imbalance, and history of afebrile seizure are excluded.
2. Epidemiology. Febrile seizures are the most common childhood seizure type, occurring in 2–4% of all children.
3. Etiology
a. The pathophysiologic mechanism is unknown.
b. Febrile seizures can be inherited, and several gene mutations have been found.
4. Classification
a. A simple febrile seizure lasts less than 15 minutes and is generalized.
b. A complex febrile seizure lasts more than 15 minutes, has focal features, or recurs within 24 hours.
5. Risk factors for first febrile seizure include having a first- or second-degree relative with a history of febrile seizures, neonatal hospital stays >30 days, developmental delay, attendance at daycare, high frequency of febrile episodes, peak body temperature and recent vaccination.
6. Diagnosis
a. The diagnosis of a febrile seizure is based on history, a normal neurologic examination, and the exclusion of CNS infection.
b. An LP is necessary if meningitis is suspected at any age. For a child 6–12 months of age, an LP should be seriously considered if the child is deficient in vaccination for Haemophilus influenzae type b (HIB) or Streptococcus pneumoniae or when immunization status cannot be determined.
c. Neither neuroimaging nor EEG is needed unless the neurologic examination is abnormal.
7. Management
a. First-time or occasional febrile seizures are not treated with anticonvulsants.
b. Antipyretic treatment during subsequent febrile illnesses is unlikely to prevent febrile seizures.
c. Frequent, recurrent, or prolonged febrile seizures do pose a risk and may require additional treatment with daily anticonvulsant prophylaxis or the use of rescue medications (e.g., rectal diazepam).
8. Prognosis. Approximately 30% of patients will have a recurrence. Recurrence risk decreases with increasing patient age. The risk of epilepsy is low (2–10%).
L. Epileptic syndromes
1. Definition. Epileptic syndromes are epileptic conditions characterized by a specific age of onset, seizure characteristic, and EEG abnormality.
2. Classification. There are many types of epilepsy syndromes recognized. Each has its own seizure type, severity, and prognosis. Three common types are infantile spasms, absence epilepsy of childhood, and benign rolandic epilepsy.
3. Infantile spasms
a. Epidemiology. Age of onset is typically 4–7 months. Infantile spasms are rare in children older than 2 years of age.
b. Etiology. Although infantile spasms are frequently cryptogenic (unknown etiology), there are a number of associations, including hypoxic–ischemic injury, tuberous sclerosis, malformations of cortical development, Down syndrome, neonatal hypoglycemia, meningitis, trauma, phenylketonuria, intraventricular
hemorrhage, pyridoxine deficiency, and infection. Tuberous sclerosis is the most commonly identified cause of this disorder.
c. Clinical features
1. Brief tonic extension of the extremities and flexion of the trunk (jackknife or salaam seizures) lasting 1–2 seconds each, occurring in clusters of 5–10 seizures spread over 3–5 minutes
2. Hypsarrhythmia is a characteristic EEG pattern consisting of a high amplitude, disorganized background with multifocal spike-wave discharges.
3. West syndrome is a triad of infantile spasms, hypsarrhythmia, and developmental delay or regression.
d. Management
1. Adrenocorticotropic hormone (ACTH) intramuscular injections for a 4- to 6- week period are effective in 50-70% of affected patients.
2. Vigabatrin is frequently effective for patients with infantile spasms associated with tuberous sclerosis and is often used in combination with ACTH.
3. Other treatments include valproic acid, topiramate zonisamide, ketogenic diet, pyridoxine, and surgery.
e. Prognosis. Outlook is poor. Despite the success of these different medications in suppressing seizures, children often develop moderate to severe intellectual disability.
4. Absence epilepsy of childhood
a. Epidemiology. Age of onset is between 4 and 8 years of age and is more common in girls.
b. Etiology. There is a presumed genetic cause, and some cases may have an autosomal dominant inheritance pattern.
c. Clinical features of absence seizures
1. Brief, lasting 5–10 seconds
2. Frequent, tens to hundreds per day
3. May be accompanied by automatisms, such as eye blinking, chewing, and incomprehensible utterances.
4. Loss of posture, urinary incontinence, and a postictal state do not occur.
d. Diagnosis. The EEG shows the characteristic generalized 3-Hz spike-and-wave discharges. Hyperventilation for 2–3 minutes frequently provokes absence seizures.
e. Management. Treatment includes ethosuximide, valproic acid, or lamotrigine.
f. Prognosis. Outlook is very good; the seizures usually resolve by adolescence without cognitive impairment.
5. Benign epilepsy with centrotemporal spikes (BECTS), which is also known as benign rolandic epilepsy
a. Definition. BECTS involves nocturnal focal seizures occasionally with secondary generalization. Focal spike discharges in the centrotemporal region is seen on EEG.
b. Epidemiology
1. Benign rolandic epilepsy is the most common partial epilepsy during childhood, accounting for 15% of epilepsy.
2. It commonly presents at 3–13 years of age. Peak incidence is at 6–7 years of age. Boys are more likely to be affected.
c. Etiology. Inheritance is autosomal dominant with age-dependent penetrance.
d. Clinical features
1. Seizures typically occur in the early morning hours when patients are asleep with oral–buccal manifestations (i.e., moaning, grunting, pooling of saliva).
2. Seizures may spread to the face and arm and then secondarily generalize into
tonic–clonic seizures.
e. Diagnosis. The EEG shows biphasic spike and sharp-wave discharges in the mid- temporal and central regions.
f. Management. Treatment includes valproic acid or carbamazepine.
g. Prognosis. Outcome is excellent. Seizures typically remit spontaneously during adolescence. There are reports of associated learning disabilities associated with BECTS.
Table 12-2
Causes of Acute Seizures During Childhood
Head
trauma Cerebral contusion, subdural hematoma
Brain tumor Astrocytoma
Toxins Amphetamines, cocaine
Infections Meningitis, encephalitis, brain abscess, neurocysticercosis
Vascular Cerebral infarction, intracranial hemorrhage
Metabolic
disturbances Hypocalcemia, hypoglycemia, hypomagnesemia, hypo- or hypernatremia, pyridoxine deficiency
Systemic
diseases Hypertension, hypoxic–ischemic injury, inherited metabolic disorder, liver disease, renal failure, neurocutaneous
disorders (e.g., tuberous sclerosis, neurofibromatosis and Sturge-Weber syndrome)
FIGURE 12.2 Classification of seizures.
Table 12-3
Differential Diagnosis of Seizure-like Events
Breath-holding spells (in infants)
Gastroesophageal reflux disease (Sandifer syndrome)
Syncope
Migraine
Vertigo
Movement disorder (e.g., tics, chorea)
Sleep disturbances (e.g., night terrors, somnambulism)
Transient ischemic attack
Rage attacks
Psychogenic nonepileptic events (pseudoseizures)
VI. Headaches in Childhood
A. Etiology. Headaches may have intracranial or extracranial causes (Figure 12-3).
1. Intracranial causes
a. Primary headaches are more common and are idiopathic, not occurring for a specific reason, or the result of an underlying disease. These are likely due to a combination of genetic, developmental, and environmental risk factors. Migraine, tension-type, and cluster are common primary headaches.
b. Secondary headaches are caused by an underlying disease process such as increased intracranial pressure (e.g., hydrocephalus), meningeal irritation (e.g., meningitis, subarachnoid hemorrhage), or inflammatory processes.
2. Extracranial causes
a. Local causes include sinusitis, perioral abscess, toothache, chronic otitis media, or refractive errors.
b. Systemic causes include anemia, hypoglycemia, depression, and hypertension.
B. Important clinical information about a patient’s headache helps to determine the cause.
1. Quality of pain. Throbbing or pounding pain suggests migraine headaches, whereas a sensation of squeezing or pressure is more common in tension-type headaches.
2. Location and radiation. Migraine headaches are frequently unilateral (although commonly bilateral in children) and may begin in the periorbital area and spread to the forehead and occiput, whereas tension-type headaches are often generalized or bitemporal.
3. Time of onset. Tension headaches occur toward the end of the day, whereas headaches from increased ICP occur in the morning.
4. Duration. The shorter the headache duration, the less likely a serious disorder is responsible.
5. Red flags indicating more serious pathology may include an abnormal neurologic examination, a new and unusual headache (especially when described as “a sudden worst headache of one’s life”), a patient with an immunocompromised state, fever, or stiff neck, and blurring of optic disc margins on examination.
C. Migraine headaches
1. Definition. Migraine headaches are prolonged (often 30–60 minutes, but may last up to 72 hours), unilateral (may be bilateral in children) headaches that are associated with nausea, vomiting, or visual changes and are caused by changes in cerebral blood flow.
2. Epidemiology
a. Migraines are the most common cause of headaches in children and adolescents. The prevalence increases from 3% in 7-year-olds, to 11% in 11-year-olds, and up to 20% in adolescents.
b. Before puberty, incidence is higher in males; after puberty, incidence is higher in females.
3. Etiology
a. Seventy to eighty percent of children with migraines have at least one affected parent.
b. The pathophysiology of migraines is complicated and evolving. Serotonin (5-HT), calcitonin gene related peptide (CGRP), inflammatory markers (substance P, vasoactive intestinal peptide), the trigeminal nerve and changes in cerebral blood flow all appear to play a role.
4. Classification
a. Migraine without aura is the most common form of migraine in children.
Headaches occur in the absence of any warning symptoms.
b. Migraine with aura. The onset of the headache is preceded by transient visual changes or unilateral paresthesias or weakness. The visual changes may include blurred vision, small areas of decreased vision (scotomata), streaks of light, or hemianopsia.
c. Migraine equivalent. In young children, the headache itself may be absent, but there is a prolonged, albeit transient, alteration of behavior that manifests as cyclic vomiting, cyclic abdominal pain, or paroxysmal vertigo.
d. Migraines associated with focal neurologic signs
1. Ophthalmoplegic migraine. Unilateral ptosis or cranial nerve III palsy accompanies this headache.
2. Basilar artery migraine. Vertigo, tinnitus, ataxia, or dysarthria may precede the onset of this headache.
5. Precipitating factors. There is no obvious precipitating cause, although many migraine sufferers have triggers such as red wine, cheese, preserved meats, and chocolate. Some patients note that stress, fatigue, menstruation, dehydration, skipping meals, or exercise induces the headache.
6. Clinical features
a. A prolonged, throbbing, unilateral headache starts in the supraorbital area and radiates to the occiput. In young children, the headache is often bifrontal.
b. Nausea and vomiting may occur. A history of motion sickness is common.
c. Visual disturbances include blurred vision, scotomata, and jagged streaks of light that take on the outline of old forts (fortifications).
d. Photophobia or phonophobia occurs. Many patients treat themselves by lying in a dark, quiet room.
e. Symptoms are improved by sleep.
f. Neurologic examination is normal.
7. Diagnosis. Diagnosis is made by history and the presence of a normal neurologic examination.
8. Management. Treatment includes rest and elimination of known triggers. Medications may be very helpful.
a. Abortive treatment includes nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans, selective 5-HT agonists, available in injectable, intranasal, and oral forms.
b. Preventive treatment options include propranolol, amitriptyline, topiramate, valproic acid and cyproheptadine.
9. Prognosis. Migraines can be a lifelong disorder with a waxing and waning course.
D. Tension headaches
1. Definition. Tension headaches are bifrontal or diffuse, dull, aching headaches that are often associated with muscle contraction.
2. Epidemiology. Tension headaches are more commonly seen in children older than 7 years with a prevalence as high as 25%.
3. Clinical features
a. Pain is described as dull, aching, and rarely throbbing, and it increases in intensity during the day.
b. The pain is usually bifrontal but may be diffuse.
c. Isometric contraction of the temporalis, masseter, or trapezius muscle often accompanies the headache.
d. No vomiting, visual changes, or paresthesias occur.
4. Diagnosis. Clinical presentation provides a clue to the diagnosis, and no laboratory or imaging study is diagnostic. Tension headaches are rare in young children, and
therefore, other diagnoses (e.g., migraines) should be preferentially considered.
5. Management. Treatment includes reassurance and pain control (e.g., acetaminophen, ibuprofen). Stress and anxiety reduction may provide long-term relief.
E. Cluster headaches. These headaches are extremely rare during childhood.
1. Diagnostic criteria includes the following:
a. Attacks of severe unilateral facial/orbital pain
b. At least five attacks that last between 15 minutes and 3 hours
c. Sense of restless agitation
d. Ipsilateral conjunctival injection, eyelid edema, lacrimation, nasal congestion, rhinorrhea, and forehead sweating.
2. Treatment includes abortive therapy with oxygen or triptans. Prophylactic treatments include calcium-channel blockers and valproic acid.
FIGURE 12.3 Causes of headache. ICP = intracranial pressure.
VII. Approach to Unsteady Gait
A. Definition. Ataxia is a disturbance in smooth coordination of movements and often manifests as unsteady gait. Ataxia can be the result of cerebellar or proprioceptive dysfunction (sensory loss ataxia).
B. Differential diagnosis. A variety of neurologic problems can give the appearance of an unsteady gait.
1. Cerebellar dysfunction. Children with a cerebellar gait have an unsteady, wide-based stance with irregular steps, also known as a “drunken gait.” See Table 12-4 for the causes of cerebellar ataxia.
2. Weakness. Any cause of muscle weakness or sensory loss, such as spinal cord lesions or acute disorders of the motor unit [e.g., Guillain–Barré syndrome, see section VII.D], can lead to an unsteady gait.
3. Encephalopathy as a result of infection, drug overdose, or recent head trauma may cause decreased levels of consciousness, which may affect gait.
4. Seizures. During a seizure, or while in the postictal period, the patient’s gait may be irregular and unsteady.
5. Vision problems can mimic the appearance of an unsteady gait.
6. Vertigo from migraines, acute labyrinthitis, and brainstem tumors may lead to unsteady walking.
C. Acute cerebellar ataxia of childhood
1. Definition. Acute cerebellar ataxia is an unsteady gait secondary to a presumed autoimmune or postinfectious cause.
2. Epidemiology
a. Acute cerebellar ataxia is the most common cause of ataxia in children.
b. Age of onset is between 18 months and 7 years. Acute cerebellar ataxia rarely occurs in children older than 10 years.
3. Etiology
a. Common preceding infections include varicella, coxsackievirus, Epstein–Barr virus (EBV), and mycoplasma. The ataxia usually follows a viral illness by 2–
3 weeks.
b. The postulated cause is thought to be molecular mimicry, where molecular similarity between antigens from the infectious entity and the patient (e.g., cerebellar structures) triggers an autoimmune response.
4. Clinical features
a. Truncal ataxia with deterioration of gait is characteristic. Young children may refuse to walk for fear of falling.
b. Slurred speech and nystagmus are often present, and hypotonia and tremors are less common.
c. Fever is absent.
5. Diagnosis. Diagnosis is by history and physical examination and by exclusion of other causes of ataxia. For patients with clear acute cerebellar ataxia, neuroimaging is generally not necessary. If there are atypical features or concern for other causes of ataxia, however, neuroimaging is necessary (e.g., to rule out acute life-threatening causes such as tumors or hemorrhage in the posterior fossa). If head CT is obtained to rule out acute life-threatening causes, it is normal in acute cerebellar ataxia. MRI provides better detail to visualize the posterior fossa for evaluation of other causes of ataxia.
6. Management. Treatment is supportive. Complete resolution of symptoms generally occurs in 2–3 weeks. Physical therapy is often needed.
D. Guillain–Barré Syndrome (acute inflammatory demyelinating polyneuropathy)
1. Definition. Guillain–Barré syndrome is a demyelinating polyneuritis characterized by ascending weakness, areflexia, and paresthesias.
2. Etiology. The most commonly associated infectious agent is Campylobacter jejuni, which causes a prodromal gastroenteritis. Many other infectious agents have been associated with Guillain–Barré syndrome, such as Mycoplasma pneumoniae, cytomegalovirus, EBV, herpes zoster virus, influenza, varicella, and coxsackievirus.
3. Pathophysiology
a. The principal sites of demyelination are the ventral spinal roots and peripheral myelinated nerves.
b. Injury is triggered by a cell-mediated immune response to an infectious agent that cross-reacts to antigens on the Schwann cell membrane.
4. Clinical features
a. Ascending, symmetric paralysis may progress to respiratory arrest.
b. No sensory loss occurs, although low-back or leg pain may be present in 50% of patients.
c. Cranial nerve involvement. Facial weakness occurs in 40–50% of patients and is often bilateral.
d. Dysautonomia, arrhythmia, orthostatic hypotension, and urinary retention may occur.
e. Miller Fisher syndrome, a variant of Guillain–Barré syndrome, is characterized by ophthalmoplegia, ataxia, and areflexia.
5. Diagnosis
a. LP shows albuminocytologic dissociation (i.e., increased CSF protein in the absence of an elevated cell count), which is usually evident 1 week after symptom onset.
b. EMG demonstrates decreased nerve conduction velocity or conduction block.
c. Spinal MRI may be necessary in children younger than 3 years to rule out compressive lesions of the spinal cord, because the sensory examination in children of this age is often difficult to evaluate.
6. Management. Treatment should be initiated as soon as the diagnosis is established because of the risk of respiratory muscle paralysis.
a. Intravenous immune globulin (IVIG), given for 2–4 days, is the preferred treatment for children because of its relative safety and ease of use.
b. Plasmapheresis removes the patient’s plasma along with the presumed antimyelin antibodies and is performed over a 4- to 5-day period.
7. Prognosis. Complete recovery is the rule in children but depends on the severity and extent of the weakness. Physical therapy may be necessary for several weeks or longer to aid recovery.
Table 12-4
Differential Diagnosis of Cerebellar Ataxia
Brain tumors Pilocytic astrocytoma (occurring in the cerebellum)
Medulloblastoma (occurring in posterior fossa)
Neuroblastoma (opsoclonus myoclonus ataxia syndrome)
Trauma Cerebellar contusion
Subdural hematoma
Toxins Ethanol
Antiepileptic medications
Vascular Cerebellar infarction or hemorrhage
Infections Meningitis
Encephalitis
Inflammatory Acute cerebellar ataxia of childhood
Demyelination Acute disseminated encephalomyelitis (ADEM)
Multiple sclerosis
Migraine syndromes Basilar migraines and familial hemiplegic migraines
Benign paroxysmal vertigo (may have history of migraine)
VIII. Movement Disorders
A. Sydenham chorea (St. Vitus dance)
1. Definition. Sydenham chorea is a self-limited autoimmune disorder and is one of the major Jones criteria for diagnosis of rheumatic fever (see Chapter 16, section VI). It presents with chorea (involuntary, brief, purposeless movements of the limbs and upper body) and emotional lability.
2. Epidemiology
a. Sydenham chorea occurs in approximately 25% of patients with rheumatic fever.
b. Onset is most common between 5 and 13 years of age.
3. Pathophysiology. Sydenham chorea occurs secondary to antibodies that cross-react with membrane antigens on both group A β-hemolytic streptococcus and basal ganglia cells.
4. Clinical features
a. Immunologic response usually follows streptococcal pharyngitis by 2–7 months.
b. Children appear restless. The face, hands, and arms are mainly affected, and the movements appear continuous, quick, and random. The chorea may begin as clumsiness of the hands.
c. Speech is also affected and can be jerky or indistinct.
d. Patients are unable to sustain protrusion of the tongue (chameleon tongue).
e. The wrist is held flexed and hyperextended at the metacarpal joints (choreic hand). On gripping the examiner’s fingers, patients are unable to maintain the grip (milkmaid’s grip).
f. Emotional lability (impulsivity, obsessive compulsive symptoms, aggression) is common and may precede signs of chorea.
g. Gait and cognition are not affected.
5. Differential diagnosis. Other conditions that may cause chorea include many acquired and congenital conditions, including N-methyl-d-aspartate (NMDA) receptor encephalitis, kernicterus, systemic lupus erythematosus, Huntington disease, and Wilson disease.
6. Diagnosis. There is no single confirmatory test for Sydenham chorea. The diagnosis is made clinically based on presumptive evidence of rheumatic fever and the exclusion of other likely causes of chorea.
a. Elevated antistreptolysin O (ASO) or anti-DNase B (ADB) titer may indicate a recent streptococcal infection.
b. Neuroimaging
1. Head MRI may show increased signal intensity in the caudate and putamen
on T2-weighted sequences.
2. Single-photon emission computed tomography (SPECT) may demonstrate
increased perfusion to the thalamus and striatum.
7. Management. Treatment should be initiated when chorea is leading to significant impairment of motor function. Treatment options include corticosteroids, haloperidol, valproic acid, or phenobarbital.
8. Prognosis. Symptoms may last from several months to 2 years. Generally, all patients recover.
B. Tourette syndrome
1. Definitions
a. Tics are brief, stereotypical behaviors that are initiated by an unconscious (premonitory) urge that can be temporarily suppressed.
b. Tourette syndrome is defined as having two or more motor tics and at least one vocal tic (do not have to occur at the same time), for at least 1-year duration and beginning before 18 years of age. In addition, symptoms cannot be secondary to other illnesses or medications.
2. Epidemiology. The prevalence of Tourette syndrome is 1 in 1000 live births. However, tics occur in 3% of children.
3. Etiology. The cause of Tourette syndrome is unknown. In some patients, there is a genetic predisposition.
4. Clinical features
a. Motor tics can be simple (e.g., eye blinking, head or shoulder shaking) or complex (e.g., bouncing, jumping, kicking).
b. Vocal tics can be simple (e.g., coughing, grunting, humming, clearing the throat) or complex (e.g., echolalia, which is the repetition of heard words or phrases).
c. Tics must be present ≥1 year, although their severity and frequency waxes and wanes.
d. Absence of any signs of a neurodegenerative disorder
e. Coprolalia, the utterance of obscene words, is a dramatic symptom that occurs in
<10% of patients.
f. Associated findings include mood disorders, anxiety, attention deficit/hyperactivity disorder, and obsessive–compulsive traits.
5. Differential diagnosis. Disorders that may cause tics include Wilson disease, Sydenham chorea, partial or myoclonic seizures, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS or PANS disorder is an autoimmune neuropsychiatric disorder which follows infection with wide variety of agents, including streptococcal or mycoplasma infection, and is characterized by dramatic and acute onset of obsessive compulsive behaviors and/or severe restricted food intake, with associated neuropsychiatric symptoms which may include tics, anxiety, emotional lability, deterioration in school performance or behavioral regression), or simple habits. (Habits differ from tics in that habits are situation-dependent and are under voluntary control.)
6. Diagnosis
a. Tourette syndrome is a clinical diagnosis based on history and neurologic findings.
b. No laboratory or imaging tests confirm the diagnosis.
7. Management
a. For tics that are mild and nondisabling, no treatment is recommended.
b. Nonpharmacologic treatment includes habit reversal therapy and comprehensive behavioral intervention for tics.
c. Pharmacologic treatment includes alpha-adrenergics (clonidine, guanfacine) and both typical and atypical neuroleptics (pimozide, haloperidol, risperidone). Botulinum toxin injection may be effective for some focal motor tics.
8. Prognosis
a. Tics wax and wane over a lifetime and tend to decrease in adulthood.
b. Pharmacotherapy is generally successful, but side effects from the medications may be limiting.
IX. Duchenne and Becker Muscular Dystrophies (DMD, BMD)
A. Definition. DMD and BMD are progressive, X-linked myopathies characterized by myofiber degeneration. DMD is more severe than BMD.
B. Epidemiology
1. These worldwide disorders occur in all ethnic groups.
2. Prevalence is 1 in 10,000 live births.
3. Onset of symptoms is between 2 and 5 years of age.
C. Etiology. These X-linked disorders are caused by a deletion in the dystrophin gene.
D. Pathophysiology
1. Dystrophin is located on the plasma membrane of muscle fibers and provides mechanical reinforcement and stabilization. It is a high–molecular weight cytoskeletal protein that associates with actin and other structural membrane elements.
2. The absence of dystrophin causes weakness and eventually rupture of the plasma membrane, leading to injury and degeneration of muscle fibers.
E. Pathology. Both DMD and BMD have the same appearance on light microscopy.
1. Degeneration and regeneration of muscle fibers
2. Infiltration of lymphocytes into the injured area and replacement of damaged muscle fibers with fibroblasts and lipid deposits
F. Clinical features
1. Slow, progressive weakness affecting the legs first
2. In DMD, children lose the ability to walk by around 12 years of age. In BMD, patients lose the ability to walk by 20 or more years of age.
3. Pseudohypertrophy of calves is present because of the excess accumulation of lipids, which replace the degenerating muscle fibers. This is more common in DMD than in BMD.
4. Gowers sign is present. Because of the weakness of pelvic muscles, patients arise from the floor in a characteristic manner by extending each leg and then “climbing up” each thigh until they reach an upright position.
5. Cardiac involvement (e.g., cardiomegaly, tachycardia, or cardiac failure) occurs in 50% of patients.
6. Mild cognitive impairment may occur in DMD, but normal intelligence is present in BMD.
G. Diagnosis
1. The presence of enlarged calf muscles in a young boy with muscle weakness suggests the diagnosis.
2. CK levels are VERY high, even before muscle weakness.
3. EMG shows small, polyphasic muscle potentials with normal nerve conductions.
4. Muscle biopsy shows the typical dystrophic pattern.
5. Absent or decreased dystrophin levels are present on immunocytochemistry or Western blot assay of muscle.
6. DNA testing may reveal the gene deletion in >90% of patients.
H. Management. There is no cure, but oral steroids can improve strength transiently and prolong duration of ambulation when the disease is in the early stages. Current research is evaluating gene replacement therapy to convert DMD to the more favorable BMD.
I. Prognosis
1. In DMD, patients are wheelchair dependent by 12 years of age and often die in their late teens from respiratory failure or cardiomyopathy. Assisted ventilation may help individuals to live longer.
2. In BMD, patients become wheelchair dependent in their twenties. Life expectancy is beyond the age of 30 years.
X. Myasthenia Gravis
A. Definition. Myasthenia gravis is an autoimmune disorder that presents with generalized weakness, fatigability of muscles, ptosis, and diplopia.
B. Etiology. Myasthenia gravis is caused by antibodies against the acetylcholine receptor (AChR) in the postsynaptic membrane of the neuromuscular junctions.
C. Classification
1. Neonatal myasthenia is a transient weakness in the newborn period secondary to transplacental transfer of maternal AChR antibodies from a mother affected with myasthenia gravis.
2. Congenital myasthenia is familial and is not transferred by the mother. There are no maternal antibodies, and this disorder consists of multiple subtypes.
3. Juvenile myasthenia gravis presents in childhood secondary to AChR antibody formation.
D. Epidemiology. Juvenile myasthenia gravis affects girls two to six times more frequently than boys.
E. Clinical features
1. In neonatal myasthenia, hypotonia, weakness, feeding problems, and weak cry are the most common findings.
2. In juvenile myasthenia gravis, several findings are characteristic.
a. Bilateral ptosis is the most common presenting sign.
b. Characteristic increasing weakness occurs later in the day and with repetitive or sustained muscle activity.
c. Diplopia secondary to decreased extraocular movements may be the only manifestation.
d. DTRs are preserved.
e. Other autoimmune disorders, including juvenile rheumatoid arthritis, diabetes mellitus, and thyroid disease, may coexist.
F. Diagnosis. Diagnosis is made by the following:
1. Tensilon test. Intravenous injection of edrophonium chloride, a rapidly acting cholinesterase inhibitor, produces transient improvement of ptosis.
2. Decremental response to low-frequency (3–10 Hz) repetitive nerve stimulation
3. Presence of AChR antibody titers
G. Management
1. In neonatal myasthenia, treatment is supportive because the disorder is self-limited. Small feedings by nasogastric tubes and assisted ventilation are provided if needed. Cholinesterase inhibitors can be used to aid with feeding and respiratory support.
2. In juvenile myasthenia gravis, treatment involves the following:
a. Cholinesterase inhibitors are the mainstay of treatment. Pyridostigmine bromide
is the drug of choice.
b. Immunotherapy
1. Corticosteroids are used when cholinesterase inhibitors fail.
2. Plasmapheresis lowers the level of AChR antibodies. It is useful when symptoms worsen, when respiratory effort is compromised, or when the patient is unresponsive to other therapies.
3. IVIG may also be effective.
c. Thymectomy is performed if there is evidence of thymoma (there is also some evidence for thymectomy even in the absence of thymoma)
H. Prognosis
1. In neonatal myasthenia, symptoms are mild and generally resolve within 1–3 weeks.
2. In juvenile myasthenia gravis, remission of symptoms can be as high as 60% after thymectomy.
Review Test
1. You are called to the nursery to examine a “floppy” female infant born within the past
24 hours. The neonate is hypotonic with diminished deep tendon reflexes. There are no tongue fasciculations. When you greet the baby’s mother, she is anxious and has difficulty releasing her grip after shaking your hand. Which of the following is the most likely diagnosis?
A. Muscular dystrophy
B. Congenital myotonic dystrophy
C. Neonatal myasthenia gravis
D. Spinal muscular atrophy, type 1
E. Infantile botulism
2. A 10-year-old girl is being evaluated for “weakness” of 3 days’ duration. Medical history is significant for a 4-day episode of diarrhea 2 weeks before her current presentation. She is otherwise well with no chronic medical conditions and is taking no medications. Physical examination reveals symmetric weakness at the ankles and knees, with normal strength at the hip joints. Deep tendon reflexes are absent in the distal lower extremities. Sensory examination is normal. Which of the following statements is most consistent with the most likely diagnosis?
A. This patient is most likely to have had a prodromal gastroenteritis with Salmonella typhi.
B. Electromyography would be expected to show normal nerve conduction.
C. Management should include intravenous immune globulin.
D. This patient is likely to have elevated antistreptolysin O or anti-DNase B titers.
E. The prognosis for complete recovery is poor.
3. A 6-month-old male infant is evaluated for lethargy and poor feeding. Recent dietary changes include the introduction of cereals, fruits, and herbal tea with honey. Physical examination reveals an afebrile infant with normal vital signs. Neurologic examination is notable for decreased muscle tone and a weak suck. Which of the following statements regarding this infant’s most likely diagnosis is most accurate?
A. Infants typically present with ascending paralysis.
B. Antibiotics should be administered immediately.
C. Infants present with brisk deep tendon reflexes.
D. Electromyography is not helpful in making the diagnosis.
E. Constipation is often the initial symptom in infants.
4. An 8-year-old girl is noted by her teacher to have brief staring spells throughout the day. She is referred to you for further evaluation. Neurologic examination is normal. You order an electroencephalogram, which shows a generalized 3-Hz spike-and-wave discharge pattern arising from both hemispheres. Which of the following statements regarding the most likely diagnosis is most accurate?
A. Further questioning would probably reveal that this patient loses control of her bladder during the event.
B. This patient’s condition is inherited in an autosomal recessive pattern.
C. This patient’s staring spells would be expected to last less than 10 seconds each.
D. This patient is likely to have prolonged postictal periods.
E. Phenobarbital is the drug of choice for this patient’s condition.
5. A 4-month-old female infant is brought to your office by her parents, who are concerned about some behaviors they have witnessed. They note that during the past week, she has had brief jerking episodes, lasting 1–2 seconds each, with sudden arm extension followed by flexion of the head. You order an electroencephalogram, which reveals a highly disorganized pattern of high-amplitude spike and waves in both cerebral hemispheres, consistent with a hypsarrhythmia pattern. Which of the following is the most commonly identified cause of the
patient’s disorder?
A. Prior episode of bacterial meningitis
B. Perinatal asphyxia
C. Shaken baby syndrome
D. Tuberous sclerosis
E. Neurofibromatosis type 1
6. A 6-year-old boy complains of a 4-day history of low-back pain and difficulty walking. On examination, you note weakness in his lower extremities and absent lower extremity deep tendon reflexes. Sensation in the lower extremities is intact. A magnetic resonance imaging scan of the spine is normal. Which of the following is the most likely diagnosis?
A. Duchenne muscular dystrophy
B. Myasthenia gravis
C. Acute cerebellar ataxia of childhood
D. Guillain–Barré syndrome
E. Becker muscular dystrophy
7. A 2-year-old boy is brought to the office by his parents, who note that their son has had weakness in his legs for the past several months that appears to be getting worse. On examination, you note that the calf muscles are enlarged. Which of the following statements regarding this patient’s condition is correct?
A. DNA testing is normal.
B. Dystrophin levels are normal.
C. Progressive weakness leads to loss of ambulation before 12 years of age.
D. Electromyography reveals delayed nerve conduction.
E. Treatment with intravenous immune globulin can transiently improve symptoms.
8. Two hours ago a 2-year-old boy had a 5-minute episode of whole body shaking associated with a temperature of 39.4°C (103°F). The boy’s parents state that their son has had runny nose and cough for the past 24 hours. He now acts normal except for his cold symptoms, according to his parents. The parents remind you that this is his second febrile seizure. Physical examination is normal, revealing no focal neurologic signs. Which of the following would be the most appropriate recommendation at this time?
A. Order a stat head computed tomography scan.
B. Order an electroencephalogram.
C. Begin treatment with phenobarbital.
D. Reassure the parents that no workup or medications are necessary at this point.
E. Admit the patient to the hospital for overnight observation.
9. A 12-year-old girl is brought to see you for evaluation of frequent headaches. She has had headaches three times per week for the past several months, and her parents are concerned that she may be having migraines. Which of the following statements would support this diagnosis?
A. The headaches are bilateral, dull, and achy, but mild.
B. The neurologic examination is abnormal during the headache.
C. The headaches awaken the patient in the early morning hours.
D. The duration of the headache is >1 hour.
E. This patient is likely to have an aura with her headache.
10. Examination of a comatose 13-year-old boy in the emergency department is significant for bilaterally nonreactive and dilated pupils. An oculocephalic maneuver is negative. Which of the following is the most likely diagnosis?
A. Postictal state from status epilepticus
B. Brainstem injury
C. Subdural hematoma with herniation
D. Opiate overdose
E. Alcohol intoxication
11. A 2-month-old boy is brought to your office for evaluation with a 2-day history of poor feeding and vomiting. Parents deny fever, cold symptoms, or diarrhea. On physical examination, the child is well hydrated but has a large anterior and posterior fontanelle and a persistent downward deviation of both eyes. This patient’s presentation is most consistent with which of the following diagnoses?
A. Cerebral infarct
B. Congenital myotonic dystrophy
C. Myasthenia gravis
D. Becker muscular dystrophy
E. Infantile hydrocephalus
The response items for statements 12–14 are the same. You will be required to select one answer for each statement in the following set.
A. Dandy–Walker malformation
B. X-linked hydrocephalus
C. Infantile botulism
D. Spinal muscular atrophy type 1 (Werdnig–Hoffman disease)
E. Juvenile myasthenia gravis
F. Congenital myotonic dystrophy
For each patient, select the most likely diagnosis.
1. A 4-month-old male infant has generalized weakness, hypotonia, areflexia, and tongue fasciculations.
2. An 8-month-old female infant with a 5-day history of constipation presents with a weak cry, hyporeflexia, ophthalmoplegia, and loss of the ability to sit without support.
3. A 6-month-old male has had hypotonia, facial weakness, areflexia, and a history of feeding problems since birth.
Answers and Explanations
1. The answer is B [I.F.3]. This patient most likely has congenital myotonic dystrophy. Patients present with hypotonia and often have feeding and respiratory problems. Facial weakness and hyporeflexia are common. Infants acquire the disorder through autosomal dominant inheritance, most commonly from an affected mother. Mothers of infants with congenital myotonic dystrophy have myotonia, an inability to relax contracted muscles, which manifests as difficulty releasing a hand grip during a firm handshake. Muscular dystrophy rarely presents during infancy. Infants with botulism have constipation, hypotonia, problems with suck and swallow, and progressive weakness that may lead to paralysis. Neonatal myasthenia is a transient muscle disorder caused by the transplacental passage of acetylcholine receptor antibodies. Weakness and hypotonia may be present, but deep tendon reflexes are preserved. Infants with spinal muscular atrophy have hypotonia but also have characteristic tongue fasciculations.
2. The answer is C [VII.D]. This patient’s presentation is most consistent with Guillain–Barré syndrome. The diagnosis of Guillain–Barré syndrome should be considered in any child with ascending symmetric weakness or paralysis, absence of deep tendon reflexes, and a normal sensory examination. Management should be initiated as soon as the diagnosis is established because of the risk of respiratory muscle paralysis. Intravenous immune globulin is the preferred treatment in children. Many infectious agents have been associated with Guillain– Barré syndrome, but the most common infectious agent is Campylobacter jejuni, which causes a prodromal gastroenteritis. Electromyography would be expected to demonstrate decreased nerve conduction velocity or conduction block. There is no known association between Guillain–Barré syndrome and prior group A β-hemolytic streptococcal infection. The prognosis for children with Guillain–Barré syndrome is excellent, and complete recovery is likely.
3. The answer is E [I.F.2]. Infantile botulism is caused by the ingestion of Clostridium botulinum spores and the release of botulinum toxin within the intestine. The toxin prevents the release of acetylcholine at peripheral cholinergic synapses, initially causing constipation, which is followed by a weak suck and swallow, cranial nerve palsies, and weakness. Patients with infantile botulism have a symmetric descending paralysis. Contaminated honey is a common source of the toxin. Physical examination is notable for diffuse weakness, hypotonia, and hyporeflexia (i.e., diminished deep tendon reflexes). The diagnosis is suggested by the history and physical examination findings and confirmed by the identification of the toxin or bacteria within the stool. Electromyography may also be helpful in diagnosis and may show brief, small-amplitude muscle potentials with an incremental response during high-frequency stimulation. Treatment includes supportive care and botulism immune globulin. Antibiotics are not helpful.
4. The answer is C [V.L.4]. This patient’s clinical presentation and electroencephalogram (EEG) are consistent with absence epilepsy of childhood. Patients usually present with multiple absence seizures, which are brief staring spells that occur without warning and are not followed by postictal drowsiness. Urinary continence and loss of posture are also not seen in absence seizures. Absence seizures last less than 10 seconds and have a very characteristic EEG pattern, showing a generalized 3-Hz spike-and-wave abnormality. Absence epilepsy of childhood is inherited in an autosomal dominant pattern with age-dependent penetrance. The antiepileptic medications usually used include ethosuximide, valproic acid, or lamotrigine.
5. The answer is D [V.L.3]. This clinical presentation is consistent with infantile spasms. Patients with infantile spasms typically present with brief, myoclonic jerks, lasting 1–2 seconds each, occurring in clusters of 5–10 seizures spread out over 3–5 minutes. Patients may have sudden
extension of the arms and sudden flexion of the head (jackknife or salaam seizures). A variety of different prenatal, perinatal, and postnatal insults to the central nervous system may result in infantile spasms. Tuberous sclerosis is the most commonly identified cause of this disorder. Perinatal asphyxia, intraventricular hemorrhage, and meningitis are other causes of infantile spasms. Neurofibromatosis type 1 is not typically associated with infantile spasms.
6. The answer is D [VII.D]. Guillain–Barré syndrome (acute inflammatory demyelinating polyneuropathy) typically presents with ascending paralysis without sensory loss. Despite this finding, about 50% of children complain of low-back pain or discomfort in their legs. Deep tendon reflexes are absent, and spinal magnetic resonance imaging is normal. The diagnosis is based on the findings of albuminocytologic dissociation in the cerebrospinal fluid and by decreased nerve conduction velocity on electrophysiologic studies. In both Duchenne and Becker muscular dystrophy, the onset of weakness is slow and progressive. Myasthenia gravis, which is more common in girls, presents with weakness that increases during the day and normal deep tendon reflexes. Acute cerebellar ataxia of childhood presents with ataxia (unsteady gait or truncal unsteadiness) rather than weakness.
7. The answer is C [IX.B, IX.E, and IX.I.1]. This patient’s presentation with increasing weakness in the lower extremities and calf enlargement is consistent with Duchenne muscular dystrophy, an X-linked progressive degenerative muscle disorder for which there is no cure. Children typically present between 2 and 5 years of age with gait problems and weakness, and they are often wheelchair dependent by around their 12th birthday. On examination, patients have enlarged calf muscles (pseudohypertrophy) as a result of fatty infiltration of the degenerating muscles, and laboratory studies reveal elevated creatine kinase levels. The diagnosis can be made by DNA testing of the dystrophin gene, which shows a deletion in more than 90% of patients. Electromyography shows small, polyphasic muscle potentials but normal nerve conduction velocities. Intravenous immune globulin has no role in the management of Duchenne muscular dystrophy.
8. The answer is D [V.K.7]. Febrile seizures are defined as any seizure that accompanies a fever owing to a non-CNS (central nervous system) cause in patients between the ages of 6 months and 6 years. Febrile seizures are benign events that are not generally associated with serious acute or long-term neurologic sequelae. A computed tomography scan is not indicated in the absence of papilledema or focal neurologic deficits. An electroencephalogram is useful when the diagnosis of epilepsy is being considered but not in recurrent febrile seizures. A complex febrile seizure is distinguished from a simple febrile seizure if it lasts more than 15 minutes, has focal features, or recurs within 24 hours. For simple febrile seizures, anticonvulsant treatment is usually not initiated until a patient has multiple febrile seizures. Febrile seizures do not require inpatient observation.
9. The answer is D [VI.B and VI.C]. Migraines are characterized by unilateral, or sometimes bilateral, frontal throbbing headaches that last for at least 1 hour. The neurologic examination of patients with migraines is usually normal. Headaches that occur on awakening in the morning are more characteristic of headaches resulting from increased intracranial pressure. Migraine without aura is the most common form of migraine in children.
10. The answer is B [IV.C.6]. The physical examination of this patient’s eyes, including both the negative oculocephalic test and bilateral dilated nonreactive pupils, is most consistent with brainstem injury. The oculocephalic maneuver is also termed doll’s eyes, and an abnormal response (when the head is turned, the eyes follow the head and continue to look straight ahead rather than drifting to midline) suggests a damaged vestibular system. Pupils may also be dilated during and immediately after a seizure or after topical ophthalmic application of a dilating agent, but the vestibular nerve is usually unaffected in these situations (the oculocephalic maneuver would be positive). An enlarging subdural hematoma can cause uncal herniation with a unilateral dilated, nonreactive pupil. Opiate ingestion causes
constricted pupils. Alcohol intoxication less frequently causes coma and more often leads to somnolence. Alcohol intoxication can cause pupils to be slow to react but pupils would not be nonreactive.
11. The answer is E [II.D]. This patient’s eye findings are termed the setting-sun sign, or a tonic downward deviation of the eyes. The setting-sun sign is suggestive of hydrocephalus. Increased pressure in the third ventricle from noncommunicating hydrocephalus injures the upward gaze center in the midbrain, causing this downward deviation of the eyes. In contrast, patients with myasthenia commonly present with ptosis. There are no specific eye abnormalities in congenital myotonic dystrophy, muscular dystrophy, or cerebral infarcts.
12. The answers are D, C, and F, respectively [I.F.1–3]. The 4-month-old infant has spinal muscular atrophy type 1 (Werdnig–Hoffman disease), an autosomal recessive disorder that presents with hypotonia, weakness, problems with suck and swallow, and tongue fasciculations. It presents within the first 6 months of life. The 8-month-old infant has infantile botulism, an environmentally acquired disorder of the neuromuscular junction in which botulinum neurotoxin blocks release of acetylcholine at the neuromuscular junction. The toxin is released from the spores of Clostridium botulinum, which are found in contaminated honey or soil. Constipation is often the presenting symptom, followed by weakness, cranial nerve findings, poor abilities to feed, and paralysis. The 6-month-old infant has congenital myotonic dystrophy, an autosomal dominant disorder presenting in infancy with hypotonia, facial weakness, and feeding problems. The diagnosis may be missed if the mother of the patient is not seen or examined because the typical myotonia (i.e., inability to relax contracted muscles) is most apparent in adults.