CHAPTER 182 Weakness and Hypotonia
ETIOLOGY
The corticospinal tract and its neurons from the cerebral cortex through the spinal cord that control voluntary motor activity are known as the upper motor neuron. The anterior horn cells, their motor roots, peripheral motor nerves, neuromuscular junctions, and muscles represent the lower motor neuron. Maintenance of normal strength, tone, and coordination requires integrated communication between the motor nuclei of the cerebral cortex, spinal cord, cerebellum, brainstem, thalamus, basal ganglia, and motor cortex of the cerebrum. The cerebellum and basal ganglia facilitate volitional movement. The cerebellum provides dynamic feedback regarding joint position, and the basal ganglia modulate agonists and antagonistic muscle groups.
Dysfunction of the upper motor neuron causes loss of voluntary control, but not total loss of movement. Motor nuclei of the basal ganglia, thalamus, and brainstem have their own tracts that innervate anterior horn cells and produce simple or complex stereotyped patterns of movement. Damage of the spinal cord leaves simple, stereotyped reflex movements coordinated by local spinal reflexes below the level of the lesion intact. Destruction of the lower motor neuron leads to total absence of movement because it is the final common pathway producing muscle activity.
CLINICAL MANIFESTATIONS
Weakness caused by upper motor neuron disease or corticospinal tract lesions is different in quality from weakness produced by the lower motor unit (Table 182-1). The corticospinal tract permits fine motor activity and is best tested by asking the patient to perform rapid alternating movements of the distal extremities. Mild dysfunction produces slowed, stiff motions. More severe dysfunction produces stiff, abnormal postures (spasticity) that do not respond to voluntary command. The posture in corticospinal tract disease consists of the forearm being flexed at the elbow and wrist and adducted close to the chest, with the leg extended and adducted. Disease of the lower motor unit produces progressive loss of strength with hypotonia and no abnormality of posture. Function is best tested by measuring the strength of individual muscle groups or, in a young child, by observing the ability to perform tasks requiring particular muscle groups (walk up or down stairs, arise from the ground, walk on toes or heels, raise the hands above the head, and squeeze a ball).
TABLE 182-1 Clinical Distinction between Upper Motor Neuron and Lower Motor Neuron Lesions
| Clinical Sign | Upper Motor Neuron (Corticospinal Tract) | Lower Motor Neuron (Neuromuscular) |
|---|---|---|
| Tone | Increased (spastic) | Decreased |
| Reflexes | Increased | Decreased |
| Babinski reflex | Present | Absent |
| Atrophy | Absent | Possible |
| Fasciculations | Absent | Possible |
DISEASE OF THE UPPER MOTOR NEURON
Etiology and Epidemiology
Tumors, trauma, infections, demyelinating syndromes, infarction, metabolic diseases, and degenerative diseases may injure the corticospinal tract, producing an upper motor neuron pattern of weakness coupled with increased deep tendon reflexes, spasticity, and extensor plantar responses (Babinski sign).
Clinical Manifestations
The distribution of weakness depends on the location of the lesion. A tumor in the left parietal region may produce a right hemiparesis. A brainstem glioma may produce a slowly progressive quadriparesis. Compression of the spinal cord in the thoracic region from a tumor, such as neuroblastoma or lymphoma, would produce a spastic paraparesis, affecting only the legs. A disorder of myelin synthesis, such as a leukodystrophy, would produce a progressive symmetrical quadriparesis.
DISEASES OF THE SPINAL CORD
Acute spinal cord lesions, such as infarction or compression, may produce a flaccid, areflexic paralysis that mimics lower motor neuron disease. A child who exhibits an acute or subacute flaccid paraparesis is most likely to have either an acute cord syndrome or Guillain-Barré syndrome. The acute cord syndrome may be the result of transverse myelitis, a cord tumor, infarction, demyelination, or trauma. The hallmarks of spinal cord disease are a sensory level, a motor level, disturbance of bowel and bladder function, and local spinal pain or tenderness. Transverse myelitis, an acute postinfectious demyelinating disorder of the spinal cord, is treated with high-dose steroids. Trauma and tumors (neuroblastoma, lymphoma, sarcoma) compressing the spinal cord necessitate immediate neurosurgical management to preserve vital function.
DISEASES OF THE LOWER MOTOR NEURON
Each anterior horn cell in the spinal cord and brainstem gives rise to a single myelinated axon that extends to muscle. The lower motor unit consists of the anterior horn cell, the peripheral nerve, the neuromuscular junction and the muscle. Neuromuscular disease affects any component of the lower motor neuron unit. The distribution of muscle weakness can point toward specific diseases (Table 182-2). Diseases may affect each component of the motor unit.
TABLE 182-2 Topography of Neuromuscular Diseases
| Location | Clinical Syndromes/Disorders |
|---|---|
| Proximal muscle weakness | |
| Distal limb weakness | |
| Ophthalmoplegia and limb weakness | |
| Facial and bulbar weakness |
DISEASES OF THE ANTERIOR HORN CELL
Spinal Muscular Atrophy
Etiology
Progressive degeneration of anterior horn cells is the key manifestation of spinal muscular atrophy (SMA), a genetic disease that may begin in intrauterine life or any time thereafter and may progress at a rapid or slow pace. The earlier in life the process starts, the more rapid the progression. Infants who are affected at birth or who become weak within the first several months of life usually progress to flaccid quadriplegia with bulbar palsy, respiratory failure, and death within their first year. This early severe form of the illness is called Werdnig-Hoffmann disease. A milder form of the illness, Kugelberg-Welander syndrome, begins in late childhood or adolescence with proximal weakness of the legs and progresses slowly over decades. Variants of SMA between these age extremes occur with unpredictable courses.
SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50. All types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA; homozygous absence of SMN2, found in about 5% of control subjects, has no clinical phenotype. The number of SMN2 copies modulates the SMA phenotype.
Clinical Manifestations
SMA may begin between 6 months and 6 years of age, may progress rapidly or slowly or may progress rapidly initially, then seemingly plateau. The clinical manifestations include progressive proximal weakness, decreased spontaneous movement, and floppiness. Atrophy may be marked. Head control is lost. With time, the legs stop moving altogether. The range of facial expression diminishes, and drooling and gurgling increase. The eyes remain bright, open, mobile, and engaging. Weakness is flaccid, with early loss of reflexes. Fasciculations (quivering of the lateral aspect of the tongue) are best identified by inspecting the mouth when the child is asleep. Infants have normal mental, social, and language skills and sensation. Breathing becomes rapid, shallow, and predominantly abdominal. In an extremely weak child, respiratory infections lead to atelectasis, pulmonary infection, and death.
Laboratory and Diagnostic Studies
The level of creatine phosphokinase may be mildly elevated. The electromyelogram (EMG) shows fasciculations, fibrillations, positive sharp waves, and high-amplitude, long-duration motor units. Muscle biopsy specimens show grouped atrophy. The diagnosis is established by specific DNA probe for SMA.
Treatment
No treatment for SMA exists. Symptomatic therapy is directed toward minimizing contractures, preventing scoliosis, aiding oxygenation, preventing aspiration, and maximizing social, language, and intellectual skills. Respiratory infections are managed early and aggressively with pulmonary toilet, chest physical therapy, oxygen, and antibiotics. The use or nonuse of artificial ventilation must be individualized for each patient in each stage of the illness.
POLIOMYELITIS
Poliomyelitis is an acute enteroviral illness with prodromal vomiting and diarrhea associated with an aseptic meningitis picture during which the patient experiences the evolution of an asymmetrical flaccid weakness as groups of anterior horn cells become infected (see Chapter 101).
PERIPHERAL NEUROPATHY
There are three principal peripheral nerve diseases in childhood:
Peripheral neuropathy produced by diabetes mellitus, alcoholism, chronic renal failure, amyloid, exposure to industrial or metal toxins, vasculitis (often as mononeuritis multiplex), or the remote effects of neoplasm is a common cause of weakness and sensory loss in adults but is rare in children.
Guillain-Barré Syndrome
Etiology
Guillain-Barré syndrome is a postinfectious autoimmune peripheral neuropathy that often occurs after a respiratory or gastrointestinal infection. Infection with Campylobacter jejuni is associated with a severe form of the illness.
Clinical Manifestations
The characteristic symptoms are areflexia, flaccidity, and relatively symmetrical weakness beginning in the legs and ascending to involve the arms, trunk, throat, and face. Progression can occur rapidly, in hours or days, or more indolently, over weeks. Typically symptoms start with numbness or paresthesia in the hands and feet, then a heavy, weak feeling in the legs, followed by inability to climb stairs or walk. Deep tendon reflexes are absent even when strength is relatively preserved. Objective signs of sensory loss are usually minor compared with the dramatic weakness. Bulbar and respiratory insufficiency may occur rapidly. Close monitoring of respiratory function is essential. Dysfunction of autonomic nerves can lead to hypertension, hypotension, orthostatic hypotension, tachycardia, and other arrhythmias; urinary retention or incontinence; stool retention; or episodes of abnormal sweating, flushing, or peripheral vasoconstriction. This polyneuropathy can be difficult to distinguish from an acute spinal cord syndrome. Preservation of bowel and bladder function, loss of arm reflexes, absence of a sensory level, and lack of spinal tenderness would point more toward Guillain-Barré syndrome. A cranial nerve variant of Guillain-Barré syndrome called the Miller Fisher variant manifests with ataxia, partial ophthalmoplegia, and areflexia.
Porphyria and tick paralysis may simulate Guillain-Barré syndrome. Other causes of peripheral neuropathy include vasculitis, heredity, nutritional deficiency (vitamins B1, B12, and E), endocrine disorders, infections (diphtheria, Lyme disease), and toxins (organophosphate, lead).
The illness may resolve spontaneously; 75% of patients recover normal function within 1 to 12 months. Twenty percent of patients are left with mild to moderate residual weakness in the feet and lower legs. The mortality rate is 5%, and death is caused by autonomic dysfunction (hypertension-hypotension, tachycardia-bradycardia, and sudden death), respiratory failure, mechanical ventilation complications, cardiovascular collapse, or pulmonary embolism.
Laboratory and Diagnostic Studies
The cerebrospinal fluid (CSF) in Guillain-Barré syndrome is often normal in the first days of the illness, but later in the disease shows elevated protein levels without significant pleocytosis. Nerve conduction velocity (NCV) and EMG may be normal early, but then show delay in motor NCV and decreased amplitude and temporal dispersion of the evoked compound motor action potential.
Treatment
Children with moderate, severe or rapidly progressive weakness should be cared for in a pediatric intensive care unit (ICU). Pulmonary and cardiac functions are monitored continuously. Endotracheal intubation should be performed electively in patients who exhibit early signs of hypoventilation or accumulation of bronchial secretions. Therapy is symptomatic and rehabilitative and directed at blood pressure control and cardiac arrhythmia; nutrition, fluids, and electrolytes; pain control; prevention of complications (skin, cornea, and joints, infection); bowel and bladder management; psychological support; and communication therapy. Most patients are treated initially with intravenous (IV) immunoglobulin (total dose 1–2 g/kg given for 2 to 5 days). Plasma exchange and IV immunoglobulin are beneficial in rapidly progressive disease.
Hereditary Motor Sensory Neuropathy (Charcot-Marie-Tooth Disease)
Etiology
Hereditary motor sensory neuropathy (HMSN), commonly called Charcot-Marie-Tooth disease, is a chronic, genetic polyneuropathy characterized by weakness and wasting of distal limb muscles. The most common form (Charcot-Marie-Tooth type 1A) is due to a duplication of DNA at 17p11.2-12, a region containing the peripheral myelin protein (PMP 22) gene. A deletion in this region gives rise to a much milder condition, known as hereditary neuropathy with liability to pressure palsies. An X-linked form of HMSN is caused by mutations of the gap junction protein, connexin 32. HMSN type II is a neuronal form with normal or mildly decreased NCV and no hypertrophic changes. Type I HMSN and type II HMSN are inherited as autosomal dominant traits with variable expressivity.
Clinical Manifestations
Most often, complaints begin in the preschool years with pes cavus deformity of the feet and weakness of the ankles with frequent tripping (see Chapter 201). Examination shows high-arched feet, bilateral weakness of foot dorsiflexors, and normal sensation despite occasional complaints of paresthesia. Progression of HMSN is slow, extending over years and decades. Eventually, patients develop weakness and atrophy of the entire lower legs and hands and mild to moderate sensory loss in the hands and feet. Some patients never have more than a mild foot deformity, loss of ankle reflexes, and electrophysiologic abnormalities. Others in the same family may be confined to a wheelchair and have difficulties performing everyday tasks with their hands.
Tick Paralysis
Tick paralysis produces an acute lower motor neuron pattern of weakness clinically similar to Guillain-Barré syndrome. An attached female tick releases a toxin, similar to botulism, blocking neuromuscular transmission. Affected patients present with a severe generalized flaccid weakness, including ocular, papillary, and bulbar paralysis. A methodical search for an affixed tick, particularly in hairy areas, must be made in any child with acute weakness. Removal of the tick results in a prompt return of motor function.
NEUROMUSCULAR JUNCTION DISORDERS
Myasthenia Gravis
Etiology and Epidemiology
Myasthenia gravis is an autoimmune condition in which antibodies to the acetylcholine receptors at the neuromuscular junction block and, through complement-mediated pathways, damage the neuromuscular junction.
Clinical Manifestations
Classic myasthenia gravis may begin in the teenage years with the onset of ptosis, diplopia, ophthalmoplegia, and weakness of extremities, neck, face, and jaw. Fluctuating and generally minimal symptoms are present on awakening in the morning and gradually worsen as the day progresses or with exercise. In some children, the disease never advances beyond ophthalmoplegia and ptosis (ocular myasthenia). Others have a progressive and potentially life-threatening illness that involves all musculature, including that of respiration and swallowing (systemic myasthenia).
Neonatal Transitory Myasthenia Gravis
A transitory myasthenic syndrome develops in 10% to 20% of neonates born to mothers with myasthenia gravis. Symptoms persist for 1 to 10 weeks (mean, 3 weeks). Almost all infants born to mothers with myasthenia have antiacetylcholine receptor antibody, but neither antibody titer nor extent of disease in the mother predicts which neonates have clinical disease. Symptoms and signs include ptosis, ophthalmoplegia, weak facial movements, poor sucking and feeding, hypotonia, and variable extremity weakness. The diagnosis is made by showing clinical improvement lasting approximately 45 minutes after intramuscular (IM) administration of neostigmine methylsulfate, 0.04 mg/kg. Treatment with oral pyridostigmine or neostigmine 30 minutes before feeding is continued until spontaneous resolution occurs.
Congenital Myasthenic Syndrome
A variety of rare disorders of the neuromuscular junction have been reported that are not autoimmune mediated. The conditions manifest as hypotonic infants with feeding disorders and varying degrees of weakness. Some of the identified variants include abnormalities of the presynaptic region (familial infantile myasthenia), synaptic defects (congenital end plate acetylcholinesterase deficiency), or postsynaptic disorders (slow channel myasthenic syndrome).
MUSCLE DISEASE
Duchenne Dystrophy
Etiology
Duchenne muscular dystrophy, a common sex-linked recessive trait (Xp21) appearing in 20 to 30 per 100,000 boys, results from absence of a large cytoskeletal protein called dystrophin. Becker muscular dystrophy arises from an abnormality in the same gene locus, resulting in abnormal dystrophin function with more indolent symptoms and later onset than Duchenne dystrophy.
Clinical Manifestations
At about 2 to 3 years of age, boys develop an awkward gait and an inability to run properly. Some have an antecedent history of mild slowness in attaining motor milestones, such as walking and climbing stairs. Examination shows firm calf hypertrophy and mild to moderate proximal leg weakness with a hyperlordotic, waddling gait and inability to arise from the ground easily. The child typically arises from a lying position on the floor by using his arms to climb up his legs and body (Gower sign). Arm weakness is evident by 6 years of age, and most boys are confined to a wheelchair by 12 years of age. By age 16, little mobility of arms remains, and respiratory difficulties increase. Death is caused by pneumonia or congestive heart failure resulting from myocardial involvement.
Laboratory and Diagnostic Studies
Serum creatine phosphokinase levels are always markedly elevated. Muscle biopsy shows muscle fiber degeneration and regeneration accompanied by increased intrafascicular connective tissue. Diagnosis is established by DNA probe for Duchenne muscular dystrophy. Prenatal diagnosis of both diseases is possible by genetic testing. Approximately one third of cases represent new mutations.
Other Forms of Muscular Dystrophy
Limb-girdle dystrophy is usually an autosomal recessive disease presenting with proximal leg and arm weakness. The genetic defect lies within one of the many muscle proteins that compose the muscle fiber plasma membrane cytoskeleton complex. The clinical manifestations are similar to those of Duchenne dystrophy, but are seen in an older child or teenager and progress slowly over years. By midadulthood, most patients are wheelchair bound.
Facioscapulohumeral dystrophy is usually an autosomal dominant disease presenting in teenagers. Genetic diagnosis is possible by finding a characteristic 4q35 deletion. The child has mild ptosis, a decrease in facial expression, inability to pucker the lips or whistle, neck weakness, difficulty in fully elevating the arms, scapular winging, and thinness of upper arm musculature. Progression is slow, and most patients retain excellent functional capabilities for decades.
Myotonic Dystrophy
Etiology and Epidemiology
Myotonic dystrophy is an autosomal dominant genetic disease caused by progressive expansion of a triplet repeat, GCT, on chromosome 19q13.2-13.3 in a gene designated myotonin protein kinase (MP-PK).
Clinical Manifestations
Myotonia is a disorder of muscle relaxation. Patients grasp onto an object and have difficulty releasing their grasp, peeling their fingers away slowly. Myotonic dystrophy presents either at birth, with severe generalized hypotonia and weakness, or in adolescence, with slowly progressive facial and distal extremity weakness and myotonia. The adolescent type is the classic illness and is associated with cardiac arrhythmias, cataracts, male pattern baldness, and infertility in males (hypogonadism). The facial appearance is characteristic, with hollowing of muscles around temples, jaw, and neck; ptosis; facial weakness; and drooping of the lower lip. The voice is nasal and mildly dysarthric.
Some mothers with myotonic dystrophy give birth to infants with the disease who are immobile and hypotonic, with expressionless faces, tented upper lips, ptosis, absence of sucking and Moro reflexes, and poor swallowing and respiration. Often, weakness and atony of uterine smooth muscle during labor lead to associated hypoxic-ischemic encephalopathy and its sequelae. The presence of congenital contractures, clubfoot, or a history of poor fetal movements indicates intrauterine neuromuscular disease.
Congenital Myopathies
Etiology
Congenital myopathies (nemaline rod, central core, myotubular) are a group of congenital, often genetic, nonprogressive or slowly progressive myopathies characterized by abnormal appearance of the muscle biopsy specimen (Table 182-3).
TABLE 182-3 Congenital Myopathies
Congenital structural myopathy
Central core
Nemaline rod
Centronuclear
Congenital fiber type of disproportion
Myotubular
Congenital muscular dystrophy
Miscellaneous types
Metabolic myopathies
Glycogen storage disease II (Pompe disease)
Carnitine metabolism abnormalities
Mitochondrial abnormalities
Endocrine myopathies
Thyroid myopathies
Clinical Manifestations
A child with a congenital myopathy is profoundly hypotonic with moderately diffuse weakness involving limbs and face. Associated conditions include congenitally dislocated hips, a high-arched palate, clubfoot, and contractures at hips, knees, ankles, or elbows secondary to intrauterine weakness. The attainment of motor milestones is moderately to severely delayed. The clinical course is either static or slowly progressive. Progressive kyphoscoliosis represents a significant problem in some children. Reflexes are diminished.
Dermatomyositis
Etiology and Epidemiology
The etiology and epidemiology of dermatomyositis are discussed in Chapter 91.
Clinical Manifestations
The clinical features include progressive proximal muscle weakness coupled with dermatologic features, including erythematous rash around the eyes (heliotrope) and plaques on the knuckles (Gottron papules) and on the extensor surfaces of the knees, elbows, and toes. Subcutaneous calcinosis is a late finding (see Chapter 91).
Diagnostic Studies and Therapy
Myositis-specific autoantibodies may be identified in the serum. Diagnostic testing includes measurement of serum creatine phosphokinase levels, EMG, magnetic resonance imaging (MRI) of muscle, and muscle biopsy. See Chapter 91 for therapy.
Metabolic Myopathies
Glycogen storage disease type II (Pompe disease) and muscle carnitine deficiency are discussed in Chapter 52. Mitochondrial myopathies are characterized by muscle biopsy specimens that display ragged red fibers, representing collections of abnormal mitochondria (see Chapter 57). Typical symptoms include hypotonia, ophthalmoplegia, and progressive weakness, but the phenotype of these disorders is broad. Endocrine myopathies, including hyperthyroidism, hypothyroidism, hyperparathyroidism, and Cushing syndrome, are associated with proximal muscle weakness. Hypokalemia and hyperkalemia produce fluctuating weakness (periodic paralysis) and loss of tendon jerks.
Treatment of Neuromuscular Diseases
The major complications of neuromuscular disorders are the development of joint contractures, scoliosis, and pneumonia. Active range of motion exercises and bracing prevent and treat contractures, minimizing pain and maximizing function. Surgery to release contractures or to realign tendons is most helpful in nonprogressive or in very slowly progressive conditions. Kyphoscoliosis produces loss of function, disfigurement and, when severe, life-threatening decrease of ventilatory reserve. Prevention or delay in the development of these complications can be achieved by maintaining ambulation for as long as possible, ensuring a properly fitted wheelchair, bracing, and surgery. Pneumonia may be associated with thick secretions that are difficult to clear, progressive atelectasis, and respiratory failure. Anticipatory treatment with antibiotics, hospitalization, chest physical therapy, oxygen, and ventilatory support helps in most cases.
Laboratory and Diagnostic Studies
See Table 182-4 and text for individual disorders.
TABLE 182-4 Evaluation of Neuromuscular Disease
Complete medical history
Complete family history
Complete neurologic examination
Complete blood count with differential, ESR
Electrolytes, BUN, creatinine, glucose, calcium, phosphate, alkaline phosphatase, magnesium
Muscle chemistry studies: CK, aldolase
Metabolic studies: lactate, pyruvate
Chest radiograph
ECG
Stool: botulism culture and toxin testing, Campylobacter culture
CSF examination (protein, cells)
Tensilon test, neostigmine test, acetylcholine receptor antibody assay
EMG-NCV
Muscle biopsy
MRI of spinal cord
BUN, blood urea nitrogen; CK, creatine kinase; ECG, electrocardiogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; NCV, nerve conduction velocity [testing].
Malignant Hyperthermia
Patients with Duchenne muscular dystrophy, central core myopathy, and other myopathies are susceptible to the life-threatening syndrome of malignant hyperthermia. Malignant hyperthermia is manifested as a rapid increase of body temperature and PCO2, muscle rigidity, cyanosis, hypotension, arrhythmias, and convulsions. This syndrome may occur during administration of muscle relaxants (succinylcholine) or inhalation agents such as halothane. Malignant hyperpyrexia can also occur in children without muscle disease as an autosomal dominant genetic disorder. A family history of unexplained death during operations is often noted. Diagnosis of idiopathic malignant hyperthermia is possible with genetic testing or the in vitro muscle contraction test. Excessive tonic contracture on exposure to halothane and caffeine in vitro indicates susceptibility. Treatment with IV dantrolene, sodium bicarbonate, and cooling is helpful.
Neonatal and Infantile Hypotonia
The clinical distinction between upper and lower motor neuron disorders in infants is blurred because incomplete myelinization of the developing nervous system limits expression of many of the cardinal signs, such as spasticity. Neuromuscular and cerebral disorders may produce hypotonia in a young child or infant. The two critical clinical points are whether the child is weak and the presence or absence of deep tendon reflexes. Hypotonia and weakness coupled with depressed or absent reflexes suggest a neuromuscular disorder. A stronger child with brisk reflexes suggests an upper motor neuron source for the hypotonia.
Hypotonia without Significant Weakness (Central Hypotonia)
Some infants who appear to move well when supine in their cribs are floppy when handled or moved. These infants are bright-eyed, have expressive faces, and can lift their arms and legs from the bed without apparent difficulty. When lifted, their heads flop, they slip through at the shoulders, do not stand upright, and form an inverted U in prone suspension (Landau posture). When placed prone as neonates, they may lie flat instead of having their arms and legs tucked underneath them. Passive tone is decreased, but reflexes are normal. This clinical picture may be associated with significant cerebral disease or may be a benign phenomenon that is outgrown.
Prader-Willi syndrome presents with severe neonatal hypotonia; severe feeding problems leading to failure to thrive; small hands and feet; and, in boys, small penis, small testicles, and cryptorchidism. Severe hyperphagia and obesity develop in early childhood. Approximately 60% to 70% of affected individuals have an interstitial deletion of paternal chromosome 15q11q13. Many other syndromes also present with severe neonatal floppiness and mental dullness (Table 182-5).
TABLE 182-5 Approach to Differential Diagnosis in the Floppy Infant
HYPOTONIA WITH WEAKNESS
HYPOTONIA WITHOUT WEAKNESS
Infants who have a connective tissue disorder, such as Ehlers-Danlos syndrome, Marfan syndrome, or familial laxity of the ligaments, may exhibit marked passive hypotonia, double jointedness, and increased skin elasticity. They have normal strength and cognition and achieve motor and mental milestones normally. They have peculiar postures of their feet or an unusual gait.
Infants with benign congenital hypotonia typically exhibit the condition at 6 to 12 months old, with delayed gross motor skills. They are unable to sit, creep, or crawl, but have good verbal, social, and manipulative skills and an intelligent appearance. Strength appears normal, and the infants can kick arms and legs briskly and bring their toes to their mouths. The children display head lag, slip-through in ventral suspension, and floppiness of passive tone. The infant seems floppy from birth. The differential diagnosis includes upper and motor neuron disorders and connective tissue diseases. Extensive laboratory investigation is often unrevealing. Most of these children catch up to peers and appear normal by 3 years of age. Often, other family members have exhibited a similar developmental pattern.
STROKE IN CHILDHOOD
Etiology
Cerebrovascular infarction or hemorrhage is uncommon in children. The incidence is 2.5 to 10 per 100,000 children and is higher in neonates. A wide spectrum of conditions can produce stroke in childhood (Table 182-6). The most common causes are congenital heart disease (cyanotic), sickle cell anemia, meningitis, and hypercoagulable states.
Heart disease and its complications (endocarditis) may give rise to thromboses in cerebral arteries or veins or to emboli in cerebral arteries. Cerebral venous and arterial thromboses occur in 1% to 2% of infants with unrepaired cyanotic congenital heart disease and probably are related to local congestion of blood flow, right-to-left cardiac shunting, and polycythemia. Predisposing factors include acute episodes of severe cyanosis, febrile illnesses, dehydration, hyperventilation, and iron deficiency anemia. Sources of emboli include mural thrombi from poorly contracting cardiac chambers, bacterial or nonbacterial endocarditis, valvular disease, atrial myxoma, cardiac catheterization, and cardiac surgery. Septic emboli producing cerebral infarcts occur in 10% to 20% of patients who develop bacterial endocarditis.
Clinical Manifestations
Cerebral embolization characteristically occurs without warning, produces its full deficit within seconds (hyperacute), and may be associated with focal deficits, seizures, sudden headache, and hemorrhagic infarction. The most common sources of cerebral emboli are the heart and the carotid artery. Cerebral thrombosis may be preceded by transient ischemic attacks that resolve completely. The deficits evolve over hours in a stepwise or stuttering progression. The sudden emergence of neurologic deficits implies cerebrovascular disease, and the site of occlusion is suggested by the neurologic deficits.
Occasionally a thorough evaluation of a child with a stroke fails to reveal the etiology. Angiography or magnetic resonance angiography may disclose the site of vascular occlusion, but the pathogenetic mechanism remains unknown. This condition is termed acute hemiplegia of childhood.
Congenital hemiplegia becomes apparent in infants 4 to 6 months old with decreased use of one side of the body, early handedness, or ignoring one side. CT reveals an area of encephalomalacia in the contralateral cerebral hemisphere. The details of the child’s intrauterine, labor, delivery, and postnatal history often are unremarkable. Some neonates present with focal seizures. The timing of the injury is unknown, but the injury may represent an embolus from the fetal-placental unit.
Diagnostic Tests and Imaging
If clinical assessment does not reveal the cause of the stroke, a complete laboratory investigation should be undertaken promptly based on suspected etiologies (see Table 182–6). On initial presentation, a non-contrast head CT scan is warranted, but acute, nonhemorrhagic stroke may not be seen on routine CT. More detailed investigation must include MRI and MRA (magnetic resonance angiography). Newer generations of MRI scan can detect an evolving stroke and patterns of ischemia by abnormal findings on diffusion-weighted images.
Treatment
There is no treatment to repair the neurologic injury after the stroke, so prevention of future stroke must be the focus in children, if the etiology can be identified. The role of anticoagulants (IV heparin, subcutaneous low-molecular-weight heparin, and oral warfarin), platelet anti-aggregants (aspirin and dipyridamole), and thrombolysis via arterial or venous catheters for strokes that present in evolution, recurrent transient ischemic attacks, or ongoing cerebral embolization, appears to have some evidence of benefit despite significant risks.