Neonatal Hypotonia

Abstract

Neonatal hypotonia can be caused by diseases that impair both the central and the peripheral nervous systems; it represents a diagnostic challenge to both the experienced neonatologist and pediatric neurologist because the differential diagnosis is very broad. First, a systematic methodology to collect information on family, pregnancy, and prenatal and birth clinical data is helpful for the diagnostic workup. After the clinical information is gathered, an accurate clinical examination should follow, including neurologic assessment to address differential diagnosis and to avoid needless or invasive diagnostic tests. In newborns and older infants, there is an overlapping significance between tone versus strength and hypotonia versus weakness. Clinical assessment of a floppy infant includes the evaluation of muscle tone, primitive reflexes, deep tendon reflexes, placing reactions, resting postures in prone and supine positions, antigravity movements, and visual following⁄alertness. Moreover, since there is a higher prevalence of cognitive delay in infants with hypotonia of central origin, a standardized assessment of cognitive development and observational assessments of the infant’s affective behavior development are important as well. Generalized hypotonia associated with muscle weakness and preserved social orientation suggests a neuromuscular disorder. Spinal muscular atrophy type 1 and congenital myotonic dystrophy are the most common neuromuscular causes of “floppy infant syndrome.”

Keywords

congenital muscular dystrophy, congenital myasthenia, congenital myopathy, neonatal hypotonia, neuromuscular disorders in infants, neuromuscular disorders in newborn

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Neonatal hypotonia can be caused by diseases of the central and/or peripheral nervous systems.
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A systematic collection of family, pregnancy, and prenatal and birth clinical data is helpful for diagnostic workup.
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Accurate clinical examination, including neurologic assessment, is needed to address the differential diagnosis and to avoid needless or invasive diagnostic tests.
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Generalized hypotonia associated with muscle weakness and preserved social orientation suggests a neuromuscular disorder.
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Spinal muscular atrophy type 1 and congenital myotonic dystrophy represent the most common neuromuscular causes of “floppy infant syndrome.”

Neonatal hypotonia, also defined as “floppy infant syndrome,” represents a diagnostic challenge for both the experienced neonatologist and pediatric neurologist. Hypotonia is a manifestation reflecting either a disorder of the central nervous system (CNS), the peripheral nervous system (PNS), or both ( Box 13.1 ) and thus the differential diagnosis is very broad. More than 600 conditions are reported in the Online Mendelian Inheritance in Man (OMIM) compendium as being associated with early-onset hypotonia. Moreover, transitory hypotonic posturing and behavior can be part of the normal variability in the premature infant, typically accompanying acute illness or systemic illnesses. Based on clinical estimates of large series of patients, hypotonia of central origin accounts for about 66% to 88% of cases, with PNS involvement or unknown causes accounting for the remaining cases.

Box 13.1

Central nervous system involvement

Systemic diseases

Congenital heart disease

Sepsis

Inborn errors of metabolism

Maternal infection

Syndromic central hypotonia

Hypoxic-ischemic encephalopathy

Chromosomal defects

Lemli-Opitz syndrome

Prader-Willi syndrome

Cerebro-occulo-facial syndrome

Coffin-Lowry syndrome

Angelman syndrome

Sotos syndrome

Joubert syndrome

Marfan syndrome

Osteogenesis imperfecta

Nonsyndromic central hypotonia

Cerebral malformation

Schizencephaly

Lissencephaly

Holoprosencephaly

Delayed myelination

Congenital ataxia

Peripheral nervous system involvement

Spinal muscular atrophy

Metabolic myopathies (Pompe disease)

Peripheral neuropathies

Congenital myasthenic syndromes

Congenital myopathies

Botulism

Spinal injury or other horn cell diseases

Central and peripheral nervous system involvement

Congenital muscular dystrophies

Congenital myotonic dystrophy

Metabolic diseases (mitochondrial disorders)

Congenital myasthenic syndromes

Disorders of the Central or Peripheral Nervous System Leading to Neonatal Hypotonia

Improving the methodology in decision making to detect causes of hypotonia is important to avoid needless or invasive diagnostic tests, to offer an effective clinical assessment and suitable genetic counseling to the family, and finally to inform about prognosis and future medical intervention.

In this chapter, we analyze the stepwise diagnostic approach to the investigation of neonatal hypotonia and discuss the differential diagnosis of hypotonia, summarizing the most common neuromuscular disorders that manifest principally with hypotonia or early-onset weakness.

Clinical History Collection

A detailed family, pregnancy, prenatal, and birth clinical history should be conducted first to collect important information than can help in the diagnostic process. The family history should include any other family members with hypotonia, muscle diseases, or genetic disorders and should explore for parental consanguinity. A family history of neurologic or neuromuscular conditions has been reported in about 50% of hypotonic infants, and parental consanguinity increases the risk of autosomal recessive disorders.

The prenatal and perinatal history should include the mother’s description of fetal movements; polyhydramnios or oligohydramnios; any maternal illness or maternal exposure to infectious agents, drugs, or alcohol; abnormal fetal presentation; the need for respiratory support; feeding difficulties; and seizures. The developmental history in infants older than a few months should include the age when major milestones are attained. Intrauterine growth restriction associated with oligohydramnios may suggest a CNS involvement related to poor maternal nutrition or chromosomal/genetic syndromes. A history of seizures, head growth failure, and global developmental delay are also evocative of brain involvement. Conversely, a clinical history of maternal polyhydramnios, reduced fetal movement, breech presentation, respiratory distress, swallowing problems, and poor suck at birth are strong indicators of a neuromuscular disorder.

Clinical Evaluation

The general physical examination of a floppy infant may reveal organomegaly, abnormalities of the genitalia, skin changes, dysmorphic features, contractures, or skeletal abnormalities that are suggestive of genetic syndromic disease, including some connective disorders such as Marfan and Ehlers-Danlos syndromes, because hyperlaxity of the ligaments can also manifest as hypotonia.

Neurologic Examination of the Hypotonic Infant

In the newborn and infant, there is an overlapping significance between tone versus strength and between hypotonia versus weakness. Clinical assessment of a floppy infant should include the evaluation of muscle tone, primitive reflexes, deep tendon reflexes, placing reactions, resting postures in prone and supine positions, antigravity movements, and visual following ⁄ alertness. Moreover, because there is a higher prevalence of cognitive delay in infants with central hypotonia, a standardized assessment of cognitive development and observational assessment of the infant’s affective behavior development are important as well.

A clinical diagnosis of hypotonia is based on three features: (1) bizarre and unusual distribution of tone, (2) diminished resistance to passive movements, and (3) excessive range of joint movements. Muscle tone can be further evaluated by performing simple maneuvers such as “pull to sit,” the “scarf sign,” and “ventral suspension.”

The “ pull to sit ” maneuver evaluates axial tone of the neck and back and appendicular tone of the shoulder and arms. It also tests strength to some extent because the normal response from the infant being tested is to resist pulling on the arms and shoulders. The hypotonic infant tends to have significant head lag when pulled to the seated position and does not keep the head erect when sitting.

The “ scarf sign ” is observed as an infant’s arm is pulled across the chest to the opposite shoulder and there is minimal resistance. Normally, the elbow can be brought to the midline of the infant’s chin and chest. In the hypotonic infant, the elbow can easily be brought well beyond the midline before encountering resistance.

On ventral suspension , the normal term infant will keep the arms and legs flexed and will be able to lift the head above the horizontal position for a few seconds. A floppy infant “slips through” at the shoulder and assumes the position of a rag doll.

Once the infant has clearly been identified as hypotonic, it is important to complete the neurologic examination to understand the neuroanatomic site of the lesion and to determine whether hypotonia is accompanied by weakness because the presence of a profound muscle weakness suggests the involvement of the PNS. The assessment of muscle strength of infants can be limited to inspection.

At clinical inspection, a weak infant assumes a frog-leg position. Spontaneous antigravity movements of limbs may be absent or decreased, although social interaction is preserved. Other clinical indicators of weakness are weak cry, poor suck, poor swallowing ability, and a paradoxical breathing pattern (intercostal muscles paralyzed with intact diaphragm). Normal head circumference may also suggest the isolated involvement of PNS. Pronounced head lag on traction response and inverted- U posture at ventral suspension are indicative of weakness of axial and trunk muscles.

Conversely, an infant affected by a CNS disorder general manifests global developmental delay and visual contact, consciousness, and social interactions are generally poor. Early-onset strabismus is highly evocative of a CNS origin of hypotonia. Significant axial and trunk hypotonia with relative sparing of limb tone is often observed. Tendon reflexes are brisk together with sustained ankle clonus and extensor plantar response and persistence of primitive reflexes. Abnormal head size, microcephaly or macrocephaly, seizures, and dysmorphia are also additional useful indicators of CNS involvement.

Central hypotonia can be related to systemic diseases (e.g., cardiac failure, sepsis, or inborn errors of metabolism) or to genetic syndromic and nonsyndromic diseases. Finally, mixed signs of central and peripheral hypotonia can be observed in several diseases involving both the CNS and PNS (e.g., congenital muscular dystrophy and congenital myotonic dystrophy as reported in Box 13.1 ). Differential clinical features and distinct patterns of weakness are very useful for the differential diagnosis as reported in Table 13.1 .

Table 13.1

Distinct Patterns of Weakness and Differential Clinical Features Aiding Differential Diagnosis of Neonatal Hypotonia

Pattern of Weakness
Central Hypotonia	Peripheral Hypotonia
Increased tendon reflexes Extensor plantar response Sustained ankle clonus Global developmental delay Microcephaly Seizures	Poor antigravity movements Hypo- to areflexia Selective motor delay Preserved social interaction Weak cry Respiratory distress

Differential Clinical Signs
Spinal muscular atrophy	Generalized weakness with sparing of the diaphragm and facial muscles tongue fasciculations
Pompe diseases	Generalized weakness with sparing of the diaphragm and facial muscles enlargement of the tongue Cardiomegaly Increased creatine phosphokinase levels in blood
Congenital myopathy Myasthenic syndrome Myotonic dystrophy Botulism	Bulbar and oculomotor muscles involvement Respiratory weakness
Peripheral neuropathy	Distal muscle group involvement, distal contractures
Congenital muscular dystrophy	Structural brain and eye abnormalities contractures

Diagnostic Investigation

Hypotonia can be related to disorders that affect any level of the nervous system. A clinical history and physical examination of the brain, cerebellum, brainstem, spinal cord, peripheral nerves, neuromuscular junction, and muscle should guide the investigations.

The initial laboratory evaluation of a floppy infant is directed to rule out systemic disorders. Routine tests should include blood and urine cultures; serum electrolytes; liver function tests; determination of ammonia, glucose, and creatinine levels; and a complete blood cell count. When a metabolic disorder is suspected, an immediate search for disorders of energy metabolism, amino acid metabolism, fatty acid metabolism, and urea cycle function should be undertaken if the child shows signs of metabolic decompensation because metabolic disorders may be more easily suspected and detected during a metabolic crisis than in the intercritical period. Screening for toxoplasmosis; other (congenital syphilis and viruses), rubella, cytomegalovirus, and herpes (TORCH) screening; and urine drug screening should be undertaken to exclude maternal infection or drug exposure. Brain imaging in parallel with metabolic screening are appropriate if a CNS disorder is suspected. The presence of particular dysmorphic features may prompt karyotyping, array comparative genomic hybridization (CGH), methylation study for chromosome 15q11.2 deletion (Prader-Willi/Angelman syndrome), or other specific molecular tests.

When a neuromuscular disorder is suspected, a creatine phosphokinase (CPK) test may be useful; however, it must be noted that most congenital myopathies (CMs) are associated with a normal CPK level and that a transitory high CPK level in newborns can be observed in fetal asphyxia or following a vaginal delivery, especially if complicated by forceps, vacuum, and breech presentation. Persistent high CPK values are highly suggestive of a muscular dystrophy, whereas in anterior horn cell disease the CPK level is generally normal or mildly increased. If spinal muscular atrophy 1 is suspected, current guidelines suggest a prompt request for molecular genetic testing to rule out a survival motor neuron (SMN) defect, because treatment options should follow shortly. Electromyography and nerve conduction studies are useful diagnostic tests if a neuromuscular junction defect or neuropathy is suspected, whereas a muscle biopsy is required to investigate a myopathy or a metabolic myopathy (e.g., mitochondrial disease).

Muscle ultrasound is noninvasive and very useful for the assessment of a floppy infant. It can be used as a first screening option. Screening results are normal in children with hypotonia of cerebral origin, Prader-Willi syndrome, ligamentous laxity, or other “nonneuromuscular” causes.

Finally, some conditions warrant specific testing, such as echocardiogram in Pompe disease or brain magnetic resonance imaging (MRI) in congenital muscular dystrophy, to support the diagnosis. A schematic approach to the diagnosis of a floppy infant is shown in Fig. 13.1 .