Traction response (pull-to-sit).

The traction response is the most useful and most sensitive of the postural reflexes in infants. With the infant lying supine, the infant’s hands are grasped, and the infant is pulled up to a sitting position. Once the sitting posture is attained, the head is held erect in the midline. During the maneuver, the examiner notes the infant’s attempt to counter the traction by flexion of the arms (see Fig. 29.3 B ).

In an infant younger than 3 months, the plantar grasp should also be evident. In addition, there should be flexion at the elbow, knee, and ankle in response to the maneuver. The degree to which the head and neck pull up along with the trunk depends on the child’s age.

In infants younger than 33 weeks’ gestation, there is no traction response. From 33 weeks to term, the infant has head lag but responds to the traction maneuver by flexing the neck flexors in an attempt to lift the head. The full-term infant exhibits a traction response with minimal head lag, and when the sitting posture is attained, the head may be held erect momentarily and then falls forward.

By age 3 months, there should be no head lag, and the head should be aligned with the plane of the back as the child is pulled to sitting. The absence of flexion of the limbs in response to the examiner’s pull and the presence of head lag inappropriate for age suggests hypotonia (see Figs. 29.4 D and 29.5 C ).

Axillary suspension.

The response to axillary suspension allows assessment of generalized and shoulder girdle tone. The infant is held under the arms, lifted, and suspended from the axillae without the thorax being grasped. In infants with normal tone and strength, the shoulder girdle muscles exert enough strength to allow the infant to be suspended without slipping through the examiner’s grasp. In addition, the infant’s head is held midline and the legs are held with some flexion at the hips, knees, and ankles (see Fig. 29.3 D ). The hypotonic infant droops with legs extended and head falling forward, and the absence of resistance of the muscles of the shoulder girdle allows the infant to slip through the grasp of the examiner as the baby’s arms fling upward (see Fig. 29.5 B ).

Ventral suspension.

The response to ventral suspension allows assessment of tone of the trunk, neck, and extremities. The examiner holds the infant, who is lying prone. The infant is supported only by the examiner’s hand on the abdomen. A normal infant holds the head erect and the back straight and holds the extremities with some flexion at the elbows, hips, knees, and ankles (see Fig. 29.3 C ). A full-term neonate makes intermittent attempts to hold the head straight, maintains the back straight, and can flex the limbs. The hypotonic infant droops in the examiner’s palm, as if in the shape of an inverted “U,” with the head and legs dangling limply (see Fig. 29.4 C ).

Hypoxic-ischemic encephalopathy.

Brain injury resulting from asphyxia, hypoxia, or ischemia is an important cause of neonatal neurologic morbidity. Tissue oxygen deficiency is presumed to underlie the neurologic injury caused by hypoxic-ischemic insults. An oxygen deficit may be incurred by either hypoxemia or ischemia. Hypoxemia is defined as diminished oxygen content of blood. Ischemia is characterized by reduced blood perfusion in a particular tissue bed. Hypoxemia and ischemia often occur simultaneously or in sequence. Ischemia is likely to be the more important of these 2 insults.

Asphyxia denotes an impairment in gas exchange, which results not only in a deficit of oxygen in blood but also in an excess of carbon dioxide and thereby acidosis. Furthermore, sustained asphyxia usually results in hypotension and ischemia, which is consistent with the likely predominant importance of ischemia as the final common pathway to brain injury. Asphyxia is the most common clinical insult resulting in brain injury during the perinatal period.

Evidence of hypoxic-ischemic injury to the neonatal nervous system is reflected by a constellation of signs noticed early after birth. The asphyxiating event or events may occur at any point in the antepartum, intrapartum, or postpartum periods. On the basis of admittedly imprecise historical data, it has been concluded that insults sustained by the fetus during the antepartum period account for approximately 20% of cases of hypoxic-ischemic encephalopathy (HIE). Maternal cardiac arrest or hemorrhage leading to transplacental and fetal hypotension represents such prenatal insults. Intrapartum events, such as placental abruption, uterine rupture, and traumatic delivery, may account for 35% of cases of HIE. In an additional 35% of infants displaying signs of HIE, markers of intrapartum fetal distress and antepartum risk, such as maternal diabetes, intrauterine growth restriction, or maternal infection, are found. Postpartum difficulties, such as cardiovascular compromise, persistent fetal circulation, and recurrent apnea, account for approximately 10% of HIE cases. Postpartum difficulties are found more commonly in premature than in full-term infants. Therefore, for at least 65% of cases of neonatal HIE, difficulties of the intrapartum period alone do not explain the encephalopathy.

Recognition of neonatal HIE requires careful observation and examination of the newborn in the context of a detailed history of pregnancy, labor, and delivery. Newborns who have sustained hypoxic-ischemic insults severe enough to cause permanent neurologic injury usually demonstrate abnormalities on neurologic examination. Indeed, a combination of low Apgar scores, fetal acidosis or distress, and abnormal neurologic examination findings help define HIE. Nonetheless, if the hypoxic-ischemic damage has occurred well in advance of parturition, it may be asymptomatic in the neonate.

Mild HIE (stage 1) may be characterized by hyperalertness or by mild depression of the level of consciousness, which may be accompanied by uninhibited Moro and brisk deep tendon reflexes, signs of sympathetic activity (dilated pupils), and a normal or only slightly abnormal EEG. Typically, these symptoms last less than 24 hours. Moderate HIE (stage 2) may be marked by obtundation, hypotonia, diminished number of spontaneous movements, and seizures. Infants with severe HIE (stage 3) are ill for more than 24 hours and are comatose. In addition, they are markedly hypotonic and display bulbar and autonomic dysfunction. The EEG is abnormal and may demonstrate a burst-suppression pattern or seizures, or it may be isoelectric.

Neonates with moderate or severe HIE may show variation in level of consciousness during the 1st days after birth. Initially, depression of level of alertness may appear to improve after the first 12-24 hours after birth. However, specific signs of improving alertness such as visual fixation or following are lacking. In addition, other persistent or progressive neurologic deficits, as well as functional deterioration of other extraneural systems, are inconsistent with a true improvement in neurologic state. Coma may persist, supervene, or even progress to brain death by 72 hours of life. If the infant survives 72 hours without losing all cerebral function, a variable amount of improvement may be observed.

Diffuse hypotonia accompanied by a lack of movement constitutes the most frequently observed motor deficit found early in the course of neonatal HIE. By the end of the 1st day, patterns of weakness that reflect the distribution of cerebral injury from a generalized hypoxic-ischemic insult may emerge. Affected full-term infants may demonstrate quadriparesis with predominant proximal limb weakness. This pattern of weakness derives from ischemia in the watershed or parasagittal region of the brain, which corresponds to the border zones of circulation between the anterior and the middle cerebral arteries and the middle and the posterior cerebral arteries. Affected premature infants may have weakness primarily in the lower extremities because of perinatal ischemic injury of motor fibers serving the legs. These fibers lie dorsal and lateral to the external angles of the lateral ventricles. Focal injury resulting from focal ischemia (stroke) may result in focal deficits reflective of the vascular territory in which the injury has occurred. These patterns are relatively subtle. As many as 70% of infants with moderate or severe HIE experiences seizures by the end of the 1st day of life.

Focal and multifocal ischemic brain injury may occur during the perinatal period. Such injury, most often infarction, occurs in a vascular distribution. Prenatal cerebral infarctions have been identified by intrauterine ultrasonography. In one autopsy study of neonates, 32 of 592 (5%) infants had cerebral infarctions. Among neonates surviving only a few hours after birth, several had infarctions with subacute or chronic histologic characteristics, indicating that the ischemic insult occurred before parturition. Focal seizures are the heralding sign of neonatal stroke. Although clinical signs corresponding to the area of infarction are expected, they may be absent. Neonatal strokes may follow uneventful deliveries and may occur in otherwise normal-appearing infants. Stroke may also accompany asphyxia, coagulopathy, polycythemia, and sepsis. A predilection for these ischemic lesions to occur in the territory of the middle cerebral artery, especially the left, has been noted and remains unexplained.

A direct relationship between motor and cognitive deficits at 1 year of age and the severity of acidosis observed at birth in asphyxiated and symptomatic neonates has been described. The extent of these sequelae is dependent not only on the occurrence of asphyxia but also on its duration. The 3 stages of HIE also correlate with outcome at 1 year of age. Those neonates with mild (stage 1) HIE or those who demonstrate moderate (stage 2) HIE for less than 5 days usually develop normally. Persistence of moderate encephalopathy or appearance of severe (stage 3) HIE is associated with seizures and motor and cognitive delay during follow-up. Children with mild HIE as neonates tend to be free of handicap in motor, cognitive, and school performance. Greater impairment of performance in each of these developmental spheres is found among children who exhibited moderate or severe neonatal HIE.

The likelihood of long-term neurologic sequelae after HIE is increased by the presence of neonatal seizures. The EEG may provide valuable prognostic information after the occurrence of seizure. Interictal background abnormalities, such as a burst-suppression pattern, persistently low voltage, and electrocerebral inactivity, are highly correlated with poor outcome. Conversely, infants with normal EEGs or those revealing only maturational delay have much more favorable prognoses.

Neuroimaging is useful in determination of prognosis. Head ultrasonography has shown that severe periventricular intraparenchymal echodensities followed by evidence of tissue injury (cyst formation) are correlated with later motor and cognitive deficits in premature infants. MRI performed early in the neonatal course of hypoxic-ischemic brain injury provides useful prognostic information. Most infants with MRI evidence of basal ganglia “hemorrhage,” periventricular leukomalacia, or multicystic encephalomalacia after asphyxia ultimately demonstrate neurodevelopmental abnormalities. Diffusion-weighted imaging (DWI) reveals evidence of neonatal brain injury earlier than T1 and T2 weighted pulse sequences. Indeed, DWI reveals focal injury when standard MRI and CT are normal ( Fig. 29.7 ).

A and C, Predominant patterns of brain injury in newborns with hypoxic-ischemic brain injury. These apparent diffusion coefficient maps performed on day 3 of life and ( B and D ) T1 weighted images performed on day 10 of life are typical of the 2 major predominant patterns of brain injury seen in term newborns with hypoxic-ischemic encephalopathy. A, In the “watershed” pattern, areas of restricted diffusion are seen in the parasagittal regions (arrows). B, One week later, very subtle hyperintensities can be seen in the same areas on the T1 weighted images (arrows). C, In the “basal nuclei” predominant pattern, the areas that show restricted diffusion are the thalami and basal ganglia (white star) bilaterally. In this example, part of the optic radiation is also affected (black arrow). D, On day 10, the injury in the thalami and basal ganglia (black star) appears as T1 hyperintensities bilaterally.

Brain malformations.

Brain malformation can arise as a result of a chromosomal disorder, as a component of a multiple malformation syndrome, or as an isolated abnormality. When associated with a chromosomal disorder or multiple malformation syndromes, the other associated features are the primary clues to diagnosis. In isolated brain malformation, the primary features are microcephaly (in most cases) and cognitive and motor developmental impairment. The MRI scan can detect abnormalities of development of the hemispheric structures (agenesis of the corpus callosum, holoprosencephaly), abnormalities of cortical cellular migration (lissencephaly, pachygyria), and cerebral heterotopias as well as brainstem and cerebellar malformations (e.g., Joubert syndrome).

Progressive encephalopathies of infancy.

Progressive encephalopathies of infancy account for a small number of children with persistent hypotonia (see Chapter 24 ). These disorders are recognizable by a progressive deterioration of neurologic function and by diagnostically specific clues. The infant’s development is normal for some time and then plateaus; this is followed by developmental regression with loss of previously acquired skills. Hypotonia is a feature of many of these disorders, at least at some point during the course of the illness. Some disorders feature hypotonia as the result of the combination of CNS injury and an associated polyneuropathy (Krabbe disease and metachromatic leukodystrophy). Progressive disorders that may be associated with hypotonia include neonatal adrenoleukodystrophy, mannosidosis, fucosidosis, Gaucher disease types 2 and 3, GM ₁ gangliosidosis, infantile neuroaxonal dystrophy, infantile Refsum disease, Krabbe disease, metachromatic leukodystrophy, mucolipidosis type IV, and Tay–Sachs disease. The diagnosis of these disorders is based on recognition of clinically suggestive clues and on results of specialized biochemical and molecular genetic testing. If such a disorder is suspected, the infant should be referred to appropriate genetic and neurologic specialists.

Mitochondrial diseases.

Mitochondrial diseases often affect both the brain and muscle and clinically manifest as hypotonia, probably as a combination of both cerebral dysfunction and myopathy ( Tables 29.10 and 29.11 ). The diagnosis is based on recognition of clinical symptoms, presence of lactic acidosis, presence of ragged red fibers on muscle histologic examination, and mitochondrial abnormalities identifiable on a muscle electron microscopic examination ( Fig. 29.8 ). The diagnosis of many mitochondrial diseases is possible by specific mitochondrial DNA testing. Other inborn errors of metabolism may produce hypotonia by central mechanisms (organic acidurias, hyperammonemia) or by interfering with muscle metabolism ( Table 29.12 ).

Pathologic changes seen in mitochondrial myopathy. Hematoxylin and eosin stain (A) demonstrating increased fiber size variation and subsarcolemmal basophilic deposits (arrows) correlating with ragged red fibers (arrows) on Gomori trichrome (B) oil red O (C) and toluidine (D) staining showing increased lipid deposition in the fibers (arrows) indicative of marked mitochondrial dysfunction due to defects in β-oxidation. (E) COX (brown stain) with SDH counterstain (blue stain) showing many COX-negative fibers (blue staining fibers) indicative of mitochondrial dysfunction since the COX enzyme is partly encoded within mitochondrial DNA. (F) Electron microscopy showing classic paracrystalline “parking lot” inclusions within the mitochondria located immediately underneath the sarcolemma that correlate highly with mitochondrial dysfunction (arrows ; inset with higher magnification) and increased lipid deposition (arrowheads).

( A, Courtesy Michael Lawlor, MD, PhD, Medical College of Wisconsin, Milwaukee, WI; C, D, and F courtesy Karra Jones, MD, PhD, UC San Diego, San Diego, CA; B, E, courtesy Chamindra Konersman, MD, Medical College of Wisconsin, Milwaukee, WI.)

Brain malformation syndromes.

Miller–Dieker syndrome is characterized by severe lissencephaly (“smooth brain” with agyria), severe developmental impairment, hypotonia early in life, and hypertonia with age. The facial changes include bitemporal hollowing, upturned nares, thin vermilion border, and small jaw. Fluorescence in situ hybridization–detectable microdeletions of 17p13.3 in the PAFAH1B1 and YWHAE genes cause 80% of de novo mutations, whereas the remaining 20% are inherited from a parent with a balanced chromosomal rearrangement.

Muscle-eye-brain diseases (MEB) are an expanding category of congenital muscular dystrophies with eye abnormalities and an assortment of brain malformations including cobblestone lissencephaly type II, focal pachygyria, polymicrogyria, pontocerebellar hypoplasia, and occipital encephalocele. These diseases are characterized by hypotonia in infancy due to a concomitant muscular dystrophy and CNS disease and variable degrees of intellectual disability. Walker–Warburg syndrome is the most severe form of MEB, usually resulting with early demise. Genes associated with MEB are increasing rapidly: POMT1 , POMT2 , POMGnT1 , FKTN , FKRP , LARGE , ISPD , GTDC2 , B3GALNT2 , B3GNT1 , TMEM5 , POMK , DPM1 , DPM2 , DPM3 , DOLK , GMPPB , and DAG1.