Courtney J. Wusthoff, MD and Robert Ryan Clancy, MD

Neurologic Examination of the Newborn Infant

The ideal state for a neurologic examination, state 3, is usually achieved 1 to 2 hours after feeding or, conversely, 1 to 2 hours before the next feed. ¹

Acute neonatal encephalopathy (ANE) refers to the clinical syndrome of global brain dysfunction in the newborn, diagnosed through the history and examination. Babies with ANE have depression at birth, impaired mental status (lethargy or coma), hypotonia, inactivity, disordered sucking and swallowing, diminished primitive and postural reflexes, and reduced or absent deep tendon reflexes. Many, but not all, have clinical or subclinical seizures. ANE has numerous potential etiologies, such as acquired brain injury (e.g., hypoxic-ischemic encephalopathy, trauma, stroke, hemorrhage); infection; metabolic disease; or even severe, catastrophic types of neonatal epilepsy, which will be discussed later. Neonatal encephalopathy must always be distinguished from the term hypoxic-ischemic encephalopathy (HIE), which specifically refers to the clinical syndrome of acute encephalopathy in a newborn owing to hypoxic ischemia. The majority of neonates with ANE do not have HIE.

Developmental reflexes include both primitive and postural reflexes. Primitive reflexes are patterns of behavioral responses to stimulation that arise and extinguish at predictable ages in healthy newborns and infants. The familiar Moro reflex is elicited by sudden extension of the head in relation to the body, as with a light drop of the head ( Fig. 14-1). A newborn will respond by opening the hands and abducting and extending the arms and legs, followed by flexion. The Moro reflex is abnormal if asymmetric or depressed. Other examples of primitive reflexes include the palmar grasp, plantar grasp, glabellar, root, and suck reflexes. Postural reflexes determine the distribution of flexion or extension tone in the trunk and limb muscles depending on the orientation of the head and neck in space. The familiar “fencing posture” arises from the asymmetric tonic neck reflex, which is elicited by turning and holding the supine baby’s head to the left or right side for several seconds. The newborn reflexively responds by extending the arm and leg (by way of increased extension tone) on the side to which the face is pointing, while the other arm and leg flexes (by way of increased flexion tone) ( Table 14-1).

The maneuver is performed by grasping the baby’s hand and trying to bring the baby’s elbow across the midline. In a healthy term infant the elbow can be brought no further than the midclavicular line on the same side. In the case of prematurity, hypotonia, or brachial plexus injury, the elbow is easily brought past the midline, like a scarf. ²

The plantar response is extensor (upward response of the hallux) in most neonates for at least the first month up through the first year of life. A flexor response (toes turning down and inward, with foot everting) is also normal and not of concern. A definite and reproducible assymetry could be abnormal.

The term newborn should be able to follow an object both horizontally and vertically with the eyes. This may be assessed using a picture with contrasting black and white lines (e.g., Teller acuity targets); an object of a single bright color; or the examiner’s face, at about 10 inches from the baby. The examiner can move the object slowly across the field of vision to assess if eye movements are full and conjugate. Another method is to use a striped cloth or drum to elicit opticokinetic response and determine that eye movements are symmetric. Pupillary constriction responses to light develop between 30 and 32 weeks. ³

The glabellar tap is performed by tapping between the eyes to elicit bilateral blinking. It is a “poor man’s” corneal reflex that tests the afferent loop (cranial nerve V) and the efferent loop (cranial nerve VII). The same goal may be accomplished by stroking the eyelashes to elicit a blink. Facial nerve function is evident with good bilateral eye closure and symmetry of the face during crying. Auditory function is tested by behavioral responses to sound. A coordinated sucking and swallowing reflex should develop at approximately 35 weeks’ gestation, and poor sucking in a term newborn is of concern. Observe the tongue for fasciculations. Listen to the cry. An encephalopathic neonate may have a characteristic cry that is shorter and higher pitched. An infant who has been intubated may be hoarse; however, one with laryngeal palsy can be stridorous or hoarse. An infant with neuromuscular weakness may make the facial grimace of a cry, but be unable to generate sound.

A central facial paralysis (or “central seventh”) is caused by a lesion in the brain somewhere in the pathway from the primary motor cortex down to the nucleus of the seventh cranial nerve. A central facial palsy (i.e., central seven palsy) produces a gradation of weakness, which affects the lower face and mouth much more severely than the forehead muscles, which are less weak. Central facial paralysis may also have an associated hemiplegia. A peripheral facial palsy is caused by a lesion in the facial nerve nucleus or anywhere along the nerve’s track. A peripheral facial palsy affects the upper and lower face equally. For example, a “10%” injury of the peripheral 7th nerve will cause an equal 10% weakness of the forehead muscles, nasolabial fold, and lower mouth muscles.

Sometimes confused for a true facial palsy is an absence or hypoplasia of the left or right “depressor anguli oris” muscles. These muscles insert on the angle of the mouth and pull down or depress the corners of the mouth when an infant is crying. If the muscle from one side is missing or underdeveloped, that side of the mouth does not pull down as far during crying. To those not aware of this condition, this may be misinterpreted as “facial drooping” or weakness on the good side. Of course, without crying, the two sides of the mouth appear even. This condition is occasionally associated with congenital heart disease.

First, observe the position of the baby and the spontaneous movements. Observe the quantity and quality of the movements. Examine the tone by gentle flexion and extension of the limbs. Is there an associated paucity of movement of an arm or leg? Observe the rebound of the extremity; the rate at which a limb returns to its original position is helpful in gauging tone ( Fig. 14-3). Measuring the popliteal angle (which may be as great as 180 degrees at 28 weeks’ gestation but decreases to 110 degrees at term) allows for objective interobserver comparison of lower extremity tone. Head control can be gauged by either sitting the infant in the neutral position with good shoulder girdle support or pulling the baby off the surface of a bed (traction maneuver). ⁴⁵

The deep tendon reflexes develop, as does tone, several weeks earlier in the legs than in the arms, and the patellar and Achilles responses are attainable by 33 weeks’ gestation in most neonates. Note that when a knee-jerk response is obtained, a crossed adductor response may also occur as a normal variant up through 6 months of age.

Bilateral ankle clonus of 3 to 5 beats may be a normal finding, especially in infants who are crying, hungry, or jittery. Sustained ankle clonus is abnormal.

Myoclonus is a brief, involuntary twitch or jerk of a muscle or group of muscles. It is frequently seen in healthy newborns, particularly when they are drowsy or sleeping. Benign neonatal myoclonus is very common, may persist for several weeks, and does not indicate a brain abnormality. Much less common are myoclonic seizures in newborns; these are myoclonic jerks that are shown on electroencephalography (EEG) to have an ictal correlate, meaning they are true epileptic seizures. Many babies with myoclonic seizures will have other abnormalities on exam to suggest their myoclonus is not benign; in some cases EEG is necessary to make the distinction. ⁶

Jitteriness describes a pattern of rapid, high frequency, vibratory, shaking movements that may fluctuate in amplitude and frequency. These movements may be spontaneous or may be triggered by touch or startle. Jitteriness is more common in babies with hypoglycemia or other metabolic disturbance, drug withdrawal, or mild encephalopathy. Jitteriness differs from myoclonus because myoclonus is a very brief, twitching contraction of muscles, whereas jitteriness is more often a sustained pattern of tremulous movements lasting seconds or longer. Jitteriness may be distinguished from seizures in that jitteriness tends to resolve by holding the baby or changing position of the baby or limb. Furthermore, jitteriness does not involve altered consciousness or autonomic changes. Myoclonus and jitteriness are but two examples of conditions that could be confused for genuine epileptic seizures in the neonate. ⁷⁸

The Skull, Spine, and Brachial Plexus

The 50th percentile is 35 cm. Normal head circumference involves approximately 2 cm growth per month for 3 months, 1 cm growth per month for 3 more months, and then roughly 0.5 cm growth per month for the next 6 months, for a total of 12 cm in the first 12 months after birth. Premature infants should attain the head circumference of a healthy term infant, but illness and nutritional factors may slow the rate of growth. Relative to term infants, the head circumference of an otherwise healthy preterm infant may even be greater for the first 5 postnatal months, after which differences are less pronounced ( Table 14-2).

Asymmetric IUGR is restricted growth affecting weight and sometimes length but with normal head growth (“head sparing”). This is thought to reflect a protective mechanism in the face of extrinsic factors, by which the developing fetal brain is spared at the cost of other aspects of growth. Symmetric IUGR refers to restricted growth in all dimensions of growth, including head circumference, and carries a more worrisome neurologic prognosis.

The examination of the anterior fontanel is somewhat subjective and inexact, but it is useful nonetheless. The anterior fontanel should be slightly depressed and pulsatile when a neonate is sleeping comfortably. Sitting the baby up should depress the fontanel further in a normal newborn. A sunken anterior fontanel suggests dehydration. When the anterior fontanel is bulging, increased intracranial pressure may be a cause of concern. The normal anterior fontanel should remain open for at least the first 6 months. Premature closure is a concern for craniosynostosis.

The neonate with increased ICP may show poor feeding, lethargy, and irritability. Vomiting may increase or become more forceful. Bulging of the anterior fontanel, particularly while the baby is calm, is worrisome because ICP may be increased. With progression there may be bulging at the posterior fontanel or separation of the cranial sutures. Changes in pupils, eye movements, and autonomic function are late signs of increased ICP in the neonate. Although the open anterior fontanel may offer a limited outlet for increased ICP (when bulging), neonates can incur permanent injury or death from increased ICP.

Craniosynostosis is the result of premature closure of a cranial suture. Normal cranial sutures are shown in Figure 14-4. Premature closure results in the arrest of growth perpendicular to the affected suture. Types of craniosynostosis and their appearance are illustrated in Figure 14-5. They involve the following:

See Table 14-3.

Fortunately, spinal cord injury is uncommon in neonates. One instance in which it can occur, however, is when excessive traction is applied to the neck during a difficult delivery, especially if there is shoulder dystocia. The resulting cord injury causes a flaccid quadriplegia with sparing of the face and cranial nerves. Secondly, an indwelling umbilical arterial catheter misplaced at T11 can obstruct the artery of Adamkiewicz, which feeds the anterior spinal artery. The resulting cord ischemia causes an irreversible paraplegia.

Erb palsy is an injury to the brachial plexus, particularly the upper trunk. This causes weakness in flexion at the shoulder and elbow. At rest, the arm of a baby with Erb palsy hangs by the side and is internally rotated, and there are limited or no spontaneous movements of the hand. The most common cause is injury to the brachial plexus during delivery, particularly in babies who are large for gestational age, or in cases of shoulder dystocia ( Table 14-4).

Most babies with brachial plexus injury recover well, although this may take as long as 6 months. As many as 30% of cases may have lasting deficits or will require intervention. In the initial weeks and months, physiotherapy may be useful. If problems persist, nerve and muscle transfer surgery may be warranted. ⁹

Malformations of the Central Nervous System

A meningocele is the protrusion of only the meninges through a bony defect in the spine, whereas in meningomyelocele, both meninges and spinal cord protrude through bone. Spina bifida occulta is a vertebral cleft without spinal cord or meningeal herniation; it is a frequent incidental finding when neuroimaging the lumbar spinal region.

The incidence of meningomyelocele is approximately 0.5 to 1 per 1000 live births. Prophylaxis is accomplished in most cases by the intake of 0.4 mg of folic acid daily, starting, if possible, before the pregnancy begins. If the parents have had a previous child with spina bifida, 4 mg/day is recommended. With supplementation there has been a significant decrease in neural tube defects in the United States.

Until recently, standard treatment for meningomyelocele was surgery after birth. However, a randomized trial showed that prenatal surgery (i.e., fetal surgery performed before 26 weeks of gestation) led to a reduction in the need for CSF shunt in the first year and improved motor outcomes at 30 months. Because of the maternal and fetal risks of this operation, treatment is now available only at highly specialized fetal surgery centers. ¹⁰

The Arnold–Chiari type II (ACTII) malformation is frequently associated with meningomyelocele. ACTII consists of a low-lying cerebellar vermis and a ventral medulla that often protrudes into the foramen magnum. By obstructing the flow of CSF, it leads to hydrocephalus. Aqueductal stenosis may be found with ACTII malformation or in isolation, again leading to CSF flow obstruction. Agenesis of the corpus callosum can also be associated with meningomyelocele.

Many factors should be considered in formulating a neurologic prognosis. In general, the lower the level of the lesion, the better the prognosis. However, the presence and degree of hydrocephalus present at birth, in addition to the need for and any complications in shunting procedures (e.g., infection), also significantly affect outcomes. Any associated central nervous system (CNS) malformations, including agenesis of the corpus callosum, also contribute to morbidity. A child with a relatively low-lying lesion with an ACTII lesion and who has hydrocephalus is likely to have cognitive development in the normal range if there are no complications related to the shunting procedure. ¹¹

This assessment is accomplished by determining motor level and reflex level on examination ( Table 14-5). Sensory level assessment is less reliable in the newborn.

A tethered cord is a low-lying lumbosacral cord anchored posteriorly by a thickened filum terminale. It can occur in association with meningomyelocele or with other lumbosacral abnormalities such as lipomeningocele. It may be overlain by a dermal defect such as a hair tuft or sacral dimple. The lesion may be asymptomatic, but with growth it may lead to problems with sphincter control and walking and may also cause lumbar back pain. When a newborn has a sacral tuft or dimple suspicious for underlying cord abnormality, ultrasound is often used for immediate assessment, and magnetic resonance imaging (MRI) provides a definitive diagnosis.

The components of the Dandy–Walker malformation are cystic dilation of the fourth ventricle, partial or complete agenesis of the cerebellar vermis, and enlargement of the posterior fossa with a high attachment of the tentorium cerebelli. The Dandy–Walker malformation is frequently associated with hydrocephalus, which may not be present at birth but develops in the first year of life. Agenesis of the corpus callosum or cortical migrational defects (or both) coexist in many cases and increase the risk for intellectual disability when present. Treatment consists of observation and shunting of the ventricles. Sometimes the cyst itself needs to be shunted.

Porencephaly is an acquired abnormality that is seen as CSF-filled cysts at the site of injury, often adjacent to or connecting with the ventricular system. It usually is the result of an early parenchymal bleed, infarction, or infection. Schizencephaly represents a “split” or “cleft” in the cortex resulting from a congenital migrational defect and appears in one or both hemispheres from the surface of the brain down to the ventricular surface. In schizencephaly the walls of the cleft are lined with abnormal cortex (e.g., polymicrogyria), further dinstinguishing it from porencephaly.

Lissencephaly means “smooth brain.” With this condition there are few if any gyri formed on the brain’s surface. Lissencephaly is a severe migrational disorder of genetic etiology. There are two basic types. Type I is characterized by diffuse failure of migration on histology. These infants have an initially normal head size, but they also have hypotonia and seizures. A majority of these cases are caused by mutations affecting the genes LIS1, XLIS, or DCX. Type II lissencephaly is characterized by a “bumpy” or “pebbly” brain surface on pathology and is associated with congenital muscular dystrophy.

Holoprosencephaly reflects an early failure of the rudimentary forebrain to divide into two halves, resulting in various kinds of single-ventricle anomalies. These range in severity from alobar, in which there are no distinct cerebral hemispheres, to lobar variants, in which division between cerebral lobes is incomplete. The alobar form is particularly severe in terms of neurologic dysfunction, may result in a wide spectrum of facial abnormalities, and may be observed in infants with trisomy 13 or 18 syndrome. ¹²

Hydrocephalus is a build-up of CSF, usually owing to obstruction in the outflow of the CSF pathways. By conventional definitions, the obstruction can be “communicating,” in which the block is outside the ventricular system, or “noncommunicating,” in which the block is within the ventricular system. Choroid plexus papillomas (90% benign) are a rare cause of nonobstructive hydrocephalus; these tumors oversecrete CSF and lead to hydrocephalus that is often present at birth.

Structural malformations, such as aqueductal stenosis and ACTII malformation (usually associated with meningomyelocele and the Dandy–Walker malformation), are the most common causes of fetal hydrocephalus ( Table 14-6).

With hydrocephalus the CSF is under pressure, causing a dilation of the ventricles proximal to the cause of obstruction. This condition will often worsen until surgical correction of the obstruction or placement of a CSF shunt. Ventriculomegaly, in contrast, occurs when ventricles are of a larger size than normal, but no evidence of increased CSF pressure exists. In cases of ventriculomegaly the cause is an underlying difference in brain development, and surgery is not indicated.

Posthemorrhagic hydrocephalus resulting from intraventricular hemorrhage (IVH) is by far the most frequent cause of acquired hydrocephalus in the neonatal period. Other causes of hydrocephalus include blocked reabsorption of CSF by the meninges, as occurs with inflammation associated with subarachnoid hemorrhage or meningitis.

The vein of Galen malformation is rare overall, but it accounts for 30% of intracranial pediatric vascular abnormalities. A characteristic feature of the malformation is the presence of an arteriovenous shunt, which typically presents as high-output congestive heart failure in the neonatal period. There may be a bruit, sometimes quite loud, best heard over the posterior aspect of the newborn’s head. Sometimes there is head enlargement caused by an extrinsic aqueductal stenosis produced in the pons and midbrain by the bulk of the malformation. Only very rarely do these malformations present as bleeds at birth. Diagnosis is through neuroimaging (color Doppler and MRI and magnetic resonance angiography); ultimate treatment is through intravascular embolization or neurosurgery. ¹³

Neurocutaneous Syndromes

The term phakomatosis is derived from the Greek phakos, meaning “lentil” or “lens,” and refers to the patchy, circumscribed dermatologic lesions that are their hallmark. Because both skin and CNS tissue arise from the same ectodermal precursors, conditions that affect the CNS may have pathognomonic skin features. In addition to dermatologic features, these syndromes have hamartomata (errors in development) with involvement of multiple tissues. More commonly, the term neurocutaneous syndrome is used when referring to this group of diseases.

Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are both autosomal dominant conditions; the majority are sporadic. The prevalence of NF1 is about 1 in 3000 live births, and the incidence of NF2 is 1 in 100,000 live births. The prevalence of TSC is 1 in 6000.

Café-au-lait spots are present in as many as 2% of infants; these vary in prevalence and are not always indicative of NF. Children with NF1 may have few or no café-au-lait spots at birth; these may become more obvious within the first year. Because of the high spontaneous mutation rate for this autosomal dominant disease, only about 50% of newly diagnosed cases of NF1 are associated with a positive family history. ¹⁴¹⁵

NF1 is an autosomal dominant disorder of a tumor-suppressor gene located on chromosome 17q11.2 that encodes neurofibromin, a negative regulator of the Ras oncogene. Characteristic café-au-lait-spots may appear at birth. Osseous lesions are usually apparent within the first year of life, and tumors of the optic chiasm present relatively early in life. Axillary freckling and peripheral, spinal, or central nerve NFs may develop in later childhood. Early ascertainment is difficult, and almost half of infants younger than 1 year of age do not fulfill the full criteria for this disorder. ¹⁶

TSC is characterized by multiple and variable organ involvement. Commonly recognized clinical features include hypomelanotic skin macules, facial angiofibromas, periungual fibromas, delayed development, epilepsy, and autism. The kidney, heart, and retina are among other commonly affected organs. Abnormalities on brain imaging include subependymal nodules, cortical tubers, radial white matter lines, and subependymal giant cell astrocytomas (SEGAs). In 2010 everolimus was approved for the nonsurgical treatment of SEGAs (U.S. Food and Drug Administration Bulletin 2010). Sometimes computed tomography (CT) may be superior to MRI in detecting calcified cortical tubers. Seizures may begin in the neonatal period and are one example of a “well baby with seizures.” At the same time, symptoms for a given individual may be subtle; it is possible for a parent to have undiagnosed TSC come to light only when their affected baby is born.

Port-wine stains can occur as isolated cutaneous birthmarks or in association with structural abnormalities

of choroidal vessels of the eye leading to glaucoma and of the leptomeningeal vessels in the brain leading to seizures (Sturge–Weber syndrome). Almost invariably, the hemangioma in Sturge–Weber syndrome involves the trigeminal V1 area or is bilaterally distributed. Ophthalmologic assessment and radiologic studies (CT or MRI) are indicated for children who exhibit hemangiomas in the upper eyelid or forehead. This neurocutaneous syndrome arises sporadically and is not known to result from a specific genetic mutation. ¹⁷

Incontinentia pigmenti, or Bloch–Sulzberger syndrome, is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; mental retardation; seizures; skewed X-inactivation; and recurrent miscarriages of male fetuses. The first stage (i.e., vesicular stage) is characterized by lines of blisters, particularly on the extremities in newborns, that disappear in weeks or months. This is followed by stage 2 (i.e., verrucous stage), in which lesions develop at approximately age 3 to 7 months that are brown and hyperkeratotic, resembling warts. The final stage, stage 3 (i.e., pigmented stage), is characterized by whorled, swirling (marble cake–like) macular hyperpigmented lines that may fade with time. Rarely, neonatal seizures have been reported in this condition. ¹⁸

Hypomelanosis of Ito was originally described as a purely cutaneous disease with a swirling pigmentary pattern, sometimes visible in the neonatal period, but subsequent reports have included a frequent association with multiple extracutaneous manifestations, mostly of the central nervous and musculoskeletal systems. Neurologic complications include mental retardation, autism, brain malformations, microcephaly, and epilepsy. When associated with structural brain malformations such as hemimegalencephaly, neonatal seizures may arise. Miscellaneous chromosomal mosaicisms have been demonstrated in some but not all affected persons. Additional associated abnormalities include limb length discrepancies, facial hemiatrophy, scoliosis, sternal abnormalities, dysmorphic facies, and genitourinary and cardiac abnormalities.

Intracranial Hemorrhage

It is important to note that a small intracranial hemorrhage is a common and often asymptomatic finding. In one series of neonates with MRI in the first 3 weeks, more than 50% of those born vaginally had some degree of intracranial hemorrhage. Therefore such findings on MRI should be interpreted with caution. ¹⁹²⁰

Most SDHs are asymptomatic and are usually identified as incidental findings on CT and MRI scans. They may not be visible on ultrasound scans. When caused by a tentorial or a falx tear, a newborn’s condition can rapidly deteriorate as a result of blood loss and brainstem herniation. More often, an infant with symptomatic subdurals will be lethargic and may have seizures. Examination may reveal an enlarged head; bulging fontanel; excessive retinal hemorrhages; and focal weakness in the face, leg, or arm on one side of the body. Diagnosis is made by CT scan that shows a bright signal (i.e., blood) over one or both hemispheres, or by MRI. Treatment consists of watchful waiting most of the time. On occasion, sequential subdural taps may be necessary. Only rarely is surgical evacuation or a subdural-peritoneal shunting required.

The subependymal germinal matrix is the most common site for IVH in VLBW babies; venous hemorrhagic infarction of the white matter, which shares some of the pathogenesis with germinal matrix hemorrhage, may contribute to the injury. In term infants bleeding usually originates in the choroid plexus of the lateral ventricle.

Cranial ultrasound is a reliable, portable, safe, and cost-effective method for evaluating infants for IVH. It allows for visualization of the subependymal germinal matrix, which is the most common site for IVH in VLBW babies. Cranial ultrasound can be performed at the bedside with minimal disturbance of the infant and is the study of choice.

Although there are variants, the most widely used systems group IVH into four categories.

Many of the following factors may be simultaneously present and contribute to neonatal IVH:

Of the persistent SPVD group, approximately 67% will have a spontaneous arrest, whereas 33% will continue to progress. In the spontaneous arrest group, 5% will have late progressive dilation. ²¹

The incidence of neurologic sequelae is linked not only to the grade of hemorrhage but also to gestational age of the patient and the degree of parenchymal insult resulting from infarction and periventricular leukomalacia (PVL). Some series have shown a 5% incidence of neurologic sequelae (e.g., intellectual disability, spastic diplegia, and seizures) for grade I IVH, 15% for grade II, 33% for grade III, and almost 90% for grade IV with large infarction. However, long-term studies have demonstrated that at least 50% of ELBW and VLBW babies go on to have scholastic and behavioral abnormalities, with IVH being only one contributor to adverse outcomes. Recent data indicate that IVH that is not accompanied by white-matter injury has a better prognosis. ^25262728

Preterm Brain Development and Periventricular Leukomalacia

Gestational age significantly affects later prognosis. Overall, infants born extremely premature (22 to 25 weeks) are at a higher risk (50% to 75%) for death or neurodevelopmental impairments, including moderate or severe cerebral palsy (CP), bilateral blindness, and lower cognitive performance at age two. However, these risks are influenced not only by gestational age but also by sex, exposure to antenatal corticosteroids, twin or other multiple gestation, and birth weight. The EPICure study found fewer than half (41%) of children with a history of extreme prematurity (<26 weeks’ gestation) when tested at age 6 years were cognitively impaired compared with their classmates. The rates of severe, moderate, and mild disability were 22%, 24%, and 34%, respectively. Disabling CP was present in 12% ( Fig. 14-7).

Although prognosis is much more optimistic for infants born late preterm, some increased risk of learning or behavior problems remains. One recent study found the risk of developmental delay or disability was increased by 36% among babies born between 34 and 36 weeks’ gestation compared with those born at term. ²⁹³⁰³¹

Periventricular leukomalacia (PVL) is white matter necrosis, seen mostly in preterm babies. This white matter necrosis surrounding the ventricular walls may be cystic (with fluid-filled cavities) or noncystic. However, white matter injury can extend far beyond the periventricular region; the anterior and posterior periventricular regions are most commonly affected. The former region is where white matter fibers pass to the legs, accounting for subsequent leg spasticity, and the latter, posterior area is responsible for the visual abnormalities of PVL.

Underdevelopment of the white matter and hypomyelination are seen at term in 50% of VLBW survivors as diffuse excessive high signal intensity (DEHSI) in the centrum semiovale of the white matter on T2 MRI sequences. As injured white matter fails to grow, ex vacuo ventriculomegaly becomes visible on ultrasound, CT, and MRI scans. Even in the absence of marked ventriculomegaly, many premature infants will demonstrate overall loss of white matter volume.

The two most common factors that may increase the risk of white matter injury in the preterm infant are hypoxia-ischemia and infection. However, PVL can definitely occur in the absence of either documented hypoxia-ischemia or infection.

In the first days and weeks after injury, PVL may appear as a bright “periventricular flare.” Approximately 2 to 3 weeks later, some infants may exhibit cystic changes which can be detected on cranial ultrasound. When VLBW babies reach term gestation, DEHSI and ventriculomegaly can be observed on T2 MRI images, in addition to the aforementioned cysts and infarcts. After 6 months to 2 years, the MRI will demonstrate periventricular hypomyelination and white matter scarring (particularly, but not exclusively, in the frontal and posterior periventricular areas), ventriculomegaly, ventricular wall scalloping and irregularity, thinning of the corpus callosum, and brain atrophy. In the setting of PVL, volumetric MRI studies also commonly show shrinkage of gray matter in the cortex and the deep lentiform nuclei. ³⁴

The principal sequelae include spastic diplegia and visual and cognitive deficits.

Hypoxic Ischemic Encephalopathy (HIE)

Recall first that the syndrome of ANE (see Question 3) is not synonomous with HIE. HIE is a specific neurologic syndrome in the newborn infant that results from low oxygen and blood delivery to the brain. For an intrapartum event to contribute to neonatal brain injury, the following should be present: (1) a history of intrauterine distress, (2) depression at birth, and (3) an obvious neonatal neurologic syndrome in the immediate postnatal period. ³⁵

Essential criteria (must meet all four):

Criteria that collectively suggest an intrapartum timing (within close proximity to labor and delivery, [e.g., 0–48 hours]) but are nonspecific to asphyxial insults:

Although definitions and methods of study vary, most research suggests that ANE is not usually the result of isolated intrapartum HIE. For example, one case-control study identified numerous risk factors for ANE, such as maternal infertility treatment, maternal thyroid disease, and severe preeclampsia, all of which were antenatal. Similarly, a Scottish neuropathology study examined the brains of infants with ANE who died soon after delivery. Among 53 neonates initially thought clinically to have “birth asphyxia,” the majority had histopathologic evidence of brain injury that could have only predated labor and delivery. ³⁶³⁷

Some babies with ANE have evidence of hypoxic-ischemic injury that started before labor and delivery. For example, one retrospective series of babies with ANE found that at initial presentation to the hospital 70% already had absent fetal movements and nonreactive fetal heart rate tracings (absence of spontaneous cardiac accelerations), and many had chronic meconium staining. This constellation of findings is consistent with a prior hypoxic-ischemic event. Additional evidence has recently emerged that babies with an admission history of “reduced fetal movements” had already sustained a brain injury; these patients may not benefit from therapeutic hypothermia and may show a “subacute” injury pattern on MRI. ³⁸³⁹

The use of the Sarnat scoring system gives clinicians a shorthand method to categorize the severity of infants’ ANE.

When hypoxia-ischemia does produce ANE, it is typically expected that other body organs and systems are also affected, although this does not occur in every case. This could clinically include (1) hypoxic-ischemic depression of the myocardium (hypotension requiring volume expanders and pressor support); (2) acute renal failure (low urine output, hematuria, and climbing creatinine values); (3) hepatopathy with elevated liver enzymes and sometimes coagulopathy owing to multiple clotting factor deficiencies; (4) necrotizing enterocolitis; and (5) muscle ischemia resulting in excessively elevated serum creatine kinase. Multisystem dysfunction is not unique to HIE, however, and can be seen in other conditions, such as septic shock ( Table 14-7).

Brain monitoring is the only direct way to measure the function of the brain after HIE or any cause of ANE. The gold standard for neonatal brain monitoring is continuous video-EEG recording. This allows the most accurate description of the EEG background, a sensitive and specific tool to formulate a neurologic prognosis. It is also the most objective method to diagnose and accurately quantify electrographic seizures, which occur in up to two of every three neonates after HIE. When continuous video-EEG monitoring is unavailable, amplitude-integrated EEG ([aEEG], popularly called cerebral function monitoring) or a series of routine EEG examinations are also very useful. ⁴⁰

The patterns of brain injury vary with gestational age and the duration and severity of the asphyxia event ( Table 14-8).

There are several different HIE pathways, which are associated with their own distinctive pattern of neonatal brain injury. In acute, profound, near total asphyxia, the hypoxia-ischemia is actually caused by an abrupt prolonged terminal bradycardia. Prolonged terminal bradycaria results from a uterine rupture, cord prolapse, sudden total placental abruption, or maternal cardiac arrest, among other conditions. In acute, near total asphyxia, brain injury is mostly confined to the deep gray structures (globus pallidus, caudate, putamen, and thalami) and sometimes the gray and white matter of the bilateral perirolandic regions. A different type of injury is seen in partial prolonged asphyxia owing to a progressive but more gradual loss of brain oxygenation and perfusion. Slowly progressive placental abruption is an example of one condition that leads to a partial prolonged type of asphyxia causing a watershed brain injury pattern with prominent edema of the deep white matter, creating slitlike lateral ventricles. These patterns of insult are not mutually exclusive, and some babies show both watershed and deep gray lesions. There is growing evidence that maternal–fetal inflammation or infection may predispose the fetus to hypoxic-ischemic injury. Furthermore, maternal–fetal infection or inflammation can produce a clinical syndrome and MRI pattern that closely mimic genuine HIE. ^41424344

The initial deprivation of oxygen causes swelling and necrotic cell death in the susceptible areas described previously. Thus early on an area of necrosis appears, surrounded by a penumbral area of brain in which reperfusion and reoxygenation takes place. In this area further cellular damage is created by glutamate release, which in turns leads to free radical and calpain (apoptotic death factor) release that causes programmed cell death. This is a secondary process that may go on for days to weeks after the initial asphyxial insult. Treatments for HIE target these elements of “secondary energy failure” in the days after the acute event.

Clinically, judicious use of the previously discussed Sarnat scoring method is helpful. Newborns with stage I generally do well. Surviving stage III newborns are at very high risk for spastic quadriplegia, intellectual disability, and seizures. Outcomes after Sarnat stage II are the most difficult to predict, and additional investigations may be very useful to refine the neurologic prognosis ( Table 14-9). An initial cord pH below 7, elevated serum lactate levels, evidence of multisystem involvement, and increased creatine kinase values in blood also have been correlated to guarded prognosis.

The EEG may be very useful. A normal EEG background in the first 3 days has 90% to 100% specificity for a good outcome. Interictal EEG patterns of burst suppression and inactive low-voltage background have extremely guarded prognoses. This is particularly true when still present 24 hours after birth. MRI may also be helpful. Abnormalities appear early on diffusion-weighted images in 3 to 6 hours, and then 2 to 3 days later on T1- and T2-weighted sequences. An abnormal signal in the posterior limb of the internal capsule has a positive predictive value for motor impairment of nearly 100% when performed in infants of term equivalent age. Magnetic resonance spectroscopy (MRS) may also help define functional abnormality. ⁴⁵⁴⁶

Apparent diffusion coefficient values from the posterior limb of the internal capsule are significantly greater in term infants with HIE who ultimately survive. Among survivors a reduced apparent diffusion coefficient value in the posterior limb on the internal capsule is associated with a greater probability of an abnormal neuromotor outcome. In contrast, an elevated N-acetylaspartate–to–total–creatine ratio is associated with a higher likelihood of a normal outcome at 18 months. Most important, the presence of an abnormal lactate peak predicts an abnormal outcome with a sensitivity of 100% and a specificity of 80%. ⁴⁷⁴⁸⁴⁹

Multiple large, randomized, controlled trials have now shown therapeutic hypothermia is efficacious in reducing neurodevelopmental disability after HIE ( Fig. 14-8). Therapeutic hypothermia (or “cooling”) must be initiated within 6 hours of birth and continued for 72 hours to lower the neonate’s body temperature to a target of 33.5° to 35° centigrade. Cooling may either be implemented through cooling blankets or selective head-cooling devices.

All affected newborns require supportive treatment. This includes maintenance of cardiorespiratory function, including ventilation when needed. Newborns with HIE require careful fluid, glucose, and electrolyte management, and the clinician must remember that the asphyxial insult may involve myocardium, kidneys, liver, and gastrointestinal tract. Finally, there must be a high suspicion for, and appropriate treatment of, seizures. ^5051525354

Stroke

In any sick newborn with seizures or a focal neurologic abnormality, the suspicion for an underlying structural lesion should be high. Ultrasound examination may be useful at the bedside for detecting strokes, though sensitivity is highly user dependent. CT scans are superior to ultrasound in the acute setting; however, they lack the detail of MRI and expose the infant to radiation. MRI is thus the diagnostic test of choice. Diffusion-weighted images can detect recent strokes from as little as 6 hours to 7 days after the event. Traditional MRI sequences (T1 and T2) are adequate for more remote strokes. ⁵⁵

Once stroke is diagnosed, an etiologic work-up should be undertaken, along with evaluation for comorbidities. The placenta should undergo a careful histopathologic examnination because it is a likely source for emboli. Infants with stroke should undergo a complete blood count to rule out polycythemia; lupus anticoagulant and protein C, protein S, and antithrombin III levels should be measured. Genetic tests looking for factor V Leiden mutation, MTHFR mutation, and prothrombin 20210G mutation are indicated. An echocardiogram to rule out a cardiac source of emboli should also be done, particularly if any cardiac signs are present or if the infant has experienced a multifocal stroke. An EEG might demonstrate electrographic seizures, slowing, or attenuation. Magnetic resonance angiography and venography help visualize the cerebral vessels to rule out pathology. ⁵⁶

Initial management includes general medical support and administration of antiseizure medications if the child has seizures. Anticoagulation is controversial and is probably not indicated unless an active source of emboli is apparent. In a recent review of outcomes in infants with strokes in the perinatal period, 40% of infants were judged to be normal, 57% were neurologically or cognitively abnormal, and 3% died. ⁵⁷⁵⁸

Sinovenous thrombosis has been increasingly recognized, and its true incidence likely exceeds early estimates of 1 per 100,000. Identifiable causes are those that would increase the overall risk of thrombosis in a newborn. They include dehydration, extracorporeal membrane oxygenation (ECMO), and congenital heart disease. Similarly, genetic thrombophilias are a risk factor. Many cases are multifactorial. Newborns have a higher risk for sinovenous thrombosis than members of any other age group. ⁵⁹

The clinical presentation is usually nonspecific; lethargy and poor feeding are the most common signs. Seizures are another initial early sign. Neuroimaging is required for diagnosis. Although thrombus may be directly visualized on MRI, other supportive findings are absence of Doppler flow through the affected vein on cranial ultrasound and decreased flow on magnetic resonance venography. The straight sinus and superior sagittal sinus are most often involved, although multiple sinuses are often affected. The diagnosis may be difficult because deeper thrombosis is harder to visualize. ⁶⁰⁶¹

Some cases of sinovenous thrombosis disrupt blood flow out of parenchymal tissue such that there is a resulting blockade of arteriolar blood perfusing that tissue. This disruption of blood flow can cause brain infarction and secondary hemorrhagic transformation. Venous infarction is often distinguished from arterial infarction on MRI by its distribution. Arterial infarction more likely appears as a wedge-shaped stroke in an arterial vascular distribution, whereas venous infarction arises in the context of sinovenous thrombosis and is more likely to result in hemorrhage.

Although the location and size of injury play important roles in shaping outcomes, prognosis after sinovenous thrombosis is generally worse than that after arterial stroke. One prospective study of 104 newborns found 61% at follow-up had either died or experienced a disability, including epilepsy, moderate to severe language deficits, and CP. ⁶²

Perinatal Illness and Later CP

CP is a nonprogressive disorder of motor function (“a palsy”) of CNS (“cerebral”) origin occurring usually in utero or early in life (up to age 2 years). Intellectual deficit is not implicit in CP, although it accompanies the motor disability in a high percentage of cases. The overall prevalence of CP is 1.7 to 2 of 1000 among survivors at the age of 1 year. Premature infants have the highest incidence of CP, although most infants with CP have birth weights greater than 2500 g. The lower the birth weight and gestational age, the greater the chance for the child to develop CP. Although the CNS injury that leads to CP usually occurs in the perinatal period, the signs of CP may not be obvious until after the first year. ⁶³

In a very broad sense, all healthy neonates show motor signs similar to those of CP. All healthy neonates lack purposeful, voluntary movements, and their motor activities are dominated by developmental reflexes. They have reflex overflow of deep tendon reflexes, clonus (unsustained), and Babinski signs. As they age and mature, they become able to subjugate their involuntary reflexes and gain mastery and control over their motor systems. Consequently, the neonate with damaged motor systems may not look entirely different from a healthy baby during examination. Keep in mind that in babies with CP, the following is true:

Maternal temperature above 38˚ C (100.4˚ F) during labor or a clinical diagnosis of chorioamnionitis is associated with a markedly (ninefold) increased risk of CP, especially spastic quadriplegic CP (19-fold increase). Remember that approximately 50% of maternal cases of chorioamnionitis are subclinical. ⁶⁴⁶⁵

The inflammatory response to infection activates a number of cytokines and chemokines, which in turn may trigger preterm contractions, cervical ripening, rupture of the membranes, and prematurity. The levels of interleukin (IL)-1, IL-8, IL-9, and tumor necrosis factor are independent risk factors for the subsequent development of CP at the age of 3 years. ⁶⁶⁶⁷

The prevalence rose approximately 20% from the early 1960s to the late 1980s, almost entirely because of increased survival of low-birth-weight and VLBW infants. Since the 1980s there has been no significant change.

Neonatal Seizures

There are two ways to define neonatal seizures: electrographically and clinically. EEG seizures are defined as a sudden (paroxysmal) attack of abnormal, hypersynchronous electrical discharges in the brain. Clinical seizures are a sudden (paroxysmal) attack of abnormal-appearing movements, behaviors, or autonomic functions. There is a very imperfect overlap between clinical and EEG seizures. Clinical seizures that are specifically linked to simultaneous EEG seizures are called electroclinical. Abnormal-appearing clinical seizures that occur without simultaneous EEG seizures are classified as non-epileptic seizures. EEG seizures that do not provoke any outwardly visible motor or autonomic signs are called subclinical, silent, or occult seizures.

Multiple studies have shown that upward of 80% of confirmed EEG seizures in the neonate are invisible to the naked eye and have no outward signs detectable by bedside caregivers. Accurate detection and diagnosis of neonatal seizures therefore requires EEG monitoring. ⁶⁸

The sensitivity of aEEG for seizure detection depends in part on the experience of the user in interpreting these recordings. Although experts have reported theoretical sensitivity of approximately 80%, most users correctly identify fewer than half of seizures using aEEG alone. ⁶⁹

Seizures are the most common clinical sign of neonatal cerebral dysfunction and may occur in up to 1% of all newborns. The reported incidence of neonatal seizures, however, varies with the population studied, gestational age, and risk status. It also depends on the standard used to diagnose seizures.

Most neonatal seizures are symptomatic of an acute illness. ANE is the most frequent cause of neonatal seizures. HIE is but one specific type of ANE. Other common causes of brain injury include stroke, hemorrhage, infection, cerebral malformation, drug withdrawal, and metabolic causes. The latter include hypoglycemia and electrolyte abnormalities, hyponatremia, hypocalcemia, hypomagnesemia, and inborn errors of metabolism (e.g., urea cycle defects, phenylketonuria, maple syrup urine disease, lactic and organic acidurias, and nonketotic hyperglycinemia). A small percentage of unprovoked neonatal seizures are caused by specific genetic disorders.

Vitamin-responsive neonatal seizures, especially vitamin B₆ dependency, should always be considered in seizures refractory to treatment, particularly without a clear symptomatic etiology. Other vitamin and cofactor deficiencies with the potential to cause seizures include molybdenum, pyridoxal phosphate, and folinic acid. ⁷⁰

There are increasing numbers of recognized malignant epilepsy syndromes with onset in the neonatal period. Many of these are characterized by refractory seizures, a characteristic EEG pattern, and a poor prognosis. Examples include early infantile epileptic encephalopathy with burst-suppression (Ohtahara syndrome) and early myoclonic epilepsy. Some of these syndromes are now understood to have multiple underlying causes, including structural lesions, metabolic disease, and genetic mutations. A malignant epilepsy syndrome should be suspected when no symptomatic cause for seizures can be found and when seizures remain refractory to initial treatment. ⁷¹⁷²⁷³

Seizures in a “well baby” may be caused by simple hypocalcemia or hypoglycemia or may be the first sign of a benign neonatal epilepsy. Hypocalcemia and hypocalcemic tetany resulting from milks with a high phosphate load are now rarely seen in the United States. Benign neonatal epilepsy syndromes have been described and have a relatively good prognosis for seizure remission and development. The familial syndromes are associated with genetic mutations in sodium or potassium channels. ⁷⁴

The work-up should include a bedside glucose measurement followed by a laboratory glucose measurement and determination of calcium, magnesium, sodium, and acid–base status. A blood culture and lumbar puncture should be performed. A cranial ultrasound scan may confirm suspected hemorrhage and hydrocephalus, but MRI is best to evaluate for malformations of cortical development and the extent of any acquired injury such as stroke or sinovenous thrombosis. Testing should not delay symptomatic treatment of seizures.

Continuous EEG monitoring is the most accurate and comprehensive method to confirm the diagnosis and measure the abundance and spatial distribution of EEG seizures. It is also useful in monitoring ongoing treatment. Ideally, treatment with antiseizure medications should terminate all EEG seizures, but that is not always the case. When continuous EEG monitoring is not available, aEEG or a series of routine (60 minute duration) EEGs remains very helpful.

The initial treatment of neonatal seizures should always be aimed at correcting the underlying disorder and maintaining hemodynamic and respiratory stability. First-line pharmacologic treatment for neonatal seizures is usually phenobarbital, followed by phenytoin. Although their efficacy has never been demonstrated by a randomized, placebo-controlled trial, these drugs have the advantage of having been used for a long time in newborns. Phenobarbital or phenytoin are effective in suppressing seizures in less than half of neonates. When one drug fails, adding a second results in a 70% success rate. Third-line treatments (e.g., benzodiazepenes) are variable ( Table 14-11). ⁷⁵⁷⁶

In the well-appearing baby with a normal EEG, early discontinuation of medication is recommended while the neonate is still in the intensive care unit or soon after discharge. Some clinicians prefer to continue treatment for 3 to 6 months after discharge.

The ultimate prognosis is determined by the severity of the seizures’ etiology and if the infant experienced status epilepticus. EEG background activity and MRI and MRS are also useful in predicting prognosis. Depending on etiology, between 25% and 33% of those with neonatal seizures go on to display chronic postnatal epilepsy, including serious conditions such as infantile spasms or the Lennox–Gastaut syndrome.

Neuromuscular Disorders

Central hypotonia results from a CNS lesion—a problem in the brain or spinal cord. Peripheral hypotonia results from a lesion in the peripheral nervous system—the nerves, neuromuscular junction, or muscles. Central should not be confused with axial or “truncal” hypotonia, which describes hypotonia affecting primarily the core trunk muscles. Similarly, peripheral hypotonia should not be confused with “appendicular” hyptonia in the extremities.

See Table 14-12.

It is useful to think anatomically because clinical localization is facilitated in this way ( Table 14-13). The components of the lower motor neuron from the spinal cord to most peripheral part are as follows:

The physical examination shows weakness, atrophy, diminished to absent deep tendon reflexes, and sometimes fasiculations. Ancillary testing includes blood creatine phosphokinase measurement, serum carnitine measurement, motor nerve conduction velocities, needle electromyography (EMG), DNA testing, and muscle biopsy.

Unilateral ptosis is most commonly familial. Sometimes it is part of Horner syndrome, which also includes miosis (smallness) of the pupil and decreased sweating on the same side of the face. Neck masses, iatrogenic injury during cardiac surgery, and birth injury to the lower brachial plexus are other causes. Facial swelling after delivery may cause a temporary pseudoptosis. Bilateral ptosis is seen in centronuclear (myotubular) myopathy, myotonic dystrophy, and myasthenic syndromes.

Transient neonatal myasthenia occurs in 15% of deliveries to mothers with autoimmune myasthenia gravis because of the transplacental passage of maternal acetylcholine receptor (AChR) antibodies. Predominant symptoms include respiratory and swallowing difficulties. There may be ptosis and generalized weakness with intact reflexes. AChR antibodies are present. Repetitive stimulation on EMG shows a decrement in muscle amplitude potentials. Treatment is supportive, but supplementation with subcutaneous or oral pyridostigmine is often necessary. Symptoms may persist for 1 to 5 weeks.

See Table 14-15.

Genetic studies have shown that the defect in myotonic dystrophy is an expansion of a trinucleotide (CTG) repeat in a gene on the long arm of chromosome 19 that codes for a protein kinase. In successive generations this repeating sequence has a tendency to increase, sometimes into the thousands (normal is <40 CTG repeats), and the extent of repetition correlates with the severity. Thus an affected mother may have mild or subclinical symptoms, whereas the neonate with increased CTG repeats may be more severely affected.