Neurological Neuromuscular Disorders

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A central objective of perinatal medicine is survival of the infant without neurodevelopmental impairment. Improvements in obstet-rics and neonatology have greatly reduced neonatal mortality in recent decades, and traumatic brain injury has decreased as well as spina bifida. However, increasing survival of extremely low gestation infants and those with previously lethal conditions has meant that, overall, the incidence of neurologic disorders in infants has not been substantially reduced. Brain injury during pregnancy, delivery, and the newborn period is an important cause of permanent disability and laboratory, and clinical research is beginning to deliver treat-ments that can prevent brain injury or assist recovery of the brain after injury. In addition to cerebral disorders, there is increased need for accurate diagnosis and prognosis in neuromuscular disorders so that families and rehabilitation services can plan ahead and genetic counseling can be given before the next pregnancy. Because win-dows of therapeutic opportunity require early diagnosis and have serious consequences if missed, neurologic assessment and diagno-sis has acquired a new urgency for the neonatologists.

In this chapter, we discuss the clinical neurologic examination of a newborn infant and outline how to approach common neuro-logic problems as they present to a neonatologist, including the following:

The full-term infant with encephalopathy after birth asphyxiaThe full-term infant in good condition at birth who later develops

seizuresThe preterm infant with respiratory distress at high risk for intra-

ventricular hemorrhage (IVH)The preterm infant in apparently good condition but at high risk

for periventricular leukomalacia (PVL)The newborn infant with marked hypotonia with or without mus-

cle weakness

Congenital malformations of the nervous system, bacterial and viral infections, and metabolic derangements are discussed in Chapters 35, 38 and 44.

NEUROLOGIC EXAMINATION OF THE NEWBORN INFANT

The neonatologist needs to know the gestational age of the infant and the postnatal age if the infant is not newborn. The nervous sys-tem is in continual development; the brain of an infant at 26 weeks of gestation is anatomically and functionally very different from the brain of an infant at 40 weeks. The pathogenesis of brain injury, anatomic site, clinical presentation, diagnosis, prognosis, and treat-ment possibilities are very different between 26 and 40 weeks, in ways that they are not between 5 and 10 years of age. Muscle tone and reflexes develop with gestational age.

In addition to the neonatologist’s usual detailed review of the pregnancy, labor, and delivery, the history must include a review of the family medical history and complications encountered dur-ing past pregnancies, including a history of congenital anomalies, stillbirths, and genetic or syndromic conditions. The follow-ing neurologic examination is modified from that developed by Dr. Lilly Dubowitz (1).

In urgent clinical situations, the neonatologist must examine immediately and will have to adapt the order and content of the examination to the infant’s clinical status. However, in stable situations, the state of quiet alertness is best, not too hungry and not too sleepy, optimally around 2 hours after feeding. There should be sufficient, but not excessive, light. The examiner’s hands should be warm.

Much information can be gained by careful observation without touching:

Is the infant awake and alert? (Fig. 46.1A)Is the infant excessively irritable? If crying, is the character of

the cry unusual?Are there external signs of congenital anomaly?Are there signs of injury, for example, bruising or swelling?What is the infant’s spontaneous posture? A term infant will usu-

ally have flexed limbs (Fig. 46.1B).Are there spontaneous movements of the limbs? Are there trem-

ors or rhythmic movements?Are eye movements in all directions and coordinated? Is there

nystagmus?

Level of ConsciousnessIf the neonatologist is lucky, the infant is already awake, alert, and responding to sound, light, and touch.

Reaction to SoundHowever, if the infant appears to be asleep, it is useful to begin by shaking a rattle or a bell about 15 cm from each ear. Usually, this will stimulate movement of the limbs or face. This stimulus is about 80 dB and will therefore provide evidence that the infant is not completely deaf. If the sound is repeated a number of times, the infant will eventually stop responding. This “habituation” is a nor-mal response. A healthy term infant will orient toward the source of sound by turning the head toward it (Fig. 46.1C).

Reaction to Visual StimulusShining a light in front of a newborn infant will normally induce blinking. If the eyes remain open, pupillary constriction can be observed. If the eyes remain closed, holding the infant verti-cally and away from bright lights may open the eyes. A healthy, alert term infant will move the eyes (track) to follow a red object (Fig. 46.2A) or a face (Fig. 46.2B) moving horizontally across the visual field. This maneuver may need to be repeated if the infant is not initially in the optimal state; it also reveals abnormal eye move-ments such as nystagmus, sunsetting, etc.

Examination of the HeadThe tension in the anterior fontanelle increases during crying, but a continually tense fontanelle, even when the infant is held upright, suggests raised intracranial pressure. The head circumference should be reviewed and if over 37 or under 32 cm at term, should be remeasured carefully (fronto-occipitally).

Passive Tone in the LimbsWith the infant supine, pull the wrists gently vertically in sequence; observe the angle at the elbow. A term infant will hold the elbow at 100 degrees or less, and an infant under 32 weeks of gestation will have an elbow angle greater than 140 degrees.

Popliteal angle can be measured by flexing each thigh over the abdomen and then, with one finger behind the heel, attempting to straighten the knee. The popliteal angle at term is around 110 degrees, but before 32 weeks is over 140 degrees. Leg traction is measured by holding the foot and lifting the leg vertically. A term infant will hold the knee at 140 degrees, but in an infant of less than 32 weeks, the angle will be larger. Note asymmetry.

Tone in the Neck and TrunkHold the infant in the sitting position, and then move the trunk slightly forward and allow the head to flex onto the chest

Neurological & Neuromuscular DisordersAndrew Whitelaw, Damjan Osredkar, and Marianne Thoresen

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2 PART 4 • The Newborn Infant

(Fig. 46.3A). Wait 30 seconds. A healthy term infant will try to lift the head to the vertical but may not manage or maintain this (Fig. 46.3B). A preterm infant will not achieve this.

Gently incline the infant backward 30 to 40 degrees. A healthy term infant will maintain the head in line with the trunk (Fig. 46.4A–C), but a preterm infant will not. Neck flexion is normally as good as, or better than, neck extension.

With the infant supine, use gentle traction holding the wrists to pull the trunk up to 45 degrees to the horizontal. A healthy term infant will flex the head in line with the trunk. Preterm infants and those with hypotonia cannot achieve this. It is important to differentiate “head lag” due to general hypotonia from neck extensor hypertonia, in which neck flexion is present but is overcome by tense neck extension.

When in prone suspension (Fig. 46.5A), a healthy infant will normally hold the head in line with the trunk. A hypotonic infant

lets the head flop down (Fig. 46.5B), while neck extensor hyperto-nia will keep the head above the line of the trunk.

Primitive ReflexesThe history of feeding will give important information on the pres-ence of several integrated functions of the nervous system. If the infant has not yet been fed, the sucking reaction to a gloved finger is an important sign. The rooting reflex is elicited with a gentle stroke to the side of the mouth.

The Moro reflex is elicited by holding the infant supine with arms crossed, at a slight angle to the horizontal and then allowing the upper trunk and head to drop toward the horizontal. In a nor-mal term infant, the arms abduct and extend and then adduct and flex (Fig. 46.6A–C). In a normal premature infant, the abduction and extension will occur, but the subsequent adduction and flexion

FIGURE 46.1 A: This term infant is awake, alert, and look-ing around. B: This term infant shows a normal posture with arms flexed, hands open (not fisted), and legs semiflexed. C: Shaking a bell beside the head to arouse the infant from sleep and check response to sound.

FIGURE 46.2 A: The infant is visually following a red object moving horizontally. B: The infant is visually following a face moving horizontally.

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CHAPTER 46 • Neurological & Neuromuscular Disorders 3

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FIGURE 46.3 A: From sitting, the infant is gently flexed forward. Initially the head flexes onto the chest. B: The infant tries to extend the head in line with the trunk.

FIGURE 46.4 A: The infant is gently tilted backward and manages to hold the head in line with the trunk. B and C: The infant is tilted further backward and continues to keep the head in line with the trunk without head lag.

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FIGURE 46.5 A: In ventral suspension, a healthy infant holds the head in line with the trunk without head lag. B: In ventral suspension, this “floppy infant” has dangling head and limbs.

FIGURE 46.6 A: In preparation for the Moro reflex, the head and the hands are in the midline. B: The Moro reflex. The head is allowed to fall backward. The arms abduct and extend. C: The Moro reflex. After abduction, the arms then flex and adduct and the hands return to the midline. D: Right-sided brachial plexus injury (Erb palsy). The biceps, deltoid, and supinator are flaccid.

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against gravity may be limited. We reserve testing for the Moro reflex for infants with suspicion of brachial plexus injury, for example, after shoulder dystocia. If there is full flexion of the biceps and the whole shoulder can be lifted (deltoid), as in the Moro reflex, this rules out the commonest brachial plexus injury, Erb palsy. Erb palsy involves C5 and C6 and weakens the biceps, deltoid, and supinator muscles (Fig. 46.6D). Asymmetric movement may also be due to pain from a fracture or bone/joint infection. Asymmetric movement is not usu-ally a feature of unilateral cerebral infarction (unlike adult stroke).

Tendon ReflexesPatellar reflexes can be elicited using two fingers. Clonus at the ankle is an indication of abnormality if maintained for more than three beats. We have not found the grip reflex, the stepping reflex, or the placing reflex useful for neurologic diagnosis.

Neurologic examination in the preterm infant differs from that in a term infant (Table 46.1).

Certain physical signs, if definitely present, should alert the neonatologist (Table 46.2).

DIAGNOSIS OF BRAIN DEATH IN NEWBORN INFANTS

Until recently, diagnosis of brain death in newborn infants (<7 days) was not considered sufficiently reliable to be used for legal purposes. In 2011, the American Academy of Pediatrics and the Society of Critical Care Medicine published guidelines for determination of brain death, which included infants greater than 37 weeks of gesta-tion under 30 days of age (2). Table 46.3 summarizes the clinical criteria. Investigations such as EEG or blood flow studies were not considered to be obligatory. Diagnosis of brain death was not con-sidered to be reliable in infants of less than 37 weeks of gestation.

THE FULL-TERM INFANT WITH ENCEPHALOPATHY AFTER BIRTH ASPHYXIA

Birth asphyxia means a critical shortage of oxygen during labor and delivery sufficient to produce a lactic acidosis and delay the onset of respiration. Thus, the criteria for birth asphyxia involve low Apgar score, low pH, and increased base deficit. In a much-cited article on the link between birth asphyxia and subsequent cerebral palsy, an Apgar score of 6 or less for more than 5 minutes and a base deficit of greater than 12 mmol/L or pH below 7.0 were chosen as criteria for significant asphyxia (3). Continued need for ventilation at 10 minutes is also evidence that the Apgar score could not have been higher than 6 at 10 minutes. Birth asphyxia does not, per defini-tion, mean that the brain has been injured. A low Apgar score with normal pH and base deficit in umbilical cord blood suggests that the low Apgar score is not due to hypoxia during the hour before deliv-ery and may be due to another cause such as infection, antenatal injury, or congenital anomaly. It is particularly helpful to have both arterial and venous cord blood samples because compression of the umbilical cord (or a knot) may result in normal pH in venous blood from the placenta but low pH in arterial blood from a hypoxic fetus.

Neonatal EncephalopathyEncephalopathy means a clinically apparent disturbance in brain function. In the context of a newborn infant, the tone, activity, and responsiveness of the infant are abnormal (4). Clinical seizures are not an essential criterion, but, if present, they indicate encephalop-athy. The term neonatal encephalopathy is used because, initially, the clinician can recognize the disturbance in brain function, but causation requires more time for investigation.

The term hypoxic–ischemic encephalopathy (HIE) is used when encephalopathy follows delivery with persistently low Apgar scores, a significant metabolic acidosis, and no evidence of other causes of encephalopathy. In some centers, clinical signs of encephalopathy are sufficient, but in other centers, electroencephalography (EEG) is used as confirmation. Modern amplitude-integrated EEG (aEEG) equip-ment is sufficiently user friendly that a busy neonatologist or neonatal nurse can apply electrodes and can produce useful aEEG record-ings with acceptable impedance, particularly if needle electrodes are used in emergency settings. It is important that all term or near-term infants with significant birth asphyxia are urgently assessed neuro-logically because a provisional diagnosis of HIE now means that the infant should receive therapeutic hypothermia as soon as possible.

Pathophysiology of Hypoxic–Ischemic EncephalopathyAnimal models of HIE have been important in understanding patho-physiologic processes. Myers (5) pioneered such studies in pregnant monkeys in the late 1960s and distinguished between acute total asphyxia and prolonged partial asphyxia.

• Posture is more extended.• Muscle tone is reduced in the neck/trunk and in the limbs.• Muscle strength is reduced.• Sucking and swallowing reflexes are often inadequate for nutrition

until 34 wk, and coordination of sucking, swallowing, and breathing may not be present before 32 wk.

• Breathing is more periodic with lower gestational age.• The Moro reflex consists only of abduction and extension before 32 wk,

and below 28 wk, may be limited to opening of the hands.• Reaction to sound is present down to 24–26 wk of gestation, and some

orientation may be found at 28 wk.• Blinking to light is present at 25–26 wk, but pupil constriction may not

be present below 29 wk of gestation. Visual fixing and following are usually present from 32 to 36 wk.

TABLE 46.1

Neurologic Examination in the Preterm Infant Differs from That in the Full-Term Infant

• Persistent hypotonia in a term infant (see section on hypotonia).• Persistently increased muscle tone. This may be seen in infants

with moderate encephalopathy after birth asphyxia (see section on encephalopathy), traumatic subarachnoid hemorrhage, and meningitis.

• Asymmetric reflexes or movements.• Persistent absence of visual following on repeated examinations under

optimal conditions. The eyes must be examined for microphthalmia, cataract, retinoblastoma, nystagmus, etc.

• Persistent inability to become awake, alert, and responsive (see sec-tion on encephalopathy).

• Persistent inability to suck and swallow (see section on hypotonia).

TABLE 46.2

Warning Signs in Neonatal Neurology

1. Gestational age 37+ wk2. Identified cause of encephalopathy with reversible causes excluded,

e.g., sedative drugs, metabolic intoxication, neuromuscular blockade3. Temperature, oxygenation, pCO2, and blood pressure normalized4. Flaccid tone with no response to painful stimuli5. Pupils midposition or fully dilated and unresponsive6. Corneal, cough, gag reflexes absent, sucking and rooting reflexes

absent7. Oculovestibular reflex (ice water ear irrigation) absent8. Apnea. No spontaneous respiration, despite pCO2 rising to 60 mm Hg (8

kPa) and pCO2 increasing by 2.6 kPa

This examination must be confirmed by a second examination at least 24 h later.

TABLE 46.3

Criteria for Diagnosis of Brain Death in Newborn Infants

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The acute total asphyxia model involved opening the uterus just before term, clamping the umbilical cord and preventing the fetal monkey from breathing. Blood pressure briefly rose then rapidly decreased, as did pH, which was below 7.0 after 10 minutes. Base deficit typically reached 16 mmol/L by 12 minutes. If cord clamping lasted less than 10 minutes, the fetus could be resuscitated with-out neuropathologic injury. If cord clamping lasted between 10 and 25 minutes, the fetus could be resuscitated but with neuropathology in the spinal cord, brainstem, and thalamus. If cord clamping contin-ued beyond 25 minutes, the fetal monkey could not be resuscitated.

Prolonged partial asphyxia was produced either by inducing hypotension in the pregnant monkey with halothane anesthesia or by using intravenous infusion of oxytocin to produce prolonged, frequent uterine contractions. If prolonged partial asphyxia was maintained for 2 to 4 hours, the fetal monkey could be resuscitated but usually devel-oped extensor posture and seizures. Neuropathology showed a com-pletely different pattern from that resulting from acute total asphyxia, there being widespread injury to the cerebral hemispheres, particu-larly frontally and occipitally, the watershed areas between the two main cerebral arteries, and no injury to the brainstem and spinal cord. Basal ganglia injury was only seen in fetal monkeys who had expe-rienced prolonged partial asphyxia followed by acute total asphyxia.

In a newborn pig model, reducing oxygen saturation to around 30% for 45 minutes resulted in encephalopathy with seizures and widespread neuropathology in basal ganglia, thalamus, cortex, and hippocampus (6).

Uterine Contractions and Fetal HypoxiaDuring labor, every uterine contraction compresses the arteries bringing oxygenated blood from the mother’s circulation to the pla-cental bed. Normally, the human fetus tolerates this arterial com-pression because the uterine contractions are short enough and the relaxation periods are long enough to avoid critical fetal hypoxia. In human obstetrics, examples of sentinel events corresponding to acute total asphyxia are umbilical cord prolapse, uterine rup-ture, shoulder dystocia, and placental abruption. Prolonged partial asphyxia may be seen in the postmature fetus (>42 weeks) in labor with an aging placenta, an intrauterine-growth restricted fetus in labor with placental insufficiency, and in cases of uterine hyperto-nus due to excessive doses of intravenous oxytocin. In practice, it is likely that many fetuses are subjected to longer than 25 minutes of partial hypoxia but with briefer periods of more severe hypoxia.

Anaerobic MetabolismInitially, hypoxia–ischemia results in cells switching energy pro-duction from aerobic metabolism in the mitochondria to anaero-bic glycolysis in the cytoplasm. Glycolysis produces less than 10% of the ATP per gram of glucose than does aerobic metabolism. Thus, essential functions can be maintained for a time during severe hypoxia but at the cost of rapid consumption of glucose and buildup of lactic acid.

Posthypoxic Cell Death and Secondary Energy FailureAn important realization in the 1980s was that processes contin-ued to injure and kill brain cells for hours and days after oxygen-ation and circulation had been restored. These processes include free radical injury, calcium entry, excitotoxicity from extracellular glutamate, inflammation, and apoptosis. Magnetic resonance spec-troscopy showed that the energy status of the brain was restored after resuscitation but then declined after about 24 hours (7). These insights provided a window of opportunity and models of neonatal hypoxic–ischemic brain injury then enabled testing of therapies.

Clinical Signs of HIEAfter resuscitation, the neonatologist must look for abnormal neurologic signs to see if encephalopathy develops. The pattern of clinical signs allows the neonatologist to grade the severity of

encephalopathy. This was first systematized by Sarnat and Sarnat (4) and is summarized in Table 46.4. The Sarnat grading concerns patterns, and it is not necessary to have all the features listed to allocate a grade. For example, some infants with grade 3 enceph-alopathy do not have clinical seizures, but they are completely unresponsive and hypotonic and require ventilation. Not all infants with grade 2 encephalopathy have clinical seizures. Some will show hypotonia, but others show pathologically increased trunk tone with neck extensor hypertonia, hands held in a fist, legs adducted, and exaggerated knee and ankle tendon reflexes (Fig. 46.7).

Since moderate and severe grades have a poor prognosis and mild encephalopathy does not, two combinations of signs have been used as criteria for moderate/severe HIE (Table 46.5) (8,9,10).

Following resuscitation, encephalopathy develops with signs changing over time. Initially, some severely injured infants hyper-ventilate, probably because of lactic acidosis. The majority have not demonstrated clinical seizures within the first 6 hours but have done so by the end of the 1st day of life. Some infants show grade 2 encephalopathy signs and then improve, reaching normality within 3 to 5 days. Others will first be in grade 2 and then worsen to grade 3 without ever normalizing.

Grade 1 (Mild <24 h) Grade 2 (Moderate) Grade 3 (Severe)No seizures Clinical seizures Persistent seizuresMild alterations in tone

Marked abnormalities of tone

Severe hypotonia

Suck intact Weak suck Absent suckExaggerated Moro Moro incomplete Moro absentPupils react normally Pupils constricted Deviated, dilated, or

nonreactiveHyperalert Reduced responsiveness

to sound, light, touchUnresponsive

Jittery, tremor on handling

Reduced activityDistal flexion, proximal extension

No activityExtendedImpaired breathing

Modified from Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976;33:696–705; Levene MI, Sands C, Grindulis H, et al. Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet 1986;8472:67–69; Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet 2005;365:663–670; Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574–1584.

TABLE 46.4

Grade of Neonatal Encephalopathy

FIGURE 46.7 A 3-day-old infant with hypoxic-ischemic encephalopathy. The head is partly extended, the arms flexed with the hands tightly fisted, and the legs are extended and adducted.

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Electroencephalography to Support a Diagnosis of HIEThe rapid confirmation of encephalopathy has been facilitated by the use of aEEG. In addition to being relatively straightforward to apply, the screen display shows, in a compressed form, the amplitude and pattern of EEG over several hours. The awake full-term infant has continuous EEG activity, with the amplitude being well over 10 μV (Fig. 46.8A) (11). The mildest response to a hypoxic insult is for the EEG to change from continuous to discontinuous, that is, having periods where the EEG is less active and the amplitude reduces for some seconds and then reverts to the previous normal amplitude (Fig. 46.8B). This is called “discontinuous normal volt-age.” If the injury is more severe, the EEG reduces to a low-voltage background with periodic brief bursts of normal amplitude for 1 to 2 seconds with longer periods (over 20 seconds of very low-voltage background in between) (Fig. 46.8C). This is “burst suppression.” If the disturbance is even more severe, there are no bursts, only con-tinuous low-voltage activity. If the disturbance is worse still, there is no electrical activity at all (flat trace) (Fig. 46.8D).

aEEG is valuable because it provides an objective record that can be reviewed by an expert if there is doubt. Animal modeling of hypoxia–ischemia shows that during severe hypoxia–ischemia, the EEG becomes a flat trace or very low voltage. After reoxygenation, the amplitude of the EEG gradually increases over time, the speed of normalizing being inversely proportional to the severity of the brain injury on subsequent neuropathologic grading (6). If one waits long enough in some cases, the EEG will show continuous normal ampli-tude activity even in the presence of severe brain injury and subse-quent cerebral palsy. Continuous aEEG during the first 72 hours is valuable in confirming encephalopathy and in showing trends.

Clinical Chemistry to Support a Diagnosis of HIEElevated creatinine, liver enzymes, and cardiac troponin I; prolonged coagulation times; and thrombocytopenia indicate multiorgan dys-function, useful evidence of total body hypoxia.

Neuroimaging in Diagnosis of HIECranial ultrasound should be done on admission, as it may show evidence of antenatal injury or anomaly, for example, dilated ven-tricles, corpus callosum agenesis. Apparently normal anatomy on cranial ultrasound on days 1 to 2 does not exclude encephalopathy.

Cerebral magnetic resonance imaging (MRI) taken 4 to 14 days after birth is valuable in confirming HIE and in excluding congenital anomalies and prenatal developmental disturbances. In HIE follow-ing acute total asphyxia, MRI typically shows abnormal signal in the basal ganglia and thalamus (BGT) and absence of myelin signal in the posterior limb of the internal capsule (PLIC) (Fig. 46.9A). The brain-stem and rolandic cortex may also show abnormal signal (12–14) (Fig. 46.9B). Following a more prolonged period of hypoxia, there is typically abnormal signal in the watershed areas (frontal and occip-ital cortex and subcortical white matter). In severe cases, brain injury in both distributions may be seen in the same child.

Prediction of Outcome in Birth Asphyxia and HIEAn Apgar score of 0 at 10 minutes was followed by death or disability in 94% (15).

In the original study by Sarnat and Sarnat (4), infants with grade 2 encephalopathy who normalized within 5 days had normal devel-opmental outcome, whereas those who had not normalized by 7 days died or were neurodevelopmentally abnormal, typically with cerebral palsy. Overall, grade 2 HIE has been associated with later disability in 20% to 40% and grade 3 HIE with a very high rate of death or disabil-ity. The figures vary widely, probably reflecting different definitions of grade 3 and different thresholds for withdrawing life support.

Lactic DehydrogenaseLactic dehydrogenase (LDH) sampled within 6 hours of birth gives prognostic information. In one study, all infants with HIE and LDH values less than 2,085 U/L survived without disability, whereas those who died or were disabled had a median LDH value of 3,555 U/L (IQ range 3,003 to 8,705) (16).

Doppler Cerebral Blood Flow VelocityWhile ultrasound images are being obtained, pulsed Doppler can be used to measure Pourcelot resistance index, (systolic velocity minus diastolic velocity)/systolic velocity on the anterior cerebral artery. After about 24 hours of HIE, there is pathologic cerebral vasodilatation with, paradoxically, the highest cerebral blood flow being found in the most severely injured infants. This cerebral vasodilatation may be reflected in a low cerebral resistance index (below 0.55). A low cerebral resistance has been found to have a positive predictive value for death or disability of 84% (17).

ElectroencephalographyVan Rooij (11) showed that aEEG at 6 hours was predictive of out-come. If the trace showed very low voltage or a flat trace at 6 hours, only 5 out of 65 had normal outcome. If the aEEG had normalized by 24 hours, then 5 out of 6 had normal outcome. If there was burst suppression at 6 hours, 6 out of 28 had normal outcome or mild disability later, and all of these had achieved normal aEEG by 24 hours. All of those who still had burst suppression at 24 hours had poor outcome. The usefulness of aEEG at 6 and 24 hours has been further confirmed in a meta-analysis of prognostic tests (18).

NeuroimagingCerebral ultrasound and CT do not provide sufficient detail of injured areas to be useful for prognosis in a clinical setting. On conventional MRI, abnormal signal in the BGT is highly predictive of subsequent cerebral palsy, as is absence of myelin signal in the PLIC. The severity of basal ganglia lesions is useful in predicting the severity of subsequent motor impairment. In a large study of 175 infants with HIE and basal ganglia lesions, the predictive accuracy of severe BGT lesions for severe motor impairment was 0.89 (13). Abnormal PLIC signal intensity predicted the inability to walk inde-pendently by 2 years (sensitivity 0.92, specificity 0.77, positive pre-dictive value 0.88, negative predictive value 0.85). Brainstem injury was the only factor with an independent association with death.

Abnormal signal in the cortex and white matter, in the absence of basal ganglia and thalamic abnormality, is not so predictive of cere-bral palsy (only 5 out of 84), but severe changes were associated with cognitive impairment, epilepsy, and visual impairment, and there were a variety of behavioral and communication problems (14).

Other Conditions That Can Mimic HIENot every infant born with low Apgar scores has suffered critical hypoxia; a number of long-standing disorders of the nervous system can present with a hypotonic infant who does not breathe. This is especially true of congenital myotonic dystrophy and congenital mus-cular dystrophies and myopathies. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency can cause seizures of prenatal

1. Reduced responsiveness with hypotonia or incomplete reflexes (including weak suck)OR clinical seizures (9)

2. At least 3 signs from the following categories: Reduced responsiveness Reduced activity Abnormal posture Abnormal tone Incomplete reflexes Abnormal pupil response, heart rate, or respiration (10)

TABLE 46.5

Combinations of Signs Used as Criteria for Moderate or Severe HIE

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onset, so that the infant is observed to have seizures very soon after birth (19). High-dose magnesium, benzodiazepine, or opiate therapy to the mother may produce low Apgar scores and a hypotonic, poorly responsive infant but without a severe metabolic acidosis, burst sup-pression, or seizures. Rarely, severe birth trauma can injure the brain to such an extent that there is delayed onset of respiration. If there is a consistent sequence of obstetric sentinel events, fetal distress, low

Apgar score for more than 5 minutes, marked lactic acidosis, clinical encephalopathy, low voltage or burst suppression EEG, and initial cra-nial ultrasound showing normal anatomy, the diagnosis of HIE is not in doubt. In the cases where important pieces of the HIE jigsaw are miss-ing, other investigations need to be considered including MR imaging, blood levels of ammonia, uric acid and amino acids, urine sulfite reac-tion and S-sulfo-l-cysteine, and organic acids (see also Chapter 38).

FIGURE 46.8 A: The upper trace shows aEEG with about 3 hours of EEG compressed. In this healthy term infant, there is continuous activity with the upper margin being above 10 μV and the lower margin above 5 μV. The lower trace shows a few seconds of the “raw” EEG with continuous activity at normal voltage. B: The upper trace shows an EEG with the upper margin above 10 μV, but the lower margin is below 5 μV. The lower two traces of “raw” EEG show periods with reduced activity and periods with normal activity. This is discontinuous normal voltage.

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FIGURE 46.9 A: T1-weighted MRI axial scan at 8 days. There is abnormal signal (white) in the BGT. The myelin signal in the PLIC is absent. B: The same infant with MRI section at a higher level. There is abnormal signal in the rolandic cortex.

FIGURE 46.8 (Continued) C: Burst suppression. The upper trace (aEEG) shows the baseline (dark line) has a low upper margin around 5 μV. The vertical lines are brief “bursts” of higher voltage. D: Flat trace. The upper trace shows the base line is around 0 and the lower trace (raw EEG) shows no activity.

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Evidence Base for Therapeutic Hypothermia in HIEFor many decades, the one aspect of neonatal care on which all nurses and neonatologists were agreed was that it was harmful to let a sick baby get cold. It had been known for decades that being cooled during hypoxia protected the brain. This had made possible some early open heart surgery. The demonstration of a lengthy posthypoxic cascade of molecular and cellular processes ending in cell death raised the question of whether hypothermia after hypoxia might reduce brain injury.

First Laboratory Evidence of Hypothermia’s BenefitThe first convincing demonstration in a newborn animal model was in the newborn pig in 1995. Temporary bilateral carotid artery occlusion produced, on MR spectroscopy, severe deple-tion of energy nucleotides that returned to normal for some hours and then declined in irreversible secondary energy failure. Post-hypoxic cooling to 35°C prevented secondary energy failure (20). More research in rats, sheep, and pigs showed that cooling by 2 to 6 degrees for 6 to 72 hours reduced neuropathologic injury, neu-robehavioral deficits, cerebral edema, excitotoxic amino acids, free radical indicators, inflammation, and apoptosis. Furthermore, no adverse effects of cooling were identified.

Pilot Clinical TrialsEvidence from three species of newborn animal made it ethical to start clinical trials in human infants in 1998. Because there was still concern that cooling might have harmful effects, the brain was cooled more than the rest of the body using a cooling cap, thereby lowering rectal temperature to 34.5°C. Blood pressure rose dur-ing active cooling and could fall significantly during rapid warming (21). Heart rate fell by an average of 14 beats/°C, and rates of 70 to 80 were tolerated without evidence of inadequate perfusion.

Large Randomized TrialsThe first large randomized trial (CoolCap) of selective head cool-ing for 72 hours enrolled infants with asphyxia, signs of encepha-lopathy, and abnormal aEEG (9). This trial showed a reduction in death or disability at 18 months in the infants who had less severe EEG changes at enrollment. The next trial was conducted by the US National Institute of Child Health and Development Network and used cooling of the whole body to 33.5°C (10), showing signifi-cant reduction in death or disability. The TOBY (Total Body Hypo-thermia) trial cooled the whole body of the infant at 33.5°C for 72 hours, showing a significant increase in survival without neuro-logic impairment (22). All three of these early trials have followed up infants and have evidence that the protection at 18 months lasts into the school years. A meta-analysis of hypothermia trials in intensive care settings has confirmed that hypothermia reduced both disability and mortality (23) (Table 46.6).

Practical Aspects of Therapeutic HypothermiaTime Is BrainCooling is more effective the earlier it is applied. In animals, most benefit was lost after a 5.5-hour delay; there was no benefit by 8.5 hours. There must be no delay in identifying candidates. If a term infant still needs resuscitation at 10 minutes, turn the over-head heater off to avoid hyperthermia and check the cord blood or neonatal acid–base analysis while you continue resuscitation. The infant will start to cool passively, and it is essential that the core temperature is monitored rectally (6 cm) or via the esophagus, while the infant is being moved to the neonatal intensive care unit (24).

Allow passive hypothermia to occur by not actively rewarming the infant. Suggested target temperature for initial passive hypo-thermia is 34°C to 35°C (to avoid accidental overcooling during transport to NICU). The sicker the infant, the faster the tempera-ture will fall passively. In many centers, if the infant fulfils asphyxia criteria and shows neurologic criteria, this will be sufficient indica-tion to cool at 33.5°C for 72 hours; however, we recommend the use of aEEG to confirm encephalopathy and assess severity.

Cooling During TransportIf the infant has to be transported to a tertiary center for thera-peutic cooling, core temperature must be monitored continuously during transport and cooling/warming adjusted. For short periods, low-tech cooling techniques can be used within a transport incu-bator. We initially used surgical gloves filled with cold water and applied around the axilla, groin, and trunk. Do not use ice or any-thing colder than 10°C as this is painful.

Cooling EquipmentFigure 46.10A shows an infant with HIE being cooled with a water-filled wrap around the trunk and thighs. This is connected to a servo system, which automatically adjusts the temperature of the water to maintain rectal temperature at 33.5°C. A specially designed selective head cooling system is also available, but this is not servo-controlled.

Temperature ProbeIt is essential that the rectal (or esophageal probe) does not slide out as it will then register a temperature lower than the true core temperature, resulting in overheating.

StressIn animal models, stress during hypothermia blocks the protective effect. Infants being cooled should be assessed for signs of stress/pain. Unless the infant is already comatose, we use a continuous infusion of morphine, starting at 20 μg/kg/h and then reducing to 5 μg/kg/h titrated to the infant’s need.

Skin CareProtect the skin at pressure points by periodic adjustment of pos-ture. We have seen one infant with extensive skin necrosis resulting from lying supine with an adrenaline infusion on a cold mattress for 72 hours.

Drug MetabolismDrug metabolism is slowed during hypothermia. If continuous infu-sions of drugs or repeated doses are used, drug accumulation will occur more readily than at normal temperature. This means that continuous infusions of drugs such as benzodiazepines and opi-ates need to be carefully assessed to avoid misinterpreting a drug-induced coma as brain death!

Blood GasesBlood gas and pH measurements change with temperature. Analyzed at 33.5°C, a blood sample shows higher pH, lower pCO2 and lower pO2 than the same sample analyzed at 37°C. Hypocapnia must be avoided.

Relative Risk Risk Difference Number Needed to Treat

Death or major disability

1,344 0.75 (0.68–0.83) −0.15 (−0.20 to −0.10) 7 (5–10)

Mortality 1,478 0.75 (0.64–0.88) −0.09 (−0.13 to −0.04) 11 (8–25)Major disability

917 0.77 (0.63–0.94) −0.13 (−0.19 to −0.07) 8 (5–14)

From Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349–1358.

TABLE 46.6

Meta-analysis of 10 Randomized Trials of Hypothermia for Term Infants with HIE

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RewarmingAlthough initial cooling can be rapid, rewarming must be carried out no faster than 0.5°C/h. Rapid rewarming can precipitate hypo-tension and seizures.

Hypothermia has changed early prognostic indicators (25) (Table 46.7). Other aspects of intensive care are important for HIE and are listed in Table 46.8.

Despite therapeutic cooling, 30% to 40% of infants with HIE still die or are disabled, and Table 46.9 shows interventions in addition to hypothermia that are being currently investigated in clinical trials for HIE.

FIGURE 46.10 A: A term infant with HIE receiving therapeutic hypothermia via a cooling wrap around the trunk and thighs. B: The upper EEG trace shows normal activity. The lower EEG trace shows a seizure with rhythmic sharp waves.

• Apgar 0 at 10 min has a better prognosis if cooled; 94% reduced to 76% dead or disabled.

• Burst suppression on aEEG at 24 h has a better prognosis if cooled; 100% poor outcome reduced to 70% if cooled.

• Doppler resistance index <0.55 at 24 h has a better prognosis if cooled; reduced from 84% to 60% poor outcome.

• HIE grade 2 clinical assessment on day 4 has a better prognosis if cooled; 64% poor outcome reduced to 31%.

• MR imaging at median 8 d is not changed by cooling and is highly predictive.

From Thoresen M. Hypothermia after perinatal asphyxia: selection for treatment and cooling protocol. J Pediatr 2011;158(2 suppl):e45–e49.

TABLE 46.7

Hypothermia Changes Prognosis

• Monitor arterial blood pressure and assess hypotension with echocardiography to guide volume replacement or choice of inotrope

• Maintain oxygen saturation 93%–98% or paO2 60–100 mm Hg (8–13 kPa)• Maintain PCO2 45–58 mm Hg (6–8 kPa) with blood analyzed at 37°C• Monitor Na, K, Ca, and Mg. Correct hypocalcemia and hypomagnese-

mia as they may contribute to seizures• Monitor and maintain a safe blood glucose (60–140 mg/dL, 3.5–8 mmol/L)

TABLE 46.8

General Support for Infants with HIE

THE TERM INFANT WHO LATER DEVELOPS A SEIZURE

What Is a Seizure?A clinical seizure is an episode of paroxysmal abnormal cerebral activity, which is visible to the observer and/or experienced by the subject. An electrical or subclinical seizure is a paroxysmal electro-graphical discharge in the brain with rhythmic sharp waves/spikes lasting over 10 seconds (Fig. 46.10B).

Causes of Neonatal SeizuresNeonatal seizures usually have an identifiable cause (Table 46.10). Prompt diagnosis of the underlying condition is important as some of the etiologies have specific treatments that, when applied early, may improve the outcome. Apart from HIE, focal cerebral infarction and intracranial hemorrhage are the most common causes of seizures (26). Infarction typically presents with seizures late on day 1 or on day 2.

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Hypoglycemia and meningitis are the most urgent causes to iden-tify. Primary subarachnoid hemorrhage may result from compres-sion/decompression during delivery and can present with seizures around 24 hours. The diagnosis is made by finding uniformly blood-stained CSF with xanthochromia in the absence of any infarction, or intraventricular, subdural, or cerebellar hemorrhage. The prognosis is nearly always good. Neonatal seizures, which begin at several days of age, are a common manifestation of inborn errors of metabolism.

There are several epilepsy syndromes that may present during the newborn period. Benign familial neonatal convulsions constitute a rare autosomal dominant epileptic syndrome characterized by frequent brief seizures within the first days of life. Early myoclonic encepha-lopathy is one of two severe epilepsy syndromes that presents within hours of birth with severe, fragmentary, refractory myoclonus, which often is worsened by handling or stimulation (27). The initial neuro-imaging is normal, but diffuse cerebral atrophy develops, and affected infants may die before 2 years of age. Another entity, early infantile epileptic encephalopathy (Ohtahara syndrome) may present with severe burst-suppression pattern on the EEG and cerebral dysgenesis.

Clinical FeaturesNeonatal seizures differ considerably from seizures observed in older children, principally because the immature brain is less capable of propagating electrical discharges. Clinical signs can be absent, subtle, or misleading, as movement patterns resembling seizures may be of nonepileptic origin (i.e., physiologic move-ments, jitteriness, benign sleep myoclonus, and hyperekplexia). The classification of clinical manifestations of neonatal seizures is presented in Table 46.11 (28,29). Focal infarction and encephalitis tend to initially present with focal seizures. Otherwise, seizure type does not indicate etiology.

DiagnosisA diagnosis of seizures commits the infant to investigations and the possibility of treatment and follow-up. Because of the uncertainty in identifying seizures from clinical signs alone, it is very helpful to confirm seizures by rapid access to EEG or aEEG. Some infants with suspect movements do not show any electrical correlate, but persistent paroxysmal neurologic signs may need extended place-ment of EEG electrodes over long periods before it can be con-cluded that there is no electrical correlate. Only about one-third of neonatal seizures detected with EEG display clinical signs on simultaneous video recordings (30).

A maternal history of drug abuse, intrauterine infection, and genetic or metabolic conditions is important. The labor, delivery and condition at birth must be reviewed. Temperature instabil-ity, dysmorphic features, skin lesions, or clear focal signs should be noted. Initial laboratory investigations should address treat-able causes (e.g., hypoglycemia, hypocalcemia, hypomagnesemia, hyperammonemia). Lumbar puncture may identify intracranial infection, hemorrhage, and treatable inborn errors of metabolism, for example, folinic acid–responsive seizures and disorders of glu-cose transport (31,32). Cranial ultrasound should be carried out urgently and may show hemorrhage, cysts, or abnormal ventri-cles. If the initial screening investigations fail to identify a specific etiology, additional studies should be considered, including MRI, metabolic investigations, for example, plasma amino acids (and CSF glycine), lactate, urine organic acids, and screening for drugs.

TherapyIn addition to treating any identified treatable cause of seizures, anticonvulsant therapy should be considered for repeated or pro-longed seizures. There is no hard evidence that a few brief neo-natal seizures cause or worsen brain injury, but status epilepticus (>30 minutes of seizure activity) is associated with worsening of neurologic outcome, and there is limited laboratory evidence that prolonged neonatal seizures increase injury.

Clonic Rhythmic movement involving the face, arms, legs, or trunk at a single or multiple sites of the body, often shifting from one site to another. The clonic movements usually have a fast and a slow component, are unstimulated, and do not stop when restrained. Some newborn seizures appear as “cycling” leg movements or “boxing” movements of the arms. Such movements are often accompanied by disturbed eye movements, respiration, heart rate, and blood pressure. Some neonatal seizures take the form of a prolonged tonic episode of the trunk and limbs. Clonic seizures represent about 25% of seizures in newborns.

Myoclonic Resemble clonic movements, but the frequency of jerky movements is higher. Flexor muscles are often affected. Myoclonic seizures represent about 20% of seizures in newborns.

Tonic Resemble decerebrate rigidity (presenting as both upper and lower extremities in extension) or decorticate postur-ing (tonic flexion of the arms with extension of the legs). Sometimes only deviation of the head or eyes is present. Tonic seizures represent about 5% of seizures in newborns.

Subtle Horizontal eye deviation or nystagmoid movement of the eyes, sustained eye opening or blinking, chewing move-ments of the mouth or repetitive sucking, limb posturing, or pedaling movements. Autonomic manifestations commonly occur with motor manifestations, such as paroxysmal changes of heart rate, respiration, and systemic blood pressure. Subtle seizures are quite common and represent about 50% of all neonatal seizures.

TABLE 46.11

Classification of Clinical Neonatal Seizures• Allopurinol• Erythropoietin• Melatonin• Xenon

TABLE 46.9

Treatments Under Investigation to Add to Hypothermia for HIE

Hypoxic–ischemic brain injury

Global: hypoxic-ischemic encephalopathyFocal: cerebral infarction

Intracranial hemorrhage IntraventricularIntracerebralSubarachnoid

Central nervous system infection

MeningitisEncephalitis

Metabolic HypoglycemiaHypocalcemiaHypomagnesemiaInborn errors of metabolism

Drug withdrawal or intoxication

Methadone

Developmental abnormalities of the brain

Migration disorders

Epilepsy syndromes Benign familial neonatal convulsionsEarly myoclonic encephalopathyEarly infantile epileptic encephalopathy (Ohtahara syndrome)

TABLE 46.10

Causes of Neonatal Seizures

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For persistent seizures (e.g., three or more in an hour), a single loading dose of phenobarbital (20 mg/kg) should be administered intravenously over 20 minutes, which may be followed by addi-tional doses of 10 mg/kg to a total loading dose of 40 mg/kg, as required. If seizures are still uncontrolled, a single loading dose of phenytoin (20 mg/kg) or possibly fosphenytoin (1.5 mg of fos-phenytoin yields 1.0 mg of phenytoin) may be administered over 20 minutes with cardiac monitoring. If seizures remain refrac-tory to therapy, the use of a benzodiazepine may be considered, for example, lorazepam (0.05 to 0.1 mg/kg), clonazepam (0.1 to 0.2 mg/kg), and midazolam in a loading dose of 0.05 to 0.2 mg/kg, followed by 0.1 to 0.5 mg/kg/h (32). Levetiracetam is effective and well tolerated for seizure control in newborns (33,34). Seizure con-trol was achieved within 1 hour in 86% of neonates treated with levetiracetam 20 to 50 mg/kg intravenously (35).

Lidocaine is effective for refractory seizures. For term neonates undergoing hypothermia, the loading dose of 2.0 mg/kg is followed by continuous infusions of 7 mg/kg/h (for 3.5 hours), 3.5 mg/kg/h (for 12 hours), and 1.75 mg/kg/h (for 12 hours) before stopping (36,37).

Because the commonest neonatal seizures are due to an acute cerebral “insult,” maintenance anticonvulsant therapy is usually not needed. The loading dose(s) of anticonvulsant needed to stop the seizures will often provide therapeutic blood concentrations for several days. We have reserved maintenance anticonvulsant therapy for infants who develop further seizures after effective loading doses, because of concerns about possible deleterious effects of unnecessary anticonvulsants on the immature nervous system (38).

When seizures persist in spite of treatment with different anti-epileptic drugs, one should always consider pyridoxine-dependent epilepsy or pyridoxine phosphate oxidase deficiency as possible causes. Pyridoxine dependency may be diagnosed by a therapeutic trial of intravenous pyridoxine (100 mg) with EEG monitoring or oral treatment (100 to 200 mg daily), which should be continued for approximately 2 weeks. A trial of pyridoxal 5′-phosphate would help diagnose pyridoxine phosphate oxidase deficiency.

NEUROLOGY OF THE PRETERM INFANT WITH RESPIRATORY DISTRESS

In addition to taking great care over differential diagnosis, lung function, blood gases, and the techniques of continuous positive airway pressure (CPAP) and/or ventilation, a neonatologist needs to think neurologically when caring for a preterm infant with respira-tory distress. IVH is the typical pattern of brain injury in a preterm infant with respiratory distress, although hypoxia/ischemia during labor and delivery and infection may also contribute to subsequent brain injury. Clinical neurologic examination is made difficult by the presence of an endotracheal tube or CPAP tubes and the drugs used to facilitate intubation and to maintain sedation during venti-lation. Thus, diagnosis is heavily dependent on imaging.

Intraventricular HemorrhagePathophysiologyIVH was first described as a postmortem diagnosis and assumed to be fatal in preterm infants. The bleeding originates in the subependymal germinal matrix ventrolateral to the lateral ven-tricles (Fig. 46.11). The germinal matrix produces neuronal precursors during gestational weeks 10 to 20 and then produces glial precursor cells. When the fetus reaches full term, the germi-nal matrix has almost completely involuted. While the germinal matrix is producing new brain cells, it requires a rich blood sup-ply, but the blood vessels are not built to last. The hemorrhage is from capillaries or small venules in which endothelial cells are poorly supported by pericytes, muscle, and glial fibrillary acidic protein (39).

After very preterm birth, respiratory distress syndrome is likely. The struggling to breathe and interventions such as intubation and mechanical ventilation are associated with fluctuating arterial and venous blood pressure. Instability of pCO2 and pO2 produce, in addition, changes in cerebral blood flow. The combination of fluc-tuating blood pressure and fragile blood vessels in the middle of the brain explain the high frequency of IVH. Once bleeding has started, it may continue unchecked as the premature skull can expand without increasing pressure enough to tamponade the hemor-rhage. Table 46.12 lists the more important risk factors associated with IVH.

Hemorrhage may be restricted to the subependymal germi-nal matrix, may enter the lateral ventricles, or may give rise to periventricular hemorrhagic infarction through the mechanism of obstruction to the terminal vein. A frequent complication of a large IVH is progressive ventricular enlargement (dilatation) leading to hydrocephalus.

How Common Is IVH in Preterm Infants?In the early 1980s, almost 50% of infants with birth weights less than 1,500 g had IVH. This incidence has decreased markedly since then in infants with birth weights 1,000 to 1,500 g (40). However, during the same period, survival of extremely-low-birth-weight infants has increased. Forty-five percent of infants with birth weights 500 to 749 g had IVH in the 1990s. There does not appear to have been a decrease in IVH during the 2000s, with 6.2% of infants with birth weights 500 to 1,500 g having severe IVH (41). Allowing for infants over 1,500 g who also have IVH, applying these

FIGURE 46.11 Cerebral hemisphere of a preterm infant at autopsy. There is a small hemorrhage (arrowed) just below the ependymal lining of the lateral ventricle.

• Very short gestation• Male gender• Vaginal delivery• Birth asphyxia• Respiratory distress syndrome• Pneumothorax• Coagulopathy and thrombocytopenia• Early hypothermia (may be a marker for prolonged resuscitation)• Fluctuating blood pressure and cerebral blood flow with pressure pas-

sive circulation• Early hypotension and rapid correction

TABLE 46.12

Risk Factors for Intraventricular Hemorrhage

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figures to the United States would mean approximately 5,000 new cases of severe IVH annually.

Clinical Features of IVHIn many cases, IVH of moderate size occurs without any obvious clinical signs, and this justifies routine ultrasound scanning of all infants with birth weight less than 1,500 g. A larger IVH may mani-fest itself by destabilization of respiration, blood pressure, heart rate, and a fall in hemoglobin. Neurologic signs may be masked by the routine use of sedation, but, if specifically sought, decreased responsiveness, trunk hypotonia, tight popliteal angle, and abnor-mal eye movements can usually be detected (42). Coma and flaccid quadriparesis are relatively rare. Seizures do not commonly mani-fest as clonic movements; they may consist of cycling or boxing movements, mouthing or repetitive eye movements.

Diagnosis of IVHCranial ultrasound provides good views of the periventricular areas in preterm infants without disturbing life support. Scanning should be carried out in all infants with respiratory distress and gestation below 34 weeks. Papile IVH grading (1–4) has been widely used since 1978 (43) (Table 46.13 and Fig. 46.12A–D). We recommend scan-ning on admission to the Neonatal Intensive Care Unit to rule out prenatal abnormality or injury, for example, holoprosencephaly or dilated ventricles. A small number of infants will already have IVH at this time. Parenchymal infarction, if substantial, will usually liquefy over 7 days leaving a fluid-filled space, a porencephalic cyst, which communicates with the lateral ventricle as shown in Figure 46.12E.

Prognosis of IVHIt used to be thought that milder grades (1,2) of IVH did not increase the risk of neurodevelopmental impairment, but more recent work with larger study cohorts has shown that the risk of impairment is approximately doubled (44). Grade 3 IVH has been found to be associated with more neurodevelopmental impairment than grades 1 and 2 but with a wide spread in the frequency of disability. This spread may result from variability in the definition of grade 3 IVH. For grade 4 IVH, the literature is consistent in reporting a high rate of cerebral palsy (mainly hemiparesis). However, with small paren-chymal infarctions, some infants survive without disability. Bas-san documented that infants with larger parenchymal infarction (involving two or more brain regions) had a higher rate of cerebral palsy than infants with lesions involving only one brain region (45). Some infants with grade 4 IVH with hemiplegia become ambulant and have cognitive function within the normal range.

Prevention of IVHInterventions shown in randomized trials to prevent IVH are listed in Table 46.14. The most important intervention to prevent IVH is maternal corticosteroid administration 24 hours or more before pre-term delivery. A large number of randomized controlled trials have

supported this finding, and incidence of IVH is reduced by almost half (46). The most common regime studied was betamethasone in a total dose of 24 mg divided over 24 hours. The effect is probably due mainly to surfactant production maturing the fetal lungs. Sta-bilization and slightly higher blood pressure may also contribute to prevention of IVH. Postnatally, indomethacin (47), muscle relax-ation (48), ethamsylate (49), and vitamin E (50) all show evidence of reducing IVH in at least one randomized trial but, because of lack of evidence that disability is reduced, have not been widely utilized. Volume-targeted ventilation has been shown to reduce IVH when compared to pressure-limited ventilation; this effect is prob-ably secondary to superior stabilization of blood pressure and cere-bral blood flow using volume-targeted ventilation (51). Delayed cord clamping, when compared to immediate clamping, has been shown to reduce IVH, probably because hypovolemia and hypotension are prevented (52). Although not proven by randomized trial, correc-tion of severe coagulopathy or thrombocytopenia probably reduces the risk of subsequent IVH. Severe IVH can, in turn, consume clot-ting factors and platelets with a risk of further bleeding.

Acute treatment after IVH follows the accepted principles of correcting hypovolemia, thrombocytopenia, coagulopathy, ane-mia, and hypoglycemia.

Posthemorrhagic Ventricular DilatationPathophysiologyThe term posthemorrhagic ventricular dilatation (PHVD) is often used by neonatologists and radiologists to identify the early stages of hydrocephalus before there is excessive head enlargement. Although the ventricles are enlarged when there is atrophic loss of white mat-ter, the term, PHVD, is intended to apply to CSF-driven ventricular enlargement with raised intraventricular pressure. A minority (30% to 49% depending on definitions) of cases of PHVD are transient and do not progress. The initial mechanism of PHVD is thought to be multiple blood clots obstructing the channels for reabsorption of CSF. When older infants with posthemorrhagic hydrocephalus came to autopsy, fibrosis of the basal cisterns and meninges together with subependymal gliosis was described (53) (Fig. 46.13).

The development of PHVD can be likened to scar formation or repair gone wrong. Intraventricular injection of blood in rat pups produced PHVD in the majority and showed parenchymal and peri-vascular deposition of extracellular matrix proteins, probably due, in part, to up-regulation of transforming growth factor beta (TGF-β) (54). Extracellular matrix proteins such as laminin, fibronectin, and vitronectin act like cement between cells and, together with TGF-β, are involved in many fibrotic diseases. Releasing “cement” in and around the CSF spaces over a period of weeks is thought to be the mechanism by which reabsorption of CSF is inhib-ited. TGF-β1 is stored in platelets and is thereby present in large amounts in grades 3 and 4 IVH.

Although some premature infants can expand their ventricles with very little elevation of intracranial pressure, some do have elevated pressure up to levels than can interfere with cerebral per-fusion, that is, 150 to 200 mm H2O (55), with resulting injury to periventricular white matter. With the breakdown of large amounts of heme, considerable amounts of non–protein-bound iron are released into CSF; this may injure white matter through free radi-cal generation (56) as can hypoxanthine, which is also released into posthemorrhagic CSF. High concentrations of proinflamma-tory cytokines in the CSF in PHVD provide further support for the role of inflammation in the pathophysiology of periventricular damage (57).

Blood clot within CSF is cleared very slowly, and some blood is often visible on scans 2 to 3 months after hemorrhage. Fibrinolysis is relatively ineffective in CSF, probably because concentrations of plasminogen are very low and there are high concentrations of plasminogen activator inhibitor (57).

Grade 1 IVH Small hemorrhage confined to the subependymal germinal matrix (Fig. 46.12A)

Grade 2 IVH Small hemorrhage extending into the lumen of the ventricles but not distending them (Fig. 46.12B)

Grade 3 IVH Hemorrhage volume large enough to distend the ventricle and with the clot extending more than half the length of the ventricle (Fig. 46.12C)

Grade 4 IVH IVH with, in addition, a parenchymal hemorrhagic infarction (Fig. 46.12D)

From Horbar JD, Carpenter JH, Badger GJ, et al. Mortality and neonatal morbidity among infants 501–1500 grams from 2000 to 2009. Pediatrics 2012;129:1019–1026.

TABLE 46.13

Papile Grading of IVH

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FIGURE 46.12 A: Coronal view cranial ultrasound of a 28-week-gestation infant. The arrow points to a hemorrhage in the subependymal germinal matrix. This is Papile grade 1 IVH. B: Coronal view cranial ultrasound scan of a 27-week-gestation infant. Papile grade 2 IVH. The arrows point to small echo-genic blood clots, which clearly lie within the lumen of each lateral ventricle. C: Coronal view cranial ultrasound scan of a 25-week-gestation infant. Papile grade 3 IVH. The arrow indicates a large amount of blood clot distending the lateral ventricle. D: Coronal view cranial ultrasound of a 28-week-gestation infant. Papile grade 4 IVH. There is echogenic blood clot within both lateral ventricles and the third ventricle, and, in addition, the arrow indicates an echo-genic area adjacent to the lateral ventricle. This is a hemorrhagic parenchymal infarction. E: The same infant as in figure 4 but 9 days later. The periventricular infarct area, previously echogenic, is now echolucent (arrowed) as it has lique-fied, and the porencephalic cyst is communicating with the lateral ventricle.

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DiagnosisAfter the ultrasound diagnosis of IVH, it is important to carry out follow-up cranial ultrasound scans so that PHVD can be detected. It is also important to regularly measure the head circumference, but ventricular enlargement can precede excessive head enlargement by 7 to 14 days. Between 24 and 32 weeks of gestation, average head enlargement is about 1 mm per day, but from 32 to 40 weeks, the growth velocity is less, being around 0.7 mm/d (58).

Measurements of ventricular size to define PHVD have been widely used. The most commonly used measurement is the ven-tricular index of Levene (59). Measured in the mid-coronal view, this index is the dimension from midline of the brain to the lateral border of the lateral ventricle (Fig. 46.14).

Prognosis of PHVDThe ventriculomegaly (60) and PHVD drug (61) trials used a ventricu-lar index 4 mm above the 97th centile as entry criterion (Fig. 46.15) and used a standardized developmental assessment. If there were no parenchymal lesions seen on ultrasound, the incidence of cerebral palsy was approximately 40%, and, of these, about 25% had multiple impairments. If parenchymal echodensity or lucency was seen, in addition to PHVD, cerebral palsy was found in 80% to 90%. A large recent study of 998 infants with birth weight below 1,000 g showed that, in infants with grade 3 PVH, the subsequent need for shunt sur-gery greatly increased the rate of cerebral palsy and cognitive dis-ability. With grade 4 IVH, the need for a shunt was also associated with an increased rate of disability, with 48% having Bayley mental development index below 50% and 80% having cerebral palsy (62).

Treatment of PHVDThe traditional treatment for hydrocephalus, insertion of a ven-triculoperitoneal shunt, is not feasible in an unstable baby of less than 1,000 g who is only a few days old, because of the fragility of

the skin, and the very high risk of infection and shunt blockage with blood clot. Thus, alternative treatments have to be considered before an infant reaches a size and degree of clinical stability that would allow for shunt placement.

Repeated lumbar or ventricular taps have been tested in four randomized trials without any evidence that this reduces either the need for shunt surgery or the incidence of long-term disability (63). Acetazolamide and furosemide reduce CSF production, but, when tested in randomized trials, the infants in the drug group had worse outcome than the control group (64).

Intraventricular injection of a fibrinolytic agent in a local dose insufficient to produce a systemic effect has been studied. Experi-ence in infants with PHVD has been inconsistent, and two small randomized trials of intraventricular streptokinase showed no evi-dence of benefit (65).

External ventricular drain and repeated tapping of a ventricular reservoir have their advocates, but no results of randomized tri-als have been published. However, a nonrandomized Dutch retro-spective study of 144 infants with PHVD found that those in whom treatment had started coincident with a ventricular index mini-mally exceeding the 97th centile had better development at 2 years than those in whom treatment started after the ventricular index

FIGURE 46.13 Postmortem brainstem and cerebellum at 3 months of age of a preterm infant with IVH and PHVD showing deposition of connective tissue around the brainstem.

FIGURE 46.14 Midcoronal view cranial ultrasound scan showing ventricu-lar width from midline to lateral ventricle border (ventricular index of levene) and third ventricular width.

268

10

12

14

16

20 Ventricular width mm

18

28 30 32 34 36 38 40

97th centile

4 mm above97th centile

Gestation (weeks)

FIGURE 46.15 97th centile for ventricular index (44) and the action line 4 mm above, which was used in treatment trials. Modified from Levene MI. Measurement of the growth of the lateral ventricles in preterm infants with real-time ultrasound. Arch Dis Child 1981;56:900–904.

• Maternal corticosteroid• Delayed umbilical cord clamping• Postnatal indomethacin and ethamsylate• Postnatal vitamin E• Muscle relaxation of ventilated infants with fluctuating cerebral blood

flow velocity• Volume-targeted ventilation

TABLE 46.14

Interventions That Prevent Intraventricular Hemorrhage

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had increased beyond 4 mm over 97th centile (66). Third ventricu-lostomy and choroid plexus coagulation have had very limited use in PHVD.

A new approach was developed, aimed at removing as much as possible of the free iron, inflammatory cytokines, and old blood and gently reducing pressure and distortion in the ventricle earlier than would occur with lumbar puncture (67). The method used is known as drainage irrigation and fibrinolytic therapy (DRIFT). DRIFT has been tested in a randomized trial involving 77 infants with PHVD in four centers, 39 receiving DRIFT and 38 receiving conventional treatment with lumbar puncture followed by tapping a reservoir. The trial was stopped early because of an excess of secondary intraventricular bleeding in the DRIFT group, and there was no difference in the need for shunt surgery between the two groups. However, developmental assessment at 2 years showed that severe cognitive disability was significantly reduced with DRIFT (67). Median Mental Development Index was improved by more than 18 points in the DRIFT group. Importantly, the infants in the DRIFT group who had secondary intraventricular bleeding did not have more disability than those who did not bleed. This is the only randomized trial to demonstrate benefit from any inter-vention in PHVD.

Sick preterm infants are at risk of other injuries to the nervous system such as meningitis and hyperbilirubinemia, which are cov-ered in Chapters 44 and 32, respectively.

THE PRETERM INFANT IN APPARENTLY GOOD CONDITION BUT AT HIGH RISK OF PERIVENTRICULAR LEUKOMALACIA

PathophysiologyPVL originally referred to the appearance at autopsy of softening or cysts in the white matter adjacent to the lateral ventricles of preterm infants. In the 1980s, it became possible to image PVL during life with ultrasound and MRI. The periventricular white matter of the preterm brain is an arterial watershed area, making it particularly vulnerable to injury from underperfusion. In addition, oligodendroglial precursor cells (which will later produce myelin) are particularly sensitive to injury from free radicals, excitotox-icity (glutamate), and inflammation at this stage of immaturity (Table 46.15) (see also Chapter 42).

Not only have the proinflammatory cytokines, tumor necro-sis factor alpha, and interferon gamma been shown to be toxic to oligodendroglia but also animal models have shown that endo-toxin greatly increases the vulnerability of the immature brain to hypoxia–ischemia. This means that hypoxia that would not injure the brain on its own can result in serious injury if there is preexist-ing inflammation. PVL appears, in many cases, to be triggered by a combination of ischemia and inflammation with varying contribu-tions of these two mechanisms as shown in Table 14.16.

Clinical Features of PVLPerlman et al. (68) found that cystic PVL developed in 3.2% of infants with birth weights less than 1,500 g, despite the fact that 70% of these infants had relatively benign clinical courses in the neonatal period. Noncystic PVL is perhaps five times more common

than cystic PVL. Some infants with respiratory distress and IVH will go on to show evidence of PVL, but there are important dif-ferences in the patterns of risk. While IVH is more common with decreasing gestational age, that is not the case with PVL.

Although the major underlying mechanism of PVL is ischemic in many cases, there is no obvious clinical HIE as there is in the term infant. Remarkably, there are usually no specific neurologic signs at the time of injury. As the infant approaches term, experi-enced observers may notice an excess of tremors and startles and abnormal tone, but, in practice, clinicians and parents may pass an infant who is feeding and growing as normal. However, at 1 month and 3 months past term, analysis of video recording of general movements shows a poor repertoire of movements in infants with PVL (69). There is often delayed visual maturation and, by 9 to 12 months corrected age, typical signs of spastic diplegia develop.

Particularly likely to have postnatal abnormalities, which are missed by the neonatologist, are infants born at 27 to 31 weeks of gestation with a history of prolonged rupture of membranes and maternal antibiotic therapy but without asphyxia or postna-tal respiratory distress. While a history of maternal fever or foul- smelling amniotic fluid will indicate chorioamnionitis, there are many cases in which there are no such signs, but histology of the placenta or umbilical cord or analysis of proinflammatory cyto-kines in amniotic fluid subsequently shows that inflammation was present. Thus, for the neonatologist, prolonged rupture of mem-branes in the premature infant less than 31 weeks of gestation must be considered an important risk factor for PVL.

Diagnosis of PVL by ImagingNeonatologists have sometimes been surprised by the later diagno-sis of cerebral palsy or cognitive disability in a preterm infant who avoided asphyxia, ventilation, meningitis, and hyperbilirubinemia and in whom ultrasound scanning in the 1st week showed no IVH (with no follow-up scanning). Parents may ask why brain injury was not diagnosed in the neonatal period. It has become appar-ent that preterm infants in apparently good condition may, never-theless, be developing significant brain injury. Despite the limited therapeutic opportunities to prevent this, we think diagnosis in the neonatal period is important as it ensures that infants are identi-fied early for careful follow-up assessment and appropriate physical therapy. Furthermore, the emotional roller coaster, caused when the parents are told at discharge that everything looks good and then told months later that their child has a life-long disability, is avoided.

The most obvious sequence of events underlying the above-described clinical course was the initial appearance of periventric-ular echodensities bilaterally on ultrasound (Fig. 46.16A and B), followed several weeks later by cysts that have developed in the previously echodense areas (Fig. 46.17A and B), which pres-ent now as echolucent (black) areas on ultrasound (cystic PVL). Some increase in periventricular echo can be normal and depends

• Location in the border zones between arterial territories• Immaturity-related vulnerability of preoligodendrocytes to:

°° Free radical injury °° Excitotoxicity of glutamate°° Proinflammatory cytokines

TABLE 46.15

Vulnerability of Preterm Periventricular White Matter

• Antepartum hemorrhage particularly placental abruption (mainly ischemia)

• Prolonged rupture of membranes/chorioamnionitis (mainly inflammation)

• Twin–twin transfusion syndrome (mainly ischemia)• Necrotizing enterocolitis (inflammation and ischemia)• Septicemia (inflammation and ischemia).• Hypocapnia (mainly ischemia)• Symptomatic patent ductus arteriosus (mainly ischemia)• Intraventricular hemorrhage (ischemia and inflammation)• Preterm delivery (24–34 wk)

TABLE 14.16

Risk Factors for PVL

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partly on the settings on the scanner, but clinically significant echodensities are at least as dense as the choroid plexus. Many early periventricular echodensities disappear without subsequent cyst formation, and sometimes cysts are found at the age of 4 to 6 weeks without preceding echodensity. The cysts may coalesce without communicating with the ventricular lumen, as a shown at autopsy in Figure 46.18. Typically, when the infant has reached full term, more general thinning of periventricular white matter and corpus callosum is seen on ultrasound scan, with irregular enlargement of the ventricles particularly in the occipital area (Figs. 46.19A and B and 46.20A and B).

In other cases, there may be no impressive initial echodensity and no cyst formation but a gradual thinning of periventricular white matter will occur, with mild nonprogressive ventricular dilatation (noncystic PVL). The sequence of bilateral periven-tricular echodensity to periventricular cysts is very specific for

PVL. If a cyst or cysts are found on the initial scan, the differ-ential diagnosis includes choroid plexus cysts and germinolytic cysts. Antenatal porencephaly is usually thought to be ischemic in origin, possibly thrombotic.

Prognosis of Cystic Periventricular LeukomalaciaTransient echodensities (flares) that disappear within 7 days with-out subsequent cyst formation or late ventricular dilatation are not considered to increase the risk of later disability. Bilateral flares that persist longer than 7 days are considered to be the mildest form of PVL and, even in the absence of cysts or ventricular dilatation, increase motor impairment (70). When periventricular cyst forma-tion is confirmed, the more extensive the cystic lesions, the worse the prognosis. Small frontal cysts are associated with a modest increase in motor impairment, but extensive bilateral parietooccipi-tal cysts are highly predictive of spastic diplegia with delayed visual

FIGURE 46.16 A: Parasagittal view cranial ultrasound scan at 3 days of age showing a (white arrow) echodensity beside the lateral ventricle (black). B: Coronal view cranial ultrasound scan at 3 days of age showing bilateral periventricular echodensities (white arrows). Courtesy of Dr David Evans, Southmead Hospital, Bristol.

FIGURE 46.17 A: Sagittal view cranial ultrasound scan at 6 weeks of age showing multiple cysts (black spaces) close to the lateral ventricle (white arrow). B: Coronal view showing bilateral periventricular cysts at 6 weeks of age.

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THE NEWBORN INFANT WITH HYPOTONIAHypotonia in the newborn is a common clinical sign that can be a manifestation of a systemic illness or a neurologic dysfunction of the central or peripheral nervous system. Passive muscle tone is usually defined as the resistance of muscles to passive move-ment, for example, measuring the popliteal angle. Active muscle tone is defined as ability to maintain posture, especially the neck and trunk in the case of the newborn. The “floppy infant” presents a diagnostic challenge because of the wide spectrum of etiologic causes. There are two crucial questions to address:

Did the infant have normal muscle tone and then become hypotonic or has the infant been hypotonic from (or before) birth?

Is there muscle weakness as well as reduced muscle tone?

Conditions affecting supraspinal regions (the brain, brainstem, and cervical spinal junction) cause central hypotonia without weakness, while segmental conditions (including anterior horn cell, peripheral nerve, neuromuscular junction, and muscle) cause motor unit hypotonia with muscle weakness (71). Central hypo-tonia accounts for the majority of cases of neonatal hypotonia (72–74).

Differential DiagnosisThe most frequent causes of central hypotonia in the newborn infant are systemic diseases such as sepsis, hypoxic–ischemic brain injury, or heart failure. A term infant who is born healthy but develops central hypotonia with altered consciousness within the first days of life may have an inborn error of metabolism (see also Chapter 39). Hypoglycemia is an important cause of newborn hypotonia and should always be excluded.

A significant cause of hypotonia in newborns is the presence of one of the genetic syndromes known to be associated with

maturation and cognitive impairment. Many such infants develop epilepsy in addition.

Management of PVLDiagnosis of PVL and its prognosis creates anxiety in parents; thus, it is important to convey the diagnosis along with supportive infor-mation on how the problems can be tackled and what resources are available. The infant must be prioritized for regular assessment of motor, cognitive, and sensory development. The parents may report that the infant is crying excessively and having postural spasms; they require sympathetic and expert advice. Later in the 1st year, physiotherapy is important to avoid contractures and abnormal postures.

FIGURE 46.18 Postmortem sagittal view of the right hemisphere in a preterm infant who died at age 8 weeks. A line of periventricular cysts have coalesced.

FIGURE 46.19 A: T2-weighted axial MRI scan of a normal preterm infant at full term. B: T2-weighted MRI scan of a preterm infant with PVL. There is irregu-lar enlargement of the ventricles occipitally (white arrow) with thinning of periventricular white matter. Courtesy of Dr. David Evans, Southmead Hospital, Bristol.

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FIGURE 46.20 A: T2-weighted MRI scan of a preterm infant at term. Coronal view. The lateral ventricles are mildly enlarged, and there are periventricular cysts. Courtesy of Dr. David Evans, Southmead Hospital, Bristol. B: T2-weighted MRI scan of a preterm infant at term. Axial view. The lateral ventricles are more obviously enlarged, and there are periventricular cysts frontally and parietooccipitally. Courtesy of Dr. David Evans, Southmead Hospital, Bristol.

hypotonia, such as Down syndrome and other chromosomal anomalies, Prader-Willi, fragile X, Angelman, and Smith-Lemli-Opitz syndromes. Table 46.17 presents a detailed overview.

Hypotonia may be caused by developmental abnormalities of the CNS (detectable with MRI) such as schizencephaly, lissenceph-aly, holoprosencephaly, and Joubert syndrome.

“Take a History and Examine”A family history of spontaneous abortions, stillbirths, or death in infancy is important, as is consanguinity. A history of drug or teratogen exposure (i.e., alcohol, drugs, solvents, benzodiazepines), reduced fetal movements, presence of polyhydramnios, breech fetal presentation, prolonged labor, and low Apgar scores should be noted. The gestational age must be estimated, as tone increases with gesta-tional age. The age of onset of hypotonia should also be determined.

Then, assessment of tone is introduced in the section on neuro-logic examination. When assessing muscle tone, the infant’s head must be positioned in the midline, as the asymmetric tonic neck reflex can influence tone if the head is turned to one side. The typical finding in a hypotonic newborn lying supine is the “frog-leg” sign, with hips abducted and knees flexed (Fig. 46.21). As the cause of hypotonia without muscle weakness in the great major-ity of cases is an underlying acute disease, assessment of the new-born’s general health is imperative as the first step in the evaluation of the floppy infant. The assessment of muscle strength is not easy and may not be possible because of lack of voluntary movement in an acutely ill newborn. However, sick newborns often have other signs that suggest the underlying condition. Hypotonia in itself is frequently associated with decreased spontaneous movement.

The presence of typical craniofacial dysmorphic features can suggest diagnosis in some of the more common syndromic causes of hypotonia including trisomy 21 (73). Prader-Willi syndrome is characterized by feeding problems, almond-shaped eyes, narrow bifrontal cranial diameter, small genitals, and small hands and feet (Fig. 46.21). Eye examination can reveal the presence of cataracts (peroxisomal disorders), pigmentary retinopathy (peroxisomal

disorders), and lens dislocation (sulfite oxidase/molybdenum cofactor deficiency). Abnormal fat pads and inverted nipples can point to congenital disorders of glycosylation. Cardiac enlargement and signs of cardiac failure are seen in infants with Pompe disease. Bilateral 2/3 toe syndactyly should prompt further assessment for Smith-Lemli-Opitz syndrome. Visceral enlargement (hepatomeg-aly with or without splenomegaly) suggests a lysosomal or glycogen storage disease.

Is There Muscle Weakness in Addition to Hypotonia?Lower motor neuron disorders should be considered in an alert newborn with hypotonia and weakness. If observation over time shows persistent lack of antigravity movements, poor repertoire of spontaneous activity, impaired sucking and swallowing, hypoventi-lation, and a weak cry, there is good evidence of muscle weakness. A weak cry may reflect diaphragmatic weakness, and a fatigable cry may suggest a congenital myasthenic syndrome. Taking a heel prick blood sample is a useful test of muscle strength, as the infant will usually vigorously try to withdraw the foot.

If the myotatic reflexes, such as knee and ankle, are absent, this finding suggests that the problem is in the lower motor unit.

Paucity of facial expression may be related to facial muscle weakness, as may ptosis. Muscle fasciculations in the tongue sug-gest denervation. A high-arched palate is often noted in infants with neuromuscular disorders, and an enlarged tongue suggests storage disorders (acid maltase/Pompe disease). Anterior horn cell disease usually spares extraocular muscles, while diseases of the neuromuscular junction may be characterized by ptosis and extra-ocular muscle weakness. Disorders of the motor unit are gener-ally not associated with malformations of other organs, with the exception of hip subluxation and arthrogryposis, which are signs of hypotonia in utero.

If the examination of the infant suggests a neuromuscular disor-der, ask the parents about a history of persistent or periodic weak-ness. Physical examination of the parents, who might be unaware of their (mild) neurologic condition, may also provide important

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diagnostic information. For example, transitory neonatal myas-thenia may be suspected if the mother displays fatigability of the eyelids with upward gaze or fatigability of the arms with sustained forward extension. Although rare, neonatal myasthenia and bot-ulism are important to consider because treatment is available. Infants with congenital myotonic dystrophy have severe hypoto-nia, but their mothers are typically only mildly affected. The most pathognomonic signs in mothers with myotonic dystrophy are grip myotonia and inability to bury their eyelashes when asked to tightly close their eyes. While usually absent, or more difficult to detect, in the newborn, electromyography (EMG) in the mother will demon-strate myotonic discharges.

InvestigationsHistory and physical examination should guide investigations. An infant who becomes hypotonic should be treated as infected while other investigations proceed. If there is no confirmation of infec-tion, the infant should be investigated for inherited metabolic dis-ease (see Chapter 38).

To evaluate causes of peripheral hypotonia, creatine kinase (CK) should be measured, although it has limited value in the newborn: CK and isoenzyme levels may be increased 10-fold for up to 1 week following normal vaginal delivery. Elevated CK gen-erally implies skeletal or cardiac muscle necrosis, for example, after severe asphyxia, but most congenital myopathies are asso-ciated with a normal CK levels. The blood for CK measurement should be obtained before performing the EMG or muscle biopsy, as these procedures may elevate CK. EMG can help exclude or confirm peripheral causes of hypotonia. If there is severe respira-tory muscle involvement, early muscle biopsy may be required to provide definitive diagnosis, prognosis, and the basis for treatment decisions.

For syndromic causes of hypotonia and for suspected spinal muscular atrophy and myotonic dystrophy, genetic testing is essential. The clinical findings and presence of dysmorphic fea-tures should guide specific genetic testing. Use of databases such as Oxford Medical Databases or Internet-based Online Mende-lian Inheritance in Man (OMIM; http://www.ncbi.nlm.nih.gov/omim) is helpful. For a more detailed overview on genetic test-ing available in hypotonic newborns, see the review by Prasad and Prasad (74).

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Central hypotonias

Hypotonia present from birth

Hypotonia devel-ops shortly after birth

HIEIntracranial hemorrhageGenetic/developmental: Down syndrome, Prader-Willi syndrome, peroxisomal disorders (Zellweger syndrome), cerebral dysgenesis, and other structural cerebral abnormalitiesBrain and spinal cord injury or traumaSepsis, including meningitis and encephalitisMetabolic derangements or disordersEndocrine: hypothyroidismDrug intoxication

Peripheral hypotonias

Level of anterior horn cell (lower motor neuron)

Level of peripheral nerve (motor or sensory)

Level of neuromuscular junction

Level of the muscle

Spinal muscular atrophy type I (Werdnig-Hoffmann disease)Hypoxic–ischemic myelopathyTraumatic myelopathyGlycogen storage disease type II (Pompe disease)Neonatal poliomyelitisHereditary sensory and motor neu-ropathies: congenital hypomyelinat-ing neuropathy, Dejerine-Sottas diseaseAcute and chronic inflammatory polyneuropathies: Guillain-Barré syndromeMitochondrial disordersLysosomal disorders: Krabbe diseaseTransient neonatal myastheniaCongenital myasthenia and myas-thenic syndromesMagnesium toxicityAminoglycoside toxicityInfant botulismMuscular dystrophy: congenital myotonic and congenital muscular dystrophyMetabolic myopathies: mitochon-drial, disorders of glycogen and lipid metabolismCongenital myopathies: nemaline (rod body), myotubular (centro-nuclear), and other

TABLE 46.17

Causes of Hypotonia at Different Levels of the Nervous System

FIGURE 46.21 A hypotonic infant with Prader-Willi syndrome lying in the “Frog” position.

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