Chapter 28. Newborn Neurology

The neonatal intensive care unit and newborn nursery are often chaotic and noisy environments with a whirlwind of activity and a unique language of acronyms. The goal of this chapter is to provide a systematic, concise, and clinically usable approach to guide the bedside practitioner through this sea of chaos by first reviewing the normal neurological examination of the neonate with an emphasis on normal findings at different gestational ages and possible etiologies of abnormal findings. It will then cover in more detail several neurological abnormalities that are found in the neonatal period, including hypoxic-ischemic encephalopathy (HIE), intraventricular hemorrhage (IVH), and seizures in the newborn. Although there is overlap among these abnormalities, each will be covered individually, with a brief emphasis on the incidence, pathophysiology, pertinent clinical findings, the differential diagnosis, and a brief overview of clinical management.

This work was supported by NIH 5R21NS052583-02.

The neurological examination of the neonate presents the clinician with numerous challenges. First, it tests the examiner's powers of observation. Most of the neurological examination is carried out by observing the neonate's baseline state. The baseline state changes based on the gestational age of the neonate, level of arousal, and recent experiences (eg, postmedical procedures such as IV placement). Second, the patient is unable to respond to verbal commands. And, last, the examiner uses subjective methods of evaluating the neonate's response to various stimuli and cues. This necessitates a high level of experience and knowledge to obtain a thorough and accurate assessment of the neonate's neurological status. This section is designed to briefly review the complete neurological examination of the neonate. The rationale for each portion of the examination will be reviewed, as will the potential differential diagnosis for abnormal findings. The examination is laid out in a systematic manner beginning with simple observation and proceeding to active evaluation of tone and responses to various stimuli. The examination is performed in this manner to maximize the clinician's time at the bedside while thoroughly examining the neonate's neurological status (Figure 28-1).

Review of History

The first step to a thorough examination is to review the maternal history (age, gravity, parity, pregnancy health status, fetal growth) and the history of the neonate's birth (route of delivery, anesthesia/analgesia, APGAR scores, need for resuscitation) and hospital course from the neonate's chart. Particular attention should be focused on the gestational age of the neonate (as measured by examination—see Figure 28-1). The examiner should also review the neonate's weight, head circumference, and length. It is very important to start with these physical parameters to have the proper context for the remainder of the examination. For example, infants of diabetic mothers will typically be large for gestational age for weight and length with a normal head circumference. These infants may have problems associated with hypocalcemia and hypoglycemia, which may be evident on the neurological examination with findings of jitteriness, agitation, and seizures.1 The head circumference may also present the examiner with clues to underlying neuropathology. Neonates with microcephaly may have a congenital infection (CMV, rubella, toxoplasmosis), genetic abnormality (trisomy 13, 18, 21), somatic anomalies or syndromes (CHARGE association, Meckel-Gruber syndrome, Smith-Lemli-Opitz syndrome, Cornelia de Lange syndrome, Prader-Willi syndrome), in utero drug exposure (cocaine, heroin, ethanol, inhalation of mixed solvent vapor), hormonal disorders (congenital hypothyroidism), congenital developmental abnormality (holoprosencephaly, lissencephaly, polymicorgyria, shizencephaly), or microcephaly vera. Conversely, neonates with macrocephaly may have an underlying ventricular enlargement (aqueductal stenosis, Dandy-Walker syndrome, Arnold-Chiari malformation, vein of Galen malformation) or other etiologies (Soto syndrome, Beckwith-Wiedemann syndrome, fragile X syndrome, cranial mass, familial macrocephaly).

Observation

After completing a thorough review of the history, the examiner should simply observe the neonate. With keen observation, the examiner can gain many details about the neonate's neurological status without disturbing the neonate.

Mental Status

The level of alertness is perhaps the most sensitive of all neurological functions since it is dependent on the integrity of several different levels of the central nervous system.2 Before 28 weeks gestation, the newborn states of wakefulness and sleep are difficult to distinguish, and the neonate requires persistent stimulation to arouse eye opening and alertness for a period of seconds. At 28 weeks, a change occurs, and the neonate is aroused with gentle shaking with periods of alertness lasting several minutes. By 32 weeks, stimulation is no longer necessary; the eyes remain open for long periods of time with observed sleep –waking alterations. By 36 weeks, increased alertness is observed, with vigorous crying during periods of wakefulness. By term, the infant exhibits periods of attention to visual and auditory stimuli. It is important to note that the level of alertness varies depending on the time of the neonate's last feed, environmental stimuli, and recent experiences (such as placement of IV). Several disturbances of arousal can be noted on the examination. An irritable neonate is one who is agitated and cries with minimal stimulation and is unable to be comforted.3 A lethargic or stuporous neonate will have a sluggish response to sensory stimuli, while a comatose neonate will not be arousable and will have no response to sensory input.

Motor

The examiner should focus on the resting posture of the unswaddled neonate. This observation can reveal the symmetry and maturity of the passive tone with the tone changing as a function of gestational age (Figure 28-1). Flexor tone first develops in the lower extremities and proceeds cephalad correlating with increasing myelination of the subcortical motor pathways, which originate in the brainstem.3 The examiner should also note any abnormal movements, such as choreathetoid movements, that may indicate an underlying structural or metabolic problem.3 The normal term neonate displays fisting of the hand (adduction and infolding of the thumbs [cortical thumbs]) with intermittent hand opening.

Physical Examination

Visual Inspection and Palpation

The head should be visualized and palpated for ridges along the sutures, the size and fullness of the anterior fontanel, excessive head molding or cephalohematomas, and any depressions in the skull. The spine should be carefully inspected for any patches or tufts of hairs, pits, hemangiomas, or lipomas. The entire body should be observed for birthmarks, port wine stains, ash leaf spots, or macules (Figure 28-2). Each of these findings may lead the examiner to consider underlying pathology associated with these skin findings.

Motor

The major features to be evaluated in the motor examination are muscle tone and motility. Development of tone proceeds in a caudal-rostral progression, particularly flexor tone, with maturation.2,4 A 28-week neonate has minimal resistance to passive movement in all limbs, but by 32 weeks, there is distinct flexor tone in the lower extremities. At 36 weeks, flexor tone is prominent in the lower extremities and resistance to movement is present in the upper extremities, while at term, there is strong flexor tone in all extremities.

Parallel to development of tone described above, the quality of neonatal movements advances. The 28-week neonate will have writhing movements of the extremities, while the 32-week neonate will have predominately flexor movement of the hips and knees. At 36 weeks, the active flexor movements in the lower extremities are stronger and prominent flexor movements of the upper extremities are appreciated. At 40 weeks, the neonate moves all limbs in an alternating manner. Neck flexor power also becomes apparent. This is illustrated by pulling the neonate to a sitting position using the upper extremities. During this maneuver, the head is held in the same plane as the body for several seconds.2,4

Cranial Nerves

Even though the neonate's interaction with the examiner is limited, essentially all the cranial nerves can be evaluated. Cranial nerve (CN) I, given its rare involvement in diseases and the difficulty in evaluating the neonate's response, is not usually evaluated. CN II and III can be tested by the pupillary reflex, which appears consistently at 32 to 35 weeks of gestation.3 Shining a light in the neonate's eyes will elicit a blink response, first appreciated at 28 weeks, testing CN II and VII. By 34 weeks, 90% of infants will fix and follow a fluffy ball of red wool, thus testing CN II, III, IV, and VI.5 The doll's-eye maneuver can be elicited as early as 25 weeks of gestation and further tests CN III, IV, and VI. It is important to note that spontaneous roving eye movements are common at 32 weeks of gestation, as are dysconjugate eye movement in the term infant when not fixing on an object.3 Smooth visual tracking movements do not become present until 3 months of life.6 Facial sensation (CN V) can be tested with a pinprick to different areas of the face with the neonate responding with a facial grimace or change in sucking. CN VII can be tested by observing the face at rest with particular attention to the vertical width of the palpebral fissures, the nasolabial fold, and the position of the corner of the mouth. Changes in these structures should then be observed during crying. With a facial nerve palsy, the corner of the mouth on the affected side droops and the mouth is drawn to the normal side. A coordinated suck and swallow involves the function of CN V, VII, IX, X, and XII. A suck and swallow can be noted as early as 28 weeks, but the synchrony with breathing and feeding is not well developed. As the brain matures, coordination improves at 32 to 34 weeks but is not fully achieved until at least 37 weeks.7

Reflexes

Deep Tendon Reflexes

Deep tendon reflexes (DTRs) in the neonate are elicited in a manner similar to the older pediatric patients. During testing of the DTRs, the head should be maintained in a neutral position to prevent the induction of an asymmetrical tonic neck response, which can produce asymmetrical reflex activity with stimulation. The examiner can readily elicit reflexes in the biceps, brachioradialis, and ankle, although the upper extremity reflexes are often more difficult to elicit than the lower extremities. Testing of the DTRs in the neonate can also induce clonus, which is physiologically normal (5-10 beats) if unsustained.2 The plantar response is considered of limited value since four competing reflexes lead to movement of the toes, depending on how the examination is performed.2

Developmental Reflexes

The developmental reflexes (Figure 28-3) are a set of reflexes that are found in the neonate and disappear at regular developmental periods as the neonatal brain develops. Volpe has commented that these reflexes are more valuable in assessment of disorders of the lower motor neuron, nerve, and muscle than of the upper motor neuron.2

The Moro reflex (Figure 28-3A) consists of bilateral hand opening with upper extremity extension and abduction followed by anterior flexion ("embracing") of the upper extremities, then an audible cry. The reflex is elicited by dropping the head in relation to the neonate's body. The Moro reflex can be first appreciated in a rudimentary form at 28 weeks of gestation with the neonate responding with hand opening. The reflex disappears by 6 months of age.

The tonic neck response (Figure 28-3B) can be elicited by rotating the head to one side. The neonate responds to this action with what has been described as a fencing posture: an extension of the upper extremity on the side to which the face is rotated, and flexion of the upper extremity on the side of the occiput. The response first appears at 35 weeks of gestation and disappears by approximately 6 to 7 months of age.

The palmar grasp (Figure 28-3C) is elicited by stimulating the palm of the neonate's hand with an object. The reflex is present at 28 weeks of gestation, strong at 32 weeks, and strong enough to lift the neonate off the bed by 37 weeks. This reflex disappears by 2 months of age, which coincides with the development of voluntary grasp.

The placing and stepping reflexes (Figure 28-3D) are elicited by contacting the dorsum of the foot against a flat surface. The neonate will respond by flexing the hip and knee and will appear to be taking a step. This reflex is useful if asymmetry occurs and may indicate a lesion in the basal ganglia, brainstem, or spinal cord, although it is difficult to perform in a sick neonate.

Definition and Epidemiology

Hypoxic-ischemic encephalopathy (HIE) is the brain manifestation of systemic asphyxia or hypoxia-ischemia,8 which occurs in about 20 of 1000 full-term infants and in nearly 60% of very low birth weight (premature) newborns.9-11 Between 20% and 50% of neonates who exhibit HIE die during the newborn period.12 Of the survivors, up to 25% have permanent neuropsychological handicaps in the form of cerebral palsy, with or without associated mental retardation, learning disabilities, or epilepsy.13-15

Pathogenesis

The etiologies of HIE can be grouped into the three epochs in which they occur. The first epoch occurs during the prepartum period. This time interval pertains to problems with either placental perfusion, secondary to maternal diseases or drug use, or with the placenta itself. The second epoch occurs during the delivery process and is associated with a difficult delivery, including an abnormal presentation, prolonged labor, a precipitous delivery, and a difficult delivery requiring forceps. Finally, a time interval not often associated with HIE occurs during the neonatal period. Problems occurring during the neonatal period include severe prematurity, respiratory distress, cardiopulmonary anomalies such as congenital heart disease and diaphragmatic hernia, and infectious diseases, which can produce septic shock.

Hypoxia-ischemia (HI) leads to a complex cascade of events producing cellular damage and destruction.16,17 Globally, cerebral perfusion is reduced secondary to decreasing cardiac output, depleting the cells in the brain of both oxygen and energy substrates. At the cellular level, ATP is rapidly depleted as a result of the inefficient shift to anaerobic metabolism, which is further compounded by a decrease in glucose delivery. The rapid depletion of ATP results in severe compromise in the basic metabolic processes of the cells, leading to a series of secondary intracellular events that result in cellular damage. These events can be grouped into three major categories: excitatory neurotransmitter toxicity, intracellular calcium overload, and free radical formation. All three categories overlap and are summarized in Figure 28-4. During HIE, there is an excessive release of the excitatory amino acid glutamate from the presynaptic terminal.18-20 This leads to overstimulation of the glutamate receptors (AMPA, KA, NMDA) located on the postsynaptic neuron, which leads to excitotoxicity, a term coined by Lucas and Olney.21,22 Please note that neonates are at particular risk for excitotoxicity because the distribution, electrophysiology, and molecular characteristics of excitatory amino acid receptors change markedly throughout normal brain development.23 The excitatory amino acid receptors have been linked to a variety of physiologic processes during normal neuro-development including synaptogenesis and synaptic plasticity.24 The changes in the excitatory amino acid receptors discussed earlier strongly influence the brain's vulnerability to HIE. Overstimulation of the KA and AMPA receptors leads to the entry of sodium and chloride into the cell, which increases cell osmality, leading to the influx of water. The increase in water influx results in subcellular edema, which if severe enough results in lysis of the cell. Overstimulation of the NMDA receptor triggers the influx of calcium.25 Calcium is the main second messenger in the cell and, when present in pathologic amounts, activates a series of enzymes, which results in the destruction of the cell (Figure 28-4). Calcium also contributes to the generation of free radicals, such as nitric oxide.25 Free radicals are chemical species with one or more unpaired electrons in their outer orbital. Free radicals also are generated from fatty acid and prostaglandin metabolism, leading to the formation of damaging amounts of superoxide and hydrogen peroxide.8 The three aberrant cellular processes lead to both apoptosis and necrosis. HIE pathologically produces several distinct injury patterns.2 A diffuse pattern involving the cerebral cortex, hippocampus, and deep nuclear structures can be seen with a severe, prolonged insult. Another pattern involves the cerebral cortex, basal ganglia, and thalamus, and is associated with moderate to severe, prolonged hypoxia-ischemia. Severe, abrupt hypoxia-ischemia produces injury to the basal ganglia, thalamus, and brainstem. Finally, an isolated pontosubicular pattern involving the basis pontis and the subiculum of the hippocampus can be seen. The etiology of this pattern is unknown.

Clinical Presentation and Diagnosis

Physical Exam

After stabilizing a neonate with HIE (see the "Treatment" section below), attention should be focused on the neurological examination. Clinical acuity can be staged using the system developed by Sarnat and Sarnat15 (Table 28-1). This staging system should be performed in a serial fashion since a neonate may not remain at one stage but rather improve or deteriorate over time. Volpe describes this process as occurring in defined time intervals in neonates with severe injury.2 During the first time interval (0-12 hours), the injured neonate will have a depressed level of consciousness, usually deep stupor or coma, intact pupillary and oculomotor responses, hypotonia, and possibly seizures. If the pupillary and oculomotor responses are not intact during this time, a severe injury to the brainstem is likely.2 At 12 to 24 hours, neonates will have a variable change in the level of alertness, more seizures, and apneic spells. Weakness will be noted in the proximal extremities, with the upper more than lower extremities in term neonates and the lower more than upper extremities in premature neonates. Twenty-four to seventy-two hours post-injury, the neonate may have stupor or coma, respiratory arrest, and a lack of pupillary or oculomotor responses. After 72 hours, the neonate may have persistent yet diminishing stupor, hypotonia, and disturbances of suck, swallow, gag, and tongue movement.

Neuroimaging

Neuroimaging allows injured brain regions to be visualized, adding information to the clinician's bedside assessment. The information can then be used to predict potential long-term disabilities in neonates with HIE. The first imaging technique that can be used is ultrasound (US). Ultrasound has the advantage of being a rapid bedside test, but it provides limited anatomic information. The resistive index obtained with US may be helpful in predicting long-term outcomes.26 CT is the second imaging option. A low attenuation in the basal ganglia and or thalami indicates severe injury.26 The CT scan must be repeated 2 to 6 weeks after the initial imaging study to see if the neuronal injury has progressed since the original scan. The final test, MRI, provides very good anatomic differentiation of the region of injury following HIE but has the disadvantage of requiring a relatively long time (compared with CT) for data acquisition. Diffusion-weighted imaging may detect areas of injured brain regions before changes are noted on standard T1- and T2-weighted image studies (Figure 28-5).26

Eeg

The EEG may provide valuable information on the severity of injury.15 More recently, amplitude integrated EEG has been used as a method to continuously monitor neonates and predict outcomes based on the background pattern.27,28

Treatment

The neonate suffering from HIE should be systemically stabilized. The basic concepts for stabilization are presented in the flow diagram in Figure 28-6. There currently is no specific treatment for HIE that addresses the ongoing neuronal injury. However, hypothermia appears to be the most promising therapy in decades, as demonstrated by two recent clinical trials. The hypothermia studies used either head cooling with mild systemic hypothermia (34-35°C) or whole-body cooling (33.5°C). Both studies used hypothermia for 72 hours. The systemic hypothermia study demonstrated a decrease in death and moderate or severe disability in the hypothermia group compared with a matched control.29 The head cooling study with mild systemic hypothermia demonstrated that the therapy could safely improve survival without severe neurodevelopmental disabilities in neonates with moderate encephalopathy, as defined by amplitude-integrated EEG criteria.30 Based on these results and ongoing follow-up studies of the enrolled patients, hypothermia will most likely become widespread in clinical practice.

Outcome

Based on a large cohort of neonates with HIE,14,31 neonates with mild HIE (Sarnat 1) had no long-term deficits at 8 years of age. Six percent of neonates with moderate HIE (Sarnat 2) died, and of the survivors, 20% developed handicaps (seizures, cerebral palsy, mental retardation, deafness, blindness) at 8 years of age. In the severe category (Sarnat 3), 80% died and 100% of the survivors at 8 years of age had severe handicaps.

Definition and Epidemiology

Intraventricular hemorrhage (IVH) is an injury primarily associated with prematurity, with an incidence ranging between 40% and 60% in very low birth weight (VLBW) neonates.2,32 There is an inverse relationship between the degree of prematurity and the severity of IVH with the more premature neonates suffering the more severe types of hemorrhage.33 The incidence of IVH in VLBW neonates has decreased over recent decades, from 49% to less than 20%.2 However, the survival of VLBW neonates has improved over the same period, suggesting that IVH will remain a major source of morbidity in the tiniest of NICU patients.34,35

Pathogenesis

The subependymal germinal matrix is the source of neuronal precursors between 10 and 20 weeks of gestation, and during the latter half of gestation is the birthplace of glial elements, which migrate and mature into astrocytes and oligodendroglia. As a result of the active cellular proliferation, the subependymal germinal matrix is a highly vascularized structure with a capillary bed that is a vascular end zone of its arterial supply. This makes this region very susceptible to ischemic injury. Furthermore, the capillary bed in the germinal matrix is composed of relatively large, irregular, endothelial-lined vessels that do not exhibit the characteristics of arterioles or venules, making these vessels thin-walled and fragile. The subependymal germinal matrix is the site of origin of IVH. With this anatomic information in mind, the principal mechanism by which an IVH occurs is the rupture of the fragile capillaries within the germinal matrix resulting from fluctuations of blood flow in this region. The hemorrhage most commonly occurs at the head of the caudate nucleus at the level of the foramen of Monro in neonates less than 28 weeks. And, in 80% of the cases, the hemorrhage will rupture through the adjacent ependymal wall into the lateral ventricle with spread of blood throughout the ventricular system.36

The subependymal germinal matrix begins to involute following 34 weeks of gestation. Therefore, it is important to note that IVH in the term neonate originates primarily from the choroid plexus.37

Several neuropathological processes occur as a result of or accompany IVH. IVH is associated with destruction of the germinal matrix and the glial precursor cells, which are located in the germinal matrix. Roughly 15% of the neonates with IVH will develop a periventricular hemorrhagic infarction.2 This lesion has a fan-shaped appearance that closely follows the medullary veins in the periventricular cerebral white matter.2 The incidence of periventricular hemorrhagic infarction is associated with prematurity, with one-third of the cases occurring in neonates between 500 and 800 g. It also is associated with a large IVH in 80% of cases.36 Careful anatomic studies have demonstrated that periventricular hemorrhagic infarction is not simply an extension of the IVH from the ventricular system into the surrounding parenchyma, but rather is a result of a venous infarction caused by obstruction of flow in the terminal vein in the subependymal region by a large ipsilateral IVH.

Posthemorrhagic hydrocephalus is another neuropathologic consequence of IVH and is more common in neonates with the highest grades of IVH (see the "Diagnosis" section, for grading system).33 Hydrocephalus is a progressive ventricular dilation secondary to a disturbance in CSF dynamics. Hydrocephalus may occur acutely over a period of days (associated with larger IVH) or subacutely evolving over a period of weeks (associated with smaller IVH). Acute hydrocephalus results from an obstruction of the arachnoid villi by the particulate clot impairing CSF absorption, whereas subacute hydrocephalus is caused by an obliterative arachnoiditis in the posterior fossa, resulting in obstruction of the fourth ventricle or aqueductal obstruction by blood clot, disrupted ependyma, or reactive gliosis.

Periventricular leukomalacia (PVL) is generally a symmetric injury of the periventricular white matter, located at the arterial border zones of the trigone of the lateral ventricles, and occurs more frequently in neonates who have suffered from IVH. The association is believed to occur because of decreases in cerebral blood flow that accompany IVH. The periventricular region is susceptible to ischemia; thus PVL can be considered the nonhemorrhagic infarction of the periventricular white matter watershed zone. Secondary hemorrhage into PVL may occur, and this lesion is difficult to distinguish from periventricular hemorrhagic infarction.

IVH is the end consequence of many factors that may act alone or in concert with each other and may differ over time. These factors can be broken down into three major areas: intravascular, vascular, and extravascular factors.

Intravascular

Intravascular factors involve changes in cerebral blood flow (increase, decrease, fluctations), increases in cerebral venous pressures, and coagulation abnormalities.

Cerebral autoregulation is the mechanism ensuring that cerebral blood flow remains constant over a wide range of systemic pressures by means of compensatory cerebral arteriolar dilation or constriction.36 The principle etiology of the changes in cerebral blood flow relate to impairment of cerebral autoregulation in the sick premature neonate38 and the stable premature neonate.39 When cerebral autoregulation is impaired, the cerebral circulation becomes pressure-passive and fluctuates according to changes in systemic blood pressure, with decreases during periods of hypotension and increases during periods of hypertension. Fluctuations in blood pressure are associated with rapid volume administration, the presence of a patent ductus arteriosus, respiratory distress syndrome, pneumothorax, hypercarbia, seizures, and routine bedside care (eg, suctioning of endotracheal tube). When these fluctuations do occur, injury to the vulnerable capillary bed may occur, resulting in IVH.

Vascular

Vascular factors relate to the fragility of the immature, endothelium-lined microvasculature of the germinal matrix, its rapid rate of oxidative metabolism, and its location in a vascular border zone between the thalamic and striate arteries, rendering it vulnerable to hypoxic-ischemic injury.36 These anatomic vulnerabilities can be amplified by such conditions as chorioamnionitis and neonatal sepsis, independent of these entities' effects on hemodynamics.

Extravascular

Extravascular factors relate to the space surrounding the germinal matrix capillaries and include deficient vascular support for the germinal matrix capillaries and increased fibrinolytic activity, which may allow minor capillary disruptions to evolve into a large IVH.

Clinical Presentation

Neonates with IVH have been described as having three potential clinical presentations: a catastrophic deterioration, a salutatory deterioration, and a "clinically silent" syndrome.2

Neonates who present with a catastrophic deterioration will have a very dramatic presentation that consists of a sudden change in the neonate's baseline status over a period of minutes to hours. Neurological symptoms include deep stupor or coma, respiratory abnormalities (hypoventilation, apnea), generalized tonic seizures, decerebrate posturing, and pupils fixed to light (depends on gestational age—see the "Physical Examination" section earlier in the chapter for more details). Systemic symptoms may also be present in the form of hypotension, bradycardia, a sudden metabolic acidosis, a dropping hematocrit, temperature instability, hypoglycemia, and a bulging fontanel. Experts have speculated that the described symptoms occur because of movement of blood through the ventricular system with sequential regions of the brain (diencephalon, midbrain, pons, medulla) being affected.2

A salutatory deterioration is much more subtle in clinical presentation. The clinical appearance includes an alteration in the level of consciousness, a change in the quantity and quality of spontaneous and elicited motility, hypotonia, and subtle abnormalities of eye position and movement (skew deviation, vertical drift [usually down], incomplete horizontal movement with doll's-eye maneuver).2 The salutatory syndrome evolves over many hours and may show signs of cessation only to reappear for several more hours. This waxing and waning clinical course may continue for a day or more.

The final presentation is a clinically silent syndrome. These neonates may have little in the way of neurological abnormalities and may only demonstrate an unexplained drop in hematocrit or failure of the hematocrit to rise post-transfusion.2

Diagnosis

Ultrasound scan is effective in the diagnosis of IVH, with a 76% to 100% accuracy of detecting grade 1 lesions larger than 5 mm and grade 3 and 4 hemorrhages.40-43 The scan can be used to visualize the location and severity of the hemorrhage (Figure 28-7). Two major systems are used to gauge the severity of the IVH. The first system was developed by Papile32 and the second, more recently, by Volpe.2 Both systems are compared in Table 28-2. As mentioned earlier in the "Clinical Presentation" section, IVH may present with minimal clinical symptoms in the preterm neonate. Therefore, screening procedures are in place in the NICU nationally to detect the presence of IVH in preterm neonates; however, there is no consensus on the target population for screening, the number of examinations, or the timing of the studies. Although there is no treatment for IVH, screening provides the clinician with useful prognostic information for counseling parents about potential long-term neurodevelopmental disabilities.

At the University of Florida, we have developed a screening protocol in our institute (Figure 28-8) that represents a review of the current literature, practice parameters, and a review of our patient demographics over a recent 5-year span. It is presented here as a template that may be used as a starting point for the development of a screening protocol and as a means to discuss the current literature concerning the timing, number of scans, and ages to scan patients. We chose to screen neonates who weighed 1350 g or less with routine screening. Several studies from the literature have demonstrated that 12% to 51% of neonates with a birth weight lesser than 1500 g and/or 33 weeks of gestation will have cranial abnormalities with major abnormalities such as grade 3 or 4 IVH or bilateral cystic PVL occurring in less than 20% of these neonates. Major abnormalities such as grade 3 or 4 IVH, cystic PVL, and ventriculomegaly associated with posthemorrhagic hydrocephalus, which might alter treatment or provide prognostic information, are considerably more common (20%-25%) in infants with a gestational age lesser than 30 weeks.26 Based on this information, a consensus group recommended screening all neonates lesser than 30 weeks. We modified our protocol to an older gestational age based on our past patient data because several neonates who had a grade 3 or 4 IVH would not have been screened. We also chose to use a risk-based strategy to screen for neonates between 1350 and 1500 g since neonates in this weight range in our institution usually had an IVH associated with a known risk factor. This allowed our screening protocol to fit our patient population with respect to which neonates to screen. Multiple studies before 1990 suggested that more than 90% of IVHs occurred during postnatal days 4 to 5. More recent studies have shown that approximately 65% of the cases occur within the first week, with hemorrhages detected on later scans between 10 and 14 days. We therefore chose the time interval 7 to 14 days to obtain our initial screening scan. If bedside clinicians detect symptoms consistent with an IVH, they may obtain a scan earlier based on clinical indications. Our time period for the initial screening examination is consistent with that set forth by a consensus panel.26 Finally, a screening US is performed at 6 weeks in our protocol to detect PVL. MRI provides much better anatomic information with respect to white matter injury, but currently there are insufficient follow-up studies to indicate whether the increased findings on MRI provide any additional information about the neurodevelopmental prognosis. As these studies become available, MRI will most likely become the screening tool of choice in the future. Although the consensus panel recommends screening neonates at 36 to 40 weeks post-menstrual age, we chose to have a fixed time point of 6 weeks to decrease the chance of missing a screening examination. It should also be noted that the protocol from our institute uses ultrasound to closely monitor neonates who have grade III or IV IVHs. The rationale for the use of US for this screening purpose pertains to the anatomic information—the ventricles in the neonate may dilate to an impressive degree before the development of rapid head growth and signs of increased intracranial pressure. This is due to the paucity of cerebral myelin, the relative excess of water in the centrum semiovale, and the relatively large subarachnoid space.2

Treatment

The ideal treatment for IVH is the prevention of premature births and the prevention of hemorrhages in neonates. Indomethicin-administered prophylatically in neonates has been shown to be effective in preventing grades 3 and 4 IVH.44 This short-term benefit may not have long-lasting consequences; follow-up studies in neonates treated with indomethicin prophylatically have not revealed a clear benefit or harm in long-term neurodevelopmental outcomes.45

The postnatal management of neonates who have IVH currently centers on the detection and treatment of posthemorrhagic hydrocephalus. Posthemorrhagic hydrocephalus has been shown to cause secondary injury by axonal stretching, periventricular vascular distortion, and compression that may decrease cerebral blood flow, causing ischemic injury and producing alterations in synaptogenesis that may result in abnormal organization of the cerebral cortex. A schema for potential management of posthemorrhagic hydrocephalus is shown in Figure 28-8.

As illustrated in Figure 28-9, several techniques may be used to decrease the progression of hydrocephalus, including medications and serial lumbar punctures. Medications that decrease CSF production include acetazolamide and furosemide. Although still employed in the clinical setting, a recent metanalysis concluded that the use of these medications did not reduce the need for a ventriculoperitoneal shunt. Serial lumbar punctures are used to mechanically remove CSF. A recent metanalysis from the Cochrane Collaboration concluded that routine use of serial lumbar punctures could not be supported by the current literature; however, one would find it hard to argue against the use of lumbar punctures in neonates who developed signs of symptomatic raised intracranial pressure (deterioration in neurological signs with a tense fontanelle, decreasing diastolic velocities on cerebral artery Doppler waveforms, deteriorating sensory evoked potentials, directly measured CSF pressure over 12 mm Hg).46

Outcomes

Ultrasound findings of a grade 3 or 4 IVH, cystic PVL, and moderate to severe ventriculomegaly at 36 to 40 weeks post-menstruation, have all been significantly associated with cerebral palsy at 2 to 9 years of age in VLBW preterm neonates.26 Similarly, grade 4 IVH and ventriculomegaly at 36 to 40 weeks post-menstruation have been significantly associated with mental retardation and neuropsychiatric disorders at the same time points.

Definition and Epidemiology

Neonatal seizures are poorly classified, under-recognized, especially in sick neonates, and often difficult to treat.47 Neonatal seizures are often the presenting clinical manifestation of underlying neurological conditions such as hypoxia-ischemic encephalopathy, stroke, intraventricular or intraparenchymal hemorrhages, meningitis, sepsis, or metabolic disorders. Of these, hypoxic ischemic encephalopathy is the most common etiology, accounting for 50% to 60% of patients with neonatal seizures.47

Pathophysiology

A seizure is the occurrence of an abnormal synchronous electrical discharge (depolarization) of a group of neurons within the central nervous system.47 During the normal state, the neuron depolarizes as a result of sodium influx into the cell with repolarization occurring when potassium ions are pumped out of the neuron, creating the normal baseline negative electrical potential across the cell membrane. Seizures are generally felt to be the result of excessive depolarization. Electrolyte abnormalities, such as hypocalcemia, can alter the normal membrane potential by increasing the influx of sodium, thereby promoting depolarization. Hypoxia-ischemia and hypoglycemia result in a sharp decrease in energy substrate, which produces failure of the energy-dependent sodium–potassium pump, shifting the membrane potential to a more positive state and promoting depolarization.2,47 The neonatal brain is particularly vulnerable to seizure activity as a result of an imbalance of excitatory to inhibitory circuitry. The imbalance favors excitation and does so to facilitate important developmental processes that occur during the neonatal period (synaptogenesis, apoptosis, progressive integration of circuitry, synaptic pruning). The imbalance occurs anatomically and physiologically by an overexpression of NMDA receptor in the hippocampus and neocortical regions of the neonatal brain, a delay in the maturation of the inhibitory system, and neurons in such regions as the hippocampus are excited rather than inhibited by the neurotransmitter GABA (normally the primary inhibitory neurotransmitter in the brain).

Clinical Presentation

The various types of seizures in the neonate and the clinical presentation are presented in Table 28-3.

Differential Diagnosis

The differential diagnosis and suggested laboratory tests to narrow the differential are illustrated in Figure 28-10.

Treatment

The clinician should first search for underlying etiologies producing the seizures and treat (hypoglycemia, hypocalcemia, sepsis). If the clinician cannot find a readily identifiable and treatable etiology, the front-line agent of choice for treating seizures is phenobarbital. Phenobarbital as a single agent will stop seizure activity in 42% of patients.48 When the seizure does not respond to a single agent, phenytoin is added with an increase in efficacy to 65%. Currently, fosphenytoin, the salt ester of phenytoin, is preferred in the neonate because it is an aqueous solution that is soluble in glucose-containing solutions, can be administered more quickly than phenytoin, and will not cause "purple glove syndrome."49 Purple glove syndrome is necrosis or injury of the soft tissue that can occur with intravenous infusion of the highly alkaline phenytoin. The drug of choice for neonates in status is lorazapam. This agent has several properties that make it ideal—a long half-life and a small volume of distribution, which prolongs its retention at high levels in the brain.50,51