Clinical Syndromes

Neonatal encephalopathy and seizures are the most overt manifestation of the severity of brain injury. Clinical signs and symptoms depend on the severity, timing, and duration of the insult, as well as the newborn’s maturity, even within ages considered “full term.” It is equally important to note that not all newborns with significant acquired brain injuries present with an easily recognizable encephalopathy or seizures. Some conditions, such as stroke and perinatal white matter injury, discussed in Chapters 18 and 19, may only have subtle manifestations that may not be recognized on clinical examination. This chapter will focus on the clinical syndrome of neonatal encephalopathy secondary to hypoxia-ischemia. The diagnosis and management of neonatal seizures is discussed in Chapter 16.

Neonatal Encephalopathy

The major components of the syndrome of “neonatal encephalopathy” include: alertness, tone, respiratory status, reflexes, feeding, and seizures (Table 17-1). The severity of brain injury, reflecting the duration and magnitude of the hypoxic-ischemic insult, determines the severity of evolution of this clinical encephalopathy. In newborns with moderate to severe encephalopathy, symptoms usually evolve over days, making serial detailed examinations important. As with any neurologically ill newborn, the baby’s gestational age must be considered in the interpretation of physical findings. As described by Volpe, there is a characteristic progression of signs in newborns with a severe hypoxic-ischemic insult [Volpe, 2008]. The affected neonate exhibits a depressed level of consciousness from the very first hours of life. Periodic breathing with apnea and bradycardia often heralds this initial presentation. Hypotonia with decreased movement is almost universally found. In the first day of life, the pupillary response is often preserved and abnormalities of eye movements are not detected. In severely injured newborns, seizures may be seen within 6–12 hours after birth. Seizures at this stage are often subtle, manifesting as ocular movements, lip smacking, apnea, or bicycling movements of the extremities. The nursing staff should be alerted to identify and document paroxysmal behaviors. Multifocal or focal clonic seizures may also occur, and often indicate focal cerebral infarction. In the latter hours of the first day of life, there may be a transient increase in the level of alertness that is not accompanied by other signs of neurological improvement. This should not be falsely reassuring, as this apparent increase in alertness is frequently accompanied by more seizures and apnea, a shrill cry, and jitteriness. With careful bedside examination, weakness in the proximal limbs and increased muscle stretch reflexes may be observed, but in the very severely injured newborn, diffuse weakness with absent movements and reflexes is common.

By the third day of life in newborns with severe brain injury, the level of consciousness deteriorates with symptoms of respiratory failure and other signs of brainstem dysfunction. During this period, cerebral edema resulting from hypoxia-ischemia is maximal and can further impair cerebral blood flow secondary to increased intracranial pressure. Most clinicians avoid treatment of cerebral edema in this setting, as many interventions such as corticosteroids, hyperventilation (PaCO₂ 20–25 mmHg), furosemide, or mannitol, may be harmful and no studies have shown proven benefit. Those newborns surviving beyond the third day of life begin to show improved alertness. Yet hypotonia and weakness in proximal limbs, face, and bulbar musculature persist. While less intensive care may be required with this improved level of consciousness, the clinician must be vigilant for feeding difficulties and the risk of aspiration as the newborn’s suck and swallow responses often remain impaired.

Documenting this clinical evolution is a critical component of the evaluation, and use of a simple encephalopathy score as a bedside tool can help the clinician standardize assessment of encephalopathic newborns, monitor the evolution of the clinical syndromes, and help in systematically identifying neonates who require therapeutic intervention (see Table 17-1) [Miller et al., 2004].

Table 17-1 The Encephalopathy Score

Subtle Neonatal Syndromes

Stroke and white matter injury in the term newborn may present with clinical signs that are so subtle that they remain undetected for months or years. Advances in brain monitoring (amplitude integrated EEG, prolonged video-EEG monitoring) and brain imaging (MRI) in the neonatal intensive care unit have increased recognition of these injuries. However, both stroke and white matter injury may present in the neonatal period with an overt encephalopathy [Li et al., 2009; Ramaswamy et al., 2004]. These conditions share many of the risk factors of “global” hypoxic-ischemic brain injury considered in this chapter.

Clinical Management

As many etiologies of neonatal encephalopathy have specific therapies, the clinician’s initial task is to determine the underlying etiology through careful history taking, neurological examination, and laboratory and brain imaging studies. The history should elicit indicators of intrauterine distress that may have contributed to decreased placental or fetal blood flow: fetal heart tracing abnormalities, passage of meconium, or a history of a difficulty in labor or delivery. The Apgar score will indicate who is at risk for mortality. The details of the delivery-room resuscitation, medications, and ventilatory support should be noted. Because the clinical signs of encephalopathy and seizures are often not specific for an etiology, laboratory tests are critical to exclude reversible causes of neonatal encephalopathy. The management of moderate or severe encephalopathy should occur in a neonatal intensive care unit in close collaboration with a neonatologist. Immediate management requires securing an appropriate airway and maintaining adequate circulation. Ventilatory support with mechanical ventilation or continuous positive airway pressure (CPAP) is often required. Metabolic complications, such as hypoglycemia, hypocalcemia, hyponatremia, and acidosis, frequently accompany hypoxic-ischemic encephalopathy (HIE), and should be identified and treated. Liver enzymes and serum creatinine levels should be performed to detect injury to other organs, while serum ammonia and lactate levels can screen for possible inborn errors of metabolism. Lumbar puncture to evaluate for intracranial infections should be performed if the history is not typical for HIE, or if a clinical suspicion of infection exists. If infection is suspected, ampicillin and gentamicin are started in addition to acyclovir if herpes simplex virus infection is a consideration. If the history, examination, or initial laboratory investigation points to an inborn error of metabolism, early treatment is crucial and a biochemical geneticist should be consulted. Additional diagnostic tests, such as serum amino acids and urine organic acids, as well as specific management strategies, are required (detailed in Chapter 20). The diagnosis of a severe intracranial hemorrhage should prompt consultation with a neurosurgeon to manage raised intracranial pressure from mass effect or hydrocephalus; platelet levels and coagulation function should be measured. Since the clinical syndrome evolves considerably over the first 72 hours of life, management of specific complications, such as respiratory compromise or seizures, can often be anticipated.

Investigation of term newborns with encephalopathy addresses three primary questions:

Addressing these questions is critical for the application of “neuroprotection” strategies, such as hypothermia [Eicher et al., 2005; Gluckman et al., 2005; Shankaran et al., 2005; Azzopardi et al., 2009]. To assess the encephalopathic term newborn, diagnostic tools available to the clinician include clinical features and biochemical and electrophysiological tests. However, the severity of brain injury in term asphyxiated newborns is not reliably predicted by clinical indicators commonly used during the first days of life, such as umbilical cord pH and Apgar scores [Shevell et al., 1999]. On the other hand, the severity of clinical encephalopathy is a strong predictor of neurodevelopmental outcome [Miller, 2004]. However, while the risk of motor and cognitive deficits appears to be minimal in mild encephalopathy, and pronounced at the severe end of the spectrum, it is inconsistent in neonates with moderate encephalopathy [Sarnat and Sarnat, 1976; Robertson et al., 1989; Dixon et al., 2002; Marlow et al., 2005]. Newborns with moderate encephalopathy are thus the most likely to benefit from the improved prognostic capabilities of brain imaging.

Brain Imaging of Newborns with Encephalopathy

Current guidelines for neuroimaging term newborns with encephalopathy suggest a noncontrast computed tomography (CT) scan to detect hemorrhage in infants with a history of significant birth trauma, and evidence of low hematocrit or coagulopathy [Ment et al., 2002]. If CT findings cannot explain the newborn’s clinical status, then MRI is recommended. For other encephalopathic term newborns, MRI is recommended between days 2 and 8 to assess the location and extent of injury [Ment et al., 2002]. In a recent study, the neuroimaging findings from a group of 48 term newborns with encephalopathy uniformly scanned with CT and MRI (T1 and T2-weighted images) with diffusion-weighted imaging (DWI) on the third day of life were compared [Chau et al., 2009]. On the third day of life, both CT and MRI with DWI reliably identify injury to the basal nuclei. However, DWI more readily detects cortical injury and focal and multifocal lesions, such as strokes and white matter injury, than either CT or conventional MRI. The choice of the best neuroimaging technique must balance the risk of transport and sedation involved in MRI against the risk of ionizing radiation with CT [Brenner et al., 2003; Berrington de Gonzalez and Darby, 2004; Hall et al., 2004]. With the development of MR-compatible incubators and monitoring equipment [Dumoulin et al., 2002; Bluml et al., 2004], as well as improved capacity to scan newborns without pharmacological sedation, MRI should now be the modality of choice when possible. MRI with DWI appears to be the most sensitive imaging study to detect abnormalities associated with other causes of neonatal encephalopathy, such as cerebral dysgenesis, infections, stroke, and metabolic disorders [Volpe, 2008; Cowan et al., 2003]. In order to confirm the diagnosis of hypoxic-ischemic brain injury and determine the extent of injury, MRI and DWI are optimally obtained between 3 and 5 days of life in term newborns with encephalopathy [Chau et al., 2009; Barkovich, 1997; Rutherford et al., 2004; Barkovich et al., 2006]. In newborns treated with hypothermia, further studies are needed to determine the optimal timing of MRI. The importance of rigorous imaging protocols with appropriate quality controls, and high quality neuroradiological review, must be emphasised.

Motor Function

In term survivors of hypoxic-ischemic brain injury, the risk of cerebral palsy or severe disability may involve more than one-third of affected newborns, and is most common in those with a severe encephalopathy [Volpe, 2008; Dixon et al., 2002; Barnett et al., 2002]. Spastic quadriparesis is the most common type of cerebral palsy, although athetoid or spastic hemiparesis also occurs. The diagnosis and management of cerebral palsy are addressed in Chapter 69. A complete assessment of neurosensory and cognitive functions is critical in children with cerebral palsy [Marlow et al., 2005]. Minor motor impairments that do not meet diagnostic criteria for cerebral palsy [Shevell et al., 1999] are diagnosed in more than one-third of children with moderate encephalopathy, and in more than one-quarter of children with mild encephalopathy [Van Kooij et al., 2008].

Vision and Hearing

Severe visual impairment occurs in up to one-quarter of children after moderate or severe encephalopathy [Robertson and Finer, 1985; Shankaran et al., 1991]. This may be due to injury to the posterior visual pathway, including the primary visual cortex, resulting in “cortical visual impairment” [Van Hof-van Duin and Mohn, 1984]. Injuries to the basal nuclei may also affect acuity, visual fields, or stereopsis (depth perception) [Mercuri et al., 1997]. Sensorineural hearing loss, likely secondary to brainstem injury, is also seen following neonatal encephalopathy [Robertson and Finer, 1985; Robertson et al., 1989], affecting 18 percent of survivors of moderate encephalopathy without cerebral palsy [Lindstrom et al., 2006].

Cognition

Overall, cognitive deficits are seen in 30–50 percent of childhood survivors of moderate neonatal encephalopathy [Dilenge et al., 2001]. Intellectual performance in children with severe encephalopathy without cerebral palsy is also affected [Marlow et al., 2005]. School-age survivors of moderate neonatal encephalopathy are more likely to have difficulties with reading, spelling, and arithmetic, or require additional school resources [Moster et al., 2002; Robertson et al., 1989]. Cognitive deficits, such as those in language and memory, may be seen, even when IQ scores are “normal.” [Marlow et al., 2005]. Behavioral difficulties, such as hyperactivity and emotional problems, should also be considered, even in individuals without motor disability [Marlow et al., 2005].

Brain Imaging and Outcome

The pattern of brain injury on neuroimaging conveys important prognostic information regarding the “pattern” of neurodevelopmental abnormalities. The basal nuclei pattern of injury and abnormal signal intensity in the posterior limb of the internal capsule are both predictive of severely impaired motor and cognitive outcomes [Rutherford et al., 1998; Miller et al., 2005]. The cognitive deficits associated with this pattern are not surprising, given the common involvement of the cerebral cortex [Miller et al., 2005] and cerebellum [Le Strange et al., 2004; Sargent et al., 2004]. In contrast, the watershed pattern is associated with cognitive impairments that are not necessarily accompanied by major motor deficits [Miller et al., 2005]. Importantly, the cognitive deficits following the watershed pattern may only be evident after 2 years of age [Miller et al., 2005]. In survivors of neonatal encephalopathy without functional motor deficits assessed at 4 years of age, the severity of watershed-distribution injury was most strongly associated with impaired language skills [Steinman et al., 2009]. While neurodevelopmental outcomes may be significantly better than anticipated, neurological deficits may also be found in some newborns whose brain imaging studies are normal [Bax et al., 2006]. More subtle brain injuries associated with later neurodevelopmental deficits, such as white matter injuries or hippocampal volume loss, may only be detectable with quantitative brain imaging techniques [Miller et al., 2002a; Nagy et al., 2005; Gadian et al., 2000].

Cerebral Blood Flow and Energy Metabolism

Disruption of cerebrovascular autoregulation has been implicated as an important factor in the pathophysiology of neonatal hypoxic-ischemic brain injury. It is widely accepted that preterm infants have a “pressure-passive” cerebral circulation; however, term infants may remain at risk for impairment of cerebrovascular autoregulation [Boylan et al., 2000] and susceptibility to cerebral ischemia with fluctuations in systemic blood pressure. Several basic physiologic mechanisms may contribute to impaired autoregulation in the neonate. Increased expression of inducible and neuronal isoforms of nitric oxide synthase (iNOS and nNOS), as well as endothelial NOS, may narrow the autoregulatory window, and downregulation of prostaglandin receptors in response to high circulating prostaglandin levels may blunt the prostaglandin-mediated vasoconstrictive response to hypertension and thereby contribute to inappropriately increased cerebral blood flow [Chemtob et al., 1996]. After an ischemic insult, the neonate remains at high risk for further damage in the acute recovery phase because neonatal encephalopathy is often associated with blood pressure fluctuations.

An inadequate supply of glucose or alternate substrates plays a pivotal role in hypoxic-ischemic neuronal cell death. Although overall metabolic demands are lower in the neonatal than in the adult brain, during periods of rapid brain growth, particularly the perinatal period, metabolic needs rise. The pattern of injury after hypoxia-ischemia can be explained in part on the basis of this metabolic demand; brain regions most susceptible to hypoxic-ischemic injury in the term infant (e.g., subcortical gray matter structures such as the basal ganglia and thalamus) are the same regions that are most vulnerable to mitochondrial toxins. Brain development is associated with a transition from the ability to use glucose and ketones as energy substrates in the neonate to an absolute requirement for glucose in the adult. The immature brain can use lactate as an alternate fuel source to some degree, and the deleterious effects of lactate accumulation after hypoxia-ischemia therefore may be attenuated in the neonate compared with the adult. However, normal maturation is characterized by limitations in glucose transport capacity and increased use of these alternative fuels such as lactate. The inability to transport glucose across the blood–brain barrier threatens cerebral glucose utilization. These factors illustrate the importance of understanding the use of glucose, lactate, and ketones in the newborn brain under normal and pathologic conditions [Vannucci and Vannucci, 2000; Vannucci and Hagberg, 2004].

Excitotoxicity

Glutamate can activate a variety of excitatory amino acid receptors that are broadly classified based on their selective responses to specific agonists (e.g., NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], kainate) or their signaling mechanisms (i.e., ionotropic [ligand-gated ion channel] or metabotropic [G-protein-coupled]). Excitatory amino acid neurotransmission plays a pivotal role in brain development and in learning and memory. A substantial body of data has emerged over the past 30 years documenting the fact that overactivation of excitatory amino acid receptors (i.e., excitotoxicity) contributes to neurodegeneration in a broad range of acute and chronic neurologic disorders [Johnston, 2005].

Most information about mechanisms of excitotoxicity comes from experimental studies, but studies in the human neonate have provided some evidence to support the hypothesis that hypoxic-ischemic brain injury disrupts brain glutamate metabolism. Elevated levels of cerebrospinal fluid glutamate have been documented (by direct cerebrospinal fluid measurements and by proton MRS) in infants with severe hypoxic-ischemic injury [Pu et al., 2000]; cerebrospinal fluid levels of excitatory amino acids are directly proportional to the severity of clinical encephalopathy [Hagberg et al., 1997; Riikonen et al., 1992].

Two closely linked mechanisms contribute to ischemia-induced increases in synaptic glutamate: increased efflux from presynaptic nerve terminals and impaired reuptake by glia and neurons. The initial increase in efflux is mediated by a calcium-dependent process through activation of voltage- dependent calcium channels; later, calcium-independent efflux is thought to be mediated primarily by functional reversal of glutamate transporters. Removal of glutamate from the synaptic cleft depends primarily on energy-dependent glutamate transporters, which are predominantly glial. Any pathophysiologic process that depletes energy supply (e.g., hypoxia-ischemia, hypoglycemia, prolonged seizures) will disrupt these mechanisms and result in increased synaptic glutamate accumulation [Johnston, 2005].

The structure and function of the NMDA receptor channel complex are developmentally regulated. The receptor possesses multiple functional sites that recognize glutamate, co-agonists, modulatory molecules such as glycine, dissociative anesthetics, redox agents, steroids, zinc, magnesium (which blocks permeability to calcium), and a cation-selective ion channel that admits Na⁺, K⁺, and Ca²⁺. When the neurotransmitter recognition site is activated by glutamate, the ion channel allows influx of calcium and sodium. The resulting increase in intracellular calcium is the stimulus for a multitude of downstream events, including transcription factor modulation, cell cycle regulation, and DNA replication. The NMDA receptor is relatively overexpressed in the developing brain compared with the adult brain; in postnatal day 6–14 rats (which approximates to the term human neonate), the NMDA receptor is expressed at 150–200 percent of adult levels. In humans, receptor expression is significantly higher at term than in the adult [Johnston, 2005]. The particular combination of subunits determines the NMDA receptor’s functional state, and the predominating combination in the perinatal period seems to favor a more prolonged and pronounced calcium influx. In the setting of hypoxia-ischemia, NMDA receptor overactivation leads to massive Na⁺ and water influx, cell swelling, elevated intracellular calcium and its associated mitochondrial dysfunction, increased nitric oxide production, increased phospholipid turnover and accumulation of potentially toxic free fatty acids, and cell death by apoptotic or necrotic mechanisms. However, ischemia and energy failure also result in cation influx by non-NMDA-mediated mechanisms.

In experimental rodent models, there is compelling evidence that susceptibility to NMDA- and AMPA-mediated excitotoxicity peaks in the immature and that treatment with NMDA and AMPA receptor antagonists confers robust protection against neonatal hypoxic-ischemic brain injury [Johnston et al., 2001]. However, concerns have been raised that NMDA receptor antagonists might have specific risks in the immature brain; blockade of NMDA synaptic activity could disrupt critical neurodevelopmental processes. Whether AMPA antagonists, which can block neuronal and white matter hypoxic-ischemic damage in neonatal rodent models, have fewer potential risks in the immature brain than do NMDA antagonists is an important question for study [Silverstein and Jensen, 2007].

There has been considerable interest in evaluating the neuroprotective efficacy of magnesium sulfate in experimental and clinical models of neonatal brain injury. This interest stems from the intrinsic potentially neuroprotective properties of Mg²⁺ (including blockade of NMDA receptor activation), and the many years of clinical experience in safe use of magnesium sulfate in obstetric practice. Experimental studies provide evidence that pretreatment with magnesium sulfate can limit subsequent neonatal hypoxic-ischemic injury, but treatment after hypoxia-ischemia is of limited benefit [Greenwood et al., 2000; Turkyilmaz et al., 2002]. Magnesium sulfate has many effects, including blockade of NMDA receptors. It has been found give protection in some animal models of white matter damage [Turkyilmaz et al., 2002; Marret et al., 1995; Spandou et al., 2007], but did not affect cerebrospinal fluid levels of excitatory neurotransmitters in asphyxiated human neonates [Khashaba et al., 2006]. In addition, in a multicenter clinical trial of mothers treated with magnesium who were at risk for preterm delivery, no perinatal side effects were seen and there was some benefit in the neurodevelopment of survivors [Crowther et al., 2003]. A recent study, the BEAM trial, showed that exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors [Rouse et al., 2008].