Joseph J. Volpe

Approaches to the Study of Diseases Involving Oligodendroglial Death

Oligodendrocytes (OLs) are the myelin-producing cells of the central nervous system (CNS). Myelin is the compact, multilamellar, lipid-rich sheath that envelops axons. As a result of this membrane insulation, the rate of conduction of nerve action potentials down an axon is maximized while energy and space demands within the CNS are minimized. Disorders of myelin (i.e., white matter disorders) result from a variety of causes (see representative examples in Table 1). Extensive nervous system demyelination often has devastating consequences, including paralysis, dementia, or coma. These clinical sequelae reflect the marked reduction in the ability of the nervous system to conduct nerve impulses at a normal rate. Consider, for example, one form of the developmental disorder cerebral palsy (CP), in which injury to perinatal cerebral white matter results in decreased myelination of regions subserving such neurologic functions as motor control and vision. Around 5–15% of the nearly 50,000 preterm infants born in the US each year will acquire CP related to white matter damage, and manifesting as spastic motor deficits, and another 25–50% will show evidence of learning disabilities (1). The estimated economic cost to society of CP is in excess of five billion dollars annually.

Preterm Intraventricular Hemorrhage/Posthemorrhagic Hydrocephalus

Abstract Germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is the most common variety of neonatal intracranial hemorrhage and is characteristic of the premature infant. This form of brain injury affects around 25% of all very low birthweight (

Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

Abstract Neonatal encephalopathy occurs in 2 to 5/1000 live births and is principally related to hypoxic-ischemic injury to the newborn brain in the immediate peripartum period. In the last decade, there have been significant advances in neuroprotection that have been successful in reducing the risk of death and disability in infants who have suffered from a potential hypoxic-ischemic cerebral injury. The advent of therapeutic hypothermia has led to a major focus on the early clinical recognition of infants that may benefit from such therapies. In addition, optimal recognition and therapeutic targeting of neonatal seizures, with other neuroprotective approaches, have been emphasized. This chapter will summarize the clinical presentation, neuropathological correlates, neurodiagnostic evaluation, prognosis, and management of this condition.

Chapter 27 – Amino Acids

There are numerous disorders of amino acid (AA) metabolism; although individually rare, they collectively are extremely important. First, they may result in devastating disturbances of neurological development, and, second, they provide insight into normal and abnormal brain development. Disorders of AA metabolism refer to those in which the major accumulating metabolite is an AA, with the enzymatic defect primarily involving the initial step in the metabolic pathway. These disorders of AA metabolism (e.g., nonketotic hyperglycinemia [NKH], urea cycle defects, and maple syrup urine disease [MSUD]) are extremely important in the immediate neonatal period because if not recognized promptly, the propensity for devastating neurological consequences is markedly increased. In general the major clinical features of NKH, urea cycle defects, and MSUD include stupor, seizures, hiccups, vomiting, and dystonia. Treatment for NKH includes sodium benzoate to lower glycine blood levels; benzodiazepines, which enhance GABA receptor inhibitory function; and excitatory amino acid antagonists such as dextromethorphan to control seizures. Outcome of the severe neonatal form is generally poor with notable gender differences. Thus males demonstrate better outcomes as compared with females. For urea cycle defects, early identification and prompt treatment may improve survival, although the impact on long-term outcome remains unclear. Treatment strategies include removal of ammonia, which is best accomplished with hemodialysis; stimulating alternative pathways of waste nitrogen excretion (sodium benzoate, phenylbutyrate, or glyceroltriphenylbutyrate); and providing a low-protein diet with abundant nonprotein calories and essential AA. The potential role of gene therapy and liver transplantation remains unclear. The outcome with MSUD depends on early intervention (preferably <5 days) and includes control of leucine levels, optimizing specific amino acids that compete with branch chain amino acids for entry into brain.

Encephalopathy of Prematurity: Pathophysiology

The neuropathology of the encephalopathy of prematurity (see Chapter 14) includes injury to cerebral white matter and, in a major proportion of infants, a variety of neuronal-axonal disturbances. The encephalopathy includes a broad spectrum of initiating destructive events or disturbances in cellular maturation that are followed by widespread disruptions in cerebral white and gray matter growth and neuronal connectivity. This chapter emphasizes the pathophysiology of the most consistent and well-defined feature of the encephalopathy, injury to the cerebral white matter.

Chapter 21 – Stroke in the Newborn

Abstract Perinatal stroke has become increasingly recognized with the increased application of neuroimaging for neonatal seizures and encephalopathy. The frequency of perinatal stroke is estimated at 1 in 5000 births. Perinatal arterial ischemic stroke (AIS) accounts for 80% of neonatal stroke, while cerebral sinovenous thrombosis (CSVT) accounts for 20%. This chapter will summarize the neuropathology, pathophysiology, clinical presentation, management, and prognosis of perinatal AIS and CSVT. These conditions differ in their risk factors, presentation, management, and prognosis emphasizing the importance of their accurate diagnosis in the newborn infant.

Encephalopathy of Prematurity: Neuropathology

Abstract The major neuropathological substrate of human preterm brain injury is the encephalopathy of prematurity, a term coined to characterize the multifaceted gray and white matter lesions in the preterm brain that reflect acquired insults, altered developmental trajectories, and reparative phenomena in various combinations. Because the responsible insults occur at a time of rapid brain growth, a host of developmental programs may be affected, resulting in maturational defects that compound the acquired lesion (e.g., hypoxic-ischemic injury leading to loss of preoligodendrocytes [pre-OLs] and impaired myelination). The cause of the encephalopathy of prematurity is multifactorial and includes cerebral hypoxia-ischemia and systemic infection/inflammation, resulting in glutamate, free radical, and/or cytokine toxicity to pre-OLs, axons, and neurons. Cerebral white matter injury represents a spectrum of disease by neuropathological study, with “focal necrotic/cystic” periventricular leukomalacia (PVL) the most striking and diffuse “nonnecrotic/noncystic disease” the least striking. Nonnecrotic/noncystic cerebral white matter injury, a more diffuse abnormality, in which cysts or focal necrotic lesions are either not present or are minute in size and below the level of resolution of conventional neuroimaging, accounts for the majority of white matter disease in modern neonatal intensive care units. Magnetic resonance imaging (MRI) is the most effective imaging modality for the detection of this milder form of cerebral white matter disease and shows diffuse excessive high signal intensity in cerebral white matter, possibly reflecting diffuse gliosis. The patterns and mechanisms of injury are highly dependent on the specific maturational stages of OLs, neurons, and axons over the last half of gestation (i.e., the time frame of occurrence of the encephalopathy).

Intrauterine, Intrapartum Assessments in the Term Infant

Abstract The assessment of fetal well-being is a critical tool in ensuring optimal neonatal outcomes from both pregnancy and labor. This is particularly relevant for the recognition of the infant that may be at risk of hypoxic-ischemic cerebral injury. The identification of an intrauterine disturbance in gas exchange between the human fetus and mother (i.e., asphyxia) or the likelihood that such a disturbance will occur during labor or delivery is critical to improving the neurological outcomes for all infants, particularly those at greatest risk such as the growth-restricted infant. Moreover, attempts at prevention of the brain injury caused by intrauterine asphyxia, antepartum and intrapartum, demand precise awareness of when such injury is imminent. Although the most definitive information concerning the detection of hypoxic-ischemic insult to the fetus still applies primarily to the intrapartum period, major advances in antepartum assessment have been made. Thus, this chapter reviews the major current means of antepartum assessment of the fetus and then the approach to intrapartum assessment. In addition, we briefly summarize novel fetal and placental imaging techniques using magnetic resonance imaging.

Intracranial Hemorrhage: Subdural, Subarachnoid, Intraventricular (Term Infant), Miscellaneous

Abstract Intracranial hemorrhage in the neonatal period is an important clinical problem. Its importance relates to a relatively high frequency of occurrence, accompanied at times by serious neurological sequelae. Over the last decade there have been changes in the relative frequency of intracranial hemorrhage owing to changes in obstetric practice, such as increased vacuum-assisted delivery and reduced rotational forceps, as well as the improved survival of preterm infants with complex intracranial hemorrhagic lesions. Moreover, systematic neuroimaging studies in otherwise asymptomatic term infants have led to a new awareness of the incidence of more clinically benign forms of intracranial hemorrhage. In this chapter, an overview of neonatal intracranial hemorrhage and the basic elements of recognition are presented. Detailed discussion is devoted to subdural hemorrhage, primary subarachnoid hemorrhage, intraventricular hemorrhage of the full-term infant, and certain unusual, miscellaneous examples of neonatal intracranial hemorrhage.

Pathophysiology: General Principles

Abstract Hypoxic-ischemic encephalopathy in the perinatal period is a common disorder that has an impact throughout the perinatal period in both the preterm and term-born infant. Hypoxic-ischemic encephalopathy is characterized by neuropathological and clinical features that constitute an important portion of neonatal neurology. To understand those features, which are discussed extensively in this Unit IV, it is necessary to be cognizant of the pathophysiological underpinnings, including the biochemical and physiological derangements, that lead to the structural and functional manifestations of this encephalopathy. Hypoxia refers to deficiency in oxygen within the circulation and at the cellular level. Ischemia refers to insufficient perfusion or, more specific to this setting, cerebral blood flow. This will usually be associated with concurrent hypoxia at the cellular level. The term hypoxic-ischemic injury is often used because of the intimate nature of these two components in mediating cerebral injury in the newborn infant. Thus, key to all is hypoxia and energy deprivation (including glucose) at the cellular level, resulting in alterations in cellular metabolism, with interruption of typical cellular function and a series of aberrant cellular consequences. In this chapter, we first deal with the major modes of cell death in the setting of hypoxic-ischemic injury. We then review the fundamental derangements in energy and cerebral blood flow, on a background of the normal cerebral biochemistry and circulation, of the perinatal brain. Much of what we know is based on experimental data, but translational data in humans with neuroimaging support these concepts. The secondary effects of these derangements in energy and cerebral blood flow via excitatory, oxidative, and inflammatory pathways is discussed. This will form the foundation for reviewing approaches to neuroprotection in the term and premature brain in relation to hypoxic-ischemic injury. The applications of these principles and their related neuropathologies in the setting of the preterm and term infant’s brain is discussed in more detail in the later chapters within this unit.