689 SECTION VI 58 Structure, Function, and Development of the Nervous System, 690 59 Critical Care Considerations for Common Neurosurgical Conditions, 710 60 Neurologic Assessment and Monitoring, 720[.]
SECTION VI Pediatric Critical Care: Neurologic 58 Structure, Function, and Development of the Nervous System, 690 59 Critical Care Considerations for Common Neurosurgical Conditions, 710 60 Neurologic Assessment and Monitoring, 720 61 Neuroimaging, 735 62 Coma and Depressed Sensorium, 756 63 Intracranial Hypertension and Monitoring, 768 64 Status Epilepticus, 779 65 Hypoxic-Ischemic Encephalopathy, 793 66 Pediatric Stroke and Intracerebral Hemorrhage, 811 67 Central Nervous System Infections and Related Conditions, 823 68 Acute Neuromuscular Disease and Disorders, 837 69 Acute Rehabilitation and Early Mobility in the Pediatric Intensive Care Unit, 845 689 58 Structure, Function, and Development of the Nervous System ROBERT S.B CLARK AND MICHAEL SHOYKHET PEARLS • In humans, general central nervous system anatomy is established by birth However, the brain undergoes substantial postnatal development, including changes in synaptic density and dendritic arborization, maturation of neurotransmitter systems, and experience-dependent modification of neuronal circuits Thus critical illness—and critical care—related therapeutic and environmental factors can shape ultimate central nervous system development • Normal cerebral blood flow (CBF) changes significantly with age For term human newborns, normal CBF is approximately 40 mL/100 g brain per minute CBF peaks around to years of age at approximately 100 mL/100 g brain per minute, declining to adult values of 50 mL/100 g brain per minute in older adolescents • Normal CBF regulation to changes in blood pressure, carbon dioxide (CO2), and oxygen (O2) is operative from birth in term human newborns While cerebrovascular reactivity to CO2 and O2 remains relatively unchanged with age, blood pressure– dependent autoregulation operates over a narrower blood pressure range in younger children than older children and adults The nervous system, unlike any other organ system in the human body, stands at the intersection of biology and philosophy While composed of cells and governed by chemical messages, like all biological systems, it comprises the essence of each individual as a human being The former can be quantified and studied; the latter enters the realm of religion, philosophy, and spirituality Indeed, in a “brain-centric” approach to pediatric critical care, it can be argued that all interventions are ultimately targeted at preserving and protecting the child’s nervous system function Thus knowledge of the structure and function of the nervous system, together with understanding of the developmental processes that are active in children who become patients in the intensive care unit (ICU), is essential to the practice of the pediatric intensivist Furthermore, the impact of disease and injury in the context of the developing nervous system is only now beginning to be understood, with many new advances in diagnosis and treatment undoubtedly yet to come information processing and long-distance information transfer Both neurons and glia are broad classes of cells, each containing a multitude of specialized cells dedicated to carrying out specific functions in the nervous system All neurons, regardless of type and location within the nervous system, contain several standard cellular components that allow them to receive, process, and relay information The neuronal soma (cell body) contains the nucleus where genes are transcribed into messenger ribonucleic acid (mRNA), the endoplasmic reticulum where mRNA is translated into proteins, and a multitude of mitochondria for cellular respiration and adenosine triphosphate (ATP) synthesis Originating from the soma are two types of processes: a number of dendrites and a single axon Dendrites are short, local processes specialized for receiving information transmitted from other neurons via chemical or electrical synapses (see later discussion) The axon is the output of the neuron, carrying information in the form of action potentials to be received by other neurons, muscles, and many additional body organs, at distances up to meters away Glial cells are typically divided into microglia and macroglia Microglia are phagocytic cells derived from peripheral macrophages and normally exist in a resting or quiescent state in the central nervous system (CNS) Microglia are activated by several physiologically relevant factors, including bacterial lipopolysaccharide in the setting of infection and thrombin in the setting of injury.1 Whether microglial activation is neurotoxic or neuroprotective in these settings has yet to be fully characterized In addition, Major Cell Types The nervous system contains two major cell types: neurons and glia Neurons are responsible for the major operations traditionally ascribed to the nervous system: sensation, movement, thought, memory, and emotion, as well as homeostasis of bodily functions Interconnected networks of neuronal cells carry out all brain and spinal cord–based behaviors Glia, although significantly more numerous than the neurons, function to support neuronally based 690 CHAPTER 58 Structure, Function, and Development of the Nervous System activated microglia play an important role in the neuropathology of Alzheimer disease, human immunodeficiency virus (HIV)associated dementia, and prion diseases More recent evidence indicates that microglia also play an important developmental role in synaptic maturation and plasticity, contributing to learning and memory in healthy and diseased brains.2 Therapeutic strategies targeting microglial activation are just now beginning to emerge in animal disease models3,4 and human clinical trials.5 Macroglia comprise several distinct cell subtypes within the nervous system: astrocytes and oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS) Astrocytes are by far the most numerous cell type in the brain, performing several vital functions At the synapse, astrocytes regulate ion and neurotransmitter concentrations, contributing to the modern notion that the synapse is a tripartite structure consisting of the presynaptic and postsynaptic neurons and the astrocyte At the blood-brain barrier (BBB), astrocytes direct their processes toward the endothelial cells and contribute to the proper development of tight junctions (see later discussion) In contrast to the relatively diverse functions of astrocytes, the primary purpose of oligodendrocytes and Schwann cells is to provide myelination for axons in the CNS and PNS, respectively Myelination ensures faithful signal propagation along the entire axonal length Each oligodendrocyte contributes myelin to between 10 and 15 axons in the CNS; each Schwann cell envelops a single axon in the PNS From a clinical perspective, disorders of myelination contribute significantly to a range of diseases observed in pediatric critical illness, including perinatal asphyxia-induced periventricular leukomalacia, Canavan disease due to mutation in the oligodendrocytespecific aspartoacylase gene, and Guillain-Barré syndrome, caused commonly by autoimmune-mediated injury to peripheral nerve myelin sheaths Intercellular Communication in the Nervous System Early descriptions of neuronal cell structure by Camillo Golgi and Ramon Cajal in the late 19th century gave rise to two diverging theories of neuronal communication Golgi proposed that neurons form an interconnected reticulum, much like cardiac muscle cells, and communicate directly with each other via openings in their membranes Cajal, on the other hand, argued that neurons are individual cells with contiguous cell membranes and that communication takes place chemically at the sites of contact between individual neurons Despite the radically opposed views, both theories are now known to be correct and both mechanisms contribute to aspects of neuronal communication in the mammalian brain Direct communication between neurons, known as the electrical synapse, is accomplished via gap junctions Communication across cell membranes at sites where two neurons contact each other is accomplished using neurotransmitters, with the contact site known as the chemical synapse Electrical Synapses At the electrical synapse, cell membranes of the adjoining neurons are tightly bound together into a gap-junction plaque.6 Each plaque contains numerous channels made of connexin proteins There are 24 known connexin genes in humans Each channel consists of two hemichannels, with one on each cell membrane Two hemichannels join to form a functional gap junction between 691 two neurons, allowing intercellular diffusion of ions and small molecules, such as glucose, cyclic adenosine monophosphate (cAMP), and ATP Gap junctions thus allow neurons to share information about their metabolic and excitable states, providing a mechanism for large-scale regulation of energy demands and neuronal network dynamics Additionally, gap junction channels close in response to lowered intracellular pH or elevated Ca21 levels; because both events occur in damaged cells, paired hemichannels at the gap junction may function to isolate healthy neurons from those damaged during ischemia or trauma Recent evidence suggests that unpaired hemichannels outside of the gap junction plaques may also contribute to ischemic neuronal cell death.7 Glia, like neurons, are also connected by gap junctions For example, brain astrocytes form an interconnected cellular network, which allows long-distance propagation of calcium signals across many cells Additionally, layers of myelin generated by oligodendrocytes in the CNS and by Schwann cells in the PNS are linked by gap junctions Myelin gap junctions provide structural stability to the myelin sheath and allow for rapid diffusion of nutrients and other substances across the sheath toward the underlying axon In humans, mutations in gap junction protein connexin 32 result in X-linked Charcot-Marie-Tooth disease, a demyelinating neuropathy.8 Chemical Synapses Neuromuscular Junction The neuromuscular junction (NMJ) is one of the most widely studied examples of chemical synaptic transmission in the nervous system The overall concept is deceivingly simple: An action potential at the presynaptic neuron releases a neurotransmitter that, in turn, activates ion channels on the muscle cell membrane, resulting in postsynaptic action potential Yet every step in this process is exquisitely controlled and modulated in health and may be disrupted in disease Our evolving understanding of the NMJ provides a critical window into synapse function and pathophysiology The NMJ consists of three distinct anatomic components: the presynaptic nerve terminal, the synaptic cleft containing the basement membrane, and the postsynaptic muscle fiber The presynaptic nerve terminal originates from the myelinated axon of a motoneuron in the spinal cord Lower motoneurons in the ventral gray matter of the spinal cord send their myelinated axons through the ventral root toward peripheral muscle targets As the axon approaches the muscle fibers, it loses its myelin sheath and branches into a fine network of terminals, each approximately µm in diameter Each branch has several swellings along its course, termed presynaptic boutons, where the nerve makes synaptic contact with the muscle fiber Presynaptic boutons are covered by terminal Schwann cells, which provide growth factors, recycle neurotransmitters, and may participate in recovery after nerve and muscle injury Presynaptic boutons are positioned over specialized regions of the muscle cell membrane called the end plate regions Underlying each bouton is a specialized invagination of the cell membrane that contains a high concentration of nicotinic acetylcholine (ACh) receptors and voltage-gated Na1 channels The presynaptic bouton and end plate are separated by a 100-nm-wide synaptic cleft containing the basement membrane and extracellular matrix The basement membrane anchors a number of proteins, including acetylcholinesterase, the enzyme responsible for rapid hydrolysis of ACh in the synaptic cleft 692 S E C T I O N V I Pediatric Critical Care: Neurologic Several distinct functional steps occur during synaptic transmission at the NMJ First, the action potential arriving from the motor axon depolarizes the membrane in the presynaptic boutons, causing Ca21 entry via voltage-gated Ca21 channels on the presynaptic membrane Ca21 entry results in fusion of synaptic vesicles containing ACh with the presynaptic cell membrane and release of ACh into the synaptic cleft ACh rapidly diffuses toward the postsynaptic membrane and binds to the nicotinic ACh receptor (nAChR); two ACh molecules are required to activate the nAChR On activation, the nAChR opens and allows both Na1 and K1 to flow through the ion pore The inward Na1 current, however, dominates over the outward K1 current, resulting in net depolarization of the muscle membrane at the end plate This so-called end plate potential propagates a short distance before encountering voltage-gated Na1 channels These Na1 channels open when membrane potential rises to a critical threshold value, allowing only Na1 ions to flow into the cell and generating the all-or-none muscle action potential Acetylcholinesterases in the synaptic cleft terminate the depolarizing action of ACh at the postsynaptic membrane by rapidly hydrolyzing ACh into acetate and choline A detailed understanding of diseases that affect synaptic transmission at the NMJ, as well as familiarity with clinical pharmacology as it applies to the NMJ, is essential in critical care Specific diseases affecting the NMJ include toxin-mediated botulism and autoimmune disorders such as myasthenia gravis, Lambert-Eaton syndrome, and neuromyotonia These are discussed in detail in Chapter 68 (see also Tseng-Ong and Mitchell9 and Lang and Vincent10) Among the pharmacotherapies targeted at the NMJ are some of the most commonly used drugs in the pediatric ICU (PICU): neuromuscular blockers Furthermore, a number of toxins either decrease (anticholinergic agents) or increase (acetylcholinesterase inhibitors) the amount of ACh available at cholinergic synapses, resulting in corresponding toxidromes (see Chapter 126) Chemical Synapses in the Central Nervous System Chemical synapses in the CNS operate on basic principles similar to those governing synaptic transmission at the NMJ, although the cadre of neurotransmitters and postsynaptic receptors is significantly more diverse in the CNS Importantly, a given neuron in the CNS may synthesize and store more than a single neurotransmitter, but it releases the same set of neurotransmitters at all of its synapses (the Dale principle) CNS synapses are generally divided into asymmetric (Gray type I) synapses and symmetric (Gray type II) synapses on the basis of their appearance under electron microscopy Physiologically, these correspond to excitatory and inhibitory synapses, respectively Each neuron synthesizes its own complement of neurotransmitters, which are delivered to all synaptic contact sites in the axon and packaged into synaptic vesicles When an action potential reaches the axon, Ca21 currents cause the synaptic vesicles to fuse with the cell membrane, releasing neurotransmitters into the synaptic cleft Neurotransmitters then act on their corresponding ionotropic and metabotropic receptors on the postsynaptic membrane Ionotropic receptor activation leads to either a depolarizing, excitatory current or a hyperpolarizing, inhibitory current These subthreshold currents are called excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs), respectively Temporal and spatial summation of EPSPs in the dendritic tree of the postsynaptic neuron occasionally depolarizes the somatic membrane sufficiently to cross a threshold and generate an action potential One of the distinguishing features of chemical synaptic transmission in the CNS, compared with the NMJ, is its lack of reliability on a single-cell level; an action potential in the presynaptic neuron does not necessarily cause a postsynaptic neuron to fire its own action potential Such lack of determinism likely allows for individual differences in responses to the same stimuli After interaction with the receptor, the neurotransmitter is cleared from the synapse by diffusion, active reuptake into the terminal, or enzymatic destruction, similar to ACh hydrolysis at the NMJ Neurotransmitter Systems Several substances are employed for communicating information chemically between neurons in the nervous system or between a neuron and a muscle at the NMJ These substances, called neurotransmitters, generally fall into three categories: amines, amino acids, and peptides (eTable 58.1) Each neurotransmitter requires its own synthetic machinery and exerts specific actions on the postsynaptic target Furthermore, neurons tend to be characterized anatomically, immunohistochemically, and functionally by the main neurotransmitter that they use, allowing insight into the role of each neurotransmitter system in CNS function Neurotransmitters Acetylcholine Acetylcholine is an amine that functions as a neurotransmitter at the NMJ and in the CNS At the NMJ, its actions are quick and precise, whereas in the CNS, it functions as a slow, more global modulator of synaptic activity Cholinergic CNS neurons include all motoneurons in the spinal cord and a number of cell nuclei in the brainstem reticular formation and basal forebrain Cholinergic neurons synthesize ACh using choline acetyltransferase (ChAT), which transfers an acetyl group from acetyl coenzyme A (CoA) to choline (eFig 58.1A) Choline concentration in the extracellular fluid is the rate-limiting step in the reaction Cholinergic neurons also synthesize acetylcholinesterase (AChE), the enzyme that breaks down ACh AChE is released with ACh into the synaptic cleft, where it rapidly hydrolyzes ACh into acetic acid and choline Low concentrations of choline in the CNS have been associated with neurologic impairment during fetal11 and postnatal life.12 Thus choline supplementation represents an attractive therapeutic strategy in neurologic disorders characterized by decreased CNS choline Interestingly, patients receiving long-term parenteral nutrition (TPN) occasionally develop choline deficiency, which has been associated with TPN-related liver failure13 and possibly cognitive dysfunction Hence, choline supplementation in TPN-dependent patients may ameliorate some neurologic deficits.14 Catecholamines Catecholamine neurotransmitters include dopamine, norepinephrine, and epinephrine For all three, the initial starting point in biochemical synthesis is the amino acid tyrosine (eFig 58.1B) Tyrosine is converted into an intermediate compound, called dopa, by tyrosine hydroxylase (TH) In dopaminergic neurons, dopa is converted into dopamine by dopa decarboxylase Noradrenergic neurons, which use norepinephrine as a neurotransmitter, further convert dopamine into norepinephrine using dopamine b-hydroxylase Finally, norepinephrine is converted 692.e1 eTABLE Neurotransmitter Classes 58.1 Amines Amino Acids Peptides Acetylcholine g-Aminobutyric acid Substance P Dopamine Glutamate Vasoactive intestinal peptide Norepinephrine Glycine Dynorphin Epinephrine Enkephalins Serotonin Neuropeptide Y Histamine Cholecystokinin Neurotransmitters that operative exclusively in the central nervous system are in normal font, those used in both the central and peripheral nervous systems are in italics, and those used exclusively in the peripheral nervous system are in bold ... carrying out specific functions in the nervous system All neurons, regardless of type and location within the nervous system, contain several standard cellular components that allow them to receive,... disease models3,4 and human clinical trials.5 Macroglia comprise several distinct cell subtypes within the nervous system: astrocytes and oligodendrocytes in the CNS and Schwann cells in the peripheral... channels on the muscle cell membrane, resulting in postsynaptic action potential Yet every step in this process is exquisitely controlled and modulated in health and may be disrupted in disease Our