Part 1: Principles of Neurology

INTRODUCTION

The human brain consists of 100 billion neurons that connect with more than 100 trillion synapses. The ability of neurons to form and modulate precise connections with one another is critical to every aspect of nervous system development and function. Adding to the complexity of the nervous system, glial cells (astrocytes, oligodendrocytes, microglia, and others) far outnumber neurons, and their contributions to critical brain functions are increasingly being appreciated. Malformation or dysfunction of even just a small subset of cells can manifest in neurologic symptoms. Understanding the essentials of the nervous system’s anatomy and function provides a robust basis for neurologic practice. Examining a patient who presents with a neurologic problem should lead the clinician to ask and answer 2 fundamental questions:

1. What part(s) of the nervous system is/are affected?

2. What is the nature of the dysfunction?

This approach requires the ability to localize different functions to distinct regions of the nervous system. Adding a layer of complexity, the pediatric neurologist is faced with the task of answering these questions in the setting of very dynamic changes that occur as a child’s nervous system matures. It is thus important to review the basic principles of pre- and postnatal brain development.

Over the past decades, studies in disparate fields such as molecular and cell biology, stem cell biology, genetics, neurochemistry, immunology, and imaging have shed light on the remarkable molecular and cellular bases of neurodevelopment. Spurring excitement for the neurosciences and their clinical application, we continue to learn more about the brain’s complexity as new tools are being developed. While much more needs to be learned, this chapter highlights some of the major advances in our understanding of normal brain development. Following the chronological order of development, the first part will highlight milestones of prenatal brain development such as the formation of the neural tube and regional patterning that will determine the major subdivisions of the central nervous system. The second part will review the mechanisms that lead to proper wiring of neurons in the cerebral cortex, the part of the brain responsible for most human behaviors. Finally, the third part will discuss the major subdivisions of the mature central nervous system and highlight emerging developmental links to neurologic diseases.

Normal neuronal development can be divided into a series of key steps: neurulation, regionalization, neurogenesis, migration, differentiation, apoptosis, axon guidance, synapse formation and pruning, myelination, and cortical folding. In these 10 steps, cells go from unspecified ectodermal constituents to highly differentiated neurons for which connections are being fine-tuned at the synaptic level. Neurodevelopment, however, does not stop with birth and extends through childhood, in fact likely throughout the whole life span.

PATTERNING OF THE NERVOUS SYSTEM

Neurulation

The nervous system develops from a region of the ectoderm called the neural plate. During the third week of gestation, the underlying notochord and adjacent mesoderm induce the overlying ectoderm to differentiate into the neural plate. This process is followed by invagination of the latter along its central axis, which gives rise to the neural groove with the neural folds on each end. By the end of the third week, the neural folds meet at the hindbrain/cervical boundary and fuse at the midline, which initiates the formation of the neural tube, the rudiment of the brain and spinal cord. Fusion proceeds in both the rostral and caudal directions and is finally fully achieved with the closure of the neuropore in the sacral region around day 26 to 28. As the neural folds fuse, some neuroectodermal cells detach and migrate ventrally to form the neural crest. This region later gives rise to a diverse cell lineage by providing cells that form the dorsal root ganglia, Schwann cells, the autonomic nervous system, the adrenal medulla, melanocytes, meninges, and several key skeletal and muscular components of the face.

Regionalization

During this stage, segmentation and positional identity are determined in both the rostrocaudal and dorsoventral axes. At the rostral end of the neural tube, 3 brain areas are formed: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). The prosencephalon further develops into the telencephalon (cortex, basal ganglia, olfactory system) and diencephalon (thalamus and hypothalamus), whereas the rhombencephalon is subdivided into the metencephalon (pons and cerebellum) and myelencephalon (medulla). The dorsal telencephalon forms the 2 cerebral hemispheres. Each hemisphere is further divided into subdomains, such as the functional and anatomic subdivisions of the neocortex (motor, somatosensory, auditory, visual, and others). Programs of regional identity are, at least in part, determined by gradients of secreted morphogenic molecules from at least 3 patterning centers positioned at the perimeter of the dorsal telencephalon.

Neurogenesis

During early development of the cerebral hemispheres, a progressive restriction of cell fate occurs. Neuronal fate specification of progenitor cells occurs in both a spatially and a temporally controlled manner. Coincident with the regionalization of the cerebral cortex, cortical neurons are generated from proliferating cells in the telencephalic ventricular zone. Radial glia cells are thought to be the principal precursors for most neurons and, via lineage-restricted intermediate precursors, also form astrocytes and oligodendrocytes. After their terminal mitotic division occurs, young neurons migrate outward along radial glial fibers into the cortical plate to form the 6 layers of the neocortex. Early-born neurons form the deepest layers, whereas the later-born neurons migrate past them to form the outer layers. Quantitative studies of proliferation suggest that prior to neurogenesis, ventricular zone cells divide symmetrically to expand the progenitor pool. As neurogenesis begins, progenitors increasingly divide asymmetrically, and the daughters of asymmetric divisions can differentiate into neurons. As neurogenesis ends, progenitors begin to produce macroglia.

Migration

Once born in the ventricular zone, neurons migrate to their final position within the developing nervous system. Excitatory (glutamatergic) neurons of the neocortex are generated in the dorsal ventricular zone and migrate outward along radial glia, assembling in an inside-out manner to establish 6 layers that characterize the mature neocortex. Thus, layer IV and V neurons migrate first. Layers II to IV migrate later and pass through the early generated cells to get to their final location in the neocortex. In contrast, both inhibitory (GABAergic) neurons and oligodendrocytes are generated in the germinal zone of the ventral telencephalon (the ganglionic eminences) and follow several tangential migratory routes to their final location in the neocortex. In general, neurons born at the same time reach the same layer of the cerebral cortex, regardless of their sites of origin or neurotransmitter type. Most neurons destined for the cerebral cortex migrate between the 10th and 18th gestational week, and migration is essentially completed by week 20.

WIRING OF THE BRAIN

Differentiation

The second half of gestation is characterized by the formation of connections among postmitotic neurons. After migration is completed, neurons become polarized as axons, and dendrites become evident. Typically, neurons extend a single, long axon, which serves to propagate action potentials, and several short dendrites, which receive synaptic input. Polarization is initiated when 1 of the developing neurites becomes designated as the axon. For example, dissociated hippocampal neurons in culture first form lamellipodia, which extend to become neurites. Within 24 to 48 hours, 1 of these neurites begins to elongate rapidly and will eventually develop into the axon. During the next couple of days, the remaining neurites become dendrites and first connections are formed. In the developing human brain, dendrites, axons, and synapses are formed at an astonishing pace and result in a rapid increase in the size of the brain.

Apoptosis

Curiously, approximately half of the neurons that were generated until this point in development naturally die off. This important step in normal brain developmental is mediated by apoptosis. Apoptosis is thought to be induced in those neurons that cannot successfully compete for the limited number of target-derived trophic factors. Through this selection process, only neurons with properly established synaptic connections survive.

Axon Guidance

Axons reach their final targets in the central nervous system by interacting with either attractive or repulsive cues. Some of these cues are secreted molecules that act at a distance, and others are membrane-associated molecules that act upon contact between the axon and the guiding cells. Growth cones are specialized regions at the tips of growing axons and are vital for the formation of precise connections between neurons and their targets. Growth cones are composed of fan-shaped sheets (lamellipodia) interrupted by spike-like protrusions (filopodia). Both are supported by a very dynamic actin cytoskeleton. Extending axons are navigated by a complex set of molecules, including but not limited to: netrins, slits, semaphorins, repulsive guidance molecules, and ephrins. Changes in the expression of these proteins may disrupt neural circuits and may cause neurologic diseases. In the developing neocortex, axons grow dramatically between 21 and 64 weeks after conception and reach an adult-like state by approximately 17 months postnatally.

Synapse Formation and Pruning

The transmission of information between neurons occurs at specialized sites of contact called synapses. The majority of synapses in the vertebrate central nervous system are chemical synapses, which convert a change in the membrane potential of the presynaptic neuron into a chemical signal capable of transmitting this potential to the postsynaptic compartment. Chemical synapses are asymmetric cellular junctions composed of a presynaptic bouton, the synaptic cleft, and the postsynaptic reception apparatus. Synapses can be detected in the visual cortex as early as 28 weeks of gestation. However, the synaptic density at this time is only approximately 2% of that in adults and even at birth only reaches approximately 17%. The greatest increase in synaptogenesis occurs between 2.5 and 8 months postnatally, with the most rapid surge occurring between 2 and 4 months of age. Similar to the overproduction of neurons, synapses are also overproduced, allowing for a strengthening of the most efficient connections. Excess numbers of synapses may first be generated to establish the wiring pattern of the brain, yet the formation of mature and precise circuits requires the selective pruning of inappropriate synapses. The pruning of unused synapses continues at least until late adolescence and is influenced by environmental factors and learning. On a molecular level, pruning is regulated by axon guidance, transforming growth factor β, and death receptors and may be mediated by cell-intrinsic mechanisms, such as autophagy, or external mediators, such as microglia.

Myelination

Myelin is the fatty sheet that insulates axons. In the central nervous system, it is supplied by oligodendrocytes, whereas in the peripheral nervous system, Schwann cells are the source of myelin. Myelination occurs in a spatiotemporally controlled manner. Primary sensory and motor areas are myelinated first, starting at 30 weeks of gestation. Postnatally, rapid myelination occurs in the first year of life and continues to proceed for decades in some association areas. Interestingly, there is emerging evidence that myelination may be altered by neuronal activity linking learning and experiences to dynamic changes in myelin.

Cortical Folding

The size of the cerebral cortex varies greatly among the mammalian species. One of the most prominent features of the human cortex is its intricate folding, which serves to optimize the functional organization and wiring of the brain. Cortical folding and the formation of macroscopically appreciable gyri and sulci result from an interplay of numerous molecular and cellular mechanisms as well as mechanical forces. Proper cortical folding is an important step in embryonic brain development, and its failure is often associated with intellectual disability and severe epilepsy. For example, mutations in cytoskeletal genes, such as those encoding α-tubulin and β-tubulin isotypes, can cause lissencephaly, which highlights the role of an intact and dynamic cytoskeleton for cell migration events that result in cortical folding.

THE MATURE BRAIN

Neurons: The Functional Units

Neurons are the functional units of the nervous system in the classic sense of the 19th-century cell theory, yet great diversity exists in their subtypes stemming from differences in cell size, localization, axonal projections, dendritic architecture, transcriptional profiles, and neurotransmitter repertoire.

As new tools for detailed genetic analyses of individual cells are being developed, the vast diversity of neuronal subtypes is increasingly appreciated. Subtype-specific characteristics are important factors that drive the assembly of defined neuronal circuits and help explain distinct clinical manifestations in many neurologic diseases. The emergence of direct reprogramming or transdifferentiation strategies to generate mature neuronal cells of many different subtypes from human fibroblasts or other cells in vitro has, for the first time, allowed researchers to study specific subtypes of human neurons in great number. Taking these exciting developments even further, induced human neurons have been employed to generate cerebral organoids and to model many neurologic diseases.

Neurogenetics: Changing Concepts for Brain Development

The advent and increasing diagnostic availability of next-generation sequencing technologies have advanced our understanding of the genetics behind both common and rare neurologic diseases. Changing the way we think about genetic disruption of neurodevelopment, recent high-throughput sequencing of structural brain malformations has revealed a diverse genetic landscape beyond classic Mendelian inheritance. Studies have shown that somatic mutations can arise during prenatal brain development and may result in brain malformations associated with neurologic impairment, even if present in only a small percentage of cells in the brain.

Neuronal Circuits and Networks: From Cacophony to Symphony

Synaptic connections allow neurons to transmit and possibly store information. While it has been established that neurons specifically select their synaptic partners during development, we are only beginning to understand how these decisions are made. The formation of neural circuits formation encompasses many of the developmental processes discussed above, namely cell fate determination, neuronal migration and polarization, axon guidance, synaptic formation, and pruning. Classic tracing studies conducted during the last decades and, more recently, advanced tissue clearing, labeling, and reconstruction techniques have helped to define distinct circuits. These neuronal circuits are the anatomic and functional substrate of complex learned behaviors and are shaped by both genetic and environmental influences. With novel imaging techniques and large-scale genomics, proteomics, and connectomics approaches, we are now beginning to understand the molecular restraints under which circuits develop. This information will inform therapeutic approaches aimed to restore damaged neuronal circuits in disease. Deep-brain stimulation is an exciting example of approaches that target neuronal circuits and has proven clinical efficiency for an expanding list of neurologic diseases. Transcranial magnetic stimulation, a noninvasive approach, is approved by the US Food and Drug Administration for certain cases of major depressive disorder and migraines and is being investigated for a number of other neurologic conditions. Optogenetics and related techniques are very exciting examples of approaches that have been shown to be applicable to neuronal circuits in preclinical disease models, yet await their translation into therapies for human diseases.

Macroscopic Anatomy of the Mature Brain

Localizing a deficit or symptom to a certain region of the nervous system is the first step a neurologist takes to formulate a differential diagnosis. It requires a basic understanding of the macroscopic anatomy of the developing and mature nervous system.

The spinal cord consists of segments, each of which is connected to the periphery via dorsal (sensory) and ventral (motor) roots. The anterior horn of the spinal cord contains the motor neurons, which send their axons to the skeletal muscles and are responsible for spinal reflexes. The white matter occupying the periphery of the cord includes various longitudinal fiber tracts such as the corticospinal tract, spinothalamic tract, posterior columns, and spinocerebellar tracts.

The fiber tracts of the spinal cord continue in the medulla. In addition to the long white matter tracts, the medulla contains several nuclei, such as the inferior olive and the lower cranial nerve nuclei. The pons also contains the nuclei of several cranial nerves (V, VI, and VII), motor and sensory tracts, and the cerebellar peduncles that connect the cerebellum to the rest of the central nervous system. The midbrain contains nuclei of the cranial nerves III and IV, motor and sensory tracts, the tectum, the substantia nigra, and the red nucleus. The tectum is involved in visual and auditory processing, whereas the red nucleus and the substantia nigra are parts of motor circuits. The cerebellum has many roles, which include controlling balance, muscle tone, and locomotion, as well as higher cognitive functions such as speech or motor learning. More recently, the cerebellum has been implicated in social communication and repetitive behaviors, which are impaired in autism spectrum disorder.

The thalamus, the largest component of the diencephalon, contains the sensory relay nuclei that receive input from sensory systems and project to specific sensory areas of the neocortex. Other nuclei in the thalamus are involved in motor circuits connecting the striatum, neocortex, and cerebellum. The hypothalamus is the central regulator of the autonomic and endocrine systems and contains the suprachiasmatic nucleus, the central regulator of circadian rhythms.

The telencephalon contains the neocortex, which is divided into specialized areas such as the primary motor, somatosensory, auditory, and visual cortex. Secondary association areas receive input from these primary areas. A small but important part of the telencephalon consists of the olfactory cortex, hippocampus, and entorhinal cortex, which are involved in the limbic system. Finally, the subcortical structures are completed by the basal ganglia, key areas for controlling motor function.

The plethora of neurologic and behavioral diseases that can result from insults to the developing or mature brain and their management will be discussed in the following chapters.

SUGGESTED READINGS

INTRODUCTION

This chapter is designed to help the pediatrician feel comfortable and confident with the assessment of neurologic disease. More detailed discussions of individual diseases are given in other chapters.

When tackling any case, accurate diagnosis and management start with the history. The information found in the history, starting with the chief complaint, allows the practitioner to then focus on certain elements of the neurologic examination. At the end of the encounter, the combination of information found in the history and neurologic examination will direct the practitioner to determine if specialized neurologic care is needed and, if so, whether that care can be provided in an outpatient setting or if inpatient/emergent care is needed.

The following sections will be divided into a variety of neurologic chief complaints a pediatrician could encounter. Also presented are additional elements of the history and physical examination that need to be elicited to ensure proper localization of the disease process. Once a neurologic lesion has been confidently localized, appropriate management can begin.

WEAKNESS

To understand the magnitude of potential etiologies for weakness, one must have an understanding of the intricate nature of the neurologic axis. At the time of first encounter for weakness, one should attempt to localize the lesion to the brain (cortex, white matter, basal ganglia, thalamus, brain stem), the spinal cord, the anterior horn cell, the nerve root, the nerve (axon or myelin or both), the neuromuscular junction, the muscle, or multiple components of the aforementioned.

The acuity of onset and whether the weakness is static or progressive are extremely important factors in determining the plan of care. Weakness that is long-standing (ie, months to years) is rarely going to represent a disease process that requires emergent care, and outpatient neurology follow-up should be sufficient. However, weakness that is acute to subacute in onset (minutes, hours, or days to weeks) may represent a neurologic condition requiring emergent care.

CEREBRAL LESIONS REQUIRING EMERGENT EVALUATION

Altered mental status, or encephalopathy, can occur when there is a bilateral hemispheric disturbance involving the cerebral cortex. Language dysfunction and impaired fluency or comprehension can occur if the cortices of the frontal or temporal lobes are affected, respectively. Finally, since seizures frequently originate from the cerebral cortex, lesions affecting the cortex can give rise to seizures. Neurologic disease giving rise to weakness in the setting of any of the aforementioned symptoms would suggest a disease process affecting the cerebral cortex. The differential of such a case includes intracranial hemorrhage, cerebral infarct (stroke), infectious/inflammatory encephalitis, demyelinating processes such as acute disseminating encephalomyelitis, and neoplastic processes. To evaluate for these processes, emergent imaging in the form of computed tomography (CT) scans or magnetic resonance imaging (MRI) of the brain should be pursued. Alteration of mental status will be discussed in more detail later in the chapter.

SPINAL CORD LESIONS REQUIRING EMERGENT EVALUATION

Bowel and bladder incontinence along with extremity weakness and a sensory level may indicate a spinal cord lesion, and emergent care should be sought. These lesions may be neoplastic, vascular, inflammatory, infectious, or degenerative in origin and may necessitate immunomodulatory/surgical treatment.

Weakness associated with back pain may also be indicative of a spinal cord neoplastic process or epidural abscess. The weakness within these 2 disease processes will potentially arise subacutely; however, emergent care should still be sought.

An emergent MRI of the spinal cord will be of use in characterizing spinal cord lesions.

NEUROPATHIES REQUIRING EMERGENT EVALUATION

Worsening acute/subacute lower extremity weakness that ascends from the feet is worrisome for acute inflammatory polyneuropathy or Guillain-Barré syndrome (GBS). Absent reflexes generally localize the lesion to the peripheral nervous system (anterior horn cell, nerve, neuromuscular junction, and/or muscle). GBS represents an umbrella term for a polyneuropathy secondary to an autoimmune disorder, and the autoantibodies produced with GBS can react with the myelin, axonal, or both components of the nerve. The location and severity of this reaction give rise to the many variants of GBS. The clinical course of GBS can often involve respiratory compromise and autonomic instability, rendering the early recognition of GBS and immediate hospitalization and workup imperative. (See also Chapter 561.)

WEAKNESS IN THE NEONATE AND INFANT

While it is possible for a neurologic disease to be present from birth, the diagnosis is sometimes delayed because of the difficulty in properly assessing all components of the neurologic examination. Subtle clues in the developmental screen and neurologic examination may allow the examiner to establish an earlier diagnosis, allowing for improved care of the child.

Weakness can take on many forms in infancy. Weakness may manifest as subtle delays in achieving motor milestones such as rolling over, sitting up, or crawling or as a preference to use one hand over the other before the age of 1. In extreme cases, a newborn child may have difficulty with vital tasks such as breathing and feeding, and on occasion, joint contractures may be present secondary to immobility in utero. On examination, there may be hypotonia (decreased resistance of muscle to stretch). The family may describe this finding as their child being “too loose” or “floppy.” These findings are fairly nonspecific in terms of identifying where along the neurologic axis the lesion exists; the lesion could exist in either the central or peripheral nervous system, and, thus, more information is needed. The presence of weakness in the setting of hypotonia, areflexia, and fasciculations typically points to an anterior horn cell disease such as spinal muscular atrophy. The presence of weakness and hypotonia but preserved reflexes should raise the possibility of a disorder of neuromuscular transmission such as infantile botulism or transient myasthenia gravis (especially in a newborn with a maternal history of myasthenia gravis). Congenital myotonic dystrophy should be considered in a newborn or infant with hypotonia and weakness with a maternal history of myotonic dystrophy. These are just a few examples of diseases that can cause early hypotonia and weakness, but consideration should also be given to genetic conditions such as trisomy 21 and Prader-Willi syndrome.

Consideration should also be given to cerebral lesions (eg, anoxic brain injury or remote intracranial hemorrhage), especially in the neonate/infant with an alteration of mental status as evident by lethargy, irritability, and/or feeding difficulties. Polyneuropathies, congenital myopathies, metabolic myopathies, mitochondrial myopathies, and muscular dystrophies are also within the differential. Focal upper extremity weakness from birth can also be indicative of a brachial plexopathy. An MRI of the brain, serum creatine kinase, electromyogram and nerve conduction studies (EMG/NCS), and genetic testing can help differentiate between the many etiologies giving rise to weakness in the neonate and infant.

SEIZURES

PATHOPHYSIOLOGY

Seizures are an abnormal and hypersynchronous discharge of a population of neurons. Epilepsy is defined as 2 or more unprovoked seizures. An unprovoked seizure excludes febrile seizures and seizures in the setting of acute precipitating causes such as head trauma or metabolic disturbances. It is important to first distinguish between febrile and afebrile seizures (or unprovoked seizures) as the difference in management between the 2 is different.

RELEVANT MEDICAL HISTORY

The history obtained for a patient with a seizure will help the physician in determining a potential etiology for the patient’s seizure activity. The pregnancy history including maternal drug use or infection should be obtained. Birth history is very important, especially if it was noted the baby was born premature or underwent any resuscitative measures. A child who is developmentally delayed may be delayed secondary to seizure activity, or the process that has caused the child to be delayed may also serve as the etiology for the patient’s seizure activity. A family history of seizures may point to a genetic etiology for the patient’s epilepsy.

CLINICAL CHARACTERIZATION OF SEIZURES

Once a seizure is determined to be unprovoked, it is important to distinguish whether or not the seizure was partial or generalized. A generalized seizure is characterized by an alteration of consciousness and involvement of both left and right hemispheres. This can manifest as motor activity such as generalized tonic-clonic seizure or as staring spells with an immediate return to baseline after the episode (absence seizure); “drop attacks,” as is the case in atonic seizures; or generalized myoclonic jerks. Partial seizures are characterized by a preservation of consciousness. Patients or family members may describe unilateral extremity jerking, forced deviation of the head, or forced deviation of the eyes if motor activity is present. Other patients may describe a rising epigastric sensation, a feeling of déjà vu, sensory involvement, nausea, vomiting, and autonomic and/or visual symptoms depending on the origin of the seizure. It is also important to note that it is possible for a seizure to start as a partial seizure and secondarily generalize to involve all of the brain.

Seizures can be much more subtle in a neonate and an infant. For example, seizures in the neonate can be as subtle as chewing movements or pedaling motions. Paying special attention to eye movements in the neonate can be helpful in determining if an event is truly epileptic. Neonates with seizures can present with sustained opening of the eyes with ocular fixation or with tonic horizontal deviation of the eyes. Clonic jerking and movements that do not cease with passive flexion are also characteristic of neonatal seizures. If seizures in the neonate are suspected, emergent care should be sought given the potential that the seizures represent an underlying neurologic disturbance such as central nervous system infection, intracranial hemorrhage, and stroke.

Seizures in infants can still appear different from the more frequently seen generalized tonic-clonic seizures of childhood. One such seizure type is an infantile spasm that appears as a sudden flexion or extension of the head, trunk, and extremities. Behavioral arrest during the seizure is characteristic of infantile spasms. An alternative clue that an infant may be experiencing seizures including spasms is the presence of developmental arrest or regression. Urgent evaluation for infantile seizures should be sought given that seizures could represent an underlying neurologic disturbance such as a neuronal migration disorder, metabolic disorder, or an underlying genetic epilepsy, and urgent treatment of infantile spasms has the potential to improve developmental outcome. MRI of the brain, electroencephalogram (EEG), and metabolic and genetic testing can help clarify the diagnosis.

ETIOLOGY

The etiologies of epilepsy are varied. Injuries in the form of anoxic brain injury or intracranial hemorrhage can leave a neonate susceptible to seizures. Central nervous system infections also serve as a potential etiology for seizure activity. Genetic syndromes such as childhood absence epilepsy, benign rolandic epilepsy, and juvenile myoclonic epilepsy are also within the differential. Brain malformations such as cortical dysplasias, lissencephaly, and gray matter heterotopias increase risk for epilepsy. Neoplasms can predispose to seizures and can be easily identified by neuroimaging. Neuroinflammatory disorders such as viral or postviral encephalitis are potentially treatable causes of seizures. Finally, several inborn errors of metabolism will place a child at risk for epilepsy.

INVESTIGATION

Cerebrospinal fluid (CSF) studies should be pursued if there is concern for central nervous system infection, and an EEG should be obtained for all first-time unprovoked seizures, and it may help determine the need for anticonvulsant medications. An MRI of the brain should be obtained for any child with developmental delay, in children younger than 1 year old with seizures, and in children with an abnormal neurologic examination or focal components to the seizure. Genetic testing is usually reserved for patients with refractory epilepsy or who have a strong family history of epilepsy.

TREATMENT

Daily administration of anticonvulsants is usually reserved for patients who have had 2 or more unprovoked seizures. An anticonvulsant can be started after the first unprovoked seizure if it is deemed that the child is at high risk for having additional seizures. This may be the case in patients who have an abnormal EEG, abnormal brain MRI, or a strong family history of epilepsy.

ALTERED MENTAL STATUS (ENCEPHALOPATHY)

Encephalopathy simply refers to an altered state of consciousness. Encephalopathy may be clinically evident on examination as difficulty maintaining arousal (lethargy) or as an unresponsiveness to pain (comatose state). It may also present as a change in behavior in which there is agitation, confusion, delusions, or hallucinations. Patients with encephalopathy should prompt an emergent workup for an underlying disease process, including localized cerebral pathology, ingestion of toxins, infection, or inflammation. Given that life-threatening conditions such as intracranial hemorrhage, bacterial meningitis, and sepsis can lead to an encephalopathic patient, it is extremely important that such a patient be evaluated in an emergent setting where appropriate resuscitative measures can be taken if necessary.

All encephalopathic patients should be evaluated for signs of increased intracranial pressure as it may warrant emergent neurosurgical intervention. Aspects of the history that may point to raised intracranial pressure include projectile vomiting, seizure activity, or acutely worsening headache. On examination, visual changes, papilledema, and ocular nerve palsies may be present. In a child with an open fontanelle, the presence of a bulging fontanelle may also be indicative of increased intracranial pressure. Rapidly enlarging head circumference may also be a finding of increasing intracranial pressure. The findings of increased intracranial pressure may be seen in patients with intracranial tumors, infections, hemorrhages, or the presence of hydrocephalus and warrant emergent evaluation usually with a CT scan.

Once a patient has been stabilized, the search can then focus on an etiology of encephalopathy. The presence of encephalopathy in the setting of focal neurologic deficits such as hemiparesis suggests a diagnosis of cerebral infarct. MRI of the brain can evaluate for the presence of a stroke. The presence of fever in conjunction with meningeal signs suggests a diagnosis of central nervous system infection. CSF studies and MRI of the brain can evaluate for signs of a central nervous system infection or postinfectious encephalomyelitis. The presence of altered mental status (with prominently psychiatric disturbances) in the setting of seizure activity is suggestive of a paraneoplastic or autoimmune encephalitis. This diagnosis is confirmed with paraneoplastic and autoimmune biomarkers. A patient with known epilepsy found to be encephalopathic would suggest postictal phenomenon versus ongoing status epilepticus. An EEG should be obtained for an epileptic with encephalopathy who has not returned to baseline in a timely manner to evaluate for ongoing epileptic activity. The differential also includes metabolic disturbances such as hypoglycemia and hyponatremia. Inborn errors of metabolism, endocrine disorders, hepatic disease, renal disease, and toxic ingestion can present as encephalopathy as well. Treatment of encephalopathy requires treatment of the underlying medical condition.

Encephalopathy in the neonate can be subtle and difficult to diagnose. We assess the mental status of a neonate by ensuring a neonate can readily arouse to tactile stimuli, as well as eye opening, spontaneous movement of all 4 extremities, and vocalizations. In infants and toddlers, lethargy, agitation, and/or irritability may be the signs of altered mental status. It is not until a child gets older that he or she may be able to communicate the presence of visual and auditory hallucinations or delusions.

SENSORY DISTURBANCES

Paresthesias are sensory disturbances of the skin sometimes described as “tingling” or “burning” or “pins and needles” sensations. Although the differential is broad, the presence of paresthesias can, when combined with other neurologic signs and symptoms, provide a sense of where the lesion may exist. Starting most distally in the sensory pathway, paresthesias and sensory loss in the sensory distribution of a nerve with or without weakness can be indicative of a peripheral neuropathy. Lesions involving nerve roots will present with pain, along with paresthesias that radiate down the limb. An EMG/NCS can be beneficial in evaluating for either of these conditions. The sensation of electricity moving from the neck into the extremities upon neck flexion is worrisome for a cervical spinal cord lesion. A cervical spine MRI will be helpful in evaluating for such a lesion. Sensory changes that are not in typical anatomic patterns or in multiple locations or occurring during distinct episodes, especially in adolescent children, could be presenting symptoms of multiple sclerosis, and brain and spine MRI would be useful to identify the typical lesions. Finally, lesions of the thalamus and parietal lobe (which can be seen with an acute cerebral infarct) may present as a contralateral face and body sensory loss. Lesions involving only the thalamus will produce an isolated sensory syndrome, whereas lesions involving the parietal lobe may present additionally with language deficits and a contralateral neglect.

VISUAL DISTURBANCES

In order for a visual stimulus to be perceived, light must travel through the eye and be directed onto photoreceptor cells (rods and cones) on the retina. From the retina, the signal passes through the optic nerve to the optic chiasm and then through the optic tract to the thalamus. From here, the signal is carried to the occipital cortex through optic radiations that exist in subcortical white matter. Thus, visual disturbances may represent an underlying neurologic disease that involves 1 or many components of the nervous system.

A neurologically intact infant should be able to fixate and follow the examiner horizontally and vertically. Assessing the visual system becomes easier as the child grows, when the Snellen Chart can be used to assess visual acuity. Visual changes may be difficult to communicate in an infant or toddler, but at the very least, the initial examination should involve testing the child for the ability to track, checking for a blink reflex to light, testing for a blink to visual threat, and finally, checking for pupillary constriction to light stimulus. If there are any concerns regarding functioning of the above, a neurologic and ophthalmologic workup should be initiated.

Acute visual changes including diplopia, reduced visual acuity, increased central scotoma, loss of color discrimination, patchy visual loss, and complete monocular or binocular visual loss all warrant emergent evaluation in consultation with ophthalmology and neurology. Visual changes are often accompanied by additional neurologic and nonneurologic symptoms. They include headache, painful eye movements, additional cranial neuropathies, neck and back pain, vomiting, and hemiparesis. These are additional worrisome signs and can point to specific diagnoses, as described below.

Patients with acute visual disturbances in the setting of headaches should be fully evaluated immediately as these disturbances may be indicative of increased intracranial pressure. Funduscopic examination can reveal papilledema, confirming increased intracranial pressure, although papilledema may not always be present. There can be many causes of elevated intracranial pressure including neoplasm, intracranial hemorrhage, meningitis, encephalitis, and so on. Only if all of these causes are ruled out, usually with neuroimaging, can a diagnosis of idiopathic intracranial hypertension or pseudotumor cerebri be considered (see Chapter 546). The diagnosis of increased intracranial pressure is confirmed with the finding of elevated opening pressure with a lumbar puncture.

Patients with acute to subacute monocular or binocular visual changes (decreases in visual acuity, change in color vision) along with eye pain that is worsened with eye movements may have optic neuritis. Pupillary examination will potentially reveal a relative afferent pupillary defect, and blurring of the disc margins may be seen on funduscopic examination. The diagnosis is made clinically but may be confirmed with an MRI of the brain and orbits demonstrating contrast enhancement of the optic nerves. Demyelinating diseases that can cause optic neuritis include multiple sclerosis and neuromyelitis optica, but optic neuritis can occur in isolation. Infectious and postinfectious diseases can serve as the etiology for optic nerve impairment. If suspected, cases of optic neuritis should be referred to the emergency department immediately where intravenous methylprednisolone may be used for treatment.

Acute visual disturbances in combination with headaches and possibly seizures or altered mental status should also raise suspicion for reversible posterior leukoencephalopathy syndrome (also known as posterior reversible encephalopathy syndrome [PRES]). Patients who have a history of hypertension or who are on chemotherapeutic agents are at higher risk of developing PRES. An MRI of the brain will be useful in characterizing this disease process.

Gradual onset of visual disturbances in combination with developmental regression is concerning for a leukodystrophy, a group of neurodegenerative conditions involving progressive degeneration of cerebral white matter. An MRI of the brain in combination with specific metabolic and genetic testing can help with the diagnosis of the different leukodystrophies.

DEVELOPMENTAL DELAY

The differential diagnosis for developmental delay is broad, and a thorough history (including developmental history) and physical examination are crucial to narrowing down the potential diagnosis. Development can be assessed by evaluating gross motor, fine motor, language, and social milestones. A maternal history should be obtained reviewing chronic illnesses, infections, and history of miscarriages. Maternal exposure to drugs, alcohol, cigarettes, or prescription medications during pregnancy should also be reviewed. Details of the pregnancy itself, including markers of fetal well-being such as fetal movement, should be reviewed. A child who is found to be developmentally delayed in the presence of a history of decreased fetal movement and hypotonia should raise the suspicion of a neuromuscular condition. A perinatal history should also be obtained including mode of delivery and circumstances leading to delivery (placental abruption, trauma, nonreassuring fetal heart tones—any of which can predispose a neonate to hypoxic injury). If a patient is found to be developmentally delayed and the history and/or the neurologic examination is suggestive for toxic exposures in utero, intrauterine infections, or anoxic brain injury, an MRI of the brain should be obtained to assess for the presence of central nervous system injury. A neonatal history should also be reviewed for the presence of intracranial hemorrhages or meningitis/encephalitis, which can predispose a child to developmental delay. The presence of dysmorphic features in combination with developmental delay should prompt genetic testing to assess for chromosomal abnormalities such as fragile X syndrome or trisomy 21. A family history including the presence of consanguinity may also point to genetic etiologies of developmental delay. The presence of skin lesions in the presence of developmental delay may be indicative of neurocutaneous syndromes such as neurofibromatosis type 1 and tuberous sclerosis.

While taking a developmental history, special attention should be paid to autistic features including impairments in language, impairments in social skills, and restricted patterns of behavior or interests. Poor eye contact, parallel play, and preoccupation with certain toys are just a few signs suggestive of autistic features. Genetic conditions such as Phelan-McDermid syndrome can present with autistic features. Patients with metabolic conditions and epileptic syndromes (such as Dravet syndrome) may also present with autistic features, and these disorders should be suspected when there has also been developmental regression. The presence of developmental regression can also be indicative of a progressive neurodegenerative condition prompting urgent neurologic evaluation. Language delay should prompt a thorough audiologic evaluation to ensure there are no impairments in hearing contributing to the language delays.

Developmental delay often requires a multidisciplinary approach to diagnosis, medical treatment, and management to ensure that the associated disabilities are addressed. The goal for the pediatrician and neurologist is to involve (where appropriate) the services of physical medicine and rehabilitation, orthopedics, therapies (speech, physical, and occupational), and neuropsychologists to ensure the patient can meet his or her developmental potential.

DISTURBANCES OF HEAD GROWTH

Growth of the head usually is driven by growth of the brain parenchyma; hence, the importance of the serial measurement of head circumference in neonates and infants. In addition to absolute head circumference, trends in the growth of head circumference are also important to note, especially in the neonate or infant. The presence of a rapidly enlarging head circumference in conjunction with a change in mental status and vomiting may point to increasing intracranial pressure and hydrocephalus, warranting emergent neurologic care, whereas decelerating head growth in a girl with loss of purposeful hand movements would point to Rett syndrome.

Microcephaly is the result of reduced brain growth. It can occur in certain genetic conditions, neural tube defects (eg, encephalocele), midline cerebral abnormalities (eg, holoprosencephaly), or disorders of neuronal migration (eg, lissencephaly or polymicrogyria). Microcephaly also can occur as the result of a destructive or degenerative process of the brain that is forming, which can occur with toxic exposures in utero, congenital infections, anoxic brain injuries, and chronic systemic diseases (see also Chapter 543).

Macrocephaly can have numerous etiologies including overgrowth of the brain, increased CSF, and intracranial bleeding (see also Chapter 543). Increase in brain tissue, also known as megalencephaly, can be seen with neurocutaneous disorders such as neurofibromatosis type 1 and tuberous sclerosis. In cases in which there is developmental delay or regression along with megalencephaly, neurodegenerative conditions such as Tay-Sachs disease, Canavan disease, and Alexander disease should be considered. The presence of megalencephaly can also be benign (benign familial megalencephaly), and, thus, a child with macrocephaly should prompt the measurement of the parents’ head circumference.

Hydrocephalus can cause macrocephaly. Obstruction to the CSF circulation (eg, Dandy-Walker malformation or aqueduct stenosis) can lead to a noncommunicating hydrocephalus. An inability to resorb CSF (eg, intraventricular hemorrhage or meningitis) causes communicating hydrocephalus. Benign enlargement of the subarachnoid space can occur when there is a buildup of CSF in the extraventricular system and can lead to macrocephaly. Finally, intracranial bleeds such as intraventricular, epidural, and subdural hemorrhages can give rise to macrocephaly.

Neuroimaging (brain MRI) can help in the assessment and further workup and management (eg, surgical) of the cause of micro- or macrocephaly.

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