bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurology
Authors: Harrison Mark
Published: March 2017

This chapter describes the pathophysiology of the neurological system as it applies to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of intracranial pressure, sensory pathways, motor pathways, nerve conduction, pain, sight, auditory system, brainstem reflexes, and temperature. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
Haematological system
Authors: Harrison Mark
Published: March 2017

This chapter describes the pathophysiology of the haematological system as it applies to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of erythropoiesis, blood groups, coagulation, and thrombolysis. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
Metabolic response to insult
Authors: Harrison Mark
Published: March 2017

This chapter describes metabolic response to insult as it applies to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of the control of energy production, and the metabolic response to stress including injury, infection, infarction, temperature, and burns. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
Inflammatory response
Authors: Harrison Mark
Published: March 2017

This chapter describes the pathology of inflammatory response as it applies to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of normal vs abnormal response, and inflammatory markers including C-reactive protein, rheumatoid factor, and antinuclear factor. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
Statistical terms
Authors: Harrison Mark
Published: March 2017

This chapter describes statistical terms as they apply to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of incidence, prevalence, and qualitative and quantitative data. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
2 × 2 Contingency table
Authors: Harrison Mark
Published: March 2017

This chapter describes the 2 × 2 contingency table as it applies to Emergency Medicine, and in particular the Primary FRCEM examination. The chapter outlines the key details of sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios for positive and negative results, and the 2 × 2 contingency table. This chapter is laid out exactly following the RCEM syllabus, to allow easy reference and consolidation of learning.
Respiratory Failure and Mechanical Ventilation
Authors: Lee Jan Hau , Cheifetz Ira M.
Published: March 2017

This chapter on respiratory failure and mechanical ventilation provides essential information about how to support children with severe respiratory disorders. The authors discuss multiple modes of respiratory support, including high-flow nasal cannula oxygen, noninvasive ventilation with continuous positive airway pressure and bilevel positive airway pressure, as well as conventional, high-frequency, and alternative modes of invasive ventilation. The section on invasive mechanical ventilation includes key information regarding gas exchange goals, modes of ventilation, patient–ventilator interactions, ventilator parameters (including tidal volume, end-expiratory pressure, and peak plateau pressure), extubation readiness testing, and troubleshooting. The authors also provide the new consensus definition of pediatric acute respiratory distress syndrome. Also included are multiple figures and indispensable information on adjunctive therapies (inhaled nitric oxide, surfactant, prone positioning, and corticosteroids) and respiratory monitoring (including capnography and airway graphics analysis).
Pediatric Shock
Authors: Pang Diana , Carcillo Joseph A.
Published: March 2017

The chapter on pediatric shock recognition and management provides essential information on types of shock and its management. It contains summaries of hypovolemic, hemorrhagic, cardiogenic, vasoplegic, septic, metabolic, and dysoxic shock. All types of shock are best treated when therapy is targeted toward achieving specific goals (goal-directed therapy), and this chapter provides guidelines for clinical, hemodynamic, and biochemical goals. To achieve those goals, the chapter also provides guidelines on the use of key therapies, including isotonic crystalloid and colloid, blood products, catecholamines, inodilators, vasopressors, other medications (steroids, prostaglandin, triiodothyronine), and extracorporeal life support.
Neurocritical Care
Authors: Shein Steven L. , Clark Robert S. B.
Published: March 2017

Brain injury is the most common proximate cause of death in pediatric intensive care units. For children who survive critical illness, long-standing brain damage and residual brain dysfunction can affect quality of life significantly. Therefore, minimizing neurological injury to improve patient outcomes is a priority of neurocritical care. This may be accomplished by implementing specific targeted therapies, avoiding pathophysiological conditions that exacerbate neurological injury, and using a multidisciplinary team that focuses on contemporary care of children with neurological injury and disease. This chapter reviews pertinent anatomy and physiology; general principles of pediatric neurocritical care; and specifics for caring for children with traumatic brain injury, hypoxic–ischemic encephalopathy, status epilepticus, meningitis/encephalitis, stroke, and acute hydrocephalus.
Infections in the Intensive Care Unit
Authors: Afreen Samina , Wong Hector R. , Michaels Marian G.
Published: March 2017

Infections are a frequent problem for children cared for in the intensive care setting. The child can have a primary infectious condition that is severe enough to require hospitalization in the intensive care unit (ICU). Alternatively once in the ICU setting children are at risk for nosocomial infections due to a need for catheters that breech the cutaneous barriers, mechanical ventilation and exposures to blood products. Finally, many children sick enough to be in an intensive care setting have underlying immune deficiencies which put that at increased risk. This chapter reviews some of the major underlying infections that lead to intensive care stays as well as the major nosocomial infections which can plague our patients.
Endocrine Disorders in Pediatric Critical Care
Authors: Soto-Rivera Carmen L. , Agus Michael S. D.
Published: March 2017

This chapter focuses in pediatric endocrine disorders that can present acutely and warrant intensive care. Because most of the symptoms associated with endocrine diseases are nonspecific, a broad index of suspicion and knowledge of the details of hormonal regulation are essential for accurate diagnosis and timely management. The chapter includes important information on the pathophysiology, clinical manifestations, evaluation, and management of potentially life-threatening endocrine disorders, including diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, acute primary and secondary adrenal insufficiency, disorders of calcium homeostatis, thyroid storm, and diabetic ketoacidosis. For treatment of these disorders, the authors discuss the use of vasopressin (aqueous pitressin), desmopressin, hydrocortisone, calcitonin, bisphosphonates, methimazole, iodide therapy, and insulin.
Pediatric Critical Care Pharmacology
Authors: Zuppa Athena
Published: March 2017

This chapter includes essential information about the basic principles of pharmacology and relates them to unique characteristics of critically ill children. The author provides a succinct summary of fundamentals of pharmacokinetics and pharmacodynamics, including absorption, distribution, metabolism, and elimination. First- and zero-order kinetics are reviewed, along with examples of drugs commonly used in the intensive care unit that follow those patterns of metabolism. The chapter also includes crucial information about how development from birth affects the various aspects of pharmacology. The effects on drug metabolism of shock, and renal and hepatic dysfunction are provided, along with drug–drug interactions, including commonly used drugs in critical care that induce or inhibit enzyme activity.
Pediatric Trauma
Authors: Lim Joanna C. , Goodhue Catherine , Cleek Elizabeth , Barthel Erik R. , Gaines Barbara , Upperman Jeffrey S.
Published: March 2017

Pediatric trauma is the leading cause of death in children 1 through 14 years old. This chapter includes key information focusing on initial evaluation, triage, and stabilization of children with blunt and penetrating trauma as well as burns (and the “rule of 9s”). The authors discuss specific injuries, including those to the head (traumatic brain injury), thorax, and abdomen; genitourinary area; and orthopedic/long-bone and nonaccidental trauma. Caring for injured children is best performed using advanced trauma life support protocols during the initial assessment. Protocol-driven examination, regardless of injury mechanism, ensures clinicians consider life-threatening injuries in an orderly fashion, starting with the primary survey and moving on to the secondary survey and definitive care. After injuries are identified, priorities shift toward involving the necessary specialists. Key mnemonics in trauma care are explained: the ABCDE initial evaluation, the AMPLE history, and the AVPU categorization of neurologic status.
Parkinson Syndromes
Authors: Kotagal Vikas , Dayalu Praveen
Published: March 2017

Progressive supranuclear palsy (PSP) is a neurodegenerative condition characterized by axial motor features, oculomotor abnormalities, and cognitive dysfunction. PSP is characterized by progressive tau deposition with neuronal loss in cortical and subcortical regions. The underlying etiology of PSP may reflect complex gene-environment interactions, though genetic heterogeneity in the microtubule-associated protein tau (MAPT) gene can confer increased risk. Clinical care of patients with PSP focuses on minimizing motor and non-motor morbidity using available symptomatic therapies.
Parkinson Syndromes
Authors: Barmada Sami
Published: March 2017

Corticobasal syndrome (CBS) is a clinically and pathologically heterogenous condition marked most often by asymmetric parkinsonism and apraxia, with or without cognitive dysfunction. This review considers the genetic and neuropathologic origins of the syndrome, and discusses how these factors interact with the anatomy and function of vulnerable brain regions to produce the distinct set of symptoms characteristic of CBS. It also discusses how these observations affect the rationale and development of therapies for CBS and other neurodegenerative disorders.
Paroxysmal Dyskinesias and Other Paroxysmal Movement Disorders
Authors: Waln Olga , Jankovic Joseph
Published: March 2017

Paroxysmal dyskinesias are episodic, recurrent movement disorders characterized by attacks of dystonia, chorea, athetosis, ballism, or any combination of these hyperkinetic movements, with variable duration and frequency of the episodes and normal interictal neurological examination. Four main types of paroxysmal dyskinesias have been described: paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and paroxysmal hypnogenic dyskinesia. The disorders are usually inherited in autosomal dominant fashion and have their onset in the first two decades of life. In addition, there are other paroxysmal or episodic movement disorders, including episodic ataxias, paroxysmal nystagmus, and other paroxysmal diseases such as epilepsy and migraines, that may be associated with movement disorders. Response to medications such as anticonvulsants or benzodiazepines can vary among different types of paroxysmal dyskinesia.
Alzheimer’s Disease
Authors: Hyman Bradley T , Perez-Nievas Beatriz G , Barroeta-Espar Isabel , Serrano-Pozo Alberto , Frosch Matthew , Gomez-Isla Teresa
Published: March 2017

Alzheimer’s disease is the most common cause of dementia in the developed world, and has a rising incidence due to the strong age-related nature of the risk for the disease. As the population as a whole ages, the number of cases of Alzheimer’s disease will rise in what is essentially an epidemic. The disease is progressive, evolves over years, but is ultimately fatal. Aside from symptomatic therapies that are weakly effective, no treatments are available. The underlying pathobiology, connections to the genetics of the disease, and prospects for research are explored.
Frontotemporal Lobar Degeneration
Authors: Graff-Radford Jonathan , Josephs Keith A.
Published: March 2017

Frontotemporal dementia (FTD) is an uncommon but important form of degenerative disease characterized by clinical syndromes that result from degeneration of the frontal and temporal lobes. FTD is divided based on clinical presentation into behavioral variant FTD (bvFTD), semantic dementia, and progressive nonfluent/agrammatic aphasia. Several recent studies have advanced our knowledge of the genetics of FTD, with the three most common FTD genes being microtubule-associated protein tau (MAPT) and progranulin (GRN), and a noncoding repeat expansion in C9ORF72. Tau and TDP-43 are the most common pathologies associated with FTD. No pharmacological therapies are currently approved for use in FTD.
Vascular Cognitive Impairment
Authors: Karamchandani Rahul , Barbas Nancy R.
Published: March 2017

Vascular cognitive impairment (VCI) refers to the spectrum of cognitive disturbances that result from cerebrovascular brain injury. Cerebrovascular disease is associated with multiple underlying pathologies. Risk factors, clinical features, and treatment options overlap with those associated with Alzheimer’s disease, another common cause of cognitive decline. The complexity of vascular cognitive impairment and, notably, the interplay between clinical, pathologic, genetic, and biomarker characteristics of VCI and Alzheimer’s disease are discussed. The chapter places an emphasis on vascular cognitive impairment resulting from disease affecting small vessels, in contrast to that due to disease involving large vessels, in an effort to focus on a large body of evolving work and ongoing attempts at improving understanding of this complex entity.
Symptomatic Management in Amyotrophic Lateral Sclerosis
Authors: Gladman Matthew , Zinman Lorne
Published: March 2017

Although ALS remains an incurable disease, there are specific treatments that can significantly improve quality of life and some that can modify survival. Patients are best followed in multidisciplinary ALS clinics where a number of medical experts can address a wide range of symptoms. Additional studies are needed to develop evidenced-based best practice guidelines to further improve care for patients with ALS. Bulbar dysfunction eventually affects the vast majority of ALS patients, and progressive dysphagia results from weakness and spasticity of the muscles involved in swallowing. Dysphagia is associated with increased risk of aspiration and choking, as well as with long-term risk of malnutrition, weight loss, and dehydration. Appropriate measures to enhance caloric intake contribute to a greater sense of well-being. Augmentative communication devices and ventilator support can also be used to reduce suffering.
Epidemiology of Amyotrophic Lateral Sclerosis
Authors: O’Reilly Éilis J
Published: March 2017

The epidemiology of ALS is an emerging field and, like the epidemiology of cardiovascular disease and cancer in the mid last century, requires time for convergence of findings. There appears to be a genetic influence, and one study of twins found that heritability of sporadic ALS is 60%. At present it is thought that 60$ to 70% of genetic mutations responsible for fALS in populations of European ancestry are known. SOD1 mutations were the earliest discoveries in fALS. Subsequently, mutations were identified in TARDBP, which encodes TDP-43 protein found in neuronal inclusions in fALS and frontotemporal dementia (FTD). High rates of ALS have also been reported in military personnel and in certain groups of elite athletes such as soccer players.
Amyotrophic Lateral Sclerosis
Authors: Ferraiuolo Laura , Kolb Stephen J.
Published: March 2017

An overriding mystery of ALS pathogenesis orbits around the molecular basis of selective motor neuron vulnerability and clouds our view. There are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Motor neuron vulnerability is likely related to the unique biological characteristics of these cells. This chapter introduces central molecular pathways that appear to be involved in the pathogenesis of ALS, and highlights why dysregulation of these mechanisms could lead to motor neuron death. Indeed, there are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Our task is to determine those mechanisms that are relevant to ALS pathogenesis that may be targeted therapeutically to prevent onset and/or halt progression.
Amyotrophic Lateral Sclerosis
Authors: Harris Brent T. , Khan Galam A. , Sadeghi Saed
Published: March 2017

Although the basic gross and microscopic pathological changes in amyotrophic lateral sclerosis (ALS) have been known for more than 100 years, emerging technology and research into the cellular and molecular changes found in this disease are challenging our understanding about the pathogenesis and pathophysiology. All cell types of the CNS/PNS as well as circulating immune cells have been implicated in the pathology of ALS. Numerous genes, their proteins, and environmental factors have also been associated. However, we still do not understand the specific gene-environmental interactions that bring about and drive this devastating disease in most cases. This short chapter does not address the causal factors and molecular pathogeneses that have been hypothesized and actively researched in the pathology of ALS-as these are discussed in other sections of this text. Here, it shows and discusses the basic pathological changes at the tissue and cellular levels that help to establish the pathological diagnosis of ALS at autopsy.
Upper Motor Neuron Disorders Hereditary Spastic Paraplegia and Primary Lateral Sclerosis
Authors: Paganoni Sabrina , Atassi Nazem
Published: March 2017

Upper motor neuron (UMN) syndromes are a group of rare, degenerative neurological disorders that are classified as either hereditary spastic paraplegia (HSP) or primary lateral sclerosis (PLS). Our understanding of their underlying pathophysiology is unfortunately very limited and has been a significant barrier to the development of disease-modifying treatments. Recent advances in genetics and in vitro and in vivo disease modeling have provided new insights into disease mechanisms and hold the promise to lead to the future development of mechanism-based therapies.
Spinal Muscular Atrophy
Authors: Monani Umrao R. , De Vivo Darryl C.
Published: March 2017

Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by insufficient SMN protein. As of yet, there is no good treatment for the disease. SMA has an incidence of ~1 in 10,000 newborns carrier frequency of 1 in 50, making it the most common inherited cause of infant mortality. Patients with severe SMA, or Werdnig-Hoffman disease, typically manifest weakness during the first 6 months of life. Such patients are so debilitated that they never sit independently, frequently succumbing to the disease before age 2 years. A much milder form of SMA, Kugelberg-Welander disease, with onset after 18 months of age, often during childhood and characterized by prolonged ambulation and a normal life expectancy, was described in 1956. In 1995 mutations in a novel gene, Survival of Motor Neuron 1 (SMN1), were determined to be the specific cause of SMA.
In Vitro and In Vivo Models of Spinal Muscular Atrophy
Authors: Arnold W. David , Burghes Arthur H. M.
Published: March 2017

Spinal muscular Atrophy (SMA) is caused by reduced levels of the SMN protein. In humans this is caused by loss of SMN1 and retention of SMN2. The challenge in modelling SMA, in either tissue culture cells or animals, is first to obtain the desired SMN levels equivalent to what is observed in SMA. Various models of SMA in tissue culture cells, invertebrates, and mammals have been created have been developed. The targets of SMN reduction that are most relevant for the pathogenesis of SMA and how the phenotype of SMA can be modified independent of SMN levels are two important questions that remain unanswered. Here the current in vitro and in vivo models of SMA are summarized.
Biological Basis of Primary Generalized Epilepsies—Pathophysiology
Authors: Youngblood Mark W. , Blumenfeld Hal
Published: March 2017

The primary generalized epilepsies include a heterogeneous group of seizures including absence, myoclonic, and generalized tonic-clonic seizures that are not strictly localized on EEG and not secondary to another disorder. The seizures are often associated with a loss of consciousness and may present with motor manifestations, including convulsions and arrest of respiration. Generalized spike-and-wave discharges on electroencephalogram are a uniting feature, and this pattern of activity is a direct manifestation of the underlying mechanism of these disorders. A review of important underlying circuitry will set the stage to discuss the pathological and genetic basis of these disorders, and the chapter will conclude with a review of current and potential therapeutics.
Epilepsies That Occur Predominantly in Girls
Authors: Sadleir Lynette G , Gecz Jozef , Scheffer Ingrid E
Published: March 2017

Availability of DNA sequencing has led to an increase in the number of children being identified with mutations in specific genes in specific epilepsy phenotypes. The presence of mutations that cause epilepsy only in females is one of the discoveries revealed in the sequencing era. Mutations in PCDH19 and CDKL5 are distinctive and identifiable forms of female-only epilepsy, and clinicians should consider PCDH19 in normal girls presenting with clusters of afebrile or febrile seizures in the first 3 years of life, and CDKL5 in girls or boys presenting with severe developmental delay within the first 6 months of life followed by intractable seizures including spasms within the first 2 years.
Clinical Presentation, Diagnosis, and Course: Epilepsy Syndromes with Focal Seizures
Authors: Boro Alex , Engel Jerome
Published: March 2017

The epilepsies are a common and often devastating group of diseases characterized by recurrent seizures and coexisting conditions including cognitive, emotional, and behavioral comorbidities. These diseases affect about 1% of the population worldwide. About 60% of patients with epilepsy have focal seizures. The goal of this chapter is to describe the clinical presentation, epidemiology, and prognosis of the epilepsy syndromes characterized by focal seizures. The biological bases of these diseases and their management are explored in detail in other chapters in this volume.
Migraine and Other Headache Disorders
Authors: Charlson Robert W. , Robbins Matthew S.
Published: March 2017

In recent years, the characterization of the neurobiology of migraine and other headache disorders has been driven by the search to better understand several key factors: genetics, the role of neuromodulators such as calcitonin gene-related peptide (CGRP), processes including central and peripheral sensitization, neurogenic inflammation, central pain networks, and areas of activation demonstrated by advancing functional neuroimaging techniques. Yet the ultimate causes of migraine remain unknown. Nonetheless, recent work has advanced our understanding of this complex disorder, and pointed toward a future where these modalities may provide an integrated understanding of its pathophysiology and provide specific treatment targets.
Neurobiology of Autism and Intellectual Disability
Authors: Budimirovic Dejan B. , Subramanian Megha
Published: March 2017

Fragile X syndrome (FXS) is a neurodevelopmental disorder that manifests with a range of cognitive, behavioral, and social impairments. It is a monogenetic disease caused by silencing of the FMR1 gene, in contrast to autism spectrum disorder (ASD) that is a behaviorally-defined set of complex disorders. Because ASD is a major and growing public health concern, current research is focused on identifying common therapeutic targets among patients with different molecular etiologies. Due to the prevalence of ASD in FXS and its shared neurophysiology with ASD, FXS has been extensively studied as a model for ASD. Studies in the animal models have provided breakthrough insights into the pathophysiology of FXS that have led to novel therapeutic targets for its core deficits (e.g., mGluR theory of fragile X). Yet recent clinical trials of both GABA-B agonist and mGluR5 antagonist revealed a lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS. Recent research shows promise for the mapping of the multitude of genetic variants in ASD onto shared pathways with FXS. Nonetheless, in light of the huge level of locus heterogeneity in ASD, further effort in finding convergence in specific molecular pathways and reliable biomarkers is required in order to perform targeted treatment trials with sufficient sample size. This chapter focuses on the neurobehavioral phenotype caused by a full-mutation of the FMR1 gene, namely FXS, and the neurobiology of this disorder of relevance to the targeted molecular treatments of its core symptoms.
The Urea Cycle Disorders
Authors: Gropman Andrea L. , Pappa Belen , Ah Mew Nicholas
Published: March 2017

The urea cycle is the primary nitrogen disposal pathway in humans. The urea cycle requires the coordinated function of six enzymes and two mitochondrial transporters to catalyze the conversion of a molecule of ammonia, the α-nitrogen of aspartate and bicarbonate into urea. Whereas ammonia is toxic, urea is relatively inert, soluble in water, and readily excreted by the kidney in the urine. The accumulation of ammonia and other toxic intermediates of the cycle lead to predominantly neurological sequelae. All of the genes have been identified. The disorders may present at any age from the neonatal period to adulthood, with the more severe patients presenting earlier in life. Patients are at risk for metabolic decompensation throughout life, often triggered by illness, fasting, surgery and postoperative states, peripartum, stress, and increased exogenous protein load. This chapter addresses common somatic and neurological presentation, differential diagnosis, laboratory testing, and treatments.
Phenylketonuria
Authors: Vernon Hilary
Published: March 2017

Phenylketonuria is an autosomal recessive biochemical disorder most often resulting from a deficiency of phenylalanine hydroxylase, the enzyme which catalyzes the conversion of phenylalanine to tyrosine. The remainder of the cases are caused by abnormalities in the phenylalanine hydroxylase cofactor, tetrahydrobiopterin. Phenylketonuria can be divided into three subgroups based on the elevation of plasma phenylalanine in the untreated state: “classical,” “variant,” and “benign.” Untreated individuals with classical phenylketonuria develop neurocognitive abnormalities including seizures, microcephaly, and severe intellectual disability. Other clinical effects include a musty body odor, eczema, and reduced skin pigmentation. Treatment, which includes dietary restriction of phenylalanine, supplementation with synthetic protein, and, in some cases, administration of a synthetic form of tetrahydrobiopterin, is successful in preventing the long-term consequences of phenylketonuria.
Lysosomal Storage Disorders
Authors: Maegawa Gustavo H. B.
Published: March 2017

The lysosomal storage disorders (LSDs) are a group of inborn organelle disorders, clinically heterogeneous, and biochemically characterized by accumulation of nondegraded macromolecules primarily in the lysosomal and other cellular compartments. Given the common and essential cellular function of the lysosomal system in different organs and systems, patients afflicted with these disorders present a broad range of clinical problems, including neurological problems, visceromegaly, and skeletal deformities. Onset of symptoms may range from fetal period to adulthood. The neurological problems include developmental delay, seizures, acroparesthesia, motor weakness, muscle wasting, behavioral/psychiatric disturbances, cerebrovascular ischemic events, and extrapyramidal signs. Patients may present with symptoms later that include psychiatric manifestations, are slowly progressive, and may precede other neurologic or systemic features. Most of LSDs are autosomal recessive; however, a few are X-linked with symptpmatic female carriers (e.g., Fabry disease). In most of them, the diagnosis is established by biochemical and/or molecular assays. In terms of management, disease-modifying therapies include enzyme replacement, hematopoietic stem cell transplantation, and substrate reduction therapy. Patients and their families require genetic counseling regarding reproductive risks, disease prognosis, and therapeutic options. Investigations of disease molecular mechanisms provide insights into potential targets for the development of therapeutic strategies. Supportive care has been the key and essential for most LSDs, resulting in substantial improvement in quality of life of patients and families.
Peroxisomal Disorders
Authors: Raymond Gerald V. , Jefri Mohamed Y. , Baranano Kristin W. , Fatemi Ali
Published: March 2017

Disorders of the peroxisome are divided into two major categories. In the first, the organelle fails to develop normally, leading to disruption of multiple peroxisomal enzymes. The second category consists of those disorders in which the peroxisome structure is normal but functioning of a single peroxisomal enzyme or protein is defective. While there is an expanding list of disorders in both categories, this chapter focuses on X-linked adrenoleukodystrophy, the most common peroxisomal disorder, and on peroxisomal assembly/biogenesis disorders.
Leukodystrophies
Authors: Schrifl Ulrike , Naidu SakkuBai , Fatemi Ali
Published: March 2017

The term “leukodystrophies” refers to a group of genetic diseases characterized by degeneration of white matter in the central nervous system. Depending on the type of leukodystrophy, the phenotype can range from early infantile-onset, rapid, progressive forms to adult-onset slowly progressive variants. The understanding, definition, and classification have been enhanced greatly by the combined use of neuroimaging, especially MRI, and genetic techniques. The window for targeted therapeutic interventions remains brief and management is often limited to symptomatic, supportive, and palliative care, and new approaches for treatment remain a great task for future research.
Smith-Lemli-Opitz Syndrome
Authors: Lee Ryan W.
Published: March 2017

Smith-Lemli-Opitz syndrome (OMIM 270400) (SLOS) is a multiple congenital anomaly disorder caused by an inborn error of cholesterol synthesis. Studies demonstrated that mutations in the gene for 3b-hydroxysterol-D7 reductase (DHCR7) result in low plasma cholesterol and corresponding increases in 7DHC. Distinctive facial features of include ptosis, small nose with anteverted nares, and micrognathia. Acral dysgenesis is common, foremost of which involve syndactyly and polydactyly. Children with SLOS often have a behavioral phenotype within the autism spectrum.
Sickle Cell Anemia
Authors: Lance Eboni I , Zimmerman Andrew W.
Published: March 2017

Sickle cell disease is a genetic hematological disorder involving red blood cells that become deformed when stressed. Patients with homozygous hemoglobin SS disease often have multiple systemic and neurologic complications, particularly stroke. Intellectual disability is commonly seen in the population, in patients with and without a history of stroke, attributed to different underlying mechanisms of brain injury. Autism is rare and not described in sickle cell disease in the literature to date. Many treatments (chronic transfusion therapy, hydroxyurea, bone marrow transplant) are in trials at this time to see if risk of stroke and other neurologic complications can be reduced (ClinicalTrials.gov identifiers: NCT01425307, NCT01389024, NCT00152113).
The Epidemiology of Multiple Sclerosis: An Historical Perspective
Authors: Munger Kassandra L.
Published: March 2017

The descriptive epidemiology has proved to be dynamic with attenuation of the latitude gradient, increase in incidence among women, and changes in the sex ratio over time, indicating that recent changes in environmental factors are responsible. Although we still do not know the causes of MS, or how to prevent it, the current evidence supports causal roles for EBV infection, vitamin D, and cigarette smoking.
Multiple Sclerosis: White Matter versus Gray Matter Involvement (The Cause of Disability in MS)
Authors: Filippi Massimo , Rocca Maria A.
Published: March 2017

The classic view of multiple sclerosis (MS) as a chronic, inflammatory-demyelinating condition affecting solely the white matter (WM) of the central nervous system (CNS) has been challenged by the demonstration, from pathologic and magnetic resonance imaging (MRI) studies, of an extensive and diffuse involvement of the gray matter (GM). This observation has driven the application of modern MR technology and methods of analysis to quantify the extent and distribution of damage to the different compartments of the CNS, with the ultimate goal of improving our understanding of the factors associated with the accumulation of clinical disability and cognitive impairment in these patients.
Multiple Sclerosis
Authors: Bhargava Pavan , Calabresi Peter A.
Published: March 2017

Multiple sclerosis is a chronic demyelinating neurological disorder of the brain and spinal cord, with both inflammatory and degenerative components. Current treatment strategies utilize immunomodulatory and immunosuppressive agents to reduce the inflammatory disease activity and retard accumulation of disability. Future challenges for treatment include identifying agents that will promote remyelination and axonal protection to help impact progressive forms of multiple sclerosis. This chapter discusses currently available disease modifying therapies, agents currently in phase 2/3 trials, and future directions in the treatment of multiple sclerosis.
Acute Disseminated Encephalomyelitis
Authors: Greenberg Benjamin M. , Desena Allen
Published: March 2017

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory disorder of the central nervous system (CNS) that can be fatal or lead to long-term disability. Various triggers have been identified in children and adults, which presumably cause an autoimmune response targeting myelin. The resulting inflammation causes demyelination and edema of the brain, spinal cord, and optic nerves. Depending on which portion of the CNS is affected, patients will experience a variety of symptoms including weakness, numbness, ataxia, encephalopathy, and seizures. Treatment is currently focused on reducing the amount of inflammation and supportive care.
Rasmussen Encephalitis
Authors: Bauer Jan , Bien Christian G.
Published: March 2017

Rasmussen encephalitis (RE) is a rare epileptic disorder that is characterized by the presence of unihemispheric seizures coinciding with inflammation. The disease mostly presents in children. Clinically, patients often reach a residual stage with drug resistant seizures and severe neurological deficits. Pathologically, at this stage, the brain shows variable neuronal loss. The etiology is unknown but the infiltration of large numbers of CD8 positive T lymphocytes suggests that this is an autoimmune disease. Treatment consists of anti-inflammatory therapy (IVIG or tacrolimus), which, however, does not reduce the drug-resistant seizures. Therefore, hemisperectomy is the most effective treatment of RE.
Neuroimaging of Acute Stroke
Authors: Kidwell Chelsea S. , Nael Kambiz
Published: March 2017

The neuroimaging workup for patients with suspected acute ischemic stroke has advanced significantly over the past few decades. Evaluation is no longer limited to noncontrast computed tomography (CT), but now frequently also includes vascular and perfusion imaging. Although acute stroke imaging has made significant progress with the development of multimodal approaches, there are still many unanswered questions regarding their appropriate use in daily patient care. It is important for all physicians taking care of stroke patients to be familiar with current multimodal CT and magnetic resonance imaging (MRI) techniques, including their strengths, limitations, and their role in guiding therapy.
Unusual Causes of Stroke
Authors: Leira Enrique C.
Published: March 2017

Unusual causes of stroke include those etiologies of cerebral infarction that are not related to the most common mechanisms of atherosclerosis or cardioembolism. This category includes non-atherosclerotic arteriopathies such as arterial dissection, moyamoya, and central nervous system (CNS) vasculitis. It also includes strokes related to a hypercoagulable state. Because the prevalence of atherosclerosis increases with age, unusual causes of stroke are more commonly seen in younger individuals in whom stroke is often not suspected, and therefore not readily diagnosed. Due to the relative rarity, these patients are difficult to test in clinical trials, which makes progress in management challenging.
Pediatric Stroke
Authors: Chung Melissa , Lo Warren
Published: March 2017

A variety of congenital and genetic disorders not seen frequently in adults may be responsible for stroke in infants and children. Stroke in newborn infants is as common as stroke in elderly individuals due to risk factor such as congenital heart disease, thrombophilia associated with polycythemia in neonates and genetic disorders, high estrogen impact from the mother during pregnancy, and inflammation due to infections. Stroke can also be caused by genetic disorders such as Ehleers-Danlos syndrome, Sturge-Weber syndrome, and vasculopathies such as lupus and fibromuscular dysplasia. Arterial dissection may be related to trauma and athletic injuries. Some drugs used to treat cancer such as asparaginase can also cause strokes, and infants and children can also present with venous sinus thrombosis associated with critical illness and dehydration.
The Natural History of Cerebral Aneurysms
Authors: Hasan David
Published: March 2017

Subarachnoid hemorrhage (SAH) secondary to rupture of cerebral aneurysms represents a relatively small fraction of strokes (5%) but morbidity and mortality associated with aneurysm rupture remain very high despite advances in the treatment of aneurysmal SAH. Cerebral vasospasm (CV) is the leading cause of delayed morbidity and mortality following aneurysmal subarachnoid hemorrhage, as well as delayed neurological dysfunction 1 to 2 weeks after rupture. Endothelial dysfunction is one of the primary contributing factors to CV following aneurysmal SAH, and this is associated with alterations in intracellular adhesion molecule-1 (ICAM-1), matrix metalloproteinases (MM), and the blood-brain barrier[p63].
Autonomic Neuropathies
Authors: Low Phillip A.
Published: March 2017

Autonomic neuropathy is a peripheral neuropathy with selective or disproportionate involvement of autonomic fibers. Because autonomic nerves innervate all organ systems, the manifestations of dysautonomia are protean. There are many causes of the autonomic neuropathies (Table 118.1). Some of the disorders in Table 118.1 are described in detail in other chapters. This chapter provides a brief description of the autonomic neuropathies, going from the acute/subacute to the more slowly evolving categories and finishing with some entities with less generalized dysautonomia.
Complex Regional Pain Syndrome
Authors: Pidcock Frank S.
Published: March 2017

Complex Regional Pain Syndrome (CRPS) is a chronic disorder that affects adults and children. It is extremely challenging to manage and results in dysfunctional patterns of behavior that have long-reaching effects on the patient and their families. New insights into the neurobiology of this condition have improved the understanding of mechanisms that alter nocioceptive perception and remodel neural circuitry in the brain and spinal cord. Traditional interventions for treating pain have little if any long-term effects. An interdisciplinary program addressing “bio-psycho-social factors” that includes graded exercise, desensitization techniques, and coping strategies has shown some success as a therapeutic approach. The reason for why certain individuals are susceptible to this condition and others are not remains elusive.
Radiculopathy and Plexopathy
Authors: Wheaton Michael , Nowacek Dustin , London Zachary
Published: March 2017

Disorders of the nerve roots and neural plexi present with pain, numbness, or weakness in the neck, back, or extremities. Although the history and physical examination provide essential diagnostic information, imaging and electrodiagnostic studies may further aid in localizing and characterizing the underlying lesion. Causes of radiculopathy include intervertebral disc herniation, spondylosis, spinal synovial cysts, infection, metastatic disease, hematoma, or infiltrative disease. The brachial and lumbosacral plexi are susceptible to trauma, structural anomalies, neoplastic infiltration, and inflammatory processes. Management of these disorders is directed at treating the underlying cause, alleviating pain, and focused physical rehabilitation.
Primary and Secondary Glioblastoma
Authors: Mammoser Aaron
Published: March 2017

Glioblastoma, formerly glioblastoma multiforme, is synonymous with WHO grade IV astrocytoma and is the most commonly diagnosed astrocytoma; it carries with it significant clinical, histologic, and molecular heterogeneity, with subtypes of the tumor and important new mutations associated with it characterized over the previous decade. Gene expression profiling has identified four tumor subgroups associated with specific mutational patterns, age of onset, and prognosis. The discovery of isocitrate dehydrogenase (IDH) mutations has led to further delineation between primary and secondary glioblastoma. Despite promising new investigational treatments, glioblastoma remains an incurable and fatal tumor.
Oligodendrogliomas
Authors: Kaley Thomas J.
Published: March 2017

Gliomas represent the most common symptomatic primary brain tumors, of which oligodendrogliomas are the least common subtype of glioma.1 The traditional thinking is that although the rarest, they also offer patients the best prognosis and they are deemed to be the most sensitive to treatment. However, although they may have a longer average survival than most other gliomas, nearly all patients with an oligodendroglioma will ultimately succumb to their illness due to either progressive and recurrent tumor or malignant transformation into a higher grade tumor. Optimal treatment of oligodendroglial tumors, especially those harboring a 1P/19Q codeletion, remains controversial.
Pediatric Brain Tumors
Authors: Ramaswamy Vijay , Huse Jason T. , Khakoo Yasmin
Published: March 2017

Cerebellar astrocytoma of childhood most commonly refers to cerebellar pilocytic astrocytoma, a World health Organization (WHO) Grade I tumor. However, on occasion cerebellar astrocytomas may demonstrate more aggressive histology including fibrillary astrocytomas, pilomyxoid astrocytomas, and rarely malignant lesions. In the near future, the diagnosis of cerebellar astrocytomas will be simplified by molecular analysis for BRAF fusions rather than a purely morphological approach. The emergence of next-generation sequencing can be expected to identify single nucleotide variations and further expand our understanding of both pilocytic astrocytomas as well as rare variants that occur in the cerebellum. Therapies targeting BRAF (B-raf protooncogene) are currently in clinical trial for adult malignancies and will eventually reach the pediatric population, allowing a targeted approach to recurrent and surgically inaccessible cases of pilocytic astrocytomas.
Chemotherapy and Radiation Therapy
Authors: Welch Mary R. , Nolan Craig
Published: March 2017

Neurotoxicity is a common problem in oncology practice and neurologists who care for cancer patients encounter a wide range of symptoms attributable to the side effects of radiation and/or chemotherapy. Complications involving the nervous system may be debilitating. Though generally improved by dose reduction or cessation of an offending agent, such symptoms can be irreversible and frequently have a profound impact on quality of life. The appropriate balance between therapeutic efficacy and drug or radiation toxicity requires close attention to the patient’s complaints as well as a thorough understanding of long-term consequences of both the disease and a given treatment’s side effects.
HIV Infection
Authors: Kannan Meena , Taylor Harrison , Tyor William
Published: March 2017

This chapter focuses on four common opportunistic infections of the nervous system associated with HIV infection, namely cryptococcal infection, cytomegalovirus infection, progressive multifocal leukoencephalitis, and toxoplasmosis. Essential features of neurobiology, clinical presentation, differential diagnosis, diagnostic workup, clinical management, and outcome are discussed for each condition. Although combined antiretroviral therapy for HIV has generally reduced the incidence of these complications of HIV infection, they remain important considerations, especially in areas in which antiretrovirals are unavailable or have limited availability.
Spinal Epidural Abscess
Authors: Shah Minal A. , Darouiche Rabih O.
Published: March 2017

Spinal epidural abscess is a rare and debilitating illness that requires prompt recognition to prevent unfavorable outcomes. Despite increased awareness of the disease and improved imaging methods, spinal epidural abscess sometimes remains a diagnostic and therapeutic challenge; as a result, morbidity and mortality can be high. Optimal management of spinal epidural abscess requires early intervention and coordination with a multidisciplinary team, including emergency medicine physicians, infectious disease specialists, radiologists, neurosurgeons, orthopedists, internists, and hospitalists. This chapter reviews the epidemiology, microbiology, pathogenesis, clinical features, diagnosis, treatment, and outcome of spinal epidural abscess.
Neurobiology of Transverse Myelitis and Infectious Myelopathies
Authors: Vodopivec Ivana , Cho Tracey A
Published: March 2017

Infectious agents cause spinal cord pathology by three different mechanisms: direct invasion/infection of neural tissues (i.e., infective myelitis), secondary inflammation and tissue bystander damage with or without autoimmune pathogenesis (parainfectious myelitis), or involvement of extra-axial structures (including the pia-arachnoid, the dura, the epidural space, or the adjacent spinal bones or intervertebral discs), resulting in compressive or ischemic myelopathy. This chapter describes the pathogenesis and treatment of these disorders.