bluuebunny/crossref_metadata_2025 huggingface dataset:
3. Freehold ownership
Authors: Gray Kevin , Francis Gray Susan
Published: May 2013

Titles in the Core Text series take the reader straight to the heart of the subject, providing focused, concise, and reliable guides for students at all levels.
The primary form of ownership in modern land law is freehold ownership – ownership of an estate in ‘fee simple’. This chapter discusses the following: the ways in which various kinds of fee simple estate may be created, transferred, and terminated; the new form of estate ownership – freehold ownership of ‘commonhold land’ – introduced by the Commonhold and Leasehold Reform Act 2002; and the rules (both at common law and in equity) under which covenants relating to land use may be enforced between owners of freehold estates.
5. Easements and profits à prendre
Authors: Gray Kevin , Francis Gray Susan
Published: May 2013

Titles in the Core Text series take the reader straight to the heart of the subject, providing focused, concise, and reliable guides for students at all levels.
This chapter focuses on two of the most important categories of entitlement that may be acquired over other people's land: easements and profits à prendre. Each of these rights comprises a species of proprietary entitlement, with the usual consequence in English law that the rights in question have the capacity to bind third parties. But, for precisely this reason, the law draws fairly stringent definitional boundaries around the kinds of incorporeal right that enjoy this potential of third-party impact. The discussions cover: the defining characteristics of easements and profits; the modes of creation and termination of easements and profits; and the transmission of the benefit and burden of easements and profits.
11. Public regulation of land
Authors: Roach Lee
Published: May 2013

Titles in the Core Text series take the reader straight to the heart of the subject, providing focused, concise, and reliable guides for students at all levels.
A significant measure of socially beneficial control over land and the local environment is achieved through various forms of state-imposed regulation. This chapter, which discusses how estate ownership is constrained by conceptions of stewardship in the public interest, examines the law and context surrounding some of the most far-reaching forms of state intervention in the area of land: control of land use and takings of land.
Visual Evoked Potentials
Authors: Carter Jonathan L.
Published: May 2013

The role of VEPs in evaluating patients with neurologic disease has evolved in an era of advanced neuroimaging techniques. MRI is clearly superior in sensitivity and specificity to VEPs in detecting retrochiasmatic lesions. However, in patients with lesions involving the optic nerve and anterior chiasm, VEPs have several important advantages: (1) VEPs are objective and reproducible and may demonstrate a functional abnormality that is not evident on physical examination or with neuroimaging studies; (2) VEP abnormalities may persist over time even when there is clinical resolution of visual symptoms; (3) VEPs may be a more reliable indicator of disease than MRI (MRI may reveal nonspecific abnormalities that do not represent a pathologic process, such as nonspecific white matter signal changes in the cerebral hemispheres); (4) VEPs may be more sensitive than MRI for detecting abnormalities in optic nerves; and (5) VEP studies are less expensive than MRI studies and can be used in situations where MRI studies are contraindicated (i.e., pacemakers, aneurysm clips, etc).
Neuro-Ophthalmology
Authors: Thurtell Matthew J. , Tomsak Robert L. , Daroff Robert B.
Published: May 2013

Neuro-Ophthalmology helps clinicians evaluate and manage patients with neuro-ophthalmic problems, and is divided into five sections: afferent (visual) disorders; efferent (eye movement) disorders; eyelid disorders; pupil disorders; and combination syndromes. It is based on the most current scholarly evidence and is filled with practical advice.
Inference 2: causation
Authors: Stewart Robert
Published: May 2013

The study of cause and effect forms the basis for most human interaction. The repetitive investigation of actions and their consequences can be readily seen in children's behaviour. Adult behaviour may be more complex but essentially involves identical principles. When we speak to someone for the first time, an initial impression is formed. If the conversation proceeds, the impression (hypothesis) is tested and refined through evaluating actions (what we say) and their consequences (the reaction or reply this provokes). If an unknown factor is present (e.g. the other person is preoccupied with something else), the relationship between cause and effect may be misinterpreted resulting in a false impression (e.g. that they are rude or unfriendly). The process can be seen as a repeated series of experiments, albeit unconscious. All of us are therefore involved in active cause–effect research for most of our waking lives. However the inferences (whether true or false) derived from these day-to-day experiments apply only to ourselves. Science and philosophy on the other hand seek to uncover truths that are generalizable beyond the individual. Because of this, their experiments require greater scrutiny.

Research may be divided into that which is observational (describing what is there) and that which is analytic (explaining why it is there). Deducing cause and effect relationships is central to analytic research. The ‘result’ of any given experiment is indisputable. What is open to interpretation is what caused that result. As discussed in Chapter 12, a series of questions have to be asked. What is the likelihood of it having occurred by chance? Was it caused by problems in the design of the study (bias), by the influence of a different factor to that hypothesised (confounding), or by a cause–effect relationship in the opposite direction to that anticipated (‘reverse’ causality)? If the anticipated cause–effect relationship is supported, what precise cause and effect were being measured in the study under consideration and how might other factors contribute to this? And what are the implications of the findings? The focus for critiquing a research report (apart from allegations of deliberate falsification) strictly speaking should not be the reported ‘Results’ but the ‘Discussion and Conclusions’—the inferences (particularly regarding cause and effect) which can be drawn from the results and therefore the generalisability of findings beyond the experimental situation.
Introduction
Authors: Weatherall D J , Hatton Chris
Published: May 2013

Almost all diseases can produce changes in the blood, and primary haematological disorders can affect any organ system. The general clinical approach to the patient with a haematological disorder involves the following:

This should place particular emphasis, depending on the presenting problem, on (1) symptoms of anaemia; (2) overt blood loss—gastrointestinal or menstrual; (3) dietary history and evidence of malabsorption; (4) weight loss, night sweats, fever, bone pain, and pruritus—which may indicate a lymphoproliferative or myeloproliferative disorder; (5) drug ingestion—many drugs produce haematological side effects; (6) bruising/bleeding—has the patient bled significantly in the past following dental extractions or minor surgical procedures?; (7) family history—may give useful clues to the cause of bleeding or anaemia, as may the ethnic origin of the patient’s ancestors....
Radiation
Authors: Meara Jill
Published: May 2013

Ionizing radiation has sufficient energy to break chemical bonds and produce charged ions in living tissue. These changes may cause cell death, but breaks of both strands of a DNA molecule that do not kill a cell may be a precursor of cancer.

Excluding medical exposures, natural radiation accounts for most human exposure, which produces health effects that may be (1) stochastic, where the probability of manifesting the effect depends on the radiation dose, including carcinogenesis and induction of heritable defects; (2) psychological, especially following accidental exposures; and (3) tissue reactions, occurring when sufficient cells are killed after exposure to radiation doses above a certain threshold, including the acute radiation syndrome (radiation sickness) and radiation burns....
Heart disease in pregnancy
Authors: Head Catherine E.G.
Published: May 2013

Pregnancy is a vasodilator state in which plasma volume and cardiac output increase such that many symptoms and signs of cardiac disease can occur physiologically. Disproportionate symptoms or abnormal signs such as a diastolic murmur require investigation as usual; necessary radiological investigations should not be withheld as the risks to the fetus are generally low....
Bronchoscopy, thoracoscopy, and tissue biopsy
Authors: Shah Pallav L.
Published: May 2013

Bronchoscopy, thoracoscopy, and radiologically guided biopsy techniques provide different methods for visualizing and sampling thoracic lesions, the approach chosen in any particular case being based on a number of factors, including the anatomical location of abnormal areas, presence of coexisting pulmonary disease, presence of comorbidities, and local expertise. CT is useful in both selection and planning of the most appropriate sampling method....
Pneumoconioses
Authors: Seaton A. , Reid P.
Published: May 2013

Pneumoconiosis describes the pathological reaction of the lung to inhaled dust, which is most frequently, but not necessarily, one of fibrosis, and most often, but not exclusively, related to exposures occurring at work. It may be more formally defined as a permanent alteration of lung structure due to the inhalation of mineral dust and the tissue reactions of the lung to its presence, excluding bronchitis and emphysema. Lung damage occurs when respirable dusts reach the acinus in sufficient quantity to overwhelm the normal phagoctyic and clearance mechanisms. The causes of pneumconiosis are many and varied, but many epidemiological studies have shown an exposure–response relationship between the total mass of respirable dust to which workers have been exposed and their risks of developing disease. These form the basis of regulations specifying limits to permitted levels of exposure. Workers, whose exposure results in pneumoconiosis, may be entitled to compensation in some countries....
Pleural diseases
Authors: Davies Robert J.O. , Gleeson Fergus V. , Gary Lee Y.C. , Porcel Jose , Brims Fraser
Published: May 2013

Case History—A 40 yr old woman with pleuritic chest pain.

This is a common clinical problem which can complicate a range of lung and systemic diseases. Most cases can be diagnosed by pleural fluid analysis and pleural biopsy, with Light’s criteria making it possible to discriminate between transudates and exudates. These state that a pleural effusion is an exudate if any of the following are present: (1) pleural fluid to serum protein ratio greater than 0.5; (2) pleural fluid lactate dehydrogenase (LDH) greater than two-thirds of the upper limit of normal serum LDH; (3) pleural fluid to serum LDH ratio greater than 0.6....
The consequences of drug use: the good, the bad, and the ugly
Authors: Plant Martin , Robertson Roy , Plant Moira , Miller Patrick
Published: May 2013

This chapter reviews recent evidence on the extent and patterns of both the positive effects (such as enjoyment and allied social and psychological benefits) and the negative effects of illicit drug use among people in the UK. Negative effects include drug-related crimes, accidents, overdoses, injuries, illness (e.g. hepatitis C, HIV/AIDS, drug dependence, and psychiatric illness), and premature mortality. The latter particularly involves young people. This chapter also presents new evidence from the 2007 European School Survey Project on Alcohol and other Drugs (ESPAD 2007; noted above) related to the consequences of drug use among UK teenagers.
Drug-control policies: a question of balance
Authors: Plant Martin , Robertson Roy , Plant Moira , Miller Patrick
Published: May 2013

There are many different views on the best way to reduce drug-related problems. Drugs are controversial. Opinions on the best way to deal with them cover the entire spectrum from legalization to tight controls backed up by severe penalties. In fact most of the ‘official’ and public debate about drug policy reflects the view that drugs are intrinsically ‘bad’ and should somehow be controlled. The authors of this book do not wish to embrace any particular approach to drug control. They do not believe that any single known approach is a magic solution, offering a panacea to something as complex and multi-faceted as drug use and its associated adverse effects. Even so, it is hoped that this chapter will provide an insight into some of the debates and arguments that relate to the nature and status of drug use and the options that are available with which to respond to it. It might also be possible to envisage ways of mitigating the damaging consequences outlined in the previous chapter without having to embark on a political crusade or to turn around the juggernaut of international condemnation of drug use and drug users.
Does drug education make any difference?
Authors: Plant Martin , Robertson Roy , Plant Moira , Miller Patrick
Published: May 2013

The good intentions of governments and educational authorities cannot be denied. Neither can the importance of doing something in an attempt to mitigate the serious consequences of young people starting to use drugs and lacking simple information about protecting themselves from harm. For educationalists and policy makers there are many complex issues which frustrate the development of programmes with an ability to influence the choices of young people. Fashion often dictates behaviour and fashion relies and depends on change, innovation, and novelty. As in other areas of human behaviour new trends arrive regularly and without warning and the serious consequences are often unintended. Almost inevitably education and public health are therefore in a position of responding to a crisis or an unexpected problem arising out of a previously unknown side effect of drug use. Numerous examples show how difficult it is to research and implement an appropriate response to an emerging problem and how often, lacking the ability to predict the future, policies seem to be misguided or ineffective.
Can drug classification and drug policy ever be evidence-based?
Authors: Plant Martin , Robertson Roy , Plant Moira , Miller Patrick
Published: May 2013

The popular and political debate about illicit drugs has been accused of being at least in part a ‘moral panic’. This, as noted above, is an expression originally used by the social scientist Stanley Cohen (1972) to describe exaggerated alarm provoked by some form of behaviour that was viewed as being socially unacceptable and menacing. Cohen applied this term to media coverage of conflict between gangs of ‘mods’ and ‘rockers’. The term moral panic has subsequently been used to imply that the debates on some issues are distorted and sensationalized. There are certainly times when popular concerns about some issues, often whipped up by the tabloid press, are exaggerated and appear to lead to moral (or immoral) outrage. During recent decades, sensationalized reports in Britain have related to a series of drug themes. These have included the use of amphetamines, cannabis, (more recently skunk), soft drugs leading to the use of harder drugs, drug dealers allegedly accosting school children, and drug adulteration. This chapter considers two main issues, the classification of drugs and the very important topic of who determines drug policy. The latter topic received enormous publicity while this book was being written.
Future directions
Authors: Plant Martin , Robertson Roy , Plant Moira , Miller Patrick
Published: May 2013

The future looks far from attractive and signs of improvement either in the size of the caseload or the ability of services to respond are hard to find. Inevitably governments are going to face difficult decisions but as time goes on expenditure will continue to rise and the needs of drug users will assume a more pressing political force. As this pressure increases the best possible understanding of the nature of drug dependence and misuse will be required and pragmatic solutions will have to be made available.
Obstetrics and gynaecology
Authors: Stacey Victoria
Published: May 2013

Abdominal pain in women - Ectopic pregnancy - Pelvic inflammatory disease (PID) - Other gynaecological causes of abdominal pain - Abnormal vaginal bleeding - Emergency contraception - Bleeding in pregnancy - Hyperemesis gravidarum - Pre-eclampsia and eclampsia - Rhesus prophylaxis—anti-D immunoglobulin - Emergency delivery - Postpartum haemorrhage - Pregnancy and trauma - SAQs
Psychiatry
Authors: Stacey Victoria
Published: May 2013

Introduction - Types of mental disorder - Self-harm - Managing the violent patient - Complications of psychiatric medications - SAQs
A wellness approach to mental health recovery
Authors: Swarbrick Margaret
Published: May 2013

Recovery in relation to mental health is a deeply personal, unique process of (re)gaining physical, spiritual, mental, and emotional balance when one encounters illness, crisis, or trauma. As a process, the individual learns to accept the illness, crisis, or trauma and its associated challenges while adjusting their attitudes, beliefs, and sometimes both life roles and goals. Recovery is a process of healing and restoring a sense of balance and wellness during episodes of stress and crisis. Social determinants of health—including income and social status, social support networks, education and literacy, employment, social and physical environments, personal health practices and coping skills, access to health services, gender, and culture—are all factors that have a significant impact on wellness and mental health recovery. Recovery is impeded by a life of poverty, poor access to quality healthcare and to other needed health and social supports, and the effects of stigma, discrimination, and social exclusion. The notion of wellness, which was initially introduced within public health, is now viewed as critical for mental health recovery. This chapter will explore mental health recovery in the context of a wellness model. Service-user-led wellness models of support will be examined as a proactive means of promoting mental health recovery and social inclusion. Individual, professional, program, and system level approaches and strategies to facilitate recovery will be proposed.
Oxford Handbook of Urology
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

The Oxford Handbook of Urology, Third Edition, covers a wide spectrum of diseases and their treatment in urology, as well as surgical aspects of kidney, bladder, prostate and scrotal disorders, and aims to give a brief overview of many different urological subjects, including urological emergencies, cancers, infections, children's disorders and kidney stone disease
Introduction
Authors: Hoskin Peter
Published: May 2013

Radiotherapy remains the most important non-surgical treatment in the management of cancer. Chapter 1 discusses the types of radiotherapy and how, in recent years, rapid advances in the technology available to radiotherapy have been made and there is a challenge to the practising clinician to remain abreast of these and harness them to their best use in the management of patients.
Skin cancer
Authors: Corner C , Hoskin Peter
Published: May 2013

Chapter 13 discusses skin tumours and that they differ in their radiotherapy planning from most other sites in that the volume definition is based principally upon clinical examination and the majority will be treated by single applied beams using low-energy X-rays or electrons with clinical verification. Three major histological groups are squamous cell carcinoma, basal cell carcinoma and malignant melanoma with a fourth comprising the rarer entities of adnexal tumours and Merkel cell tumours.
Herbert H. Jasper and the Basic Mechanisms of the Epilepsies
Authors: Avoli Massimo
Published: May 2013

This chapter covers Herbert H. Jasper and the basic mechanisms of epilepsies. This includes a look at Dr. Jasper's early years, his work at the Montreal Neurological Institute, the founding of IBRO and the BME Project, his move to the other side of Mont Royal, and his later years.
Why—and How—Do We Approach Basic Epilepsy Research?
Authors: Schwartzkroin Philip A.
Published: May 2013

Given how blurred this basic-clinical distinction is, it has become increasingly important for basic scientists to break down the basic-clinical separation, and particularly to give up the idea that clinical research is somehow inferior—lacking, perhaps, the rigor or the insights associated with laboratory work. There is, however, an important aspect of research that often (not always) separates basic from clinical studies—the availability of normal control groups. One of the major advantages of laboratory work—aside from enabling the researcher to apply invasive approaches that would not be ethically appropriate in human subjects—is the possibility of separating variables of interest and therefore creating control groups that differ only in the variable of interest. This laboratory advantage provides the basic scientist with an especially powerful (but narrow) means of drawing strong conclusions from his or her work. It is important to recognize, however, that depending on the goal of the study, isolation of single variables may not provide answers that are of clinical value, since real-life pathologies rarely appear to be dependent on single variables.
Potassium Channels (Including KCNQ) and Epilepsy
Authors: Cooper Edward C.
Published: May 2013

This chapter aims to provide a perspective on the achievements and future potential of studies of potassium channels in epilepsy research. The thesis is that the understanding obtained from recent studies justifies continued investment in K+ channels by academic and industry-based researchers. We first reintroduce the K+ channels, highlighting progress that appears particularly relevant to epilepsy. Then, as an example, we provide a detailed account of one K+ channel subfamily, the KCNQ/Kv7 family. Members of this family are mutated in benign familial neonatal seizures, an autosomal dominant syndrome. Moreover, these channels have been found to be practical targets for antiepileptic drug development, perhaps providing a model for studies of other K+ channel subgroups. We conclude with a discussion of directions for future work.
Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Ion Channelopathy in Epilepsy
Authors: Poolos Nicholas P.
Published: May 2013

This chapter describes how the unique biophysical properties of HCN channels lead to an influential role in seizure generation; whether recent evidence truly supports the existence of HCN channelopathy in human epilepsy; and how the mechanisms underlying acquired HCN dysfunction could be targeted by antiepileptic therapies.
Neuronal Synchronization and Thalamocortical Rhythms during Sleep, Wake, and Epilepsy
Authors: Timofeev Igor , Bazhenov Maxim , Seigneur Josée , Sejnowski Terrence
Published: May 2013

Neuronal synchronization can be divided into long-range and local synchrony. Long-range synchrony is usually detected with two or more electrodes placed some distance apart. It leads to brain activity that is correlated at long distances and may be seen using both local field potential (LFP) and electroencephalogram (EEG) recordings. The first tool (i.e., the LFP) provides a microscopic measure of brain activity summarizing electrical activities of possibly thousands of neurons 1–4. The second type of recording (i.e., the EEG) is a result of changes in electrical activity of multiple sources and ultimately represents activity patterns of large populations of neurons and glial cells in the brain. Local or short-range synchrony can be detected either with one relatively large field potential electrode or with two or more small [intracellular or extracellular unit (action potential) recording] electrodes located at short (less than 1 mm) distances from each other. Synchronous activity of a few neurons does not necessarily lead to measurable EEG signals, but this can be seen using LFP recordings. Because of the low-pass filtering properties of the extracellular media,5 high-frequency electric fields associated with action potentials steeply attenuate and large-amplitude slow LFP and EEG potentials are mainly generated from nearly simultaneously occurring de- and hyperpolarizing events in a large number of neighboring cells with a major contribution from large pyramidal neurons.6
Imaging of Hippocampal Circuits in Epilepsy
Authors: Takano Hajime , Coulter Douglas A.
Published: May 2013

In this chapter, we will describe the basic tools and mechanisms of functional imaging and their application to in vitro hippocampal circuit characterization in naïve and epileptic animals.
Brainstem Networks
Authors: Faingold Carl L.
Published: May 2013

Penfield and Jasper1 proposed that generalized seizures involve the brainstem reticular formation (BRF) and other brain sites that are extensively connected to most other brain regions as a centrencephalic system. Considerable subsequent research has confirmed a major role for the BRF in the neuronal networks that subserve generalized convulsive seizure generation. The BRF has been defined to include the core of the brainstem in the medulla, pons, and midbrain. The projections between brainstem nuclei, as well as those to and from the BRF, are massive, including all levels of the central nervous system (CNS) from spinal cord to cerebral cortex. Recent research on the anatomical and neurochemical diversity of nuclei within the BRF has been extensive, leading to a more complex view of the functions of the brainstem. However, these observations have not invalidated the original concept that the BRF has the potential to act as an extremely large network (reticulum) capable of “mass action” under certain circumstances, such as arousal or generalized convulsive seizure.2–4 Depression of BRF neurons was originally and is still implicated as a major mechanism of action for depressant and anesthetic drugs.2,5
On the Basic Mechanisms of Infantile Spasms
Authors: Swann John W. , Moshe Solomon L.
Published: May 2013

We are at a very early stage in studying the basic mechanisms of infantile spasms. However, features of several promising animal models have been described, and more may be forthcoming in the near future. Technical challenges are substantial in studying seizures in infant rodents, but they are not insurmountable. The basic science and clinical communities need to evaluate each of the proposed animal models and develop minimal criteria for what they consider to be a valid animal model of this disorder. Once validated, models should provide an unprecedented opportunity to study the mechanisms responsible for this catastrophic epilepsy and hopefully provide new avenues for effective therapies.
Head Trauma and Epilepsy
Authors: Pitkänen Asla , Bolkvadze Tamuna
Published: May 2013

Recent advances in model development provide a platform for studies that are aimed at understanding the post-TBI molecular and cellular alterations leading to epilepsy. Undoubtedly, the search for surrogate markers that identify subjects with the highest risk for posttraumatic epileptogenesis will benefit from novel possibilities for following candidate epileptogenic changes in neuronal circuits in vivo using structural and functional imaging. Some proof-of-principle trials already suggest that post-TBI seizure susceptibility can be favourably modified.
Role of Blood-Brain Barrier Dysfunction in Epileptogenesis
Authors: Friedman Alon , Heinemann Uwe
Published: May 2013

Focal epilepsy typically arises from neuronal tissue either within or adjacent to a cortical lesion. About 30% of epilepsies are caused by acquired etiologies such as traumatic brain injury, stroke, infection, or prolonged febrile seizures.1 Injury-related acquired epilepsy is frequently resistant to medications and may be associated with other neurological impairments. In most animal models of acquired epilepsy (similar to the situation in humans), a period of days to weeks is required for the development of seizures.2,3 Typically, the initial insult is followed by a latent interval, referred to as epileptogenesis, in which cellular and structural reorganization occurs that ultimately leads to chronic recurrent epileptic seizures. While the molecular, anatomical, and electrophysiological activities in the epileptic focus have been described in great details (e.g., in refs. 4–8), the critical changes occurring following injury and before epileptic activity develops are mostly unknown. A better understanding of the molecular and physiological events during epileptogenesis is essential for the targeted development of preventive therapeutic approaches that are presently unavailable.1
Histopathology of Human Epilepsy
Authors: de Lanerolle Nihal C. , Lee Tih-Shih , Spencer Dennis D.
Published: May 2013

Histopathological lesions that are associated with seizures are described in several neurological disease states. Such histopathological lesions are found in developmental disorders, neoplasms, microbial diseases, cerebrovascular diseases, trauma, and immune-mediated disorders, as well as in disorders primarily related to seizures such as temporal lobe epilepsy (TLE). General descriptions of these lesions have been the subject of several reviews.1,2 Temporal lobe epilepsy, a major seizure disorder that affects over 40 million people worldwide, has received the most study in relation to its histopathology, and the histological lesion is thus best understood in relation to epilepsy. This chapter will review the state of our knowledge in the histopathology of TLE.
Alterations in Synaptic Function in Epilepsy
Authors: Bernard Christophe
Published: May 2013

How do alterations in synaptic function relate to seizures and their comorbidities? This question has been particularly difficult to address since epilepsy is often a time-dependent disorder, involving (for example) an initial insult (which may involve genetic alterations, meningitis, brain trauma, etc.) and the subsequent trigger of a number of network modifications. Ultimately, some of these modifications may be directly linked to seizure generation and/or comorbidities. It is therefore important to understand the time course of these changes. This issue has been extensively investigated in experimental models of temporal lobe epilepsy, which are characterized by a latent seizure-free period of about 2 weeks following the initial insult (usually a period of status epilepticus). We will use these models to describe synaptic remodeling and its possible functional consequences in the adult brain, focusing on the hippocampus.
Neurogenesis and Epilepsy
Authors: Parent Jack M. , Kron Michelle M.
Published: May 2013

Medial temporal lobe epilepsy (mTLE) is a common and often intractable form of epilepsy. Approximately 50 million people suffer from different epilepsies worldwide,1 30%–40% of whom may continue to have poorly controlled seizures despite therapy.2,3 Medial TLE is estimated to be the most common cause of intractable epilepsy in this population.4 In addition to chronic seizures, the long-term morbidity of mTLE includes an increased incidence of depression5,6 and problems with learning and memory7,8 that may progress despite adequate seizure control.9 Thus, progress in the study of mTLE is critical for developing better therapies to ease the large burden of this disorder. Humans with mTLE often have an initial precipitating event, followed by a latent period and subsequent development of epilepsy later in life. This knowledge has led to the development of the most common animal models of mTLE. In these models, a prolonged seizure (termed status epilepticus, SE) is induced by either electrical stimulation or a chemoconvulsant, leading to injury as the initial precipitating event. After a seizure-free latent period, spontaneous seizures develop and persist for the lifetime of the animal.10,11 The two most commonly used chemconvulsant-induced SE models of mTLE are the kainic acid and pilocarpine models.
GABAA Receptor Plasticity during Status Epilepticus
Authors: Joshi Suchitra , Kapur Jaideep
Published: May 2013

Status epilepticus (SE) is a prolonged, self-sustained seizure that can manifest as a prolonged convulsion, subtle facial or limb twitching, or simply altered mental status, always in association with a persistent electroencephalographic (EEG) seizure pattern. In clinical trials, convulsive seizures lasting longer than 5 min are often treated as SE,1 whereas epidemiological studies have defined 30 min of continuous convulsive seizures or intermittent seizures without recovery of consciousness as SE.2 There are 126,000 to 195,000 episodes of SE associated with 22,000 to 42,000 deaths each year in the United States when SE is defined as 30 min of seizures.2 As many as 50% of patients older than 65 years of age who suffer from SE die within 30 days of the episode. Although mortality is far less common in younger patients, they are at risk for neurological morbidity, such as injury to the hippocampus3 and neuropsychological dysfunction.4 Prolonged seizures can also lead to significant systemic complications, including pulmonary congestion and edema, cardiac arrhythmias, hypotension, elevation of body temperature, hypoglycemia, acidosis, and rhabdomylosis. These systemic complications tend to worsen as more seizures occur.5 It has long been recognized that SE is a dynamic and rapidly evolving condition.5,6 Ongoing seizures rapidly modify neuronal activity and synaptic function.7 This rapid neuronal plasticity is manifest in changes in behavioral seizures, EEG patterns, sensitivity to drugs, and evolution of neuronal injury and death. Although these changes are continuous, it is convenient to divide SE into stages for the purposes of investigation and treatment (Table 41–1).
Astrocytes and Epilepsy
Authors: Clasadonte Jerome , Haydon Philip G.
Published: May 2013

Glia, Greek for “glue,” was discovered by Rudolph Virchow, a German anatomist, in the mid-nineteenth century. The name reflects the original view that glia played merely a structural or metabolic support role for neurons. Glial cells, especially astrocytes, are much more than glue or merely quiescent and display their own set of activities. Studies over the last 20 years show that astrocytes perform a series of complex functions that go well beyond the uptake and recycling of neurotransmitters and the buffering of extracellular potassium.1,2
Astrocyte Dysfunction in Epilepsy
Authors: Steinhäuser Christian , Seifert Gerald
Published: May 2013

The novel view of astrocytes as communication partners of neurons rather than “brain glue” has rekindled the question regarding the role of these cells in neurological disorders such as epilepsy. Indeed, an increasing body of evidence has documented astroglial dysfunction, and even dysregulation of astroglia-specific functions, in human and experimental epilepsy. This particularly concerns impaired uptake/conversion of glutamate and removal/redistribution of K+, as observed in MTLE-HS. However, a number of key questions need to be addressed before a unifying picture can be proposed. For example, it is still unclear whether the reported glial alterations are a cause or a consequence of the condition. In addition, difficulties arise from the fact that the term astrocyte covers a heterogeneous group of cells, and this complicates comparison of individual studies. It is worthwhile, however, to emphasize that the molecular, functional, and structural characterization of astroglial heterogeneity is a rapidly evolving field that may soon lead to a better definition of astroglial subtypes. In a comprehensive approach that uses modern molecular genetics and in vivo models, we may now have the opportunity to clarify the specific roles of astroglia in epilepsy and to develop novel therapeutic approaches to fight this disorder.
Mutated GABAA Receptor Subunits in Idiopathic Generalized Epilepsy
Authors: Cossette Patrick , Lachance-Touchette Pamela , Rouleau Guy A.
Published: May 2013

An increasing number of genes predisposing to epilepsy have been identified over the past 10 years. Among these genes, mutations in four subunits of the GABAA receptor appear to be important causes of familial epilepsy. So far, the majority of these mutations have been associated with a dramatic decrease of GABA-evoked currents in recombinant receptors. Because GABA is the main inhibitory transmitter in the adult brain, it is generally believed that this loss of function would cause abnormal excitability of cortical neurons, thereby leading to clinical seizures. However, in contrast to the mature central nervous system, GABA is excitatory in the developing brain. This apparent paradox is caused by an inversion in the chloride gradient across the cell membrane that occurs during the first days of life. There is now increasing evidence supporting the hypothesis that excitatory GABA transmission plays a key role in various aspects of brain development, such as neuronal migration, shaping of dendritic trees, and synaptogenesis. It is thus very likely that epilepsy-causing mutations in GABAA receptors would be associated with abnormal development of neuronal networks, which may be one of the critical mechanisms leading to the disease. However, so far, this hypothesis has not been examined. Should it be validated, it would provide an unparalleled advance in our comprehension of the IGEs.
GABAA Receptor Subunit Mutations and Genetic Epilepsies
Authors: Macdonald Robert L. , Kang Jing-Qiong , Gallagher Martin J.
Published: May 2013

Idiopathic epilepsy syndromes (IES) are common and constitute about 50% of the epilepsies diagnosed worldwide.1 They vary in severity from the relatively benign febrile seizures (FS) and childhood absence epilepsy (CAE) to the severe epilepsy syndrome Dravet syndrome. A common IES is FS plus (FS+), which develops early in childhood with multiple FS that continue to occur beyond 6 years of age or are associated with afebrile seizures.2 Generalized epilepsy with FS plus (GEFS+) is a familial epilepsy syndrome in which multiple family members have either FS, FS+, myoclonic-astatic epilepsy (MAE), and DS.2
Nicotinic Acetylcholine Receptor Mutations
Authors: Steinlein Ortrud K. , Kaneko Sunao , Hirose Shinichi
Published: May 2013

“In this chapter, we demonstrate the clinicophysiological characteristics of ADNFLE and summarize the current understanding of the molecular pathomechanisms of ADNFLE resulting from nAChR mutations.”
Rare Genetic Causes of Lissencephaly May Implicate Microtubule-Based Transport in the Pathogenesis of Cortical Dysplasias
Authors: Liu Judy S. , Schubert Christian R. , Walsh Christopher A.
Published: May 2013

Disruption of early neural development can cause severe forms of mental retardation and epilepsy associated with defects in cortical structure, such as lissencephaly (“smooth brain”), a disorder resulting from abnormal neuronal migration. Of the six causative genes for classical lissencephaly, three—LIS1, DCX, and TUBA1A—encode for microtubule-related proteins, indicating the importance of this pathway for neuronal migration (Table 60–1). The lissencephaly 1 (LIS1) protein is an adaptor for dynein, a microtubule motor protein.1 Doublecortin (DCX) encodes a microtubule-associated protein (MAP).2,3 Finally, tubulin α1a (TUBA1A) is a gene that encodes an α-tubulin subunit that is enriched during brain development.4 These lissencephalic syndromes clinically all share a widespread disruption of lamination in the cerebral cortex (Fig. 60–1). Since all three genes appear to regulate microtubule-based transport, their functional relation and regulation during development is an area of active investigation with implications that may be significant for a wider cohort of patients with focal cortical dysplasias. Cortical dysplasias are a common cause of refractory epilepsy and share some of the histological features of lissencephaly, including the dyslamination and abnormal neuronal morphology.5 Disruption of microtubule-based pathways may lead to cortical dysplasias, and the causative genes for lissencephaly are a starting point for further investigation.
The Generation of Cortical Interneurons
Authors: Gelman Diego M. , Marín Oscar , Rubenstein John L.R.
Published: May 2013

Most, if not all, mouse pallial interneurons are derived from three progenitor regions in the embryonic subpallium: MGE, CGE, and POA (Fig. 61–3). While there is controversy about this in the human, there is strong evidence that the ganglionic eminences are fundamental sources for pallial interneurons in all vertebrates. Development of these regions is regulated by multiple transcription factors. Arx, Ascl1, and Dlx1,2,5&6 have roles in all of these regions, whereas MGE development is regulated by Nkx2-1, Lhx6, Lhx8, and Sox6, and CGE development is regulated by Gsx2. Future studies should aim at elucidating the molecular mechanisms downstream of these transcription factors that regulate cell fate specification and differentiation of specific interneuron subtypes. Furthermore, because many of the transcription factors that regulate early interneuron development are expressed in mature interneurons (e.g., Arx, Dlx1,2,5&6, Lhx6, and Sox6), it is likely that they have roles in controlling interneuron function and/or survival, such as Dlx1.36 As interneuron defects that could contribute to epilepsy include abnormalities in their production, migration, differentiation, function, and survival, the mechanisms gleaned from basic studies should provide insights into the molecular, cellular, and histological underpinnings of epileptogenesis.
Haploinsufficiency of STXBP1 and Ohtahara Syndrome
Authors: Saitsu Hirotomo , Kato Mitsuhiro , Matsumoto Naomichi
Published: May 2013

Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy with suppression-burst, is one of the most severe and earliest forms of epilepsy.1 It is characterized by early onset of tonic seizures, seizure intractability, characteristic suppression-burst patterns on the electroencephalogram (EEG), and a poor outcome with severe psychomotor retardation.2,3 Brain malformations, such as cerebral dysgenesis or hemimegalencephaly, are often associated with OS, but cryptogenic or idiopathic OS is found in a subset of OS patients, in whom genetic aberrations might be involved.4 Although mutations of the ARX gene have been found in several male patients with OS,5–8 the genetic causes are unexplained in most cryptogenic OS cases. We have recently found de novo mutations in STXBP1 (encoding syntaxin binding protein 1, also known as MUNC18-1) in individuals with cryptogenic OS.9 Here we present all the mutations in STXBP1 found to date in OS patients, as well as some evidence of mutations leading to haploinsufficiency.
mTOR and Epileptogenesis in Developmental Brain Malformations
Authors: Wong Michael , Crino Peter B.
Published: May 2013

Malformations of cortical development (MCDs) are among the most common causes of epilepsy. While a wide variety of types and classifications of MCDs exists,1 a subset of focal cortical malformations (FCMs), including tuberous sclerosis complex (TSC), focal cortical dysplasia, ganglioglioma, and hemimegalencephaly, is associated with an especially high incidence of epilepsy and other neurological deficits, such as cognitive dysfunction and autism.2,3 Epilepsy related to these focal developmental brain malformations is often refractory to medical therapy. Even in patients whose seizures are well controlled with medications, currently available drugs are only symptomatic treatments that help suppress seizures; they have not been demonstrated to have antiepileptogenic or disease-modifying properties in preventing or altering the long-term prognosis of epilepsy. Although epilepsy surgery may eliminate seizures in some medically intractable cases, many patients are not good candidates for surgery or continue to have seizures despite surgical intervention. Thus, novel therapeutic strategies are needed to reduce the burden of seizures and other neurological symptoms caused by MCDs or, ideally, to prevent the development of epilepsy in the first place.
GABRB3, Epilepsy, and Neurodevelopment
Authors: Tanaka Miyabi , DeLorey Timothy M. , Delgado-Escueta Antonio V. , Olsen Richard W.
Published: May 2013

Three neurodevelopmental disorders—Angelman syndrome (AS), Rett syndrome (RS), and autism spectrum disorders (ASD)—share several clinical features, most notably neurodevelopmental delay and epilepsy. Here, we ask: what common mechanisms do these three neurodevelopmental disorders share that lead to a decline in cognitive development and epilepsy? Based on our observations concerning the genetic regulation of GABRB3 in childhood absence epilepsy (CAE), we posit that the genetic mutations in these three neurodevelopmental disorders converge on a common disease mechanism involving genetic and epigenetic regulation of GABRB3. We first explain the data on human CAE supporting this hypothesis and show that three different point mutations in an alternative signal sequence (exon 1A) and N terminus (exon 2) in GABRB3 result in hyperglycosylation and decreased gamma-aminobutyric acid (GABA) currents, all of which segregate with CAE. One of the variants of exon 1A, P11S, which is maternally transmitted, links GABRB3 dysfunction with ASD and provides a possible cause of the seizures in this syndrome. In AS, GABRB3 deletion contributes to the severe seizure phenotype. Rett syndrome is caused by mutations in MeCp2. Because MeCp2 epigenetically regulates GABRB3, reduced expression of GABRB3 and epilepsy are considered consequences of MeCp2 mutations. We then review the significance of GABRB3 in embryonic and adult neurogenesis and neuronal development in mammalian brain. We point to a master regulator of neurogenesis, RE1 silencing transcription factor (REST), which binds to repressor element 1 (RE1) in intron 3 and the 5′ region of GABRB3. REST epigenetically regulates tissue and developmental expression of GABRB3. Finally, we chart the future challenges and experiments that could prove or disprove our hypothesis that REST and epigenetic regulation are involved in neurogenesis and epileptogenesis of absence seizures.
Pathophysiology of Epilepsy in Autism Spectrum Disorders
Authors: Stafstrom Carl E. , Hagerman Paul J. , Pessah Isaac N.
Published: May 2013

Why are seizures so common in children with autism? This relatively straightforward question does not, unfortunately, have a straightforward answer. In this chapter, we explore this question from clinical, pathophysiological, and molecular perspectives, using as examples two genetic disorders that share a high prevalence of autism and epilepsy—fragile X syndrome (FXS) and tuberous sclerosis complex (TSC)—with the hope that understanding the pathophysiology of these monogenic conditions will lead to broader understanding of neural hyperexcitability in other autism syndromes. We conclude by discussing cellular and network dysfunctions that might be amenable to targeted treatments in these disorders, with potential wider applicability to idiopathic autism.