bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical meltdown—unavoidable?
Authors: Barker Richard
Published: May 2013

Chapter 3 investigates the dual pressures of new technology supply with the remorseless growth in demand, and three options to tackle the problem: lowering expectations, controlling supply, and to proactively tackle
demand growth, make new technology more affordable and turn the patient into a consumer, making informed choices and actively participating in the funding equation.
Primary immunodeficiency
Authors: Spickett Gavin P
Published: May 2013

Introduction

Classification of immunodeficiency

Clinical features of immunodeficiency

Investigation of immunodeficiency

Laboratory investigation

Major B-lymphocyte disorders

Rare antibody deficiency syndromes

X-linked agammaglobulinaemia (Bruton’s disease)

Common variable immunodeficiency (CVID)

CVID 2: complications and treatment

Selective IgA deficiency

IgG subclass deficiency

Specific antibody deficiency with normal serum immunoglobulins...
Autoimmunity of the nervous system
Authors: Spickett Gavin P
Published: May 2013

Myasthenia gravis (MG)

Lambert–Eaton myasthenic syndrome (LEMS)

Acquired neuromyotonia (Isaac’s disease) and stiff person syndrome (SPS)

Morvan’s syndrome

Rasmussen encephalitis

PANDAS

Paraneoplastic autoimmune neurological syndromes

Demyelinating diseases 1: multiple sclerosis (MS)

Demyelinating diseases 2: Guillain–Barré syndrome (GBS) and variants

Demyelinating diseases 3: chronic inflammatory demyelinating polyneuropathy (CIDP), related conditions, and Devic’s syndrome (neuromyelitis optica)...
Immunotherapy
Authors: Spickett Gavin P
Published: May 2013

Introduction

Passive immunization

Active immunization

General problems of active immunization

Additional stimulation of the immune system

Modern approaches to vaccine development

‘Replacement’ therapy

Intravenous immunoglobulin (IVIg) for replacement therapy 1

IVIg for replacement therapy 2: adverse reactions and risks of infection

IVIg for replacement therapy 3: monitoring and home therapy...
Orthopaedics and trauma of the limbs
Authors: O’Donnell Anne Marie , Little Chris
Published: May 2013

Musculoskeletal disease (MSD) remains one of the biggest causes of disability and sickness absence in the working population. As the working population ages, this is likely to continue. The occupational practitioner’s role is to reduce the impact of these problems for both employee and employer. This requires not only knowledge of the conditions, but also an understanding of the psychosocial factors underlying sickness absence and an evidence-based approach to rehabilitation. Patients generally do not have to be completely fit to commence, remain in, or return to work, and resuming work may be part of the rehabilitation process (see Chapter 4). Reasonable accommodations under the Equality Act 2010 may help overcome barriers to work to the benefit of workers and their employers (see Chapter 2). Flexible working and well-designed work environments may help retention and facilitate useful and safe work. In this context, fitness for work is a relative concept, dependent on suitable adjustments to the work environment.
Cardiovascular disorders
Authors: Price Anne E. , Petch Michael C.
Published: May 2013

Cardiovascular disorders remain one of the commonest causes of ill health and death but their incidence in Western society has been declining and there have also been significant reductions in death rates due to major advances in treatment over the last 20 years. Cardiovascular disease (CVD) affects working-age people and occupational physicians will see it regularly in the clinic. It affects fitness to work in two ways. First, an individual may suffer from symptoms on effort that limit their working capacity. Such disability is quantifiable and can often be alleviated by effective treatment. The second less common but more difficult problem is the risk of sudden incapacity, especially in individuals who appear well. This may occur for a variety of reasons including the risk of sudden cardiac death following ventricular fibrillation and whilst the instantaneous risk of sudden incapacity is very small, the consequences can be unacceptable. Assessment of this risk and its impact is possible in populations but explaining this concept to a bus driver who has lost his job is not easy. Limitation of working capacity and the risk of sudden incapacity can be well judged in populations by specialist opinion. For the individual this must be backed up by objective data, usually derived from the results of non-invasive tests such as electrocardiography (ECG) and exercise testing. Whilst disease progression can be unpredictable the use of objective data can ensure the individual is not unfairly excluded from work they can safely do. Sometimes cardiovascular symptoms are out of all proportion to the objective evidence of disease. This may arise from psychological disturbance following the development of CVD which in itself is associated with a high rate of common mental health problems. A heart attack proves devastating and the patient never returns to work despite prompt treatment, a full cardiac recovery, and only modest residual disease. The occupational physician needs to recognize the mental health problems associated with CVD and ensure that all treatment options are considered to facilitate rehabilitation to the workplace.
Respiratory disorders
Authors: Palmer Keith T. , Cullinan Paul
Published: May 2013

Respiratory illnesses commonly cause sickness absence, unemployment, medical attendance, illness, and handicap.1 Collectively these disorders cause 19 million days/year of certified sickness absence in men and 9 million days/year in women (with substantial additional lost time from self-certified illness) and, among adults of working age, a general practitioner consultation rate of 48.5 per 100/year with more than 240 000 hospital admissions/year. Prescriptions for bronchodilator inhalers run at some 24 million/year, and mortality from respiratory disease causes an estimated loss of 164 000 working years by age 64 and an estimated annual production loss of £1.6 billion (at prices in 2000). Respiratory disease may be caused, and pre-existing disease may be exacerbated, by the occupational environment. More commonly, respiratory disease limits work capacity and the ability to undertake particular duties. Finally, individual respiratory fitness in ‘safety critical’ jobs can have implications for work colleagues and the public. Within this broad picture, different clinical illnesses pose different problems. For example, acute respiratory illness commonly causes short-term sickness absence, whereas chronic respiratory disease has a greater impact on long-term absence and work limitation; and the fitness implications of respiratory sensitization at work are very different from non-specific asthma aggravated by workplace irritants. Occupational causes of respiratory disease represent a small proportion of the burden, except in some specialized work settings where particular exposures give rise to particular disease excesses. The corollary is that the common fitness decisions on placement, return to work, and rehabilitation more often involve non-occupational illnesses than occupational ones. By contrast, statutory programmes of health surveillance focus on specific occupational risks (e.g. baking) and specific occupational health outcomes (e.g. occupational asthma). In assessing the individual it is important to remember that respiratory problems are often aggravated by other illnesses, particularly disorders of the cardiovascular and musculoskeletal systems.
The older worker
Authors: Goodall Henry N. , Evans John Grimley
Published: May 2013

Throughout the world, populations are ageing, as birth rates fall and people live longer. This ‘demographic transition’ brings about a permanent change in population structure and an increase in the ratio of people traditionally regarded as being of ‘retirement age’ to those traditionally regarded as being of ‘working age’. Both for the productivity of a population and for the funding of pensions and other social benefits, the whole trajectory of working life and the social structures that underpin it have to change to match labour resources to needs. In particular, people in the developed world must expect to continue working to later ages than in the past, a change that has implications both for the employed and for employers. Occupational physicians have an important role to play in making longer working lifetimes possible, productive, and pleasant.
Viva 2
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 2 asks what is the likely diagnosis of the cystic, soft-tissue lump shown in the photograph, from what structure does it commonly arise, what clinical test, outpatient procedure, and simple imaging investigation can be performed to confirm the diagnosis, and the histological definition of this condition. It also asks what the other sites are for these cystic swellings in the wrist and hand, how would this condition be managed in a 26-year-old woman who works as a secretary and presents to you for the first time, and what is the risk of recurrence post-excision?
Viva 11
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 11 involves a 2 1/2-year-old girl who is referred to clinic with a limp. Describe the radiographic findings, how to proceed in management from here, and any open operative approaches that could be used to reduce this hip.
Viva 13
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 13 shows a pelvic radiograph of a 13 year-old boy presenting with pain in his right knee. Describe the radiograph, and classify this condition, followed by a management plan now with the right hip, and then the left hip.
Viva 21
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 21 asks what bone is, how do osteoblasts and osteoclasts differ, and what is Wolff's law?
Viva 49
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 49 shows a 32-year-old pedestrian who was hit by a car. What can be seen in these two radiographs, and what is understood by the term damage control orthopaedics (DCO)? What decides which patients require DCO and what is the alternative? What is the Injury Severity Score (ISS)? What is the expectation about operating definitively on a DCO patient?
Viva 53
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 53 shows a 25-year-old man brought into casualty with a closed isolated injury of his nondominant right arm. Describe this injury and how to classify these types of injury? How should this patient be managed? A decision is made to open and reduce the ulna fracture under direct vision and fix it with a dynamic compression plate. Describe how this plate works.
Viva 61
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 61 asks for a description of what can be seen in the image and how to assess the patient. What are the causes of this deformity? How does a patient present and what are the principles of treatment?
Viva 62
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 62 asks what implants are used for revision total knee replacements, and after being handed a hinged prosthesis, what the benefits and disadvantages of this type of component are. To revise a unicompartmental knee replacement, what implant could be chosen? What implant choice might be made for a patient with a posterior cruciate ligament (PCL) sacrificing knee with a complete medial collateral ligament disruption and dislocation?
Viva 66
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 66 asks what condition is illustrated here? What is the aetiology and what risk factors are associated this condition? What other areas are commonly affected? Describe any classification systems for this condition a nd what stage is shown in the radiographs? How should a patient presenting with this condition be managed and what treatment options are available?
Viva 70
Authors: Davies Nev , Jackson Will , Price Andrew , Rees Jonathan , Lavy Chris
Published: May 2013

Viva 70 asks what is understood by the term ‘isthmic spondylolithesis’? What are the other recognized causes of spondylolithesis? How are spondylolithesis graded and what radiographic indices may be used to predict progression? How do degenerative litheses differ from spondylolysis when considering neural involvement?
Considering recovery as a process: or, life is not an outcome
Authors: Davidson Larry
Published: May 2013

This chapter argues that in order to appreciate the nature of recovery as a process, we first have to disconnect it from any preconceived notions of desirable outcomes to which it may ordinarily be linked. Accepting that, for human beings, the only real “outcome” that is enduring is our eventual death, the author argues that a process understanding of recovery makes better sense of the longitudinal data related to the non-linearity of course and heterogeneity in clinical definitions of outcome of mental illness. If, as the consumer/survivor movement argues, each person has to be the final arbiter of what is and what is not “normal” for him- or herself, further doubts are raised about the utility of the notion of recovery as an outcome. The author connects this discussion to the civil rights dimension of recovery as promoted by the recovery movement, and shows how this understanding of recovery is consistent with the view that people may experience an increase in symptoms, or deterioration in clinical status, in response to life events without thereby no longer being considered “in recovery”. Finally, the author responds to the criticism that this definition of recovery can apply to everyone all the time, and is therefore meaningless, by illustrating how it evolves in the lives of people with serious mental illnesses.
Infertility
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

Male reproductive physiology 552

Aetiology and evaluation of male infertility 554

Investigation of male infertility 556

Oligozoospermia and azoospermia 560

Varicocele 562

Treatment options for male infertility 564

The hypothalamus secretes luteinizing hormone-releasing hormone (LHRH), also known as gonadotrophin-releasing hormone (GnRH). This causes the pulsatile release of anterior pituitary gonadotrophins called follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which act on the testis. FSH stimulates the seminiferous tubules to secrete inhibin and produce sperm; LH acts on Leydig cells to produce testosterone (...
Sexual health
Authors: Reynard John , Brewster Simon , Biers Suzanne
Published: May 2013

Physiology of erection and ejaculation 568

Erectile dysfunction: evaluation 572

Erectile dysfunction: treatment 576

Peyronie’s disease 580

Priapism 584

Retrograde ejaculation 588

Premature ejaculation 590

Other disorders of ejaculation and orgasm 592

Late-onset hypogonadism (LOH) 594

Hypogonadism and male hormone replacement therapy 596

Urethritis 600...
Treatment delivery, intensity-modulated radiotherapy, and image-guided radiotherapy
Authors: Rowbottom Carl
Published: May 2013

Chapter 3 discusses how successful delivery of external beam radiotherapy involves a number of complex processes beginning with the decision by the clinical oncologist to use radiotherapy as part of the patient’s cancer management, through the preparation and planning of the patient’s treatment, to the verification of the patient position and radiation dose delivered at the time of treatment.
Radiotherapy for thoracic tumours
Authors: Erridge Sara C , Toy Elizabeth , Campbell Sorcha
Published: May 2013

Chapter 5 discusses two main subtypes of lung cancer; small cell (SCLC) and non-small cell (NSCLC). However, the management is becoming increasingly similar so the general principles of lung cancer radiotherapy will be discussed first, followed by the specific features of management of the two pathological entities.
Vulva and vagina
Authors: Hoskin Peter
Published: May 2013

Chapter 9b discusses carcinoma of the vulva, which is primarily a surgical disease best treated by wide surgical resection, radical vulvectomy, and inguinal lymph node dissection based on presenting stage. Rarely, locally advanced primary disease may be presented for primary radiotherapy treatment. Postoperative radiotherapy is recommended for tumours invading >7 mm in a vertical direction. The first station regional lymph nodes in the inguinal region are best treated by radical surgical dissection, but fixed inoperable lymph nodes may benefit from primary radiotherapy which may be followed where appropriate by surgery if there is a residual mass. Postoperative radiotherapy should be considered for women having more than one node involved with metastatic tumour at surgery. This must be balanced against the increased risk of lymphoedema where both surgery and radiotherapy are delivered to the groins. Chemoradiation using cisplatin or 5-FU/mitomycin C-based schedules has been reported but no randomized comparison with radiotherapy alone has been undertaken; whilst high response rates are seen there is a considerable increase in acute toxicity.
Sarcomas of soft tissue and bone
Authors: Cassoni Anna
Published: May 2013

Chapter 14 discusses both soft tissue and bone tumours except for rhabdomyosarcomas which will be covered within paediatric tumours (Chapter 15).
Surgical pathology
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Cellular injury 142

Inflammation 144

Wound healing 146

Ulcers 148

Cysts, sinuses, and fistulas 150

Atherosclerosis 152

Thromboembolic disease 154

Gangrene and capillary ischaemia 158

Tumours 160

Carcinogenesis 162

Screening 164

Grading and staging 168

Tumour markers 170

Surgical microbiology 172

Surgically important organisms 174...
Practical procedures
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Endotracheal intubation 186

Cardioversion 188

Defibrillation 190

Venepuncture 192

Intravenous cannulation 194

Arterial puncture and lines 196

Insertion of central venous catheter 198

Chest drain insertion 200

Management of chest drains 202

Pericardiocentesis 204

Cricothyroidotomy 206

Nasogastric tube insertion 208

Urethral catheterization 210

Suprapubic catheterization ...
Peripheral vascular disease
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Acute limb ischaemia 642

Chronic upper limb ischaemia 644

Chronic lower limb ischaemia 647

Intermittent claudication 648

Critical limb ischaemia 650

Aneurysms 652

Ruptured abdominal aortic aneurysm 654

Vascular developmental abnormalities 656

Carotid disease 658

The diabetic foot 660

Amputations 662

Vasospastic disorders 664

Varicose veins ...
Surgery in tropical diseases
Authors: McLatchie Greg , Borley Neil
Published: May 2013

Medicine in the tropics 702

Typhoid 704

Amoebiasis and amoebic liver abscess 706

Anaemias in the tropics 708

Malaria 710

Schistosomiasis (bilharziasis) 712

Filariasis 714

Hydatid disease 716

Ascariasis 718

Leishmaniasis 719

Trypanosomiasis 720

Tuberculosis in the tropics 722

Leprosy (‘Hansen's disease’) 724

Guinea worm infestation ...
Pregnancy and Multiple Sclerosis
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

The risk of MS relapse is lower during pregnancy but significantly higher in the postpartum period. There are several key management issues to address in women of childbearing age with multiple sclerosis who are pregnant or in family planning. In this chapter, we review important therapeutic issues regarding peripartum and postpartum disease management, data regarding the prospect of breastfeeding, and the psychosocial support and counseling to help patients and their families navigate these decisions.
Rheumatoid Arthritis
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

Rheumatoid arthritis (RA) is a systemic inflammatory disease that is characterized principally by a polyarthritis, but can result in several neurologic complications involving both the central and peripheral nervous system. In addition, several immunotherapies used to treat RA have been associated with neurological complications. In this chapter, we review the characteristic neurological sequelae of RA as well as the possible neurological consequences of its therapeutic regimens.
Neuro-Behçet’s Disease
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

Behçet’s disease is a multisystemic, inflammatory, likely vasculitic disease, typically involving recurrent orogenital mucocutaneous ulcerations, in addition to arthritic, ophthalmologic, and gastrointestinal as well as neurologic manifestations. In this chapter, we review the current concepts in pathophysiology and diagnostic criteria for Behçet’s disease. In addition, we discuss the typical neurological presentations—both inflammatory and vascular—and their respective therapeutic approaches.
Dermatomyositis
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

Dermatomyositis (DM) is not purely a disorder of muscle and skin, but may affect multiple organs with cardiac, pulmonary, and gastrointestinal features. In this chapter, we review the clinical manifestations of DM as well as its occurrence as a paraneoplastic phenonomenon. In addition, we discuss the diagnostic modalities and outline therapeutic recommendations.
Myasthenia Gravis
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

Myasthenia gravis (MG) is an autoimmune disorder that results in loss of functional acetylcholine receptors (AChR) on the postsynaptic membrane of the neuromuscular junction caused by the presence of antibodies to the AChR. In this chapter, we review the cardinal clinical findings of MG, the standard diagnostic testing including electrophysiological features, and the medical and surgical treatment recommendations.
Autoimmune Limbic Encephalitis
Authors: Miller Aaron E. , DeAngelis Teresa M.
Published: May 2013

Limbic encephalitides can pose a diagnostic challenge in patients presenting with encephalopathy and seizures. Autoimmune etiologies can be either paraneoplastic or nonparaneoplastic. We discuss the approach to a patient with limbic encephalitis in this chapter and review proposed diagnostic criteria, the many antineuronal autoantibodies and respective neoplasms, as well as respective clinical outcomes and therapeutic responses.
Phasic GABAA-Mediated Inhibition
Authors: Cherubini Enrico
Published: May 2013

This review will focus on GABAA-mediated phasic inhibition which, in physiological conditions, exerts a powerful control on cell excitability and network oscillations thought to be associated with higher cognitive functions.3 An impairment of fast GABAergic signaling is involved in various psychiatric and neurological disorders including epilepsy.4
Tonic GABAA Receptor–Mediated Signaling in Epilepsy
Authors: Walker Matthew C. , Kullmann Dimitri M.
Published: May 2013

Fast inhibitory signaling in the brain has conventionally been considered to be predominantly mediated by the vesicular release of GABA from presynaptic terminals onto postsynaptic GABAA receptors.1 Transient opening of such receptors results in a brief increase in postsynaptic permeability to Cl–, generating an inhibitory postsynaptic potential (IPSP) that reduces the probability of firing of the neuron. However, there is abundant evidence that GABA can also act relatively far from its site of release, and this, together with several other discoveries in the last two decades, has contributed to a reappraisal of the roles of GABAA receptors in modulating neuronal and circuit excitability.1
Glutamatergic Mechanisms Related to Epilepsy
Authors: Dingledine Raymond
Published: May 2013

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The past 20 years have been a golden age for glutamate receptor research. Even before that time, in the early 1980s the invention of the first selective antagonists for what would come to be known as N-methyl-d-aspartate (NMDA) receptors1 triggered a flood of investigations as the realization grew that NMDA receptors were critically involved in synaptic plasticity, learning, creation of the proper wiring diagram of the brain during development, excitotoxicity, and a host of neurological disorders involving aberrant circuitry organization, including epilepsy (reviewed in refs. 2 and 3). Cloning of the first glutamate receptor subunit was reported in December 1989,4 and within the next 2 years an additional 15 subunits were cloned.3,5 The subsequent application of molecular and gene ablation technologies has revealed a wealth of subtlety regarding control of synaptic transmission highlighted, perhaps, by a resurgence of interest in how excitatory input patterns to GABAergic interneurons regulate synchronous firing throughout the brain. Over the past decade, our understanding of how these receptors work has been brought to the structural level by successful crystallization of numerous glutamate receptor subunits (see ref. 6). The mechanisms (transcriptional, translational, and post-translational) underlying seizure-induced changes in expression of glutamate receptors have been elucidated. A wealth of new pharmacologic reagents, particularly allosteric receptor modulators, have been introduced that can facilitate study of the roles of specific glutamate receptors in epilepsy. The proposal that reactive astrocytes release glutamate, which then acts to synchronize neuron firing within local microdomains, has been developed. Here I review the functional properties of glutamate receptors and discuss recent data pointing to their potential roles in epilepsy. But first, a word on nomenclature.
Limbic Network Synchronization and Temporal Lobe Epilepsy
Authors: Jefferys John G.R. , Jiruska Premysl , de Curtis Marco , Avoli Massimo
Published: May 2013

Cognitive function, including perception and the formation and recall of memories, depends on the integrated, often synchronous, activity of many neurons. The limbic system in general, and the hippocampal formation in particular, have well-developed anatomical and physiological mechanisms that promote neuronal synchronization. Examples of physiological synchronization include the theta rhythm, beta and gamma oscillations, and sharp-wave ripples. In general, the mechanisms of these synchronous activities depend on intrinsic neuronal properties and the interplay between populations of principal cells and interneurons.
Normal and Pathological High-Frequency Oscillations
Authors: Staba Richard J.
Published: May 2013

During natural waking and sleep behavior, the occurrence of spontaneous rhythmic field potentials, for example theta (3–8 Hz), gamma (30–80 Hz), and high-frequency oscillations (HFOs; 80–600 Hz), correspond with an increase in the rate and synchrony of neuronal firing. Compared to theta and gamma oscillations, networks supporting the generation of HFOs can be smaller in size and events shorter in duration, but the increase in neuronal firing and synchrony of discharges that occurs on a temporal scale of a few milliseconds or less can be much greater. Because HFOs can facilitate synaptic transmission through local networks, these events are implicated in information processing and consolidation of memory. Alterations to neuronal networks associated with epilepsy can also generate abnormal or pathological HFOs (pHFOs) that are believed to reflect fundamental neuronal disturbances associated with brain areas capable of generating spontaneous epileptic seizures. However, distinguishing normal HFOs from pHFOs is not always simple, particularly in studies involving intracranial brain recordings in presurgical patients with medically refractory epilepsy. This chapter will describe some of the spatial and temporal properties of HFOs observed in normal and epileptic mammalian brain and roles HFOs could play in normal brain function and epilepsy. Important to any description of HFOs are the putative mechanisms that support the generation of normal HFOs and pHFOs, and how pHFOs could be clinically useful in the treatment of epilepsy.
Interictal Epileptiform Discharges in Partial Epilepsy
Authors: de Curtis Marco , Jefferys John G.R. , Avoli Massimo
Published: May 2013

Seizures (also termed ictal discharges) represent the critical events and the primary clinical burden of an active epileptic condition. Between seizures, however, the brain of patients with epilepsy generates pathological patterns of activity, called interictal epileptiform discharges (IEDs), that are clearly distinguished from the activity observed during the seizure itself. The correlation between IEDs and ictal discharges in intractable partial epilepsies has been the subject of several studies (for review see refs. 1–4), yet no conclusion regarding the reciprocal relationship and interdependence of IEDs and ictal discharges has been reached to date. Indeed, the existing data findings have led to two opposite views that assign to IEDs either a preventive or a precipitating role in seizure occurrence.
GABAA Receptor Function in Typical Absence Seizures
Authors: Crunelli Vincenzo , Leresche Nathalie , Cope David W.
Published: May 2013

A typical absence is a nonconvulsive epileptic seizure that is characterized by a sudden and relatively brief impairment of consciousness, occurring concomitantly with a generalized, bilaterally synchronous spike (or polyspike) and slow wave discharge (SWD) at 2.5–4 Hz in the electroencephalogram (EEG).1,2 Typical absence seizures are part of the multifaceted clinical and EEG presentation of many idiopathic generalized epilepsies (IGEs), but in childhood absence epilepsy (CAE) these seizures are the only neurological symptom and are not accompanied by either metabolic, neuropathological, or other neurological deficits.1,2 The human studies reviewed in this chapter, therefore, will be those that relate to CAE, since this is the only IGE in which a putative causal link can be made between a typical absence seizure and the underlying genetic variants or pathophysiological mechanisms without the confounding effects of other epileptic and nonepileptic neurological phenotypes.
GABAB Receptor and Absence Epilepsy
Authors: Han Hua A. , Cortez Miguel A. , Snead O. Carter
Published: May 2013

GABABR-mediated mechanisms have been known for many years to be involved in the genesis and propagation of both TASs126–129 and AASs,78,84 as well as in the associated cognitive impairments.54,79 Moreover, the data reviewed in this chapter indicate that TAS and AAS share the same pharmacological profile, because they share common thalamic circuitry perturbations, notably nRT involvement. However, TAS and AAS phenotypes differ in seizure severity, SWD characteristics, and impairment in learning abilities, mainly because they differ in the other parts of the circuitry involved. In TAS, cognition is not affected because the SWD is constrained within thalamocortical circuits and does not involve limbic circuits. In AAS, on the other hand, cognition is impaired because of the SWD involvement of limbic circuitry that is recruited through cortico-thalamo-hippocampal pathways,130 hence the difference in seizure semiology and cognitive involvement. Because of the demonstrated efficacy of GABABR antagonists in preventing SWDs, the potential of GABABR antagonists as powerful antiabsence drugs has been long proposed,61 yet clinical trials of GABABR are lacking both in TAS and AAS. Frequent refractory seizures and severe impairment in cognition represent the most disabling aspects of pediatric epilepsy and are the major contributors to the burden of illness in children affected by epilepsy.131 Because of data suggesting that atypical absence seizures are independent of their comorbid cognitive deficits, yet both are GABABR dependent,79 there is a clinical imperative to initiate clinical trials of a GABABR antagonist in the AASs observed in Lennox-Gastaut syndrome.119,120
Computer Modeling of Epilepsy
Authors: Case Marianne J. , Morgan Robert J. , Schneider Calvin J. , Soltesz Ivan
Published: May 2013

There are 50 million people worldwide afflicted with epilepsy, and for roughly 15 million of them, existing epilepsy treatments are not sufficient.1 Such stark facts spur clinicians and researchers to consider dramatically different approaches to treatment, such as an implantable device that could characterize electrical activity in real time, immediately detect when the brain reaches a preictal state, and apply a counteracting current waveform, averting the seizure before it starts (see the next section),2 or an individualized, detailed model of the patient's brain—complete with patient-specific details such as genetic mutations or head trauma—to which doctors could administer virtual drugs to determine the best treatment regimen for that person. Such a tool would complement existing therapies by reducing the likelihood of patients being subjected to treatments to which they are unresponsive.
Traumatic Brain Injury and Posttraumatic Epilepsy
Authors: Prince David A. , Parada Isabel , Graber Kevin D.
Published: May 2013

The epidemiology of posttraumatic epilepsy (PTE) has been extensively analyzed and reviewed in a number of studies of both civilian and military brain injuries1,2 (reviewed in ref. 3). Several conclusions from this research are relevant to considerations of the potential mechanisms and prophylaxis of PTE. Results clearly show that the incidence of PTE is related to the severity of injury, and is therefore significantly higher in the military during wartime than in the civilian population, ranging up to 53% with penetrating wounds1,2 (reviewed in ref. 3). Both the increased incidence at older ages and the potential development of PTE by the large number of individuals who have survived severe concussive injury during recent conflicts suggest that the size of the affected population will increase in coming years, emphasizing the need for understanding the underlying pathophysiological processes and the development of prophylactic strategies.4,5 Although initial seizures in those who develop epilepsy most commonly have a focal origin in neocortex, both partial neocortical and temporal lobe epilepsy can follow traumatic brain injury (TBI) in humans.6 One remarkable feature of PTE is the variable, often very prolonged latency from injury to epilepsy, which can range from weeks to years.1,2,6 This provides a possible window for prophylactic intervention once more information regarding the underlying pathophysiological processes and strategies for modifying them is available. However, the long latency also represents a potential therapeutic problem, particularly in the absence of reliable biomarkers of epileptogenesis in progress. This chapter will focus on examples of aberrant excitatory and inhibitory processes in injured epileptogenic cortex and potential approaches to prevention of epileptogenesis that are focused on these pathophysiological mechanisms. Some of the challenges for the development of prophylactic therapies are also discussed. Readers are referred to a number of reviews and papers published very recently that deal with various aspects of the basic mechanisms, pathogenesis, and potential prophylaxis of PTE and complement the areas covered in this chapter.6–18
Programmed Necrosis after Status Epilepticus
Authors: Niquet Jerome , Lopez-Meraz Maria-Leonor , Wasterlain Claude G.
Published: May 2013

In this review, we will discuss the most recent advances in the field of neuronal injury following epileptic seizures, with an emphasis on the mechanism of neuronal necrosis. The ultrastructure of cell death and the ubiquity of endogenous cell death programs were first described in the 1970s, and the two main categories of cell death, apoptosis and necrosis, were originally defined according to morphological criteria.1 The role of glutamate and its analogues in excitotoxic cell death, and the concept of excitotoxicity—including its role in seizures—derived from the pioneering studies of John Olney and his disciples.2–5 Multiple cell death factors and cell death programs have been identified in developmental and disease-induced neuronal apoptosis,6–8 and there is mounting clinical and experimental evidence of their contribution to seizure-induced neuronal injury.9–16 Because these death factors were originally identified in classic apoptosis, any form of cell death in which they are expressed is often called apoptotic, even if its morphology suggests necrosis. This has caused considerable confusion in the literature and should be discouraged.17–20 In this chapter, we will discuss the involvement of cell death factors in morphologically defined necrosis, the main mode of status epilepticus (SE)-induced cell death in the adult and even in the developing brain. We find that necrosis is frequently an active form of neuronal death, requiring the expression or activation of some of the same cell death factors usually identified with apoptosis. While this finding raises the hope that targeting common cell death pathways might have therapeutic benefits for both necrosis and apoptosis, the multiplicity and redundancy of cell death pathways for both modes of neuronal death also raise formidable problems when we consider the potential therapeutic applications of these mechanisms.
Mossy Fiber Sprouting in the Dentate Gyrus
Authors: Buckmaster Paul S.
Published: May 2013

This chapter explores mossy fiber sprouting in the dentate gyrus, which includes a look at the circumstances under which sprouting occurs, how it develops, and the functional consequences of all of this.
Kainate and Temporal Lobe Epilepsies
Authors: Ben-Ari Yehezkel
Published: May 2013

Understanding the role of kainate signals in modulating ongoing neuronal and network-driven patterns of activity has enormously benefited from the parallel investigation of pathological and normal tissue. The past three decades have shown how kainate generates seizures and how neurons susceptible to kainate are also the ones that use it for ongoing biological functions. Clearly, the system relies on the unique capacity of kainate signals to generate biologically relevant patterns by activating a wide range of cellular mechanisms that converge to enhance neuronal excitability. Theses systems, however, “live dangerously,” since insults can transform these activities into severe life-long neurological disorders. It is this link that we must better understand if we want to efficiently block pharmacoresistant TLE.
Abnormal Dentate Gyrus Network Circuitry in Temporal Lobe Epilepsy
Authors: Sloviter Robert S. , Bumanglag Argyle V. , Schwarcz Robert , Frotscher Michael
Published: May 2013

The mechanisms that cause acquired temporal lobe epilepsy are unknown. Suspected mechanisms include neuron loss, synaptic reorganization, and granule cell dispersion, but determining which abnormalities mediate epileptogenesis has been problematic because the most frequently used chemoconvulsant-based animal models exhibit extreme variability and minimal evidence of hippocampal epileptogenesis. Continuous monitoring of behavior and granule cell layer activity in awake rats after hippocampal injury caused by stimulation-induced status epilepticus has now shown that granule cells generate spontaneous field depolarizations, population spikes, and epileptiform discharges in the first days post-injury, prior to each generalized behavioral seizure. Thus, injury-associated hippocampal epileptogenesis is coincident with initial neuron loss, not delayed secondary processes. We hypothesize that neuron loss in the entorhinal cortex disrupts the functional separation of Layer II “grid cells,” causing abnormal synchronous discharges that invade the dentate gyrus. This, in turn, produces population spikes and epileptiform discharges in granule cells disinhibited by injury-induced hilar neuron loss. Long delays between injury and generalized behavioral seizures, when they occur, may primarily involve a “kindling” process in which initially focal (subclinical) discharges gradually increase in duration and cause clinical seizures. Neuroprotection in the immediate post-injury period, and prolonged anti-kindling therapy, might be the most effective anti-epileptic strategy.
Seizure-Induced Formation of Basal Dendrites on Granule Cells of the Rodent Dentate Gyrus
Authors: Ribak Charles E. , Shapiro Lee A. , Yan Xiao-Xin , Dashtipour Khashayar , Nadler J. Victor , Obenaus Andre , Spigelman Igor , Buckmaster Paul S.
Published: May 2013

Granule cells of the normal adult rodent dentate gyrus generally have the typical morphology of bipolar cells. Their apical dendrites arise from one pole and arborize into the molecular layer, while the axon originates from the base of the granule cell body and extends into the hilus subjacent to the granule cell layer.1 Two exceptions to this rule have been observed. Sometimes recurrent basal dendrites arise from the base of granule cell bodies and then curve back through the granule cell layer in the direction of the molecular layer, where they join apical dendrites.2–4 Despite this unusual origination, dendrites of dentate granule cells in rodents arborize exclusively in the molecular layer. The other exception is the rare instance of an axon originating from the granule cell's apical dendrite or the apical pole of its cell body.4 In this instance, the axon descends into the hilus without giving rise to collaterals. Both of these morphologies suggest that rat granule cells are more heterogeneous than was previously indicated. Dentate granule cells from humans and nonhuman primates differ from granule cells from rodents; primate granule cells commonly have basal dendrites. Seress and Mrzljak5 were the first to show that primate granule cells display basal dendrites in normal brain. Other studies confirmed this observation and showed that many granule cells in monkey have basal dendrites that enter the hilus.6 These basal dendrites have large, complex spines and smaller “stubby” spines. About 10% of granule cells in the monkey dentate gyrus exhibit basal dendrites. Pertinent to this review is the finding that greater numbers of granule cells with hilar basal dendrites are found in the temporal lobes of epileptic humans compared to normal human control tissues.7,8 The remainder of this chapter will focus on the seizure-induced formation of hilar basal dendrites in rodents and the potential significance of hilar basal dendrites in epileptogenesis.
Alterations in the Distribution of GABAA Receptors in Epilepsy
Authors: Houser Carolyn R. , Zhang Nianhui , Peng Zechun
Published: May 2013

Changes in gamma-aminobutyric acid A receptors (GABAAR) in epilepsy are particularly complex and intriguing because of the multiple subunits that can be altered. The numerous GABAAR subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3) typically form heteropentameric receptors that are generally composed of two α, two β, and either one γ, δ, or other more minor subunit. The different subunit combinations create a diversity of receptor subtypes that differ in their function, pharmacology, and regional and cellular localization (see refs. 1 and 2 for reviews). Such diversity provides challenges for understanding the functional effects of GABAAR subunit alterations in epilepsy, but it may also offer unique possibilities for treatment of this disorder.
Plasticity of GABAA Receptors Relevant to Neurosteroid Actions
Authors: Mody Istvan
Published: May 2013

It is now widely accepted that phasic (synaptic) and tonic (extrasynaptic) GABAergic influences on neuronal excitability are mediated by different receptors with different pharmacological profiles. This chapter will focus on the plasticity of the neurosteriod-sensitive δ subunit containing gamma-aminobutyric acid A (GABAA) receptors (δ-GABAARs) in animal models of temporal lobe epilepsies (TLE) and its possible consequences for modulating the excitability of the dentate gyrus.
Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy
Authors: Miles Richard , Blaesse Peter , Huberfeld Gilles , Wittner Lucia , Kaila Kai
Published: May 2013

Defects in GABAergic signaling have often been linked to the epilepsies. Suppressing fast inhibition mediated by gamma-aminobutyric acid A (GABAA) receptors initiates interictal-like activities in healthy brain tissue,1,2 and specific subgroups of interneurons seem to be especially sensitive to the neuronal death associated with temporal lobe epileptic syndromes.3–5 However, defects in the neuronal homeostasis of chloride have only recently been linked to epileptiform activities. Intraneuronal levels of chloride control GABAergic signaling postsynaptically.6 So, changes in chloride homeostasis can affect the strength and even the sign of GABAergic signals. We will describe work on tissue from patients with pharmacoresistant epilepsies of the temporal lobe that provided the first insight that chloride homeostasis might be altered in the epilepsies.7,8 We will examine molecules that control chloride homeostasis, evidence that they are modulated by pathological stressors including denervation, anoxia and the sclerotic cell death associated with some focal epilepsies. We ask whether changes in chloride homeostasis contribute to ictal events, arguing that potassium efflux mediated by K-Cl cotransporters may contribute to prolonged ictal excitation. Finally, we examine how differences in chloride regulation may contribute to neonatal epilepsies and ask whether molecules targeting chloride homeostasis might be effective anti-epileptic drugs.
Glia–Neuron Interactions in Ictogenesis and Epileptogenesis
Authors: Vezzani Annamaria , Auvin Stephan , Ravizza Teresa , Aronica Eleonora
Published: May 2013

This chapter reports clinical observations in drug-resistant epilepsies and experimental findings in adult and immature rodent models of seizures and epileptogenesis that causally link brain inflammation to the epileptic process. We discuss the role of specific inflammatory mediators of glia–neuron communication in the etiopathogenesis of seizures.
Glia–Neuron Interactions
Authors: Biagini Giuseppe , Marinelli Carla , Panuccio Gabriella , Puia Giulia , Avoli Massimo
Published: May 2013

Overall, the evidence reviewed in this chapter indicates a complex interaction between glia and neurons in postlesional epilepsies, depicting a scenario similar to that found when analyzing the role of glial cells in the recovery from brain damage. Indeed, astrocytes may exert both pro-epileptogenic and anti-epileptogenic roles through (1) indirect modulation of neuronal function via release of inflammatory cytokines and neurosteroids, or by altering neurotransmitter release, and (2) by directly influencing neuronal activity via release of gliotransmitters.
Genetic Epidemiology and Gene Discovery in Epilepsy
Authors: Ottman Ruth , Risch Neil
Published: May 2013

Over the last two decades, more than 20 genes with a major effect on the risk for human epilepsy have been identified, providing important clues to pathogenic mechanisms and enabling some patients to discover the cause of their disorder.1 However, the genes identified so far affect risk in a very small proportion of patients—primarily those from families consistent with Mendelian modes of inheritance. Most epilepsies occur in the absence of a significant family history, and identifying and characterizing the genetic mechanisms in these complex epilepsies is a major challenge for the next decade.2 Here we discuss the meaning of complex inheritance as it applies to epilepsy, findings from current research, and approaches likely to be advantageous for gene identification in these forms of epilepsy.