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Investigating Neurological Disease
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Book description

In the clinical neurosciences, decision-making becomes ever more complicated because of rapidly emerging new diagnostic tests and treatments and increasing demands from patients to participate in their management. This concise but wide-ranging handbook reviews the epidemiology of neurological disease and the treatment and prognosis of all major diseases of the nervous system. Part one offers essential guidance for clinicians to quantitative methods in research, including genetic epidemiology, decision analysis, meta-analysis, outcomes research and survival analysis, and thus provides a good understanding of the evidence underlying clinical management. The second part is devoted to individual neurological diseases, covering etiology, diagnosis, prognosis, interventions, and implications for clinical practice. With contributions from leading international authorities, this book is an invaluable guide to clinical decision-making for neurologists and others involved in the management of neurological disease.

Reviews

‘The book provides a novel approach to neurological thinking and the subtitle indicates a refreshing population-based approach to some of the difficult issues.’

Source: Doctors.net

'While this book is predominantly aimed at neurologists with an interest in epidemiology, it also serves as a useful overview of neurological diseases for clinicians or surgeons who may also be involved in the care of neurological patients. In particular, the first section of the book is a useful introductory guide for any clinician embarking on an epidemiological study and should be recommended reading.'

Source: British Journal of Neurosurgery

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Contents

  • 1 - Clinical research design: analytical studies
    pp 3-10
  • View abstract

    Summary

    Analytic studies are increasingly important for understanding relationships between diseases and their causes. They usually take the form of observational investigations, but can also include randomized clinical trials. Risk factors are antecedents that are considered to be components of the disease pathway. Appropriate study design and consideration to systematic bias and confounding helps to establish association between the exposure and disease. The purpose for maintaining the principles of causal inference and eliminating chance, bias, and confounding is to establish validity. The most serious concern in analytic studies is maintaining validity. Confounders are extraneous factors that are related to the disease and to a risk factor or exposure related to the disease. The confounder usually predicts disease in the absence of any risk factor. Investigators have to consider cost and efficiency in their design as well as the potential public health impact of any observed association.
  • 2 - Genetic epidemiology in neurologic disease
    pp 11-20
  • View abstract

    Summary

    Rapid developments in molecular genetics in recent years have afforded tremendous growth in our understanding of the pathophysiology of many neurologic diseases. This chapter addresses the basis of the complexity in the genetic contributions to common neurologic disorders, gene-environment interaction, and the pathway for investigating the genetic contributions to disease risk. It describes the methods for collection of accurate information on disease occurrence in families, and research strategies commonly employed in genetic epidemiology. In general, complex diseases are much more common than simple genetic diseases. Some examples in neurology would include (among many others): epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), migraine, essential tremor, and amyotrophic lateral sclerosis (ALS). Variable expressivity is sometimes observed even in so-called simple genetic diseases. The genetic epidemiology of epilepsy provides a clear example of etiologic heterogeneity. Some genetic influences on susceptibility to complex diseases may involve genetic interaction (epistasis).
  • 3 - Gene–environment interaction in neurologic disorders
    pp 21-25
  • View abstract

    Summary

    This chapter discusses the basic concept of gene environment interaction including the definition and principal mechanisms. It describes the evidence for gene-environment interaction. From the perspective of a neurogenetic disorder, gene-environment interaction implies that the risk of disease associated with mutations or common genetic variations (that is, polymorphisms) in genes is altered by a nongenetic risk factor. Modifiable age-dependent environmental factors are likely to influence the risk and onset of disease. Genetic factors play an important role in the etiology of various neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease. It is becoming increasingly clear that a great number of common neurodegenerative disorders result from an interplay of genetic and environmental risk factors. The clinical and public health implications of genetic factors in terms of disease prevention and care are not straightforward if risks associated with these genetic factors are not properly quantified.
  • 4 - Analysis, reanalysis, and meta-analysis in neurology
    pp 26-42
  • View abstract

    Summary

    This chapter illustrates the problems and the methodologic issues involved in collaborative reanalyses. When reanalyses involve the pooling of data from randomized clinical trials, cohort studies, or case-control studies, the term meta-analysis has often been used in recent years. An example of collaborative reanalysis of descriptive epidemiologic data is the comparison of prevalence data of Alzheimer's disease (AD) by the European Community Concerted Action Epidemiology and Prevention of Dementia (EURODEM) group. The objective of the study was to investigate geographic differences, age and sex patterns, and time trends in the prevalence of AD. The example of collaborative reanalysis of analytic epidemiologic data is the comparison and pooling of case-control studies of AD by the EURODEM group. The objective of the study was to establish the consistency of findings across studies, to investigate rare exposures, and to conduct subgroup analyses. The most important objective was to establish consistency across studies.
  • 5 - Diagnostic research in clinical neurology
    pp 43-51
  • View abstract

    Summary

    This chapter focuses on the evaluation of diagnostic technologies for current neurological practice. New diagnostic tests may have important implications for everyday clinical practice, for research into pathogenic mechanisms, and sometimes even for classifications of diseases. In neurology, the advent of magnetic resonance imaging (MRI) has affected the diagnostic approach to a wide range of clinical problems in a fundamental way. Studies of technical capacity may identify high quality diagnostic tests which are not necessarily more accurate than the standard diagnostic approach in identifying subjects with a specific disease. Assessment of therapeutic impact requires recording of the diagnosis and treatment plan before the test under study is performed. The technical capacity and diagnostic accuracy of a (new) test in clinical neurology should ultimately translate in health benefits for patients through its diagnostic or therapeutic impact. Entirely different considerations apply to the use of diagnostic instruments in research settings.
  • 6 - Decision analysis in clinical neurology
    pp 52-69
  • View abstract

    Summary

    In the clinical neurosciences, decision making becomes more complicated every day, because of rapidly emerging new treatments and diagnostic tests, and because of increasing demands from patients to be informed and to participate in decision making. This chapter presents two outlines to illustrate the basic elements of a decision analysis. The first example concerns a diagnostic problem, and it is used to illustrate the modeling of a decision tree, the calculation of expected utility, and sensitivity analyses. In the second example, a therapeutic problem, quality adjusted survival analysis is introduced. An analysis of diagnostic and one of therapeutic decision making have been used to illustrate the key elements and methodology of clinical decision analysis in neurology. Although the results of a decision analysis can be helpful in clinical practice, the responsibility in clinical decision making will always remain with the clinician.
  • 7 - Outcomes research in clinical neurology
    pp 70-87
  • View abstract

    Summary

    All clinical medical research, ranging from observational epidemiologic studies to randomized clinical trials, could be considered outcomes research since it is concerned with the results of the presence of disease or its treatment. The role of outcomes research in clinical neurology is shown in this chapter, and examples from the neurologic literature, particularly from the authors' specialty field of stroke, are illustrated. Neurology has several features which render it especially amenable to outcomes research. Outcomes research has a role to play in determining the benefits and costs of therapy for patients when standard objective indices such as mortality or incident clinical events are impractical. Outcome studies may be either case series from a particular clinic or population-based studies which attempt to identify all the patients with a particular disease in a given population. Certain measures are particularly suited to outcomes research in its commitment to assessing overall patient well-being.
  • 8 - Survival analysis in neurological diseases
    pp 88-112
  • View abstract

    Summary

    This chapter provides an overview of survival analysis as it relates to the major disorders within neurology. Death is the predominant outcome measure in the discussion. Two commonly used methods are described in the chapter, to handle censoring and variable starting times include life table analysis and the Kaplan-Meier approach. There have been a number of studies to elucidate the survival characteristics of individuals with multiple sclerosis (MS). Other neurological diseases discussed in the chapter include stroke, HIV-related neurologic disease, dementia, primary CNS neoplasms, and status epilepticus. Cerebrovascular disease (CVD) or stroke is the third leading cause of death and a significant cause of long-term disability in most industrialized nations. Human immunodeficiency virus (HIV)-dementia is largely a subcortical disorder involving deficits in cognition, behavior, and the motor system. Within the past two decades, Alzheimer's disease (AD) has been confirmed to be responsible for the majority of primary degenerative dementias.
  • 9 - The clinical trial in efficacy research in neurological diseases
    pp 113-134
  • View abstract

    Summary

    This chapter starts with some issues that apply to clinical trials in general: pragmatic versus explanatory trials, role of sponsoring industries, methods of randomization, and double blind versus single blind design. It describes the measurement of outcome in neurology. The chapter covers certain neurological disorders such as stroke, Parkinson's disease, multiple sclerosis (MS), polyneuropathy, migraine, and epilepsy. Several phases can be distinguished in the evaluation of therapy. Phase I studies often investigate what the safe dose range is. Phase II studies are carried out in volunteers or in patients. Phase III studies are clinical studies in which the effectiveness suggested by phase II studies is put to the test. Phase IV studies are planned postmarketing studies. The most well-known and widely used clinical measure for measuring outcome in clinical trials of patients with MS is the Kurtzke Extended Disability Status Scale (EDSS).
  • 10 - Cerebrovascular ischemic disease
    pp 137-144
  • View abstract

    Summary

    Ischemic cerebrovascular disease accounts for more than 85% of all clinical stroke events with the remainder divided approximately equally between intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SH). The diagnosis of stroke requires differentiation from other diseases of the brain of acute onset based on clinical history, neurologic exam, and brain imaging. At least two-thirds of ischemic strokes result from atherothrombotic occlusive disease while embolism from a documented cardiac source and infarction of undetermined cause constitute the balance. Strokes resulting from hemorrhage, intraparenchymatous and subarachnoid, are fatal in about half the cases and hemorrhage survivors often have severe permanent disability. A number of key risk factors for stroke have been identified and their impact estimated. Hypertension is the principal risk factor for ischemic stroke with risk rising in proportion to level of blood pressure, systolic as well as diastolic.
  • 11 - Vascular dementia
    pp 145-153
  • View abstract

    Summary

    After Alzheimer's disease, vascular dementia is the second most common cause of dementia. Depending on the instrument used in the diagnosis and the age of the study population the prevalence of vascular dementia in the geriatric population ranges from 1-5%. Any patient with cognitive deficit should be investigated to detect a treatable dementia. Basic investigations should include a thyroid function assessment, serum vitamin B12 level, syphilis serology, and computed tomographic scan or magnetic resonance imaging study of the brain. The diagnosis of vascular dementia requires the demonstration of socio-professional handicap and demonstrable causal link to vascular disease of the brain. Patients with vascular dementia are prone to recurrent stroke with further worsening of the cognitive state. In patients with known symptomatic cerebral infarctions, acetylsalicylic acid, ticlopidine and warfarin have been shown to reduce the risk of recurrent stroke. Antidepressants should be prescribed for patients with symptomatic or subclinical depression.
  • 12 - Alzheimer's disease
    pp 154-173
  • View abstract

    Summary

    Alzheimer's disease (AD), alone or in combination with other disorders, is probably the most common form of dementia. The prevalence of AD is higher in men than in women among younger old people and higher among women than among men in the very old. The β-amyloid protein is one of the characteristic components of the extracellular senile plaques (SP) and is deposited in the brain of AD patients. Most investigators consider amyloid deposition to be a "central event" in the pathogenesis of AD, starting a cascade which results in neuronal destruction. Histopathology is often stated to be the "golden standard" for a diagnosis of AD. Survival is reduced in AD, and it is considered to be the fourth or fifth most common cause of death in Western society. A recent clinical trial suggested that treatment with antioxidants slows the progression of AD.
  • 13 - Parkinson's disease
    pp 174-195
  • View abstract

    Summary

    Parkinson's disease (PD) is one of the most frequent progressive neurodegenerative diseases in the elderly. This chapter reviews the recent developments in epidemiologic research of PD. It discusses the risk factors, diagnosis, disease frequency, prognosis, intervention, and implications for clinical practice. Age is the most important risk factor for PD. Smoking is one of the determinants of PD that has been studied most frequently. For the diagnosis of PD, the postmortem neuropathologic examination of the brain is generally considered to be the gold standard. For the clinical diagnosis of PD, the generally accepted prerequisite is assessment of the presence of Parkinsonism, based on a combination of four typical clinical features, referred to as cardinal signs, that is, resting tremor, bradykinesia, rigidity, and impaired postural reflexes. The rate of deterioration of nigral cells is probably most prominent and curvilinear in the preclinical or very early phase of Parkinson's disease.
  • 14 - Multiple sclerosis
    pp 196-204
  • View abstract

    Summary

    A large part of neurological disabilities of the young adult population of developed countries is due to multiple sclerosis (MS). This chapter focuses on the most prominent features of the etiology, natural history, and treatment of the disease. Hundreds of epidemiological studies on MS prevalence which have been conducted throughout the world provide evidence that the disease involves the interplay of genetic susceptibility factors and environmental exposures, possibly to infectious agents. The diagnosis for MS remains mainly based on clinical data. The expanded disability status scale (EDSS) was devised to evaluate neurological impairment in MS is widely used to describe disease progression in MS patients. Interventions in MS aim to reduce duration and severity of exacerbations, to alter the natural history of the disease, mainly by reducing the relapse rate, or to treat the consequences of neurological disorders including spasticity, chronic pain, or bowel and bladder dysfunction.
  • 15 - Myasthenia gravis
    pp 205-217
  • View abstract

    Summary

    Myasthenia gravis (MG) is a rare disease, even though its incidence and prevalence rates are growing: for example, its prevalence was 7.8-14.2 per 100 000 population in the 1970s and 1980s while it was 2.5-6.4 per 100 000 in the 1960s. Transient neonatal myasthenia occurs in 8-14% of births to myasthenic mothers. Myasthenia was also found to be relatively frequently associated with malignancy. The diagnosis of MG is based on the clinical findings of weakness and fatigue in muscle group(s), aggravated by exercise and relieved by rest. Edrophonium is a very short-acting anticholinesterase drug used as a diagnostic probe. The prognosis of MG depends upon the age of the patient at onset of the disease, the clinical stage, and the presence or absence of thymoma. Five years after MG was diagnosed, the probability of achieving complete remission reaches 13% while 33% achieve pharmacological remission, that is, symptom-free while under treatment.
  • 16 - Guillain–Barré syndrome
    pp 218-229
  • View abstract

    Summary

    Two-thirds of Guillain-Barré syndrome (GBS) patients suffer from an infection approximately one to three weeks before the onset of weakness. These infections mostly involve the upper respiratory and the gastrointestinal tract. In about 28% of GBS patients the disease runs a mild course and these patients will remain ambulant during the course of the disease. In the other patients the disease progresses and finally, artificial respiration is necessary in 20-30% of the patients. Because of the risk of autonomous dysfunction and the unpredictable course of the disease, the patient should be carefully monitored from the beginning. In doing so, one should be aware of the possibility of respiratory distress, aspiration, and cardiovascular problems. Pain often is a great burden to the patient. Although special mattresses and frequent repositioning may be helpful, epidural morphine application may be necessary.
  • 17 - Encephalitis and meningitis
    pp 230-245
  • View abstract

    Summary

    Almost all the studies on encephalitis and aseptic meningitis were hospital-based and some of them were limited to children and adolescents. The incidence of encephalitis ranged from 1 to 7.4 cases per 100 000 per year in patients of all ages and from 1 to 16.7 cases per 100 000 per year in children and adolescents. The age- and sex-adjusted incidence of aseptic meningitis was 10.9 per 100 000. Encephalitis and meningitis can be caused by many etiological agents. Arboviral, enteroviral, and parainfectious encephalitides are the commonest viral infections. Bacterial meningitis is generally a more severe disease, with a case-fatality ratio approximating 100% in untreated patients. The control of viral infections of the central nervous system (CNS) is mostly based on prevention measures. Excessive prescribing of antibacterial agents tends to increase the chance of serious adverse drug reactions and the development of drug resistance.
  • 18 - HIV infection
    pp 246-258
  • View abstract

    Summary

    Human immunodeficiency virus (HIV) infection has expanded to become a global pandemic which threatens health in most areas of the world, and is now the leading cause of death among some segments of the population. Infection with HIV-1, a member of the lentivirus subfamily of retroviruses, produces a wide spectrum of clinical manifestations, ranging from asymptomatic infection to severe, life-threatening opportunistic infections. The prevalence of HIV dementia is only 0.4% during the asymptomatic phase of infection. In patients with AIDS, dementia develops in 15-20%. The diagnosis of HIV dementia is established by a history of a progressive cognitive or behavioral decline with apathy, memory loss, or slowed mental processing and by appropriate ancillary studies. HIV-1 associated vacuolar myelopathy (HIV myelopathy) is characterized by a vacuolar degeneration affecting predominantly the thoracic spinal cord. Patients may have multiple concurrent opportunistic processes, or opportunistic processes may coexist with HIV-related neurological disorders.
  • 19 - Prion diseases
    pp 259-269
  • View abstract

    Summary

    This chapter discusses the etiology, diagnosis, occurrence, and prognosis of human prion disorders. It emphasizes on the Creutzfeldt-Jakob disease (CJD), the most common and complex prion disorder in humans. Prion diseases may be transmitted from man to man. The classical example is kuru, in which the disease has been transmitted through cannibalistic rituals. New developments may be anticipated with regard to the use of magnetic resonance imaging (MRI) in the diagnosis of CJD. For all prion disorders, DNA diagnostics may be used to support the diagnosis. Several dominant mutations in the prion protein (PRNP) gene are known to lead to CJD. The most common prion disease, CJD, is reported worldwide with a mortality of around one death per million persons. Within months after diagnosis of CJD, there is a progressive deterioration of the clinical condition to akinetic mutism.
  • 20 - Neoplastic disease
    pp 270-280
  • View abstract

    Summary

    This chapter highlights the current issues in the epidemiology of brain tumors. It describes the classification of brain tumors in epidemiologic studies, the spatial and temporal occurrence of brain tumors, and the risk factors for brain tumors. Metastatic tumors of the brain may be derived from many primary sites and are of clinical significance because of seizures and other neurologic symptoms. The geographic patterns of brain tumor incidence and mortality rates are relatively stable as is found in many other neurologic diseases such as amyotrophic lateral sclerosis (ALS) and idiopathic epilepsy. Traumatic brain injury has long been considered a risk factor for intracranial neoplasia, especially meningioma. The tumors are then usually demonstrated by magnetic resonance imaging (MRI). The onset of seizure in people aged 35-64 must first be evaluated for benign or malignant brain tumor.
  • 21 - Cerebral palsy
    pp 281-290
  • View abstract

    Summary

    Cerebral palsy (CP) may be categorized into its clinical subtypes (spastic quadriplegia, diplegia, hemiplegia; dyskinetic or ataxic forms, and mixed), by severity. It may be further grouped according to whether or not etiology is considered known through neuroimaging, chromosomal, metabolic, or other evidence. The hypothesis that birth asphyxia is a major cause of CP has not led to the development of therapies producing a net decrease in CP. Known risk factors for CP in very low birthweight (VLBW) infants differ somewhat from those in term babies. The diagnosis of CP rests on identification of abnormalities of tone, reflexes, and posture, as assessed after the first year of life and preferably not before age 3 years; earlier diagnostic assessments are unstable, especially in children born prematurely. The goals of intervention in CP are to improve function, prevent deformities and discomfort, and make care easier.
  • 22 - Migraine
    pp 291-306
  • View abstract

    Summary

    Migraine headache is an extremely common and temporarily disabling headache disorder. Most studies on migraine prevalence have reported variation by age and gender. Prevalence is generally highest between the ages of 25 and 55, often with a peak in the late 30s and early 40s. Migraine was once considered to be a disease of the affluent. The American Migraine Study showed that migraine prevalence was lower in African-Americans than Asians. Familial aggregation of migraine has long been recognized and genetic studies have generally supported a role for both genetic and environmental risk factors in the etiology of migraine. The heterogeneity of familial hemiplegic migraine (FHM) underscores the likely heterogeneity of the more common types of migraine. Diagnosis of migraine is complicated by the episodic and heterogeneous nature of the illness. Population-based studies demonstrate that migraine is comorbid with depression, anxiety disorders, and manic depressive illness as well as epilepsy.

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