At present, there are three major surgical approaches to Parkinson's disease (PD): (1) Ablative surgery (i.e. pallidotomy, thalamotomy); (2) deep brain stimulation (DBS) of the thalamus, internal globus pallidus (GPi) and subthalamic nucleus (STN); and (3) grafting fetal mesencephalic cells into the striatum. As a result of increasing understanding of the pathophysiology of the basal ganglia and the demonstration of surgical alleviation of experimental parkinsonism, surgery has regained a paramount importance in the management of PD. The aim of pallidotomy and DBS is to reduce the excessive inhibitory output from the GPi and substantia nigra reticulata (SNr). Pallidotomy and DBS of the STN or GPi aim to reverse the pathophysiological consequences of dopamine deficiency in PD, and should be considered entirely symptomatic treatments. The ideal candidates for pallidotomy are young patients in good general health in whom dyskinesias are the main reasons for disability. Patients with severe bilateral problems uncontrollable with present pharmacological tools are candidates for DBS. As yet, there are no formal data to help decide how to choose between GPi and STN stimulation. In our practice, patients are allocated to GPi stimulation when 'on' dyskinesias are extremely severe. In most other instances, we prefer to perform STN stimulation. At present there is almost no reason to decide for the thalamic stimulation since tremor is equally arrested by STN stimulation, which in addition improves all other features of PD. Equally the only indication for thalamotomy would be a patient with long-standing tremor as the main clinical manifestation, which can not be controlled with drugs. The proportion of patients in whom the thalamus will be the preferable target for either DBS or thalamotomy is small (less than 5%). Grafting aims to repair the nigrostriatal pathway and restore dopaminergic function in the striatum. In the future implants containing not only dopaminergic cells but also growth factors and a variety of other substances could become a method to not only functionally compensate the biochemical abnormalities of PD but also to arrest its progression. This technique is limited to a few centres around the world owing to the technical, logistical and ethical problems of obtaining and handling embryonic cells. At present, grafting of dopaminergic cells is perhaps best suited for patients with young-onset PD (less than 45 years old) who are at high risk of developing complications within a short time of beginning pharmacological treatment and in whom the idea of making lesions or implanting electrodes into the brain for decades seems less appealing. Consideration of surgery in any given patient should be weighed against the risks (about 1% mortality and 2-6% of severe morbidity-hemiplegia, cognitive deficit, speech problems, etc.) associated with these techniques. The development of better imaging methods and the growing expertise of multidisciplinary teams will undoubtedly make surgery for PD safer and more effective in the future.
The principal functions of the heart are regulated by the sympathetic and parasympathetic divisions of the autonomic nervous system. In general, the sympathetic nerves to the heart are facilitatory, whereas the parasympathetic (vagus) nerves are inhibitory, The kinetics of the two autonomic divisions differ substantially. The vagal effects develop very rapidly, often within one heartbeat, and they decay quickly as well. Hence, the vagus nerves can exert beat-by-beat control of cardiac function. Conversely, the onset and decay of the sympathetic effects are much more gradual; only small changes are effected within the time of one cardiac cycle. When both autonomic systems act concomitantly, the effects are not additive algebraically, but complex interactions prevail. Such interactions may be mediated either pre-junctionally or post-junctionally with respect to the neuro-effector junction.
The aetiology and pathogenesis of Parkinson's disease (PD) remain unknown. There is a consensus emerging that there are likely to be multiple aetiologies that may result in the clinical and pathological abnormalities common to the majority of patients with idiopathic PD. Genetic factors have been suggested as important in either the cause of PD or in determining susceptibility. The recent linkage in one large pedigree of a gene for autosomal dominant parkinsonism to chromosome 4q21-23 and the subsequent identification of a mutation in the alpha-synuclein gene of this region are important steps towards identifying a biochemical deficiency capable of causing selective dopaminergic cell death. However, the relevance of such a defect to the majority of patients with apparent sporadic PD remains to be established. Factors that may predispose to substantia nigral cell loss, including mitochondrial dysfunction and oxidative damage, could be common to a number of separate aetiologies. A better understanding of these and their relationship to neuronal loss may provide further clues to aetiology.
This chapter deals with the 'other causes of parkinsonism with the exclusion of idiopathic Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. It is a cursory glance over the endless list of 'secondary' causes of parkinsonism or parkinsonism due to acquired and inherited metabolic and neurodegenerative diseases. With the exception of drug-induced parkinsonism and 'vascular' parkinsonism, most such cases are rare. However, single rare causes must not be overlooked as there can be specific therapeutic consequences. Parkinsonism is often present amid a constellation of other symptoms. Careful evaluation of the personal, familial and environmental context, mode of onset and progression, clinical features, and drug response, together with imaging, biochemical and molecular tests, help in determining the underlying disease.
Neurogenic syncope is one of the most frequent causes of recurrent syncope in patients with structurally normal heart. The mechanisms leading to neurogenic syncope remain poorly understood. Evidence recently obtained from several laboratories suggests that impaired arterial baroreflex adaptation to orthostatic stress, in addition to cessation of vasoconstrictive sympathetic traffic, contributes to the development of hypotension and bradycardia that determine the vasovagal response. Neurogenic syncope encompasses a wide range of reflexogenic syncope that includes the vasovagal type, micturition syncope, carotid sinus hypersensitivity and post-prandial syncope. Head-up tilt testing has become the diagnostic tool of choice for the evaluation of patients with recurrent neurogenic syncope, providing an acceptable sensitivity and high specificity that is largely dependent on the type of tilt protocol used to induce neurogenic syncope. This chapter will review the pathophysiology, diagnosis and therapeutic approach to the patient with neurogenic syncope.
Until recently, there has been little evidence substantiating the belief that mental stress provokes myocardial infarction and stroke, and aggravates atherosclerosis. However, recent advances in methodology for demonstrating effects of stress are now beginning to build a foundation of evidence that supports those beliefs. In monkeys, social stress doubles coronary atherosclerosis, and increases coronary spasm, and treatment with oestrogen, which improves endothelial function, reduces coronary spasm in relation to stress. In human beings, mental stress provokes myocardial ischaemia, and haemodynamic responses to mental stress predict progression of left ventricular enlargement, and progression of carotid atherosclerosis. These findings suggest that it may not be safe to withhold treatment of high office pressures in patients with white coat hypertension. There is now some evidence that stress management in the form of individualized cognitive behavioural interventions reduces blood pressure. Further work is needed to determine whether it is safe to withhold treatment in white-coat syndrome, and whether stress management can reduce atherosclerosis and ischaemic events.
Dementia with Lewy bodies (DLB) is the recommended term for a common cause of dementia characterized by the histological presence of distinctive inclusions within neurons, Lewy bodies (McKeith et al, 1996). Following increasing pathological recognition, core clinical diagnostic features have been identified to allow diagnosis in life. Insights into the biology of this type of neurodegeneration suggest that the regional patterns of involvement might allow therapeutic intervention. Although Lewy bodies had long been recognized in the substantia nigra and other subcortical nuclei in patients with Parkinson's disease (PD), it was only in the 1970s that a significant number of reports began to be published from Japan describing patients with dementia and parkinsonism associated with the presence of Lewy bodies in cortical neurons (reviewed by Kosaka, 1990). Since these reports, different workers have used a variety of terms to describe this disease process, including diffuse Lewy body disease (Yoshimura, 1983), Lewy body dementia (Gibb et al, 1987), senile dementia of Lewy body type (Perry et al, 1990a) and the Lewy body variant of Alzheimer's disease (Hansen et al, 1990).
The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.
Epidemiological research has confirmed that Parkinson's disease (PD) is found throughout the world and increases exponentially with age. Few good-quality data on the temporal incidence of PD are available, although both mortality and incidence data suggest that the disease may be less common today in younger age groups. Differences in prevalence between identical ethnic groups in different countries support the role of an environmental factor. Any postulated factor must be found commonly in developed countries, among which there appears to be little difference in incidence or prevalence rates. A wide variety of aetiological agents have been considered from infectious, toxic and other exposures. The most robust finding is that non-smokers have a greater risk of disease, although the reason for this is unclear and may relate to differences in pre-morbid personality. Pesticides and head injuries also show consistently elevated risk but are prone to biased measurement. Dietary anti-oxidants require further evaluation. Future research needs to improve on current limited methods of exposure measurement and to attempt more novel designs to overcome bias. More attention should be made on examining what factors determine prognosis and using epidemiological and qualitative methods to determine the needs of patients with PD.
Focal deficits, seizures and epilepsy, altered consciousness, and disturbed behaviours can complicate heart diseases and their medical treatment as well as cardiological procedures and cardiac surgery. Neurological complications of common cardiac conditions are discussed. These cardiac conditions are acute myocardial infarction and ischaemic heart disease, atrial fibrillation and cardiac arrhythmias, congestive heart failure, valvular heart diseases, infective endocarditis, congenital heart disease, invasive cardiological procedures and cardiac surgery. As transient ischaemic attack, stroke, seizures and epilepsy are the most common neurological complications, their management is also reviewed. Precautions should be taken to prevent neurological complications of heart disease. Regular surveillance for these complications would allow early diagnosis and initiation of appropriate management.
Unlike the situation in patients with most other degenerative neurological disorders, individuals with Parkinson's disease (PD) and their physicians have a wide range of effective symptomatic drugs at their disposal. All have somewhat differing indications, potencies and side-effects, and treatment needs to be individualized and also altered as the disease and the duration of drug treatment progress and the patient ages. The main problem for most patients after prolonged treatment with L-dopa is the longterm L-dopa syndrome. Fluctuations and dyskinesias are usually the principal complaint in younger, and neuropsychiatric symptoms in older, patients. Although L-dopa is the 'gold standard' in terms of efficacy, these treatment-related problems make it necessary to regularly monitor patients' response to treatment and if necessary to modify their drug regime accordingly and, particularly in younger patients, to devise treatment strategies whereby the use of L-dopa can be limited or delayed. Currently available alternative or adjunctive treatments to L-dopa preparations include oral dopamine agonists, subcutaneous apomorphine, amantadine, selegiline and anticholinergics, and some guidelines about how and when to use all of these drugs or classes of drugs are presented in this chapter. Despite initial claims of neuroprotection by selegiline, we are still awaiting the more promising second era of drug treatment for PD, whereby hopefully we can retard, halt or prevent the disease itself.
Idiopathic Parkinson's disease (IPD) is a common and universal condition. Although its cause is still unknown, we now have some insights into pathogenetic mechanisms and genetic factors that may be important in causing the selective neuronal loss and presence of Lewy bodies that characterize its pathology. Clinically, as well as the classic features of akinesia, rigidity and often rest tremor, patients may present a wide range of other symptoms including pain, other sensory symptoms, impaired olfaction, personality change, mild executive cognitive deficits, dementia and depression, an extraordinary richness of symptoms and signs rendered even more extraordinary by the long-term effects of drug treatment. While there may be little difficulty recognizing typical cases of IPD, there has been, at least until recently, a considerable misdiagnosis rate in both atremulous (confusion with ageing, vascular disease, multiple system atrophy (MSA) or progressive supranuclear palsy (PSP)) and tremulous (confusion with essential tremor (ET), dystonic tremor, and MSA) forms. However, increasing awareness of the clinical features of all these conditions, together with adherence to exacting diagnostic criteria, is leading to improved diagnosis, which is crucial for patients (who want to know what the future holds for them), for their treatment (giving them the right drug and not the wrong one) and for research (since all the different diseases above have different aetiologies and pathology).
Positron emission tomography (PET) and single photon emission tomography (SPECT) provide sensitive means for quantifying the loss of nigrostriatal dopaminergic fibres in Parkinson's disease and for detecting the presence of dopaminergic dysfunction in asymptomatic at-risk relatives and patients with isolated tremor. Functional imaging can also be used to follow the rate of disease progression objectively, determine the efficacy of putative neuroprotective agents, and monitor the viability of transplants of fetal tissue. Additionally, in vivo pharmacological changes associated with development of treatment complications (fluctuations, dyskinesias) can be studied. Loss of dopaminergic projections produces profound changes in resting and activated brain metabolism. PET and SPECT activation studies have suggested that the akinesia of Parkinson's disease is associated with failure to activate the supplementary motor and dorsal pre-frontal areas. Activation of these cortical areas is restored towards normal by the use of dopaminergic medication, striatal transplantation with fetal mesencephalic tissue, and pallidotomy. The aim of this chapter is to review the insight which functional imaging has given us into the pathophysiology of parkinsonism.
Multiple sclerosis remains incurable. The urgency of this problem, together with the need to test an ever increasing number of promising therapeutic agents emerging from animal studies, has renewed interest in both the application and the development of efficient outcome measures for treatment trials. The selection and usage of instruments used to detect outcomes is probably the most important issue in treatment trial design. Thus, familiarity with them is essential not only for researchers, but also for clinicians who wish to interpret trial results critically. This chapter begins with a discussion of the properties of an ideal outcome instrument, then reviews the strengths and limitations of existing clinical, radiological and laboratory outcome measures. With this knowledge, the current consensus regarding appropriate outcome measure selection, as well as recommendations and future perspectives in trial design, are discussed.
The clinical and neuropathological features characteristic of progressive supranuclear palsy and corticobasal degeneration are described in detail. These disorders are not as rare as previously believed, but are poorly recognized. In patients with parkinsonism, a high index of clinical suspicion, sometimes complemented by specific laboratory tests, should improve diagnostic accuracy. Biological treatments are at present not available, but suggested symptomatic therapies may improve the quality of life of patients with these disorders.
In multiple sclerosis, partial remyelination is conspicuous in many lesions, and is thought to contribute significantly to lasting recovery from acute relapse. However, myelin repair ultimately fails during progression of the disease, as disability and handicap accumulate. In this chapter we explore the biological background to myelin repair in CNS demyelinating disease, and the reasons underlying the failure of more widespread and lasting remyelination in multiple sclerosis. Experimental studies provide clear evidence that therapies promoting myelin repair can be highly successful in the CNS, and we discuss the clinical approaches which might allow the translation of these laboratory studies to neurological practice, together with some of the potential hazards and pitfalls likely to arise.
Copolymer 1 (Cop-1) is a mixture of synthetic polypeptides composed of four amino acids. Cop-1 was very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Two principal mechanisms have been proposed to explain the suppressive activity of Cop-1 in EAE and in multiple sclerosis (MS): the induction of antigen-specific suppressor T cells and the interference with T-cell activation by competition with myelin antigens in binding to the major histocompatibility complex class II molecules. Clinical trials with Cop-1 have demonstrated that Cop-1 positively alters the course of relapsing-remitting multiple sclerosis (MS) by both reducing the relapse rate and slowing the progression of disability. In a 2-year multi-centre, randomized, double-blind, placebo-controlled trial of 251 patients, Cop-1 was shown to reduce relapses by an average of 29% when compared with placebo. A preliminary study on patients with relapsing-remitting MS treated with Cop-1 showed a reduced number of new enhancing lesions on MRI as well as a reduced accumulation of lesion load during Cop-1 treatment. Antibodies to copolymer-1, which are found during Cop-1 treatment, do not interfere with its clinical effects. The side effects of Cop-1 are minimal and acceptable. In vitro and in vivo animal studies have shown a very good safety profile of Cop-1 which is devoid of teratogenic or mutagenic effects. Cop-1 joins interferon beta as a good candidate for treatment of relapsing-remitting MS.
