Showing papers in "Lancet Neurology in 2004"

An active and socially integrated lifestyle in late life might protect against dementia.

Abstract: The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

Abstract: Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

Brain function in coma, vegetative state, and related disorders

Abstract: We review the nosological criteria and functional neuroanatomical basis for brain death, coma, vegetative state, minimally conscious state, and the locked-in state. Functional neuroimaging is providing new insights into cerebral activity in patients with severe brain damage. Measurements of cerebral metabolism and brain activations in response to sensory stimuli with PET, fMRI, and electrophysiological methods can provide information on the presence, degree, and location of any residual brain function. However, use of these techniques in people with severe brain damage is methodologically complex and needs careful quantitative analysis and interpretation. In addition, ethical frameworks to guide research in these patients must be further developed. At present, clinical examinations identify nosological distinctions needed for accurate diagnosis and prognosis. Neuroimaging techniques remain important tools for clinical research that will extend our understanding of the underlying mechanisms of these disorders.

Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics.

Abstract: The cause of Alzheimer's disease (AD) is unknown. This gap in knowledge has created a stumbling block in the search for a genuinely effective treatment or cure for this dementia. This article summarises the arguments for a causal role for either amyloid deposition or cerebrovascular pathology as the primary trigger in the development of non-genetic AD. A bare-bones survey of the published research reveals no compelling evidence that amyloid deposition is neurotoxic in human beings or that it results in neurodegenerative changes involving synaptic, metabolic, or neuronal loss in human or transgenic-mouse brains. By contrast, the data supporting AD as a primary vascular disorder are more convincing. Findings suggesting a vascular cause of AD come from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies. The consensus of these studies indicates that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.

Insulin and neurodegenerative disease: shared and specific mechanisms

Abstract: Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

Chronic epilepsy and cognition

Abstract: Cognitive profiles in epilepsy are as heterogenous as the epileptic syndromes themselves; causes, topography of epileptogenic areas, pathogenetic mechanisms, and the diverse features characterising the clinical course all contribute to the effect on cognition. Chronic epilepsy generally impairs cognition, but it also induces processes of functional reorganisation and behavioural compensation. In most idiopathic epilepsies, cognition is only mildly deteriorated or even normal by clinical standards. Localisation-related cryptogenic and symptomatic epilepsy disorders are accompanied by focal deficits that mirror the specific functions of the respective areas. Poor cognitive outcome is generally associated with an early onset and a long duration of the disease and with poor seizure control. There is evidence that cognitive functions are already impaired at the onset of the disease, and that the maturation of cognitive functions in children is susceptible to the adverse influence of epilepsy. In adults, cognitive decline progresses very slowly over decades with an age regression similar to that of people without epilepsy. Successful epilepsy surgery can stop or partly reverse the unfavourable cognitive development, but left-temporal resections in particular have a high risk of additional postoperative verbal memory impairment. Cognitive recovery in the adult brain after successful surgery indicates functional compensation and, to some degree, functional reorganisation or a reactivation of functions previously suppressed by influence from distant but connected epileptogenic areas.

Strategies for stroke rehabilitation

Abstract: Summary Rehabilitation after hemiplegic stroke has typically relied on the training of patients in compensatory strategies. The translation of neuroscientific research into care has led to new approaches and renewed promise for better outcomes. Improved motor control can progress with task-specific training incorporating increased use of proximal and distal movements during intensive practice of real-world activities. Functional gains are incorrectly said to plateau by 3–6 months. Many patients retain latent sensorimotor function that can be realised any time after stroke with a pulse of goal-directed therapy. The amount of practice probably best determines gains for a given level of residual movement ability. Clinicians should encourage patients to build greater strength, speed, endurance, and precision of multijoint movements on tasks that increase independence and enrich daily activity. Imaging tools may help clinicians determine the capacity of residual networks to respond to a therapeutic approach and help establish optimal doseresponse curves for training. Promising adjunct approaches include practice with robotic devices or in a virtual environment, electrical stimulation to increase cortical excitability during training, and drugs to optimise molecular mechanisms for learning. Biological strategies for neural repair may augment rehabilitation in the next decade.

Cognitive deficits in adult patients with brain tumours.

Abstract: Summary Cognitive function, with survival and response on brain imaging, is increasingly regarded as an important outcome measure in patients with brain tumours. This measure provides us with information on a patient's clinical situation and adverse treatment effects. Radiotherapy has been regarded as the main cause of cognitive decline in these patients, because children with brain tumours can develop intellectual deterioration caused by radiotherapy. In long-term surviving patients, radiotherapy may indeed lead to cognitive deficits, or even dementia. Recent studies, however, have made clear that focal radiotherapy in patients with glioma is not the main reason for cognitive deficits. The tumour itself and other medical treatments contribute largely to the cognitive deficits. Cognitive function is now also recognised as an independent prognostic factor in the survival of glioma patients. Additionally, cognitive deterioration can be the first indicator of progressive disease after treatment.

Genetics of multiple sclerosis

Abstract: Summary Multiple sclerosis (MS) is probably aetiologically heterogeneous. Systematic genetic epidemiological and molecular genetic studies have provided important insights. Both genetic and non-genetic (environment, stochastic) factors may be involved in susceptibility as well as outcome, but we have yet to understand their relative roles. Any environmental factor is likely to be ubiquitous and act on a population-basis rather than within the family microenvironment. Taken together, the results of genome screening studies provide strong evidence for exclusion of a major locus in MS. There are, however, many genes that seem to be associated with MS. These include, but are in no way limited to, HLA classes I and II, T-cell receptor β, CTLA4, ICAM1, and SH2D2A . The future of MS genetics, as for most common complex disorders, will be dependent on the resources available, ranging from biological samples and comprehensive databases of clinical and epidemiological information to the development of new technologies and statistical methods.

Overt versus covert treatment for pain, anxiety, and Parkinson's disease

Abstract: Summary The recent introduction of covert administration of treatment to biomedical research has produced some interesting results, with many clinical and ethical implications. Concealed treatment has been used in people with nervous system conditions including pain, anxiety, and Parkinson's disease. The main finding is that when the patient is completely unaware that a treatment is being given, the treatment is less effective than when it is given overtly in accordance with routine medical practice. The difference between open and hidden administrations is thought to represent the placebo component of the treatment, even though no placebo has been given. The decreased effectiveness of hidden treatments indicates that knowledge about a treatment affects outcome and highlights the importance of the patient-provider interaction. In addition, by use of covert administration, the efficacy of some treatments can be assessed without the use of a placebo and associated ethical issues.

The promise of minocycline in neurology

Abstract: Summary The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.

Amnestic MCI or prodromal Alzheimer's disease?

Abstract: The concept of mild cognitive impairment (MCI) draws attention to cognitive changes not severe enough to warrant the diagnosis of dementia. As used today, it covers many pathological disorders and characterises a diverse population of patients who attend memory clinics. Our concern is the underlying heterogeneity. We suggest that it will soon be possible (if it is not already) to identify the underlying pathological disorders before the affected patients meet the criteria of dementia, thanks to specific neuropsychological assessments, neuroimaging, and biomarkers. In particular, patients with Alzheimer's disease (AD), the most important subgroup of patients with MCI, can already be identified before appearance of the fully developed clinical dementia syndrome. Accordingly, this paper proposes diagnostic criteria for "prodromal AD".

PET imaging of amyloid in Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is the most common form of dementia and is characterised by progressive impairment in cognitive function and behaviour. The pathological features of AD include neuritic plaques composed of amyloid-beta peptide (Abeta) fibrils, neurofibrillary tangles of hyperphosphorylated tau, and neurotransmitter deficits. Increases in the concentration of Abeta in the course of the disease with subtle effects on synaptic efficacy will lead to gradual increase in the load of amyloid plaques and progression in cognitive impairment. Direct imaging of amyloid load in patients with AD in vivo would be very useful for the early diagnosis of AD and the development and assessment of new treatment strategies. Three different strategies are being used to develop compounds suitable for in vivo imaging of amyloid deposits in human brains. Monoclonal antibodies against Abeta and peptide fragments have had limited uptake by the brain when tested in patients with AD. When putrescine-gadolinium-Abeta has been injected into transgenic mice overexpressing amyloid, labelling has been observed with MRI. The small molecular approach for amyloid imaging has so far been most successful. The binding of different derivatives of Congo red and thioflavin has been studied in human autopsy brain tissue and in transgenic mice. Two compounds, fluorine-18-labelled-FDDNP and carbon-11-labelled-PIB, both show more binding in the brains of patients with AD than in those of healthy people. Additional compounds will probably be developed that are suitable not only for PET but also for single photon emission CT (SPECT).

Dietary factors and Alzheimer's disease

Abstract: Alzheimer's disease (AD) is increasing in prevalence, and environmental risk factors have not been identified with certainty. There is evidence that oxidative stress, homocysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Few large epidemiological studies have explored the associations between nutrients and AD, and there has been only one trial of vitamin E in the prevention of AD. Some studies suggest that high intake of vitamins C, E, B6, and B12, and folate, unsaturated fatty acids, and fish are related to a low risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a low risk of AD. Available data do not permit definitive conclusions regarding diet and AD or specific recommendations on diet modification for the prevention of AD.

Brain stimulation for epilepsy

Abstract: Neural stimulation is a promising new technology for the treatment of medically-intractable seizures. Vagus-nerve stimulation (VNS) is licensed in several countries as an adjunctive therapy. VNS is as effective as antiepileptic drug therapy, and serious complications are rare. Transcranial magnetic stimulation is simple, non-invasive, and widely used in neurophysiology. Therapeutic results in a few studies are equivocal at best. Deep brain stimulation, although experimental, has been applied to the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus, and neocortical seizure foci. Preliminary results are encouraging, but not conclusive. Electrode implantation in the brain for indications other than seizures has been associated with a 5% risk for intracranial haemorrhage and 5% for infection. A controlled study of anterior thalamic stimulation in patients with intractable partial and secondarily generalised seizures has been started. Future investigations are likely to study extrathalamic sites of stimulation, and effects of stimulation contingent upon detection of or prediction of EEG patterns of epileptiform activity.

Alzheimer's disease: the two-hit hypothesis

Abstract: Summary There are many lines of evidence showing that oxidative stress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease (AD). However, although both oxidative stress and cell cycle-related abnormalities are early events, occurring before any cytopathology, the relation between these two events, and their role in pathophysiology was, until recently, unclear. However, on the basis of studies of mitogenic and oxidative stress signalling pathways in AD, we proposed a "two-hit hypothesis" which states that although either oxidative stress or abnormalities in mitotic signalling can independently serve as initiators, both processes are necessary to propagate disease pathogenesis. In this paper, we summarise evidence for oxidative stress and abnormal mitotic alterations in AD and explain the two-hit hypothesis by describing how both mechanisms are necessary and invariant features of disease.

Medication-overuse headache: a worldwide problem

Abstract: Medication overuse and subsequent medication-overuse headache (MOH) is a growing problem worldwide. Epidemiological data suggest that up to 4% of the population overuse analgesics and other drugs for the treatment of pain conditions such as migraine and that about 1% of the general population in Europe, North America, and Asia have MOH. Recent clinical studies gave further insights in clinical and pharmacological features, such as critical monthly doses and frequencies. These features seem to vary significantly and depend on the primary headache disorder and the type of drug that is overused. Along with these findings the new international classification of headache disorders has now incorporated additional criteria and new headache entities that will facilitate the diagnosis of MOH. Withdrawal therapy is the only treatment for this disorder and clear restriction of monthly doses is the central requirement for successful prevention.

Antimuscarinics for treatment of overactive bladder

Abstract: For many years, antimuscarinic drugs have been the first-line pharmacological treatment for urgency, frequency, and urge incontinence, all symptoms of the disorder termed overactive bladder. Antimuscarinic treatment is not always effective and is associated with side-effects that limit its clinical use. The clinical significance of the effects of antimuscarinic drugs has been questioned lately. In this review, the rationale for the use of these drugs in the management of overactive bladder is re-examined and the results of treatment are discussed. I conclude that these drugs are the only treatment with undisputed effectiveness in the treatment of overactive bladder. They may not be the perfect treatment for all patients with this disorder, but their value for individual patients should not be underestimated. Further clinical trials with improvement in quality of life as the primary endpoint are needed and may give a fair reflection of the clinical value of antimuscarinic drugs.

Multiple system atrophy

Abstract: Summary Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterised clinically by any combination of parkinsonian, autonomic, cerebellar, or pyramidal signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several CNS structures. Owing to the recent advances in its molecular pathogenesis, MSA has been firmly established as an α-synucleinopathy along with other neurodegenerative diseases. In parallel, the clinical recognition of MSA has improved and the recent consensus diagnostic criteria have been widely established in the research community as well as movement disorders clinics. Although the diagnosis of this disorder is largely based on clinical expertise, several investigations have been proposed in the past decade to assist in early differential diagnosis. Symptomatic therapeutic strategies are still limited; however, several candidate neuroprotective agents have entered phase II and phase III clinical trials.

Stroke in newborn infants

Abstract: Summary The few days before and after birth are a time of special risk for stroke in both mother and infant, probably related to activation of coagulation mechanisms in this critical period. Arterial ischaemic stroke around the time of birth is recognised in about one in 4000 full-term infants, and may present with neurological and systemic signs in the newborn. Neonatal seizures are most commonly the clinical finding that triggers assessment. In other children, perinatal stroke is recognised only retrospectively, with emerging hemiparesis or seizures after the early months of life. Risk factors for perinatal stroke include hereditary or acquired thrombophilias and environmental factors. Perinatal stroke underlies an important share of congenital hemiplegic cerebral palsy, and probably some spastic quadriplegic cerebral palsy and seizure disorders. There is much to be learned about the natural history of perinatal stroke, and there are as yet no evidence-based strategies for prevention or treatment.

Environmental risk factors in multiple sclerosis aetiology.

Abstract: The epidemiology of multiple sclerosis (MS) has been intensively studied. It is conceptualised as a complex disease in which genetic and environmental factors act together to cause disease. There are temporal and geographic variations in disease risk, and risk of disease may be affected by migration between regions of differing risk. Numerous potential causal factors including infection, immunisations, physical and emotional stressors, climate, diet, and occupational exposures have been studied using various observational study designs. Thus far, no single environmental exposure has been consistently identified as a causal factor in MS, but sufficient data have accumulated that causal pathways should be postulated and tested. This review will focus on the environmental epidemiology of MS.

Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough

Abstract: Summary Levodopa remains the most effective treatment for Parkinson's disease (PD). However, the drug is complicated by a wide range of adverse effects, most notably motor fluctuations and dyskinesias. Long-acting dopamine agonists are associated with a reduced incidence of these complications and modern surgical approaches and pharmacological methods of providing more continuous dopaminergic stimulation have a substantial ameliorative effect on these problems. Despite these advances, disease progression remains unaffected. For this reason there has been much enthusiasm for cellular therapies designed to replace degenerating nigrostriatal dopaminergic neurons. However, recent fetal transplant trials have failed to show expected benefit and have been complicated by "off medication dyskinesias". Even if successful, such treatment may be predestined to provide no better outcome than available treatments given current medical and surgical experience that emphasises the increasingly critical role of "non-dopaminergic" symptoms to quality of life in late-stage PD. Knowledge of the widespread, multisystem nature of the neurodegeneration that accounts for these problems suggests that restoration of the nigrostriatal dopamine system should not be the ultimate goal of future research.

Neurosarcoidosis: a clinical dilemma.

Abstract: Summary Sarcoidosis is an inflammatory multisystem disorder of unknown cause. Practically no organ is immune to sarcoidosis; most commonly, in up to 90% of patients, it affects the lungs. The nervous system is involved in 5–15% of patients. Neurosarcoidosis is a serious and commonly devastating complication of sarcoidosis. Clinical diagnosis of neurosarcoidosis depends on the finding of neurological disease in multisystem sarcoidosis. As the disease can present in many different ways without biopsy evidence, solitary nervous-system sarcoidosis is difficult to diagnose. Corticosteroids are the drug of first choice. In addition, several cytotoxic dugs, including methotrexate, have been used to treat sarcoidosis. The value of new drugs such as anti-tumour necrosis factor α will be assessed. In this review we describe the clinical manifestations of neurosarcoidosis, diagnostic dilemmas and considerations, and therapy.

Lewy-body formation is an aggresome-related process: a hypothesis

Abstract: Summary Parkinson's disease (PD) is an age-related neurodegenerative disorder that is associated with the formation of intracytoplasmic protein aggregates (Lewy-body inclusions) in neurons of the substantia nigra pars compacta and other brain areas. These inclusions were discovered over 90 years ago, but the mechanism underlying their formation and their relevance to the neurodegenerative process are unknown. Recent studies have begun to shed light on the biogenesis of Lewy bodies and suggest that they are related to aggresomes. Aggresomes are cytoprotective proteinaceous inclusions formed at the centrosome that segregate and facilitate the degradation of excess amounts of unwanted and possibly cytotoxic proteins. The concept of Lewy bodies as aggresome-related inclusions fits well with ongoing discoveries suggesting that altered protein handling might contribute to the neurodegenerative process in familial and sporadic forms of PD.

Myoclonus: current concepts and recent advances.

Abstract: Myoclonus presents as a sudden brief jerk caused by involuntary muscle activity. An organisational framework is crucial for determining the medical significance of the myoclonus as well as for its treatment. Clinical presentations of myoclonus are divided into physiological, essential, epileptic, and symptomatic. Most causes of myoclonus are symptomatic and include posthypoxia, toxic-metabolic disorders, reactions to drugs, storage disease, and neurodegenerative disorders. The assessment of myoclonus includes an initial screening for those causes that are common or easily corrected. If needed, further testing may include clinical neurophysiological techniques, enzyme activities, tissue biopsy, and genetic testing. The motor cortex is the most commonly shown myoclonus source, but origins from subcortical areas, brainstem, spinal, and peripheral nervous system also occur. If treatment of the underlying disorder is not possible, treatment of symptoms is worthwhile, although limited by side-effects and a lack of controlled evidence.

Lifting the burden: The global campaign against headache

Abstract: On March 26, 2004—after 7 years of planning and discussions—WHO’s European Office in Copenhagen will host the launch of a global enterprise unique in the specialty of headache disorders. Headache disorders are ubiquitous. Their lifetime prevalence is over 90% in those populations that have been studied. Pain, suffering, and disability caused by headache disorders impose substantial burdens, at both personal

Treatments for dysarthria in Parkinson's disease

Abstract: Dysarthria in Parkinson's disease can be characterised by monotony of pitch and loudness, reduced stress, variable rate, imprecise consonants, and a breathy and harsh voice. Use of levodopa to replenish dopamine concentrations in the striatum seems to improve articulation, voice quality, and pitch variation, although some studies show no change in phonatory parameters. Traditional speech therapy can lead to improvement of dysarthria, and intensive programmes have had substantial beneficial effects on vocal loudness. Unilateral surgical lesions of subcortical structures are variably effective for the alleviation of dysarthria, whereas bilateral procedures typically lead to worsening of speech production. Among deep-brain stimulation procedures, only stimulation of the subthalamic nucleus improves some motor components of speech although intelligibility seems to decrease after surgery. Due to the variable treatment effects on parkinsonian speech, management of dysarthria is still challenging for the clinician and should be discussed with the patient.

Epidemiology and genetics of cluster headache

Abstract: Summary Cluster headache, the most severe primary headache, is characterised by unilateral pain, ipsilateral autonomic features, and, in many cases, restlessness. Recent epidemiological studies indicate that the prevalence of cluster headache is about one person per 500. Genetic epidemiological surveys indicate that first-degree relatives are five to 18 times–and second-degree relatives, one to three times–more likely to have cluster headache than the general population. Inheritance is likely to be autosomal dominant with low penetrance in some families, although there may also be autosomal recessive or multifactorial inheritance in others. To date, no molecular genetic clues have been identified for cluster headache. Identification of genes for cluster headache is likely to be difficult because most families reported have few affected members and genetic heterogeneity is likely. Future focus should be on ion channel genes and clock genes. This review summarises the epidemiology and genetics of cluster headache.

Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches

Abstract: Ischaemic stroke is the most common form of stroke and is caused by atherosclerosis in most patients. Several genetic determinants contribute to stroke risk. Of these, carotid intimal-medial wall thickness (IMT) is particularly relevant, because it is a surrogate measure of subclinical atherosclerosis and a strong predictor of future ischaemic stroke. Studies of twins, siblings, and families have provided significant evidence for heritability, but the genes involved have not been identified. Some researchers have reported that IMT is high in people with functional variants of genes related to matrix deposition (MMP3), inflammation (interleukin 6), and lipid metabolism (hepatic lipase, APOE, CETP, and PON1). In this review, we assess the robustness of these associations and examine whether there is any evidence of risk modification by factors, such as smoking.