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Showing papers in "Lancet Neurology in 2003"



Journal ArticleDOI
TL;DR: The review shows that the burden of stroke is high and is likely to increase in future decades as a result of demographic and epidemiological transitions in populations and further research that uses the best possible methods are urgently needed in other populations of the world.
Abstract: Summary This overview of population-based studies of incidence, prevalence, mortality, and case-fatality of stroke was based on studies from 1990. Incidence (first stroke in an individual's lifetime) and prevalence were computed by age, sex, and stroke type. Age-standardised incidence and prevalence with the corresponding 95% CI were plotted for each study to facilitate comparisons. The review shows that the burden of stroke is high and is likely to increase in future decades as a result of demographic and epidemiological transitions in populations. The main features of stroke epidemiology include modest geographical variation in incidence, prevalence, and case-fatality among the—predominantly white—populations studied so far, and a stabilisation or reversal in the declining secular trends in the pre-1990s rates, especially in older people. However, further research that uses the best possible methods to study the incidence, risk factors, and outcome of stroke are urgently needed in other populations of the world, especially in less developed countries where the risk of stroke is high, lifestyles are changing rapidly, and population restructuring is occurring.

1,802 citations


Journal ArticleDOI
TL;DR: The CSF biomarkers total tau protein, phosphorylated tauprotein, and the 42 amino-acid residue form of amyloid-beta may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet the challenge of identifying incipient AD in patients with MCI.
Abstract: Summary Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and β-secretase and γ-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-β may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.

1,222 citations


Journal ArticleDOI
TL;DR: Transcranial magnetic stimulation might provide novel insights into the pathophysiology of the neural circuitry underlying neurological and psychiatric disorders, be developed into clinically useful diagnostic and prognostic tests, and have therapeutic uses in various diseases.
Abstract: Transcranial magnetic stimulation (TMS) is a non-invasive tool for the electrical stimulation of neural tissue, including cerebral cortex, spinal roots, and cranial and peripheral nerves. TMS can be applied as single pulses of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Single stimuli can depolarise neurons and evoke measurable effects. Trains of stimuli (repetitive TMS) can modify excitability of the cerebral cortex at the stimulated site and also at remote areas along functional anatomical connections. TMS might provide novel insights into the pathophysiology of the neural circuitry underlying neurological and psychiatric disorders, be developed into clinically useful diagnostic and prognostic tests, and have therapeutic uses in various diseases. This potential is supported by the available studies, but more work is needed to establish the role of TMS in clinical neurology.

1,148 citations


Journal ArticleDOI
TL;DR: Current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions are focused on.
Abstract: Summary A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle isoform, the best-known protein product of this locus. These mutations result in the Duchenne and Becker muscular dystrophies (DMD and BMD). However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. Mutations affecting the correct expression of these tissue-specific isoforms have been associated with the CNS involvement common in DMD. Rare mutations also account for the allelic disorder X-linked dilated cardiomyopathy, in which dystrophin expression or function is affected mostly or exclusively in the heart. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has provided insights into several regulatory mechanisms governing the gene expression profile. Here, we focus on current understanding of the genotype–phenotype relation for mutations in the dystrophin gene and their implications for gene functions.

902 citations


Journal ArticleDOI
TL;DR: Clinical features of the available cholinesterase inhibitors including their pharmacological properties, the evidence for switching from one agent to another, "head to head" studies, and the emerging evidence for the use of memantine in AD are reviewed.
Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available--including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, "head to head" studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches--including those more closely targeted to the pathogenesis of the disease--will also be reviewed. These potentially disease modifying treatments include amyloid-beta-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents.

686 citations


Journal ArticleDOI
TL;DR: The main pathology seems to be Lewy-body-type degeneration with associated cellular and synaptic loss in cortical and limbic structures and Alzheimer's disease-type pathology is commonly associated with dementia but less predictive.
Abstract: Dementia affects about 40% of patients with Parkinson's disease; the incidence of dementia in these patients is up to six times that in healthy people. Clinically, the prototype of dementia in PD is a dysexecutive syndrome. Loss of cholinergic, dopaminergic, and noradrenergic innervation has been suggested to be the underlying neurochemical deficits. Nigral pathology alone is probably not sufficient for the development of dementia. Although there is some controversy with regard to the site and type of pathology involved, dementia is likely to be associated with the spread of pathology to other subcortical nuclei, the limbic system, and the cerebral cortex. On the basis of more recent studies, the main pathology seems to be Lewy-body-type degeneration with associated cellular and synaptic loss in cortical and limbic structures. Alzheimer's disease-type pathology is commonly associated with dementia but less predictive. Recent evidence from small studies suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.

660 citations


Journal ArticleDOI
TL;DR: There is growing recognition that gastrointestinal dysfunction is common in Parkinson's disease (PD). Virtually all parts of the gastrointestinal tract can be affected, in some cases early in the disease course as discussed by the authors.
Abstract: There is growing recognition that gastrointestinal dysfunction is common in Parkinson's disease (PD). Virtually all parts of the gastrointestinal tract can be affected, in some cases early in the disease course. Weight loss is common but poorly understood in people with PD. Dysphagia can result from dysfunction at the mouth, pharynx, and oesophagus and may predispose individuals to aspiration (accidental inhalation of food or liquid). Gastroparesis can produce various symptoms in patients with PD and may cause erratic absorption of drugs given to treat the disorder. Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency, and difficulty with the act of defecation itself with excessive straining and incomplete emptying. Recognition of these gastrointestinal complications can lead to earlier and potentially more effective therapeutic intervention.

570 citations


Journal ArticleDOI
TL;DR: This review attempts to recognise workable definitions of MCI to discuss the prevalence, pathophysiology, prognosis, and possibilities for treatment of this disorder.
Abstract: Summary Mild cognitive impairment (MCI) is a recently described syndrome that is currently thought of as a transition phase between healthy cognitive ageing and dementia. Although this notion seems to be reasonable, the general nature of the term MCI—including its many definitions—makes accurate accounting of the prevalence, prognosis, and potential benefit from treatment somewhat difficult. The differences in cognitive profile and clinical progression among individuals with MCI are generally recognised. However, recent evidence also suggests that the aetiological heterogeneity among individuals with MCI could be greater than previously reported. For example, cerebrovascular disease seems to be underestimated as a potential cause of MCI. In this review, I attempt to recognise workable definitions of MCI to discuss the prevalence, pathophysiology, prognosis, and possibilities for treatment of this disorder.

468 citations


Journal ArticleDOI
TL;DR: It is hypothesised that CRPS is a systemic disease involving the CNS and peripheral nervous system and there should be diagnostic reclassification and redefinition of CRPS.
Abstract: Complex regional pain syndrome (CRPS) is the result of changes to the somatosensory systems that process noxious, tactile, and thermal information; to the sympathetic systems that innervate skin (blood vessels, sweat glands); and to the somatomotor systems. The changes suggest that the CNS representations of the systems have been altered. Patients with CRPS also have peripheral changes (eg, oedema, signs of inflammation, sympathetic-afferent coupling [the basis for sympathetically maintained pain], and trophic changes) that cannot be explained by central changes. On the basis of clinical observation and research in human beings and animals, we hypothesise that CRPS is a systemic disease involving the CNS and peripheral nervous system. The most important question for future research is what causes CRPS? In this article, we suggest a change to the focus of research efforts and treatment. We also suggest there be diagnostic reclassification and redefinition of CRPS.

431 citations


Journal ArticleDOI
TL;DR: Important neuroimaging and neurophysiological studies of post-stroke brain reorganisation are discussed, including studies that assess baseline and task-related functions and measure brain function in "real time".
Abstract: Summary Recovery of function after a stroke is attributable to several factors, including events in the first few days (eg, reabsorption of perilesional oedema, tissue reperfusion). However, consistent reorganisation and recovery after a stroke takes weeks or months. In the early stages, recovery from stroke can vary greatly among patients with identical clinical symptoms. Neuroimaging techniques that enable us to assess baseline and task‐related functions, and neurophysiological techniques that measure brain function in "real time", can be used to study the recovery of brain lesions after a stroke. In this review, we discuss important neuroimaging and neurophysiological studies of post‐stroke brain reorganisation.

Journal ArticleDOI
Jun Ichi Kira1
TL;DR: In Japanese people born after modernisation in the 1960s, the ratio of conventional to opticospinal MS has increased rapidly, and this form of MS is likely to have a distinct immune-mediated mechanism, which is not operative in conventional MS.
Abstract: Multiple sclerosis (MS) in Asian populations is characterised by the selective and severe involvement of the optic nerve and spinal cord as well as low prevalence rates. 15-40% of cases of MS in Japan are of this "opticospinal" type. This form of MS generally has a higher age at onset and a higher female to male ratio than conventional MS. Opticospinal MS is also characterised by frequent relapses, severe disability, few brain lesions visible on MRI, long lesions extending over many vertebral segments visible on spinal-cord MRI, pleocytosis and an absence of oligoclonal bands in the CSF, and a pronounced shift in the responses of T-helper-1 and T-cytotoxic-1 cells throughout relapse and remission phases. Conventional MS in Japanese people is, like MS in white people, associated with HLA-DRB1*1501, whereas opticospinal MS is associated with HLA-DPB1*0501. In Japanese people born after modernisation in the 1960s, the ratio of conventional to opticospinal MS has increased rapidly. Opticospinal MS is likely to have a distinct immune-mediated mechanism, which is not operative in conventional MS.

Journal ArticleDOI
TL;DR: A new nosological entity of CSF circulatory failure is postulate, with features of AD and NPH, that may cover an important subset of patients who carry the diagnosis of either AD or NPH.
Abstract: Summary There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-β peptide (Aβ) from the interstitial‐fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimer's disease (AD) or as normal‐pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Aβ in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Aβ. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH–AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.

Journal ArticleDOI
TL;DR: The strengths and limitations of algorithms of existing computer-assisted tools at the most advanced stage of development are described, together with available and foreseeable evidence of their usefulness at the clinical and research level.
Abstract: Neuroanatomical structures may be profoundly or subtly affected by the interplay of genetic and environmental factors, age, and disease. Such effects are particularly true in healthy ageing individuals and in those who have neurodegenerative diseases. The ability to use imaging to identify structural brain changes associated with different neurodegenerative disease states would be useful for diagnosis and treatment. However, early in the progression of such diseases, neuroanatomical changes may be too mild, diffuse, or topologically complex to be detected by simple visual inspection or manually traced measurements of regions of interest. Computerised methods are being developed that can capture the extraordinary morphological variability of the human brain. These methods use mathematical models sensitive to subtle changes in the size, position, shape, and tissue characteristics of brain structures affected by neurodegenerative diseases. Neuroanatomical features can be compared within and between groups of individuals, taking into account age, sex, genetic background, and disease state, to assess the structural basis of normality and disease. In this review, we describe the strengths and limitations of algorithms of existing computer-assisted tools at the most advanced stage of development, together with available and foreseeable evidence of their usefulness at the clinical and research level.

Journal ArticleDOI
TL;DR: Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid, and the least potential interaction is associated with gabapentin and levetiracetam.
Abstract: There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

Journal ArticleDOI
TL;DR: Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.
Abstract: Antiepileptic drugs (AEDs) are commonly prescribed for long periods, up to a lifetime, and many patients will require treatment with other agents for the management of concomitant or intercurrent conditions. When two or more drugs are prescribed together, clinically important interactions can occur. Among old-generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of hepatic enzymes, and decrease the plasma concentration of many psychotropic, immunosuppressant, antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral contraceptive steroids. Most new generation AEDs do not have clinically important enzyme inducing effects. Other drugs can affect the pharmacokinetics of AEDs; examples include the stimulation of lamotrigine metabolism by oral contraceptive steroids and the inhibition of carbamazepine metabolism by certain macrolide antibiotics, antifungals, verapamil, diltiazem, and isoniazid. Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.

Journal ArticleDOI
TL;DR: These trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process.
Abstract: trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process. These studies have also provided a clear indication that grafted fetaldopaminergic neurons can be therapeutically effective. On thebasis of the limited, but encouraging, observations in theseearly open-label trials,

Journal ArticleDOI
TL;DR: Similarities between clinical and experimental findings, such as the role of pesticide exposure as a potential environmental risk factor, highlight the importance of a multidisciplinary approach to the aetiology of PD.
Abstract: Summary Recent epidemiological and experimental studies have renewed interest in the hypothesis that the environment has a role in the pathogenesis of Parkinson's disease (PD). Epidemiological studies have identified protective associations (eg, smoking) as well as adverse risk factors (eg, pesticide exposure) for PD. The concordance rate of PD in pairs of dizygotic twins is similar to that in pairs of monozygotic twins, supporting a role of non-genetic risk factors. New models of selective nigrostriatal damage—such as neurotoxicity induced by rotenone or paraquat—have emphasised that environmental agents may contribute to the neurodegenerative process in PD. Toxins interact, in vitro and in vivo, with α—synuclein, an endogenous protein that is implicated in pathology of PD. Similarities between clinical and experimental findings, such as the role of pesticide exposure as a potential environmental risk factor, highlight the importance of a multidisciplinary approach to the aetiology of PD.

Journal ArticleDOI
TL;DR: An understanding of the process of iron regulation in the brain, the proteins important in this process, and the effects of iron misregulation could help to treat or prevent neurodegenerative disorders.
Abstract: Summary High iron concentrations in the brains of patients and the discovery of mutations in the genes associated with iron metabolism in the brain suggest that iron misregulation in the brain plays a part in neuronal death in some neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases and Hallervorden-Spatz syndrome. Iron misregulation in the brain may have genetic and non-genetic causes. The disrupted expression or function of proteins involved in iron metabolism increases the concentration of iron in the brain. Disturbances can happen at any of several stages in iron metabolism (including uptake and release, storage, intracellular metabolism, and regulation). Increased brain iron triggers a cascade of deleterious events that lead to neurodegeneration. An understanding of the process of iron reglation in the brain, the proteins important in this process, and the effects of iron misregulation could help to treat or prevent neurodegenerative disrders.

Journal ArticleDOI
TL;DR: Research of the cannabinoid system is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection.
Abstract: Research of the cannabinoid system has many similarities with that of the opioid system. In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology. Few compounds have had as much positive press from patients as those of the cannabinoid system. While these claims are investigated in disorders such as multiple sclerosis spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. Large randomised clinical trials of the better known compounds are in progress. Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.

Journal ArticleDOI
TL;DR: The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD and hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification.
Abstract: Summary Background A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer's disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible. Recent developments A recent prospective study (S Seshadri and colleagues N Engl J Med ; 2002 346 : 476–83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification. Where next? 25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.

Journal ArticleDOI
TL;DR: Intriguing clinicopathological correlations in FFI and SFI suggest a role for the thalamolimbic system in the regulation of sleep and other circadian functions.
Abstract: Familial fatal insomnia (FFI)--a hereditary prion disease caused by a mutation at codon 178 of the prion-protein (PrP) gene (PRNP) that leads to a D178N substitution in the protein--and its sporadic form, sporadic fatal insomnia (SFI), have similar disease phenotypes. Both disorders have clinical features of disrupted sleep (loss of sleep spindles and slow-wave sleep and enacted dreams during rapid-eye-movement sleep), autonomic hyperactivation, and motor abnormalities (myoclonus, ataxia, dysarthria, dysphagia, and pyramidal signs). PET shows pronounced thalamic and limbic hypometabolism that becomes more widespread in later stages. Neuropathological assessment reveals severe neuronal loss and astrogliosis of the anterior medial thalamus and inferior olives, with later cerebral cortical and cerebellar involvement. Accumulation of an isoform of protease-resistant PrP fragment in FFI distinct from that found in a familial form of Creutzfeldt-Jakob disease with the same D178N mutation, shows the effect of the polymorphism at codon 129 of PRNP on phenotypic expression and the possibility of distinct prion "strains" with diverse pathological potential. Intriguing clinicopathological correlations in FFI and SFI suggest a role for the thalamolimbic system in the regulation of sleep and other circadian functions.

Journal ArticleDOI
TL;DR: A substance P receptor (neurokinin 1) antagonist has been shown to have clinical efficacy in the treatment of major depression and chemotherapy-induced emesis and several other neuropeptide receptor ligands are in clinical trials for various indications.
Abstract: Summary The role of peptides as signalling molecules in the nervous system has been studied for more than 30 years. Neuropeptides and their G-protein-coupled receptors are widely distributed throughout the body and they commonly occur with, and are complementary to, classic neurotransmitters. The functions of neuropeptides range from neurotransmitter to growth factor. They are present in glial cells, are hormones in the endocrine system, and are messengers in the immune system. Much evidence indicates that neuropeptides are of particular importance when the nervous system is challenged (eg, by stress, injury, or drug abuse). These features and the large number of neuropeptides and neuropeptide receptors provide many opportunities for the discovery of new drug targets for the treatment of nervous‐system disorders. In fact, receptor-subtype-selective antagonists and agonists have been developed, and recently a substance P receptor (neurokinin 1) antagonist has been shown to have clinical efficacy in the treatment of major depression and chemotherapy‐induced emesis. Several other neuropeptide receptor ligands are in clinical trials for various indications.

Journal ArticleDOI
TL;DR: Uncontrolled reports and two preliminary randomised controlled trials of antiepileptic treatment of TCI have suggested that suppression of discharges is associated with significant improvement in psychosocial function.
Abstract: Epileptiform EEG discharges are not confined to people with epilepsy, and their frequency is only weakly related to severity. A fundamental principle of EEG practice is, therefore, to avoid overinterpretation of epileptiform activity. Epileptiform discharges not accompanied by obvious clinical events are generally regarded as subclinical or interictal. However, in many patients sensitive methods of observation, notably continuous psychological testing, show brief episodes of impaired cognitive function during such discharges. This phenomenon of transitory cognitive impairment (TCI) is found in about 50% of patients who show discharges during testing. TCI is not simple inattention. The effects are material and site specific: lateralised discharges are associated with deficits of functions mediated by the hemisphere in which the discharges occur. Conversely, specific tasks can activate or suppress focal discharges over the brain regions that mediate the cognitive activity in question. TCI clearly contributes to the cognitive problems of some people with epilepsy and may cause deficits that pass unrecognised. TCI is demonstrable in many cases of benign partial epilepsy of childhood, a disorder once thought to have no adverse psychological effects. TCI can contribute to abnormalities of psychological test profiles and interferes with daily tasks, such as reading and driving. In children it may be associated with behavioural disorders. An important practical issue is whether TCI materially impairs psychosocial function and, if so, whether drug treatment is desirable or effective. Uncontrolled reports and two preliminary randomised controlled trials of antiepileptic treatment of TCI have suggested that suppression of discharges is associated with significant improvement in psychosocial function.

Journal ArticleDOI
TL;DR: Patients with PD and orthostatic hypotension have clear evidence for baroreflex failure and loss of sympathetic innervation, most noticeably in the heart, by contrast, patients with multiple system atrophy, which is difficult to distinguish clinically from PD, have intact cardiac sympatheticinnervation.
Abstract: Summary Symptoms of abnormal autonomic-nervous-system function occur commonly in Parkinson's disease (PD). Orthostatic hypotension in patients with parkinsonism has been thought to be a side-effect of treatment with levodopa, a late stage in the disease progression, or, if prominent and early with respect to disordered movement, an indication of a different disease, such as multiple system atrophy. Instead, patients with PD and orthostatic hypotension have clear evidence for baroreflex failure and loss of sympathetic innervation, most noticeably in the heart. By contrast, patients with multiple system atrophy, which is difficult to distinguish clinically from PD, have intact cardiac sympathetic innervation. Postmortem studies confirm this distinction. Because PD involves postganglionic sympathetic noradrenergic lesions, the disease seems to be not only a movement disorder with dopamine loss in the nigrostriatal system of the brain, but also a dysautonomia, with norepinephrine loss in the sympathetic nervous system of the heart.

Journal ArticleDOI
TL;DR: MRI, transcranial doppler, echocardiogram, Holter monitoring, and electrophysiological studies increase the ability to identify the source of cardioembolism and available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke.
Abstract: Summary Embolism of cardiac origin accounts for about one fifth of ischaemic strokes. Strokes due to cardioembolism are in general severe and prone to early recurrence. The risk of long term recurrence and mortality are high after a cardio-embolic stroke. Cardioembolism can be reliably predicted on clinical grounds but is difficult to document. MRI, transcranial doppler, echocardiogram, Holter monitoring, and electrophysiological studies increase our ability to identify the source of cardioembolism. Non-valvular atrial fibrillation is the commonest cause of cardioembolic stroke. Despite its enormous preventive potential, continuous oral anticoagulation is prescribed for less than half of patients with atrial fibrillation who have risk factors for cardio-embolism and no contraindications for anticoagulation. Alternatives to oral anticoagulation in this setting include safer and easier to use antithrombotic drugs and definitive treatment of atrial fibrillation. Available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke.

Journal ArticleDOI
TL;DR: The features of compulsive DRT-seeking and intake in PD are detailed, in relation to theories ofCompulsive drug use.
Abstract: Dopamine replacement therapy (DRT) is the most effective treatment for Parkinson's disease (PD); it provides substantial benefit for most patients, extends independence, and increases survival. A few patients with PD, however, take increasing quantities of medication far beyond those required to treat their motor disabilities. These patients demand rapid drug escalation and continue to request more DRT despite the emergence of increasingly severe drug-induced motor complications and harmful behavioural consequences. In this article we detail the features of compulsive DRT-seeking and intake in PD, in relation to theories of compulsive drug use.

Journal ArticleDOI
TL;DR: Use of enzyme-inducing AEDs should be avoided in patients with cancer, particularly in association with chemotherapy, and valproic acid-although not free from interactions-would be the agent of first choice.
Abstract: Summary Cancer and epilepsy commonly co-occur, and concomitant administration of antiepileptic (AEDS) and chemotherapeutic drugs (CTDs) is necessary in many cases. Many drugs are metabolised by the hepatic cytochrome P450 (CYP) isoenzyme system, and coadministration of AEDs and CTDs can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. These interactions can cause insufficient tumour and seizure control or lead to unforeseen toxicity. Enzyme-inducing AEDs reduce the effects of taxanes, vinca alkaloids, methotrexate, teniposide, and camptothecin analogues. Inhibition of the metabolism of nitrosoureas or etoposide by valproic acid can lead to CTD toxicity. Poor seizure control may result from the combinations of phenytoin with cisplatin or corticosteroids, and valproic acid with methotrexate. Increased toxicity of AEDs can occur when phenytoin is combined with 5-fluorouracil. Use of enzyme-inducing AEDs should be avoided in patients with cancer, particularly in association with chemotherapy. Generally, valproic acid— although not free from interactions—would be the agent of first choice. Some of the newer AEDs not metabolised by the P450 system may prove to be good alternatives.

Journal ArticleDOI
TL;DR: The results of the studies reviewed show that, although the subtypes of dementia show common neuropathological features, the degree by which they occur and affect pain-related areas determine the pattern of changes in pain experience in AD, vascular dementia, and frontotemporal dementia.
Abstract: Most clinical studies of pain in dementia have focused on assessment procedures that are sensitive to pain in "demented" or "cognitively impaired" elderly patients. The neuropathology of dementia has not played a major part in pain assessment. In this review, the neuropathological effects of dementia on the medial and the lateral pain systems are discussed. We focus on Alzheimer's disease (AD), vascular dementia, and frontotemporal dementia. Lewy-body disease and Creutzfeldt-Jakob disease are briefly reviewed. The results of the studies reviewed show that, although the subtypes of dementia show common neuropathological features (such as atrophy and white-matter lesions), the degree by which they occur and affect pain-related areas determine the pattern of changes in pain experience. More specifically, in AD and even more so in frontotemporal dementia, a decrease in the motivational and affective components of pain is generally present whereas vascular dementia might be characterised by an increase in affective pain experience. Future studies should combine data from experimental pain studies and neuropathological information for pain assessment in dementia.

Journal ArticleDOI
Bo Norrving1
TL;DR: More studies on mechanisms, prevention, and treatment are needed to provide specific guidance on the long-term management of patients with lacunar infarcts, and risk-factor modification is likely to play a large part in therapeutic interventions targeted at this stroke subtype.
Abstract: Lacunar infarcts, small deep infarcts that result from occlusion of a penetrating artery, account for about a quarter of all ischaemic strokes. These infarcts have commonly been regarded as benign vascular lesions with a favourable long-term prognosis. However, recent studies have shown that this is only the case early in the disease course. A few years after infarct, there is an increased risk of death, mainly from cardiovascular causes. The risk of recurrent stroke after lacunar infarct is similar to that for most other types of stroke, and patients have an increased risk of developing cognitive decline and dementia. Age, vascular risk factors, high nocturnal blood pressure, and severity of cerebral small-vessel disease at onset have significant prognostic implications for almost all outcomes. More studies on mechanisms, prevention, and treatment are needed to provide specific guidance on the long-term management of patients with lacunar infarcts. Risk-factor modification is likely to play a large part in therapeutic interventions targeted at this stroke subtype.