Abstract: The clinical diagnosis of Parkinson's disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson's disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.

Abstract: The relation between diabetes and major types of dementia is controversial. This systematic review examines the incidence of dementia in people with diabetes mellitus. We identified 14 eligible longitudinal population-based studies of variable methodological quality. The incidence of "any dementia" was higher in individuals with diabetes than in those without diabetes in seven of ten studies reporting this aggregate outcome. This high risk included both Alzheimer's disease and vascular dementia (eight of 13 studies and six of nine studies respectively). Detailed data on modulating and mediating effects of glycaemic control, microvascular complications, and comorbidity (eg, hypertension and stroke) were generally absent. The findings of mechanistic studies suggest that vascular disease and alterations in glucose, insulin, and amyloid metabolism underlie the pathophysiology, but which of these mechanisms are clinically relevant is unclear. Further high quality studies need to be initiated, with objective diabetes assessment, together with reliable methods to establish the contribution of vascular disease and other comorbidity to dementia.

Abstract: Summary Background Disease-modifying treatment strategies for Alzheimer's disease have led to an urgent need for biomarkers to identify the disease at a very early stage. Here, we assess the association between CSF biomarkers and incipient Alzheimer's in patients with mild cognitive impairment (MCI). Methods From a series of 180 consecutive patients with MCI, we assessed 137 who underwent successful lumbar puncture at baseline. Patients at risk of developing dementia were followed clinically for 4–6 years. Additionally, 39 healthy individuals, cognitively stable over 3 years, served as controls. We analysed CSF concentrations of β amyloid 1–42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau 181 ) using Luminex xMAP technology. Findings During follow-up, 57 (42%) patients with MCI developed Alzheimer's disease, 21 (15%) developed other forms of dementia, and 56 (41%) remained cognitively stable for 5·2 years (range 4·0–6·8). A combination of CSF T-tau and Aβ42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD in patients with MCI. The relative risk of progression to Alzheimer's disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Aβ42 at baseline (hazard ratio 17·7, p APOE genotype, and plasma homocysteine. The combination of T-tau and Aβ42/P-tau 181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19·8). Interpretation Concentrations of T-tau, P-tau 181 , and Aβ42 in CSF are strongly associated with future development of Alzheimer's disease in patients with MCI.

Abstract: Summary The past decade has resulted in a rapid increase in knowledge of mechanisms underlying brain injury induced by intracerebral haemorrhage (ICH). Animal studies have suggested roles for clot-derived factors and the initial physical trauma and mass effect as a result of haemorrhage. The coagulation cascade (especially thrombin), haemoglobin breakdown products, and inflammation all play a part in ICH-induced injury and could provide new therapeutic targets. Human imaging has shown that many ICH continue to expand after the initial ictus. Rebleeding soon after the initial haemorrhage is common and forms the basis of a current clinical trial using factor VIIa to prevent rebleeding. However, questions about mechanisms of injuries remain. There are conflicting data on the role of ischaemia in ICH and there is uncertainty over the role of clot removal in ICH therapy. The next decade should bring further information about the underlying mechanisms of ICH-induced brain injury and new therapeutic interventions for this severe form of stroke. This review addresses our current understanding of the mechanisms underlying ICH-induced brain injury.

Abstract: Summary Background Several vascular risk factors are associated with dementia. We sought to develop a simple method for the prediction of the risk of late-life dementia in people of middle age on the basis of their risk profiles. Methods Data were used from the population-based CAIDE study, which included 1409 individuals who were studied in midlife and re-examined 20 years later for signs of dementia. Several midlife vascular risk factors were studied to create the scoring tool. The score values were estimated on the basis of β coefficients and the dementia risk score was the sum of these individual scores (range 0–15). Findings Occurrence of dementia during the 20 years of follow-up was 4%. Future dementia was significantly predicted by high age (≥47 years), low education ( Interpretation The dementia risk score is a novel approach for the prediction of dementia risk, but should be validated and further improved to increase its predictive value. This approach highlights the role of vascular factors in the development of dementia and could help to identify individuals who might benefit from intensive lifestyle consultations and pharmacological interventions.

Abstract: Summary Background Few patients with amyotrophic lateral sclerosis currently receive non-invasive ventilation (NIV), reflecting clinical uncertainty about the role of this intervention. We aimed to assess the effect of NIV on quality of life and survival in amyotrophic lateral sclerosis in a randomised controlled trial. Methods 92 of 102 eligible patients participated. They were assessed every 2 months and randomly assigned to NIV (n=22) or standard care (n=19) when they developed either orthopnoea with maximum inspiratory pressure less than 60% of that predicted or symptomatic hypercapnia. Primary validated quality-of-life outcome measures were the short form 36 mental component summary (MCS) and the sleep apnoea quality-of-life index symptoms domain (sym). Both time maintained above 75% of baseline (T i MCS and T i sym) and mean improvement (μMCS and μsym) were measured. Findings NIV improved T i MCS, T i sym, μMCS, μsym, and survival in all patients and in the subgroup with better bulbar function (n=20). This subgroup showed improvement in several measures of quality of life and a median survival benefit of 205 days (p=0·006) with maintained quality of life for most of this period. NIV improved some quality-of-life indices in those with poor bulbar function, including μsym (p=0·018), but conferred no survival benefit. Interpretation In patients with amyotrophic lateral sclerosis without severe bulbar dysfunction, NIV improves survival with maintenance of, and improvement in, quality of life. The survival benefit from NIV in this group is much greater than that from currently available neuroprotective therapy. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage.

Abstract: Summary Background Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviours related to unpleasant dreams and loss of muscle atonia during REM sleep. RBD may be idiopathic or associated with neurological disease. Available data suggest that in some cases RBD might be the initial manifestation of a neurodegenerative disease. We sought to determine the frequency and nature of neurological disorders developing in patients diagnosed with idiopathic RBD at our sleep centre. Methods We retrospectively assessed 44 consecutive patients (39 men and five women with a mean age of 74 years), with at least 2 years of clinical follow-up after a diagnosis of idiopathic RBD, through a detailed clinical history, complete neurological examination, rating scales of parkinsonism, and neuropsychological tests. Findings 20 (45%) patients developed a neurological disorder after a mean of 11·5 years from the reported onset of RBD and a mean follow-up of 5·1 years from the diagnosis of idiopathic RBD at our sleep centre. Emerging disorders were Parkinson's disease in nine patients, dementia with Lewy bodies in six, multiple system atrophy with predominant cerebellar syndrome in one, and mild cognitive impairment in four in whom visuospatial dysfunction was prominent. Patients with longer clinical follow-up developed a neurological disease (OR 1·512, 95% CI 1·105–2·069; p=0·010). Interpretation Our study indicates that in people presenting to sleep centres, RBD often antedates the development of a neurodegenerative disorder. Close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative disease. This finding may be of great interest when early effective treatment strategies and neuroprotective drugs become available.

Abstract: Summary Background Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change. Methods Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset. Findings The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3·2:1 in Canada. Year of birth was a significant predictor for sex ratio (p 2 =124·4; rank correlation r =0·84). Interpretation The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene–environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why incidence of the disease is increasing are unknown, there are major implications for health-care provision because lifetime costs of multiple sclerosis exceed £1 million per case in the UK.

Abstract: Summary No single outcome measure can describe or predict all dimensions of recovery and disability after acute stroke. Several scales have proven reliability and validity in stroke trials, including the National Institutes of Health stroke scale (NIHSS), the modified Rankin scale (mRS), the Barthel index (BI), the Glasgow outcome scale (GOS), and the stroke impact scale (SIS). Several scales have been combined in stroke trials to derive a global statistic to better define the effect of acute interventions, although this composite statistic is not clinically tenable. In practice, the NIHSS is useful for early prognostication and serial assessment, whereas the BI is useful for planning rehabilitative strategies. The mRS and GOS provide summary measures of outcome and might be most relevant to clinicians and patients considering early intervention. The SIS was designed to measure the patient's perspective on the effect of stroke. Familiarity with these scales could improve clinicians' interpretation of stroke research and their clinical decision-making.

Abstract: Summary Background Motor impairment resulting from chronic stroke can have extensive physical, psychological, financial, and social implications despite available neurorehabilitative treatments. Recent studies in animals showed that direct epidural stimulation of the primary motor cortex surrounding a small infarct in the lesioned hemisphere (M1 lesioned hemisphere ) elicits improvements in motor function. Recent developments In human beings, proof of principle studies from different laboratories showed that non-invasive transcranial magnetic stimulation and direct current stimulation that upregulate excitability within M1 lesioned hemisphere or downregulate excitability in the intact hemisphere (M1 intact hemisphere ) results in improvement in motor function in patients with stroke. Possible mechanisms mediating these effects can include the correction of abnormally persistent interhemispheric inhibitory drive from M1 intact hemisphere to M1 lesioned hemisphere in the process of generation of voluntary movements by the paretic hand, a disorder correlated with the magnitude of impairment. In this paper we review these mechanistically oriented interventional approaches. What next? These findings suggest that transcranial magnetic stimulation and transcranial direct current stimulation could develop into useful adjuvant strategies in neurorehabilitation but have to be further assessed in multicentre clinical trials.

Abstract: Idiopathic intracranial hypertension is common in obese women and can lead to significant visual impairment. First described more than 100 years ago, the cause of the disorder remains unknown. Despite a multitude of proposed links, the aetiology has never been established. Impairment of cerebrospinal-fluid reabsorption is the most likely underlying pathophysiological cause of the raised pressure, but this notion has yet to be proven. Cerebral venous sinus abnormalities associated with the disorder need further exploration. Although the major symptoms of headache and visual disturbance are well documented, most data for disease outcome have been from small retrospective case series. No randomised controlled trials of treatment have been done and the management is controversial. The importance of weight loss needs clarification, the role of diuretics is uncertain, and which surgical intervention is the most effective and safe is unknown. Prospective trials to examine these issues are urgently needed.

Abstract: There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and vascular dementia in elderly people.

Abstract: The correct diagnosis of Parkinson's disease is important for prognostic and therapeutic reasons and is essential for clinical research. Investigations of the diagnostic accuracy for the disease and other forms of parkinsonism in community-based samples of patients taking antiparkinsonian medication confirmed a diagnosis of parkinsonism in only 74% of patients and clinically probable Parkinson's disease in 53% of patients. Clinicopathological studies based on brain bank material from the UK and Canada have shown that clinicians diagnose the disease incorrectly in about 25% of patients. In these studies, the most common reasons for misdiagnosis were presence of essential tremor, vascular parkinsonism, and atypical parkinsonian syndromes. Infrequent diagnostic errors included Alzheimer's disease, dementia with Lewy bodies, and drug-induced parkinsonism. Increasing knowledge of the heterogeneous clinical presentation of the various parkinsonisms has resulted in improved diagnostic accuracy of the various parkinsonian syndromes in specialised movement-disorder units. Also genetic testing and various other ancillary tests, such as olfactory testing, MRI, and dopamine-transporter single-photon-emission computed-tomography imaging, help with clinical diagnostic decisions.

Abstract: Summary Background Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. Methods 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. Findings Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0·097, SE 0·039, p=0·016, R 2 =0·295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0·011, SE 0·003, p=0·001, R 2 =0·454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. Interpretation These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

Abstract: Summary Background Depression is a common comorbid disorder in epilepsy but is not routinely assessed in neurology clinics. We aimed to create a rapid yet accurate screening instrument for major depression in people with epilepsy. Methods We developed a set of 46 items to identify symptoms of depression that do not overlap with common comorbid cognitive deficits or adverse effects of antiepileptic drugs. This preliminary instrument and several reliable and valid instruments for diagnosis of depression on the basis of criteria from the Diagnostic and Statistical Manual IV, depression symptom severity, health status, and toxic effects of medication were applied to 205 adult outpatients with epilepsy. We used discriminant function analysis to identify the most efficient set of items for classification of major depression, which we termed the neurological disorders depression inventory for epilepsy (NDDI-E). Baseline data for 229 demographically similar patients enrolled in two other clinical studies were used for verification of the original observations. Findings The discriminant function model for the NDDI-E included six items. Internal consistency reliability of the NDDI-E was 0·85 and test-retest reliability was 0·78. An NDDI-E score of more than 15 had a specificity of 90%, sensitivity of 81%, and positive predictive value of 0·62 for a diagnosis of major depression. Logistic regression showed that the model of association of major depression and the NDDI-E was not affected by adverse effects of antiepileptic medication, whereas models for depression and generic screening instruments were. The severity of depression symptoms and toxic effects of drugs independently correlated with subjective health status, explaining 72% of variance. Results from a separate verification sample also showed optimum sensitivity, specificity, and predictive power at a cut score of more than 15. Interpretation Major depression in people with epilepsy can be identified by a brief set of symptoms that can be differentiated from common adverse effects of antiepileptic drugs. The NDDI-E could enable rapid detection and improve management of depression in epilepsy in accordance with internationally recognised guidelines.

Abstract: Meningiomas account for up to 30% of all primary intracranial tumours. They are histologically classified according to the World Health Organization (WHO) classification of tumours of the nervous system. Most meningiomas are benign lesions of WHO grade I, whereas some meningioma variants correspond with WHO grades II and III and are associated with a higher risk of recurrence and shorter survival times. Mutations in the NF2 gene and loss of chromosome 22q are the most common genetic alterations associated with the initiation of meningiomas. With increase in tumour grade, additional progression-associated molecular aberrations can be found; however, most of the relevant genes are yet to be identified. High-throughput techniques of global genome and transcriptome analyses and new meningioma models provide increasing insight into meningioma biology and will help to identify common pathogenic pathways that may be targeted by new therapeutic approaches.

Abstract: Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.

Abstract: Summary Background Deep brain stimulation of the subthalamic nucleus (STN DBS) is an increasingly common treatment for Parkinson's disease. Qualitative reviews have concluded that diminished verbal fluency is common after STN DBS, but that changes in global cognitive abilities, attention, executive functions, and memory are only inconsistently observed and, when present, often nominal or transient. We did a quantitative meta-analysis to improve understanding of the variability and clinical significance of cognitive dysfunction after STN DBS. Methods We searched MedLine, PsycLIT, and ISI Web of Science electronic databases for articles published between 1990 and 2006, and extracted information about number of patients, exclusion criteria, confirmation of target by microelectrode recording, verification of electrode placement via radiographic means, stimulation parameters, assessment time points, assessment measures, whether patients were on levodopa or dopaminomimetics, and summary statistics needed for computation of effect sizes. We used the random-effects meta-analytical model to assess continuous outcomes before and after STN DBS. Findings Of 40 neuropsychological studies identified, 28 cohort studies (including 612 patients) were eligible for inclusion in the meta-analysis. After adjusting for heterogeneity of variance in study effect sizes, the random effects meta-analysis revealed significant, albeit small, declines in executive functions and verbal learning and memory. Moderate declines were only reported in semantic (Cohen's d 0·73) and phonemic verbal fluency (0·51). Changes in verbal fluency were not related to patient age, disease duration, stimulation parameters, or change in dopaminomimetic dose after surgery. Interpretation STN DBS, in selected patients, seems relatively safe from a cognitive standpoint. However, difficulty in identification of factors underlying changes in verbal fluency draws attention to the need for uniform and detailed reporting of patient selection, demographic, disease, treatment, surgical, stimulation, and clinical outcome parameters.

Abstract: As in Clark and Prout's classic work, we identify three phases of generalised convulsive status epilepticus, which we call impending, established, and subtle. We review physiological and subcellular changes that might play a part in the transition from single seizures to status epilepticus and in the development of time-dependent pharmacoresistance. We review the principles underlying the treatment of status epilepticus and suggest that prehospital treatment is beneficial, that therapeutic drugs should be used in rapid sequence according to a defined protocol, and that refractory status epilepticus should be treated with general anaesthesia. We comment on our preference for drugs with a short elimination half-life and discuss some therapeutic choices.

Abstract: Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments. In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying treatments on its progression.

Abstract: Caring for elderly people with dementia is associated with well-documented increases in burden, distress, and decrements in mental health and wellbeing. More severe behavioural, cognitive, and functional impairments in a patient are associated with higher levels of burden and distress. Distress increases with care hours per week, number of tasks, and declining coping and support resources. Demographic factors also affect levels of burden and distress. Promising, evidence-based interventions exist, but substantial economic and policy barriers preclude their widespread dissemination. Health-care policy makers should consider addressing these barriers; clinicians and families must campaign for reimbursement; and clinical researchers must develop more potent preventive interventions. In this article we review how dementia care affects the mental health of the carer and identify interventions that might be useful in mitigating carer burden and distress.

Abstract: Summary Background Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. Methods This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23–26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. Findings Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 ·3 days (95% CI 1·9–2·7) in the verum acupuncture group, 1·5 days (1·1–2·0) in the sham acupuncture group, and 2·1 days (1·5–2·7) in the standard therapy group. These differences were statistically significant compared with baseline (p Interpretation Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.

Abstract: This paper reviews the current evidence for the association between socioeconomic status and stroke incidence, survival, mortality, and other outcomes. The evidence is strongest for mortality and incidence of stroke, with high rates of stroke in low socioeconomic groups being a consistent finding. Low socioeconomic groups also have lower survival and greater stroke severity than high socioeconomic groups, although there is less evidence for this association. The mechanisms through which socioeconomic status affects stroke risk and outcomes are unclear but some studies report that differences in risk-factor prevalence could account for some of the variation. We discuss the implications of these findings and make recommendations for future research. Studies using prospective population-based methods with improved control for confounding factors are needed to confirm or refute these associations. Understanding the causal associations between socioeconomic status and stroke will allow interventions to be appropriately targeted and assessed.

Abstract: In this review we discuss the epidemiological, clinical, and genetic characteristics of early-onset parkinsonism, defined as parkinsonism starting before age 40 (sometimes 50) years. Juvenile parkinsonism is very rare and is the result of various secondary or genetic causes. In patients with onset at or above age 21 years, secondary causes require exclusion but are rare; most cases with a fairly pure parkinsonian syndrome (eg, young-onset Parkinson's disease; YOPD) are due to typical Lewy-body Parkinson's disease or, less commonly, genetic causes. In comparison with patients with late-onset disease, most patients with YOPD progress more slowly in terms of motor features and have a longer disease course with preservation of cognitive function, but typically develop motor fluctuations and dyskinesias earlier. Patients with YOPD generally experience a greater effect in their lives than those with late onset, with poorer social adjustment, higher rates of depression, and lower quality of life. Management of YOPD must therefore aim to maintain occupational, social, and daily functioning, while delaying or ameliorating motor complications of treatment, providing psychological support, and, where possible, preventing psychiatric complications including depression.

Abstract: Summary Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is characterised by loss of muscular atonia and prominent motor behaviours during REM sleep RBD can cause sleep disruption and severe injuries for the patient or bed partner The disorder is strongly associated with neurodegenerative diseases, such as multiple-system atrophy, Parkinson's disease, dementia with Lewy bodies, and progressive supranuclear palsy In many cases, the symptoms of RBD precede other symptoms of these neurodegenerative disorders by several years Furthermore, several recent studies have shown that RBD is associated with abnormalities of electroencephalographic activity, cerebral blood flow, and cognitive, perceptual, and autonomic functions RBD might be a stage in the development of neurodegenerative disorders and increased awareness of this could lead to substantial advances in knowledge of mechanisms, diagnosis, and treatment of neurodegenerative disorders

Abstract: Summary Background Although we have shown in three out of five patients with Huntington's disease that motor and cognitive improvements 2 years after intracerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. We undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. Methods Five patients with Huntington's disease from our pilot study were assessed annually with the unified Huntington's disease rating scale, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years. Findings Clinical improvement plateaued after 2 years and then faded off variably 4–6 years after surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypometabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients. Interpretation Neuronal transplantation in Huntington's disease provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure and in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.

Abstract: Summary The motor symptoms of Parkinson's disease are predominantly due to progressive degeneration of nigral dopaminergic neurons. In most cases there is a substantial asymmetry of clinical symptoms from disease onset, which occurs in sporadic and in hereditary forms of the disease. However, the mechanism of such unilaterality of symptom appearance is not understood. There is only sparse information about whether symptom-side predominance is genetically coded and determined years before symptom onset, or whether it is acquired and related to side differences in vulnerability of the degenerating neurons. In this Personal View we review data for unilaterality of symptoms at different disease stages. We also discuss several pathological, genetic, environmental, and toxic possibilities for explaining the mechanism of side predominance.

Abstract: Infants and children are at a high risk for seizures compared with adults. Although most seizures in children are benign and result in no long-term consequences, increasing experimental animal data strongly suggest that frequent or prolonged seizures in the developing brain result in long-lasting sequelae. Such seizures may intervene with developmental programmes and lead to inadequate construction of cortical networks rather than induction of neuronal cell loss. As a consequence, the deleterious actions of seizures are strongly age dependent: seizures have different effects on immature or migrating neurons endowed with few synapses and more developed neurons that express hundreds of functional synapses. This differential effect is even more important in human beings and subhuman primates who have an extended brain development period. Seizures also beget seizures during maturation and result in a replay of development programmes, which suggests that epileptogenesis recapitulates ontogenesis. Therefore, to understand seizures and their consequences in the developing brain, it is essential to determine how neuronal activity modulates the main steps of cortical formation. In this Review, we present basic developmental principles obtained from animal studies and examine the long-lasting consequences of epilepsy.

Abstract: Summary Thrombolytic therapy has led to a higher proportion of patients presenting to hospital early, and this, with parallel developments in imaging technology, has greatly improved the understanding of acute stroke pathophysiology. Additionally, MRI, including diffusion-weighted imaging (DWI) and gradient echo, or T2*, imaging is important in understanding basic structural information—such as distinguishing acute ischaemia from haemorrhage. It has also greatly increased sensitivity in the diagnosis of acute cerebral ischaemia. The pathophysiology of the ischaemic penumbra can now be assessed with CT or MRI-based perfusion imaging techniques, which are widely available and clinically applicable. Pathophysiological information from CT or MRI increasingly helps clinical trial design, may allow targeted therapy in individual patients, and may extend the time scale for reperfusion therapy.