Showing papers in "Lancet Neurology in 2007"
Pierre-and-Marie-Curie University1, University of British Columbia2, University of Pittsburgh3, French Institute of Health and Medical Research4, University of California, Los Angeles5, University of California, San Diego6, McGill University7, University of Kentucky8, Tohoku University9, Brown University10, NewYork–Presbyterian Hospital11, VU University Medical Center12
TL;DR: The NINCDS-ADRDA and DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge as discussed by the authors.
Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.
3,951 citations
TL;DR: Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica.
Abstract: Summary Neuromyelitis optica (also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease.
1,928 citations
TL;DR: In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome.
Abstract: Summary Background Malignant infarction of the middle cerebral artery (MCA) is associated with an 80% mortality rate. Non-randomised studies have suggested that decompressive surgery reduces this mortality without increasing the number of severely disabled survivors. To obtain sufficient data as soon as possible to reliably estimate the effects of decompressive surgery, results from three European randomised controlled trials (DECIMAL, DESTINY, HAMLET) were pooled. The trials were ongoing when the pooled analysis was planned. Methods Individual data for patients aged between 18 years and 60 years, with space-occupying MCA infarction, included in one of the three trials, and treated within 48 h after stroke onset were pooled for analysis. The protocol was designed prospectively when the trials were still recruiting patients and outcomes were defined without knowledge of the results of the individual trials. The primary outcome measure was the score on the modified Rankin scale (mRS) at 1 year dichotomised between favourable (0–4) and unfavourable (5 and death) outcome. Secondary outcome measures included case fatality rate at 1 year and a dichotomisation of the mRS between 0–3 and 4 to death. Data analysis was done by an independent data monitoring committee. Findings 93 patients were included in the pooled analysis. More patients in the decompressive-surgery group than in the control group had an mRS≤4 (75% vs 24%; pooled absolute risk reduction 51% [95% CI 34–69]), an mRS≤3 (43% vs 21%; 23% [5–41]), and survived (78% vs 29%; 50% [33–67]), indicating numbers needed to treat of two for survival with mRS≤4, four for survival with mRS≤3, and two for survival irrespective of functional outcome. The effect of surgery was highly consistent across the three trials. Interpretation In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome. The decision to perform decompressive surgery should, however, be made on an individual basis in every patient.
1,502 citations
TL;DR: A worldwide goal for stroke is proposed: a 2% reduction each year over and above that which may happen as a result of better case management and treatment, which would result in 6.4 million fewer deaths from stroke from 2005 to 2015.
Abstract: Summary Stroke caused an estimated 5·7 million deaths in 2005, and 87% of these deaths were in low-income and middle-income countries. Without intervention, the number of global deaths is projected to rise to 6·5 million in 2015 and to 7·8 million in 2030. The rising burden of stroke, especially in low-income and middle-income countries, leads us to propose a worldwide goal for stroke: a 2% reduction each year over and above that which may happen as a result of better case management and treatment. The experience of high-income countries indicates that sustained interventions can achieve at least the required 4% annual average decline in stroke mortality for people age 60–69 years. Achieving this goal for stroke would result in 6·4 million fewer deaths from stroke from 2005 to 2015. More of these deaths will be averted in low-income and middle-income countries than in high-income countries.
1,339 citations
TL;DR: An overview of the frequency, causes, and consequences of MRI-defined silent brain infarcts, which are detected in 20% of healthy elderly people and up to 50% of patients in selected series, is given.
Abstract: As the availability and quality of imaging techniques improve, doctors are identifying more patients with no history of transient ischaemic attack or stroke in whom imaging shows brain infarcts. Until recently, little was known about the relevance of these lesions. In this systematic review, we give an overview of the frequency, causes, and consequences of MRI-defined silent brain infarcts, which are detected in 20% of healthy elderly people and up to 50% of patients in selected series. Most infarcts are lacunes, of which hypertensive small-vessel disease is thought to be the main cause. Although silent infarcts, by definition, lack clinically overt stroke-like symptoms, they are associated with subtle deficits in physical and cognitive function that commonly go unnoticed. Moreover, the presence of silent infarcts more than doubles the risk of subsequent stroke and dementia. Future studies will have to show whether screening and treating high-risk patients can effectively reduce the risk of further infarcts, stroke, and dementia.
1,095 citations
TL;DR: In this paper, the authors used MRI with T1, T2, fluid-attenuated inversion recovery, and T2* sequences combined with magnetic resonance angiography to diagnose cerebral venous thrombosis.
Abstract: Cerebral venous thrombosis (CVT) is a rare type of cerebrovascular disease that can occur at any age, including in neonates, and it accounts for 0.5% of all stroke. The widespread use of neuroimaging now allows for early diagnosis and has completely modified our knowledge on this disorder. CVT is more common than previously thought and it is recognised as a non-septic disorder with a wide spectrum of clinical presentations, numerous causes, and usually a favourable outcome with a low mortality rate. MRI with T1, T2, fluid-attenuated inversion recovery, and T2* sequences combined with magnetic resonance angiography are the best diagnostic methods. D-dimer concentrations are raised in most patients but normal D-dimers do not rule out CVT, particularly in patients who present with isolated headache. Heparin is the first-line treatment, but in a few cases more aggressive treatments, such as local intravenous thrombolysis, mechanical thrombectomy, and decompressive hemicraniectomy, may be required.
994 citations
TL;DR: The optimum dose of parenteral thiamine required for prophylaxis and treatment of Wernicke's encephalopathy and prevention of Korsakoff's syndrome associated with alcohol misuse is emphasised.
Abstract: Wernicke's encephalopathy is an acute neuropsychiatric syndrome resulting from thiamine deficiency, which is associated with significant morbidity and mortality. According to autopsy-based studies, the disorder is still greatly underdiagnosed in both adults and children. In this review, we provide an update on the factors and clinical settings that predispose to Wernicke's encephalopathy, and discuss the most recent insights into epidemiology, pathophysiology, genetics, diagnosis, and treatment. To facilitate the diagnosis, we classify the common and rare symptoms at presentation and the late-stage symptoms. We emphasise the optimum dose of parenteral thiamine required for prophylaxis and treatment of Wernicke's encephalopathy and prevention of Korsakoff's syndrome associated with alcohol misuse. A systematic approach helps to ensure that patients receive a prompt diagnosis and adequate treatment.
975 citations
TL;DR: Risks of cognitive side-effects with antiepileptic drugs can add to previous damage by surgery or radiotherapy, and therefore appropriate choice and dose of antiePileptic drug is crucial.
Abstract: Epilepsy is common in patients with brain tumours and can substantially affect daily life, even if the tumour is under control. Several factors affect the mechanism of seizures in brain tumours, including tumour type, tumour location, and peritumoral and genetic changes. Prophylactic use of antiepileptic drugs is not recommended, and potential interactions between antiepileptic and chemotherapeutic agents persuades against the use of enzyme-inducing antiepileptic drugs. Multidrug-resistance proteins prevent the access of antiepileptic drugs into brain parenchyma, which partly explains why seizures are frequently refractory to treatment. Lamotrigine, valproic acid, and topiramate are first-line treatments of choice; if insufficient, add-on treatment with levetiracetam or gabapentin can be recommended. On the basis of clinical studies, we prefer to start treatment with valproic acid, adding levetiracetam if necessary. Risks of cognitive side-effects with antiepileptic drugs can add to previous damage by surgery or radiotherapy, and therefore appropriate choice and dose of antiepileptic drug is crucial.
716 citations
TL;DR: A new theory is suggested suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.
Abstract: Summary Focal cerebral ischaemia and post-ischaemic reperfusion cause cerebral capillary dysfunction, resulting in oedema formation and haemorrhagic conversion. There are substantial gaps in understanding the pathophysiology, especially regarding early molecular participants. Here, we review physiological and molecular mechanisms involved. We reaffirm the central role of Starling's principle, which states that oedema formation is determined by the driving force and the capillary "permeability pore". We emphasise that the movement of fluids is largely driven without new expenditure of energy by the ischaemic brain. We organise the progressive changes in osmotic and hydrostatic conductivity of abnormal capillaries into three phases: formation of ionic oedema, formation of vasogenic oedema, and catastrophic failure with haemorrhagic conversion. We suggest a new theory suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.
686 citations
TL;DR: The main findings suggested that total age-adjusted incidence of first-ever stroke in China is not very different from that in developed countries.
Abstract: Summary In this review, we examine the current status of stroke epidemiology, prevention, and management strategies in mainland China. The main findings suggested that total age-adjusted incidence of first-ever stroke in China is not very different from that in developed countries. Stroke incidence, mortality, and prevalence varied widely among different regions within China, with a noticeable north–south gradient. The proportion of intracerebral haemorrhage was high and reached 55% in one city. Hypertension is the most important risk factor for stroke. The mass approach combined with a high-risk approach for stroke prevention showed encouraging effects, and various unconventional local therapeutic traditions are commonly used to treat stroke in China. Several national guidelines on stroke prevention and treatment have been developed. Because of methodological limitations in the epidemiology studies, data are unreliable in terms of making any firm conclusions. Up-to-date, well-designed, and well-done epidemiological studies and therapeutic trials in China are urgently needed.
658 citations
TL;DR: The reported early risks of stroke after TIA were highly heterogeneous, but this could be largely accounted for by differences in study method, setting, and treatment, with lowest risks in studies of emergency treatment in specialist stroke services.
Abstract: Summary Background Stroke is often preceded by transient ischaemic attack (TIA), but studies of stroke risk after TIA are logistically difficult and have yielded conflicting results. However, reliable estimation of this risk is necessary for planning effective service provision, clinical trials, and public education. We therefore did a systematic review of all studies of stroke risk early after TIA. Methods All studies of stroke risk within 7 days of TIA were identified by use of electronic databases and by hand searches of reference lists, relevant journals, and conference abstracts. Stroke risks at 2 days and 7 days after TIA were calculated overall and analyses for heterogeneity were done, if possible, after categorisation by study method, setting, population, and treatment. Findings 18 independent cohorts were included, which reported stroke risk in 10 126 TIA patients. The pooled stroke risk was 5·2% (95% CI 3·9–6·5) at 7 days, but there was substantial heterogeneity between studies (p vs 8–90 days, r =0·89, p Interpretation The reported early risks of stroke after TIA were highly heterogeneous, but this could be largely accounted for by differences in study method, setting, and treatment, with lowest risks in studies of emergency treatment in specialist stroke services.
TL;DR: Use of TIA clinics with 24-h access and immediate initiation of preventive treatment might greatly reduce length of hospital stay and risk of stroke compared with expected risk.
Abstract: Summary Background Diagnosis and treatment of cerebral and retinal transient ischaemic attacks (TIAs) are often delayed by the lack of immediate access to a dedicated TIA clinic. We evaluated the effects of rapid assessment of patients with TIA on clinical decision making, length of hospital stay, and subsequent stroke rates. Methods We set up SOS-TIA, a hospital clinic with 24-h access. Patients were admitted if they had sudden retinal or cerebral focal symptoms judged to relate to ischaemia and if they made a total recovery. Assessment, which included neurological, arterial, and cardiac imaging, was within 4 h of admission. A leaflet about TIA with a toll-free telephone number for SOS-TIA was sent to 15 000 family doctors, cardiologists, neurologists, and ophthalmologists in Paris and its administrative region. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death within 1 year. Findings Between January, 2003, and December, 2005, we admitted 1085 patients with suspected TIA; 574 (53%) were seen within 24 h of symptom onset. 701 (65%) patients had confirmed TIA or minor stroke, and 144 (13%) had possible TIA. 108 (17%) of the 643 patients with confirmed TIA had brain tissue damage. Median duration of symptoms was 15 min (IQR 5–75 min). Of the patients with confirmed or possible TIA, all started a stroke prevention programme, 43 (5%) had urgent carotid revascularisation, and 44 (5%) were treated for atrial fibrillation with anticoagulants. 808 (74%) of all patients seen were sent home on the same day. The 90-day stroke rate was 1·24% (95% CI 0·72–2·12), whereas the rate predicted from ABCD 2 scores was 5·96%. Interpretation Use of TIA clinics with 24-h access and immediate initiation of preventive treatment might greatly reduce length of hospital stay and risk of stroke compared with expected risk.
TL;DR: The epidemiological, cognitive, and radiological features of semantic dementia are described and structural and functional studies in SD emphasise the role of the temporopolar and perirhinal cortices.
Abstract: Semantic dementia (SD), one of the main clinical variants of frontotemporal dementia, presents a unique combination of clinical and imaging abnormalities. We describe the epidemiological, cognitive, and radiological features of SD. The distinctive and consistent neuropsychological deficits in this disorder have had a major effect on current conceptions of the organisation of semantic memory and its links to episodic memory, language, and perceptual processes. Structural (MRI) and functional (fluorodeoxyglucose-PET) studies in SD emphasise the role of the temporopolar and perirhinal cortices. Unlike other frontotemporal dementia syndromes, the neuropathological findings in SD are fairly predictable: most patients have ubiquitin-positive, tau-negative neuronal inclusions.
Columbia University1, California Pacific Medical Center2, Washington University in St. Louis3, Mayo Clinic4, University of California, San Francisco5, University of Colorado Hospital6, University of California, Irvine7, University of Medicine and Dentistry of New Jersey8, Virginia Mason Medical Center9, Duke University10, University of California, Los Angeles11, University of Pennsylvania12, University of Kansas13, University of Vermont14
TL;DR: The finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocyCline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in Patients with ALS.
Abstract: Summary Background Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). Methods We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. Findings ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (−1·30 vs −1·04 units/month, 95% CI for difference −0·44 to −0·08; p=0·005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (−3·48 vs −3·01, −1·03 to 0·11; p=0·11) and MMT score (−0·30 vs −0·26, −0·08 to 0·01; p=0·11), and greater mortality during the 9-month treatment phase (hazard ratio=1·32, 95% CI 0·83 to 2·10; p=0·23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. Interpretation Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.
TL;DR: Treated with glucose-potassium-insulin GKI infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days, although the study was underpowered and alternative results cannot be excluded.
Abstract: Summary Background Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days. Methods Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6·0–17·0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4–7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803) Findings The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1·14, 95% CI 0·86–1·51, p=0·37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0·57 mmol/L, p Interpretation GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.
TL;DR: This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit, and miglustat improves or stabilises several clinically relevant markers of NPC.
Abstract: Summary Background Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. Methods Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. Findings At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0·028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. Interpretation Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.
TL;DR: The findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB and the diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.
Abstract: Summary Background Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand 123 I-2β-carbometoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ( 123 I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. Methods We did a phase III study in which we used a 123 I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0·80) and specificity (0·85) targets and prespecified lower thresholds (sensitivity 0·65, specificity 0·73) using one-sided binomial tests with a significance level of α=0·025. Findings Abnormal scans had a mean sensitivity of 77·7% for detecting clinical probable DLB, with specificity of 90·4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85·7% was achieved for overall diagnostic accuracy, 82·4% for positive predictive value, and 87·5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's κ=0·87). The procedure was well tolerated with few adverse events. Interpretation A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with 123 I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.
TL;DR: Understanding of cognitive impairment in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. ALS is the most common neurodegenerative disorder of young and middle-aged adults, and few treatments are available. Although the degeneration predominantly affects the motor system, cognitive and behavioural symptoms have been described for over a century, and there is evidence that ALS and frontotemporal dementia overlap clinically, radiologically, pathologically, and genetically. Cognitive decline in ALS is characterised by personality change, irritability, obsessions, poor insight, and pervasive deficits in frontal executive tests. This presentation is consistent with the changes to character, social conduct, and executive function in frontotemporal dementia. We highlight genetic, imaging, and neuropathological evidence that non-motor systems are affected in ALS and explain the importance of recent discoveries. We review studies of cognitive impairment in ALS and common neuropsychological test results. We also provide advice about clinical assessment of frontotemporal dysfunction in patients with ALS, and suggest future research. Understanding of cognitive impairment in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration.
TL;DR: MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective.
Abstract: Summary About 10–15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.
TL;DR: In this article, patients with transient ischaemic attack (TIA) or minor stroke were randomly assigned to clopidogrel (300 mg loading dose then 75 mg daily; 198 patients), placebo (194 patients), and simvastatin (40 mg daily, 199 patients) or placebo (193 patients).
Abstract: Summary Background Patients with transient ischaemic attack (TIA) or minor stroke are at high immediate risk of stroke. The optimum early treatment options for these patients are not known. Methods Within 24 h of symptom onset, we randomly assigned, in a factorial design, 392 patients with TIA or minor stroke to clopidogrel (300 mg loading dose then 75 mg daily; 198 patients) or placebo (194 patients), and simvastatin (40 mg daily; 199 patients) or placebo (193 patients). All patients were also given aspirin and were followed for 90 days. Descriptive analyses were done by intention to treat. The primary outcome was total stroke (ischaemic and haemorrhagic) within 90 days. Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin. This study is registered as an International Standard Randomised Controlled Trial (number 35624812) and with ClinicalTrials.gov (NCT00109382). Findings The median time to stroke outcome was 1 day (range 0–62 days). The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins. 14 (7·1%) patients on clopidogrel had a stroke within 90 days compared with 21 (10·8%) patients on placebo (risk ratio 0·7 [95% CI 0·3–1·2]; absolute risk reduction −3·8% [95% CI −9·4 to 1·9]; p=0·19). 21 (10·6%) patients on simvastatin had a stroke within 90 days compared with 14 (7·3%) patients on placebo (risk ratio 1·3 [0·7–2·4]; absolute risk increase 3·3% [−2·3 to 8·9]; p=0·25). The interaction between clopidogrel and simvastatin was not significant (p=0·64). Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo (absolute risk increase 1·0% [−0·4 to 2·4]; p=0·5). There was no difference between groups for the simvastatin safety outcomes. Interpretation Immediately after TIA or minor stroke, patients are at high risk of stroke, which might be reduced by using clopidogrel in addition to aspirin. The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit. We were unable to provide evidence of benefit of simvastatin in this setting. This aggressive prevention approach merits further study.
TL;DR: In this paper, it was shown that central motor lesions are associated with loss of supraspinal drive and defective use of aff erent input with impaired behaviour of short-latency and long-latencies refl exes.
Abstract: In clinical practice, signs of exaggerated tendon tap refl exes associated with muscle hypertonia are generally thought to be responsible for spastic movement disorders. Most antispastic treatments are, therefore, directed at the reduction of refl ex activity. In recent years, however, researchers have noticed a discrepancy between spasticity as measured in the clinic and functional spastic movement disorders, which is primarily due to the diff erent roles of refl exes in passive and active states, respectively. We now know that central motor lesions are associated with loss of supraspinal drive and defective use of aff erent input with impaired behaviour of short-latency and long-latency refl exes. These changes lead to paresis and maladaptation of the movement pattern. Secondary changes in mechanical muscle fi bre, collagen tissue, and tendon properties (eg, loss of sarcomeres, subclinical contractures) result in spastic muscle tone, which in part compensates for paresis and allows functional movements on a simpler level of organisation. Antispastic drugs can accentuate paresis and therefore should be applied with caution in mobile patients.
TL;DR: The current knowledge on the contribution of autophagy to the maintenance of normal cellular homoeostasis, its changes in neurodegenerative disorders, and the role of aggravating factors such as oxidative stress and ageing on autophagic failure in these pathologies are summarized.
Abstract: Intracellular accumulation of altered and misfolded proteins is the basis of most neurodegenerative disorders. Altered proteins are usually organised in the form of toxic multimeric complexes that eventually promote neuronal death. Cells rely on surveillance mechanisms that take care of the removal of these toxic products. What then goes wrong in these pathologies? Recent studies have shown that a primary failure in autophagy, a mechanism for clearance of intracellular components in lysosomes, could be responsible for the accumulation of these altered proteins inside the affected neurons. In this Review we summarise our current knowledge on the contribution of autophagy to the maintenance of normal cellular homoeostasis, its changes in neurodegenerative disorders, and the role of aggravating factors such as oxidative stress and ageing on autophagic failure in these pathologies.
TL;DR: The biological, medical, and neurological aspects of acute, latent, and reactivated infections with the neurotropic herpes viruses are reviewed.
Abstract: Summary Herpes simplex viruses types 1 and 2 (HSV1 and HSV2) and varicella-zoster virus (VZV) establish latent infection in dorsal root ganglia for the entire life of the host. From this reservoir they can reactivate to cause human morbidity and mortality. Although the viruses vary in the clinical disorders they cause and in their molecular structure, they share several features that affect the course of infection of the human nervous system. HSV1 is the causative agent of encephalitis, corneal blindness, and several disorders of the peripheral nervous system; HSV2 is responsible for meningoencephalitis in neonates and meningitis in adults. Reactivation of VZV, the pathogen of varicella (chickenpox), is associated with herpes zoster (shingles) and central nervous system complications such as myelitis and focal vasculopathies. We review the biological, medical, and neurological aspects of acute, latent, and reactivated infections with the neurotropic herpes viruses.
TL;DR: The authors assesses two methodological limitations of rating scales that might help to answer this question and show that improvements in the scientific rigour of ratings can improve the chances of reaching the correct conclusions about the effectiveness of treatments for neurodegenerative diseases.
Abstract: Have state-of-the-art clinical trials failed to deliver treatments for neurodegenerative diseases because of shortcomings in the rating scales used? This Review assesses two methodological limitations of rating scales that might help to answer this question. First, the numbers generated by most rating scales do not satisfy the criteria for rigorous measurements. Second, we do not really know which variables most rating scales measure. We use clinical examples to highlight concerns about the limitations of rating scales, examine their underlying rationales, clarify their implications, explore potential solutions, and make some recommendations for future research. We show that improvements in the scientific rigour of rating scales can improve the chances of reaching the correct conclusions about the effectiveness of treatments.
TL;DR: The pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2 are discussed and the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease are examined.
Abstract: Historically, neurofibromatosis 1 (NF1) has been inextricably linked with neurofibromatosis 2 (NF2). Both are inherited autosomal-dominant neurocutaneous disorders that have high de novo mutation rates and carry a high risk of tumour formation. However, they are clinically and genetically distinct diseases and should be considered as seperate entities. NF1 is a common disease that mainly affects the skin and peripheral nervous system and causes characteristic bony dysplasia. By contrast, NF2 is a rare disorder with a relative paucity of skin manifestations and high-grade malignancy is unusual. Neurological symptoms are the predominant problem and the cardinal sign is bilateral vestibular schwannomas. In this Review, I discuss the pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2. I also examine the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease.
University Hospital of Basel1, French Institute of Health and Medical Research2, Istanbul University3, Aristotle University of Thessaloniki4, University of Düsseldorf5, Charles University in Prague6, Karolinska University Hospital7, Ludwig Maximilian University of Munich8, Sapienza University of Rome9, Catholic University of Leuven10, University of Vienna11, Washington University in St. Louis12, University of California, San Francisco13, National Institutes of Health14, St. Michael's Hospital15, Brigham and Women's Hospital16, Ruhr University Bochum17, Royal Melbourne Hospital18
TL;DR: This Review revisits and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.
Abstract: Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.
TL;DR: A clinically oriented approach to neurological gait disorders in the elderly population is presented and a practical three-step approach to categorise gait Disorders is proposed based on clinical signs and symptoms.
Abstract: Gait disorders are common and often devastating companions of ageing, leading to reductions in quality of life and increased mortality. Here, we present a clinically oriented approach to neurological gait disorders in the elderly population. We also draw attention to several exciting scientific developments in this specialty. Our first focus is on the complex and typically multifactorial pathophysiology underlying geriatric gait disorders. An important new insight is the recognition of gait as a complex higher order form of motor behaviour, with prominent and varied effects of mental processes. Another relevant message is that gait disorders are not an unpreventable consequence of ageing, but implicate the presence of underlying diseases that warrant specific diagnostic tests. We next discuss the core clinical features of common geriatric gait disorders and review some bedside tests to assess gait and balance. We conclude by proposing a practical three-step approach to categorise gait disorders and we present a simplified classification system based on clinical signs and symptoms.
TL;DR: In this article, the authors identify individuals with newly diagnosed epilepsy as a vulnerable group that require special attention, and show that individuals with epilepsy have a higher risk of suicide, even if coexisting psychiatric disease, demographic differences, and socioeconomic factors are taken into account.
Abstract: Summary Background Studies have linked epilepsy with an increased suicide risk, but the association might be modified by psychiatric, demographic, and socioeconomic factors. Methods Suicide cases were identified in the Cause of Death Register in Denmark from 1981 to 1997. Up to 20 controls, matched by sex, birth year, and calendar date, were assigned to each suicide case. Findings We identified 21 169 cases of suicide and 423 128 controls. 492 (2·32%) individuals who committed suicide had epilepsy compared with 3140 (0·74%) controls, corresponding to a three times higher risk (rate ratio [RR] 3·17 [95% CI 2·88–3·50]; p Interpretation Individuals with epilepsy have a higher risk of suicide, even if coexisting psychiatric disease, demographic differences, and socioeconomic factors are taken into account. Our study identifies people with newly diagnosed epilepsy as a vulnerable group that require special attention.
TL;DR: Data are insufficient to support widespread use of these drugs in vascular dementia, and individual patient analyses are needed to identify subgroups of patients with vascular dementia who might benefit.
Abstract: Summary Background Cholinesterase inhibitors and memantine do not have regulatory approval in most of the world for treatment of vascular dementia. A systematic review and meta-analysis was undertaken to assess the evidence for efficacy and safety of cholinesterase inhibitors and memantine in vascular dementia. Methods PubMed, BIOSIS, International Pharmaceutical Abstracts, and Cochrane registries were searched for randomised, placebo-controlled trials on cholinesterase inhibitors and memantine in patients with vascular dementia. Trial methods, clinical characteristics, outcomes, and adverse events were extracted and checked. Meta-analytic methods using fixed-effects models were used to give summaries of each drug's effects. Findings Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer's Disease Assessment scale were significant for all drugs, ranging from a −1·10 point mean difference (95% CI −2·15 to −0·05) for rivastigmine to −2·17 for 10 mg daily donepezil (95% CI −2·98 to −1·35). Only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale (odds ratio 1·51 [95% CI 1·11–2·07]). No behavioural or functional benefits were observed, except for a −0·95 point difference (95% CI −1·74 to −0·16) with 10 mg daily donepezil on the Alzheimer's Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse events (anorexia, nausea, vomiting, diarrhoea, and insomnia) occurred with the cholinesterase inhibitors, but not with memantine. Interpretation Cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance in patients with mild to moderate vascular dementia. Data are insufficient to support widespread use of these drugs in vascular dementia. Individual patient analyses are needed to identify subgroups of patients with vascular dementia who might benefit.
TL;DR: Cognitive and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions, and Mild long-term improvements in quality of life and attention were also observed.
Abstract: BACKGROUND: We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS: We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS: Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION: Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.