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    ABSTRACT: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009. To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use. We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation. No studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine. Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.
    Cochrane database of systematic reviews (Online) 11/2013; 11:CD010567.
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    ABSTRACT: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009. To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use. We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation. No studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine. Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.
    Cochrane database of systematic reviews (Online) 11/2013; 11:CD010567.
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    ABSTRACT: Background: Mild cognitive impairment (MCI) is at least as prevalent as dementia after transient ischaemic attack (TIA)/stroke and is increasingly recognised as an important outcome in observational studies and randomised trials. However, there is no consensus on how impairment should be defined, and numerous different criteria exist. Previous studies have shown that different criteria for cognitive impairment impact on prevalence rates in epidemiological studies. However, there are few data on how operational differences within established criteria (e.g. Petersen-MCI) affect measured impairment rates and the performance of short cognitive tests such as the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), particularly in cerebrovascular disease. We therefore evaluated the effect of different operational definitions on measured rates of Petersen-MCI and on reliability of short cognitive tests in patients with TIA and stroke. Methods: Consecutive patients underwent the MMSE, MoCA and neuropsychological battery ≥1 year after TIA or stroke in a population-based study. MCI was defined using the Petersen method and subclassified as single or multiple domain, both with (original) and without (modified) subjective memory impairment. Different cut-offs (>1, >1.5 and >2 standard deviations, SD) on a given test relative to published norms were compared together with use of single versus multiple tests to define domain impairment. Results: 91 non-demented subjects completed neuropsychological testing (mean age ± SD 69.7 ± 11.6 years, 54 male, 49 stroke) at a mean of 3.1 ± 1.9 years after the index event. Rates of cognitive impairment ranged from 14/91 (15%) for MCI-original at >2 SD cut-off to 61/91 (67%) MCI-modified at >1 SD cut-off, and the proportion of MCI that was multiple domain varied, e.g. 24/46 (52%) versus only 5/27 (20%) at 1 versus 2 SD cut-off for MCI-modified. Requirement for subjective memory complaint approximately halved estimates [e.g. 17 (19%) vs. 39 (43%) for MCI at 1.5 SD cut-off, single test definition], whereas use of multiple tests versus a single test to define a cognitive domain had less impact. In general, diagnostic accuracy was higher, and optimal cut-offs lower, on MMSE and MoCA for multiple-domain versus single-domain MCI, but the MoCA appeared superior for detecting MCI-modified, whereas the MMSE performed well in detecting MCI-original. Conclusion: Even within established criteria for MCI, differences in operational methodology result in 4-fold variation in MCI estimates. Optimal MMSE and MoCA cut-offs are lower, and reliability more similar, when criteria for MCI are more stringent. Our findings have implications for sample size and adjusted relative risk calculations in randomised trials and for comparisons between studies. © 2013 S. Karger AG, Basel.
    Cerebrovascular Diseases 11/2013; 36(5-6):355-362.
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    ABSTRACT: Congenital myasthenic syndromes (CMS) result from the failure to achieve muscle depolarisation due to disorders in the structure and/or function of the neuromuscular synapse. Mutations of the nicotinic acetylcholine receptor (nAChR) form a major subset of CMS. We describe a patient who presented with recurrent apnoeic crises in the neonatal period requiring ventilator support. Electromyography revealed compound muscle action potential decrement upon repetitive stimulation. Sequencing of nAChR subunit genes revealed two missense mutations. One previously reported null mutation p.εTyr15His, and a second novel missense mutation, p.εThr38Lys, that is well expressed in mammalian cell culture and thus likely to exert its effect via alteration of ion channel kinetics. Functional analysis revealed abbreviated ion channel bursts characteristic of a fast channel CMS. The mutation p.εThr38Lys occurs at the interface between the α and ε subunits of the nAChR pentamer and leads to instability of the open channel. The effects of this mutation on channel function were investigated in relation to other fast channel mutants at an analogous subunit interface within the nAChR pentamer. Fast channel syndromes are frequently characterised by severe myasthenic weakness with apnoeic crises; knowledge of the underlying mutation and its functional consequences can be vital for appropriate therapy and patient management.
    Neuromuscular Disorders 11/2013;
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    ABSTRACT: Hypertension is a major treatable cause of incident and recurrent stroke. However, it can be missed by one-off clinic measurements. Hypertension guidelines therefore currently recommend ambulatory monitoring (ABPM) prior to treatment in primary prevention. Given high rates of under-treatment of hypertension in secondary prevention after TIA and stroke, we compared Bluetooth home BP monitoring (HBPM) and ABPM in identifying hypertension missed at initial assessment, with validation against pre-morbid BP and markers of hypertensive arteriopathy. Consecutive patients recruited to the Oxford Vascular Study with TIA or minor stroke underwent HBPM (3 measurements, 3 times daily for 7 days) and ABPM at 1 month after presentation. Mean SBP was related to premorbid hypertension (defined as mean SBP>140 or mean DBP>90 based on all BP measurements during the previous 10 years in primary care or a formal diagnosis of hypertension in primary care) and markers of hypertensive arteriopathy (creatinine, aortic stiffness-pulse wave velocity-and leukoaraiosis on brain imaging). Among 500 eligible patients, those with premorbid hypertension (n=307) were better identified (p<0.001) by mean SBP on HBPM than by mean awake SBP on ABPM (area under ROC curve: 0.73, 95%CI 0.67-0.78 vs 0.60, 0.54-0.65). This difference was also present for identification of patients (n=205) with mean pre-morbid BP>140/90 but no formal premorbid diagnosis of hypertension (0.77, 0.69-0.85 vs 0.57, 0.46-0.69), including those who were normotensive in the stroke clinic (0.84, 0.73-0.96 vs 0.64, 0.40-0.89). HBPM SBP was also more strongly associated than ABPM with creatinine (r=0.24, p<0.001 vs r=0.14, p=0.002), aortic stiffness (r=0.21, p=0.01 vs r=0.13, p=0.13) and moderate/severe leukoaraiosis (AUC: 0.61, 0.55-0.67 vs 0.49, 0.43-0.55). In patients with TIA or minor stroke, HBPM was more reliable than ABPM at identifying missed hypertension and hypertensive arteriopathy. Its use could significantly reduce the risk of recurrent stroke.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2.
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    ABSTRACT: The neurobiological basis of psychogenic movement disorders (PMDs) has been elusive, and they remain difficult to treat. In the last few years, functional neuroimaging studies have provided insight into their pathophysiology and neural correlates. Here, we review the various methodological approaches that have been used in both clinical and research practice to address neural correlates of functional disorders. We then review the dominant hypotheses generated from the literature on psychogenic paralysis. Overall, these studies emphasize abnormalities in the prefrontal and anterior cingulate cortices. Recently, functional neuroimaging has been used to specifically examine PMDs. These studies have addressed a major point of controversy: whether higher frontal brain areas are directly responsible for inhibiting motor areas or whether they reflect modulation by attentional and/or emotional processes. In addition to elucidating the mechanism and cause, recent work has also explored the lack of agency that characterizes PMDs. We describe the results and implications of the results of these imaging studies and discuss possible interpretations.
    Current Neurology and Neuroscience Reports 11/2013; 13(11):402.
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    ABSTRACT: Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.
    Journal of neurology, neurosurgery, and psychiatry 11/2013;
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    ABSTRACT: Some preventive treatments, such as statins and antihypertensive drug classes, differ in their relative effectiveness in preventing stroke versus coronary events. However, guidelines for secondary prevention of stroke are based partly on observations that fatal coronary events on long-term follow-up after TIA and stroke exceed fatal recurrent strokes. However, given the substantial fall in population incidence of coronary events in recent decades, it is uncertain whether this excess coronary risk remains. We prospectively ascertained all TIA, minor stroke (NIHSS≤5) and major stroke in a population based study (2002-2010). Patients received best secondary prevention according to current guidelines and were followed-up face-to-face for up to 8 years. Acute coronary events included fatal and non-fatal myocardial infarction and sudden cardiac death. Of 2035 consecutive patients with cerebrovascular events, 1928 were ischaemic (832 TIA; 778 minor stroke; 318 major stroke). Mean (SD) time to death or final follow-up was 3.1 (2.4) years, during which time there were 328 first recurrent strokes (8-year actuarial risk=24.6%, 95% CI 21.5-27.7) and 96 first acute coronary events (8-year actuarial risk=10.4%, 6.7-14.2; difference p<0.0001). The excess of recurrent stroke versus coronary events remained after exclusion of recurrences during the first 7-days: 214 vs 88 events. Death during follow-up was due to recurrent stroke in 88 patients and due to a coronary event in 42 (8-year risk: 5.4%, 12-15.2 vs 2.7%, 1.9-3.5; difference p<0.0001). The long-term risk of major vascular events after TIA and stroke remains substantial, but about 70% of fatal and non-fatal events are now accounted for by recurrent stroke rather than acute coronary events.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2.
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    ABSTRACT: The altered state of consciousness produced by general anesthetics is associated with a variety of changes in the brain's electrical activity. Under hyperpolarizing influences such as anesthetic drugs, cortical neurons oscillate at ~1 Hz, which is measurable as slow waves in the electroencephalogram (EEG). We have administered propofol anesthesia to 16 subjects and found that, after they had lost behavioral responsiveness (response to standard sensory stimuli), each individual's EEG slow-wave activity (SWA) rose to saturation and then remained constant despite increasing drug concentrations. We then simultaneously collected functional magnetic resonance imaging and EEG data in 12 of these subjects during propofol administration and sensory stimulation. During the transition to SWA saturation, the thalamocortical system became isolated from sensory stimuli, whereas internal thalamocortical exchange persisted. Rather, an alternative and more fundamental cortical network (which includes the precuneus) responded to all sensory stimulation. We conclude that SWA saturation is a potential individualized indicator of perception loss that could prove useful for monitoring depth of anesthesia and studying altered states of consciousness.
    Science translational medicine 10/2013; 5(208):208ra148.
  • Pain 10/2013;
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