Transient ischemic attacks: an update

This is a review of extant concepts of transient ischemic attacks (TIAs), their definitions, prognostic significance, pathogenesis, physiology, and management. The natural history of TIAs depends upon the risk factors of the population group studied, so that therapeutic trials should be controlled and randomized and not dependent upon published natural history data. A strong association between TIAs and coronary artery disease has now been established. It may be difficult to establish the cause or pathogenesis of TIAs in any given patient in view of the relatively poor correlation between the patient's symptoms and location of arterial plaques. Recent studies have suggested mechanisms aside from impaired perfusion or embolization from carotid plaques or vertebral basilar disease. There are no proven indications for carotid endarterectomy, a procedure which has been excessively used in the United States, but presently ongoing prospective, randomized, controlled multi-center studies will likely resolve this important issue. Neither is there scientific validation for the use of long-term anticoagulants, but data support the efficacy of ASA in reducing the incidence of stroke and myocardial infarction in patients with TIAs.     

Effectiveness of psychotherapy for personality disorders.

OBJECTIVE: The authors examined the evidence for the effectiveness of psychotherapy for personality disorders in psychotherapy outcome studies. METHOD: Fifteen studies were located that reported data on pretreatment-to-posttreatment effects and/or recovery at follow-up, including three randomized, controlled treatment trials, three randomized comparisons of active treatments, and nine uncontrolled observational studies. They included psychodynamic/interpersonal, cognitive behavior, mixed, and supportive therapies. RESULTS: All studies reported improvement in personality disorders with psychotherapy. The mean pre-post effect sizes within treatments were large: 1.11 for self-report measures and 1.29 for observational measures. Among the three randomized, controlled treatment trials, active psychotherapy was more effective than no treatment according to self-report measures. In four studies, a mean of 52% of patients remaining in therapy recovered--defined as no longer meeting the full criteria for personality disorder--after a mean of 1.3 years of treatment. A heuristic model based on these findings estimated that 25.8% of personality disorder patients recovered per year of therapy, a rate sevenfold larger than that in a published model of the natural history of borderline personality disorder (3.7% recovered per year, with recovery of 50% of patients requiring 10.5 years of naturalistic follow-up). CONCLUSIONS: Psychotherapy is an effective treatment for personality disorders and may be associated with up to a sevenfold faster rate of recovery in comparison with the natural history of disorders. Future studies should examine specific therapies for specific personality disorders, using more uniform assessment of core pathology and outcome.     

Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence

Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation data were extracted and categorized according to study type (randomized controlled trial or observational) and study duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments.     

Does vascular MCI progress at a different rate than does amnestic MCI?

This article reviews the evidence available from natural history studies and randomized clinical trials (RCT) concerning what is now coined as amnestic MCI and vascular MCI and will answer the question about the similarity and difference of their progression toward dementia. The issues to be resolved prior to the use of a survival design for conversion from vascular MCI to dementia will be discussed.     

Pediatric traumatic carotid, vertebral and cerebral artery dissections: a review

Traumatic cerebral dissections are rare but potentially dangerous conditions that through improved diagnostics have recently gained increased interest. However, there is still a significant lack of knowledge on the natural history, as well as on the best treatment options. Most of the literature on this topic consists of case reports and retrospective studies with no prospective randomized controlled studies. In our review, we highlight the fact that there is no level 1 evidence for the natural history of cerebral dissections or for the best treatment. We present 26 case studies derived from 70 pediatric patients affected by dissections, occlusions, and pseudoaneurysms.     

Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy

Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.     

A cumulative meta-analysis of selective serotonin reuptake inhibitors in pediatric depression: did unpublished studies influence the efficacy/safety debate?

OBJECTIVE: The aim of this study was to assess whether unpublished trials of serotonin reuptake inhibitors in pediatric depression impacted efficacy or safety conclusions, and to examine the evolution of information contributing to the safety/efficacy debate. METHOD: From 939 potentially relevant studies extracted from Medline, Cinahl, Biosis, and Cochrane databases, and from the United Kingdom's Committee on Safety of Medicines website, we examined 38 studies: Ten published and five unpublished randomized, controlled trials, 22 observational studies, and one crossover trial. We performed cumulative and non-cumulative meta-analyses and generated pooled relative rates of response and serious adverse events for high-quality randomized, controlled trials. RESULTS: Unpublished studies did not substantially alter the risk-to-benefit determination. Cumulative meta-analyses of seven randomized, controlled trials for efficacy and 11 randomized, controlled trials for safety suggest an adverse safety/efficacy profile for selective serotonin reuptake inhibitors (SSRIs) overall. Fluoxetine and citalopram appear to offer favorable risk to benefit profiles, while shorter-acting agents pose greater risks and provide marginal benefit. CONCLUSIONS: While simple meta-analysis across all SSRIs for treatment of pediatric depression provided general efficacy and safety information, meta-analysis of individual drugs and use of cumulative meta-analytic techniques may have expedited our ability to formulate conclusions about safety and efficacy of SSRIs in pediatric depression.     

Starting and Stopping Treatment for Seizures and Epilepsy

Summary:  Decisions about when to start or to stop antiepileptic drug (AED) treatment must be informed by reliable information of the natural history of epilepsy, the effect of treatment, and the social context of the individual. Ultimately the patient will be the decision maker, the clinician or health-care professional, the provider and interpreter of information. While observational studies will provide information on natural history, the most reliable information on the effect of intervention will come from randomised controlled trials in relevant populations of patients. However, these need to be large enough to allow interpretation not just of the average effect across the recruited patients, but also some estimate of the effects for an individual based on the prognostic effects that most effect outcomes. When trials are of sufficient size they can allow the development of predictive models that assist decision making. The Medical Research Council studies of AED withdrawal and early epilepsy and single seizures provide examples of such trials.     

Summary of Evidence on Immediate Statins Therapy Following Aneurysmal Subarachnoid Hemorrhage

Statins were shown to have neuroprotective effects, with reduced vasospasm and delayed ischemic deficits in statin-treated patients after aneurysmal subarachnoid hemorrhage in two small, randomized, controlled clinical trials published in 2005. This review consolidated data from available published studies evaluating statin treatment for subarachnoid hemorrhage. A literature search was conducted to identify original research studies published through October 2010 testing immediate treatment with a statin in statin-na?ve patients following aneurysmal SAH. Six randomized controlled clinical trials and four observational studies were identified. Despite inconsistent results among studies, a meta-analysis of randomized controlled data showed a significant reduction in delayed ischemic deficits with statins. Effect on vasospasm was more difficult to determine, due to differences in definitions used among studies. Interpretations from observational studies were limited by the use of relatively small sample sizes, historical controls, and treatment variability.     

Anger Management and Intellectual Disabilities: A Systematic Review

We conducted a systematic literature review of anger management in people with intellectual disabilities (ID). We identified 2 studies that used randomized controlled trials and 6 that used pretest-posttest nonequivalent control group designs. The mean between-group effect size was 1.52 for randomized controlled trials and 0.89 for the other studies; however, no studies were well controlled. Thus, anger management is not an empirically supported treatment for individuals with ID. The need for further research in this area and methods of strengthening said research are discussed.     

The Efficacy of Treatment for Drinking Problems

Examination of the alcohol treatment literature reveals conflicting opinions on the efficacy of various therapies. To a large extent this reflects the professional background of the reviewer and what is regarded as acceptable evidence. The results of randomised controlled trials are often difficult to interpret since the very acceptance of therapy is often a protracted process, treatment itself even more so and therefore ‘contamination’ by other interventions and life events almost invariable. In this review evidence from natural history studies as well as controlled trials will be taken into consideration. The efficacy of cognitive-behavioural strategies is well documented, at least in the short term, and cue-exposure, response-prevention offers promise. Psychoanalytically-based therapies seem unhelpful. The alcohol-sensitizing drug, disulfiram, appears to improve outcome over the first 3–6 months and is most beneficial when given under supervision. Serotonin uptake inhibitors reduce alcohol consumption and may assist behavioural interventions. Correlational and natural history studies point to the value of Alcoholics Anonymous membership in fostering stable abstinence, though its overall impact is unclear. Greater emphasis is now placed on systematic screening and early intervention for harmful alcohol consumption, and the results from recent studies are highly encouraging. A clearer definition of the scope of individual clinicians and the role of structured programmes is much needed.     

Yoga as an ancillary treatment for neurological and psychiatric disorders: a review

Yoga is gaining acceptance as an ancillary medical treatment, but there have been few studies evaluating its therapeutic benefits in neurological and major psychiatric conditions. The authors reviewed the literature in English on the efficacy of yoga for these disorders. Only randomized, controlled trials were included, with the exception of the only study of yoga for bipolar disorder, which was observational. Trials were excluded if yoga was not the central component of the intervention. Of seven randomized, controlled trials of yoga in patients with neurological disorders, six found significant, positive effects. Of 13 randomized, controlled trials of yoga in patients with psychiatric disorders, 10 found significant, positive effects. These results, although encouraging, indicate that additional randomized, controlled studies are needed to critically define the benefits of yoga for both neurological and psychiatric disorders.     

Pharmacotherapy for the treatment of aggressive behavior in general adult psychiatry: A systematic review

OBJECTIVE: To systematically review the evidence for pharmacologic management of outwardly directed aggressive behavior in general adult psychiatry. DATA SOURCES: Literature searches in PubMed, EMBASE, PsycINFO, and Cochrane libraries from 1966 through March 2005 were used to identify relevant studies. The keywords aggression, violence, anger, and hostility combined with drug therapy, psychotropic drugs, adrenergic beta-antagonists, anticonvulsants, anti-depressants, antipsychotic agents, benzodiazepines, and lithium were searched. Furthermore, the retrieved publications were searched for additional references. STUDY SELECTION: All randomized controlled trials addressing pharmacotherapy for aggression or aggression-related symptoms were included, except studies addressing the "emergency situation" and studies conducted in specialized psychiatric or non-psychiatric settings. DATA EXTRACTION: Evidence synthesis was performed using the "best-evidence principle." Two authors independently adjudicated methodological quality and generalizability to daily clinical practice. DATA SYNTHESIS: Thirty-five randomized controlled trials met the inclusion criteria and were evaluated. On the basis of a best-evidence synthesis model, weak evidence for antiaggressive effects of antipsychotics, anti-depressants, anticonvulsants, and beta-adrenergic-blocking drugs was found. Atypical antipsychotics appeared superior to typical antipsychotics. The use of various outcome measures and insufficient data reporting in the individual studies hampered the quantitative assessment of efficacy across studies. Further limitations of the available randomized controlled trials included small sample sizes, short study duration, and poor generalizability to daily clinical practice setting. CONCLUSIONS: Whereas pharmacotherapy is frequently applied in aggressive patients, only weak evidence of efficacy of various drug classes was found. Consensus about the use of aggression measurement scales in clinical trials is necessary for future research. Furthermore, large-scale trials with more naturalistic designs, as opposed to classical randomized controlled trials with strict inclusion and exclusion criteria, may be advisable in order to obtain results that are more generalizable to daily clinical practice.     

整群随机试验

整群随机试验在临床研究中应用较为广泛,其以“群”为随机单位,一个群中的所有个体接受相同的干预,因此与以个体为随机单位的随机对照试验相比,整群随机试验能够减少“沾染”,组织实施更为简便,更适合公共卫生措施评价和医疗质量改进研究。然而,整群随机试验组间可比性欠佳,存在设计效应,因此需要较大的样本量。本文将从整群随机试验的历史渊源、基本概念、研究设计、应用场景和案例解读、报告规范等方面进行全面总结,以期帮助临床研究者认识、了解、掌握此类研究设计。     

Ataxia Rating Scales—Psychometric Profiles, Natural History and Their Application in Clinical Trials

We aimed to perform a comprehensive systematic review of the existing ataxia scales. We described the disorders for which the instruments have been validated and used, the time spent in its application, its validated psychometric properties, and their use in studies of natural history and clinical trials. A search from 1997 onwards was performed in the MEDLINE, LILACS, and Cochrane databases. The web sites ClinicalTrials.gov and Orpha.net were also used to identify the endpoints used in ongoing randomized clinical trials. We identified and described the semiquantitative ataxia scales (ICARS, SARA, MICARS, BARS); semiquantitative ataxia and non-ataxia scales (UMSARS, FARS, NESSCA); a semiquantitative non-ataxia scale (INAS); quantitative ataxia scales (CATSYS 2000, AFCS, CCFS and CCFSw, and SCAFI); and the self-performed ataxia scale (FAIS). SARA and ICARS were the best studied and validated so far, and their reliability sustain their use. Ataxia and non-ataxia scores will probably provide a better view of the overall disability in long-term trials and studies of natural history. Up to now, no clear advantage has been disclosed for any of them; however, we recommend the use of specific measurements of gait since gait ataxia is the first significant manifestation in the majority of ataxia disorders and comment on the best scales to be used in specific ataxia forms. Quantitative ataxia scales will be needed to speed up evidence from phase II clinical trials, from trials focused on the early phase of diseases, and for secondary endpoints in phase III trials. Finally, it is worth remembering that estimation of the actual minimal clinically relevant difference is still lacking; this, together with changes in quality of life, will probably be the main endpoints to measure in future therapeutic studies.     

Migraine,allodynia, and implications for treatment

Allodynia – perception of pain from non‐noxious stimuli – is a common clinical feature in various pain syndromes. The significance for migraine has increasingly been recognized and the pathophysiology has been investigated in detail. Allodynia is a marker for sensitization of central trigeminal neurons. Intensity and persistence of allodynic symptoms are a function of duration of migraine attacks, frequency of attacks, and migraine history. It has been hypothesized that treatment success with triptans may be severely impaired in the presence of allodynia. However, randomized controlled trials did not confirm that. Treatment with cyclooxygenase inhibitors and dihydroergotamine does not seem to be limited by allodynia; these medications may be able to reverse allodynia. Data on the new class of calcitonin‐gene related‐peptide antagonists are not yet available. Additional and more refined randomized controlled trials, focusing on methodological issues pertaining to the determination of allodynia, are warranted to resolve the true relationship between allodynia and treatment response. Regardless – based on available randomized controlled trials – the recommendation prevails to initiate abortive treatment as soon as possible after attack onset when pain is still mild.     

Clinical and genetic update of hereditary spastic paraparesis

Hereditary spastic paraparesis is a group of inherited neurological diseases characterized by underlying wide genetic heterogeneity. It should be suspected if there is a positive familial history, a common genetic alteration (i.e. SPG4, the most overall frequent form), or association with other signs, such as cerebellar ataxia (i.e. SPG7), early cognitive impairment or even cognitive deficit (i.e. SPG11), or peripheral neuropathy (i.e. SACS). The natural history is known for certain genetic subgroups, with genotype-phenotype correlations partially explaining childhood or late onset. However, the search for genetic modifying factors, in addition to the causal pathogenic variant or environmental influencers, is still needed. Novel approaches to provide etiological treatment are in the pipeline for SPG11. Symptomatic treatments are available but would benefit from randomized controlled trials.     

Role of MRI in diagnosis and treatment of multiple sclerosis

Magnetic resonance imaging (MRI) has played a unique role in the diagnosis and management of patients with multiple sclerosis (MS). In the recent years, there have been considerable changes in the diagnostic criteria for MS as MR-based studies demonstrated its power in earlier and more accurate diagnosis of the disease. Moreover, MRI metrics have become key supportive outcome measures to evaluate the efficacy of experimental treatments in randomized, controlled trials. MRI can also be used as a prognostic tool in patients with clinically isolated syndrome. Although advanced quantitative MRI measures such as magnetization transfer, spectroscopy, and diffusion imaging have added much more to our knowledge about pathogenesis and natural history of the disease but their cost, availability, complexity and lack of validation have limited their use in routine clinical practice. Conventional MR techniques including proton density, T1/T2-weighted images and fluid-attenuated inversion recovery sequences are now accepted in standard protocols for diagnosis and treatment outcome measures in clinical trials for MS.     

单病例随机对照试验

设计良好、管理严格、分析严谨的随机对照试验是评价群体治疗效果的金标准,但是因其严格的纳入与排除标准无法为特定患者的治疗决策提供证据。单病例随机对照试验是对患者个体进行的多轮交叉随机对照试验,以患者为中心,旨在确定该患者的最佳治疗策略。本文简要介绍单病例随机对照试验的基本概念、历史渊源及发展、研究设计、统计方法及报告规范等,以期帮助临床研究者更好地认识、了解、掌握运用此类研究设计。     

Cervicocerebral arterial dissection

Dissection of the cervicocerebral arteries is an infrequent occurrence but is a leading cause of stroke in young and otherwise healthy patients. A brief review of the history, pathogenesis, and management is presented. The proper management for stroke prevention in dissection is unclear as there have been no randomized, controlled trials performed; small trials are under way.