Substituting behavioural treatment for drugs in the treatment of insomnia: an exploratory study

There is need to investigate directly the generalizability of psychological treatment effects to clinical populations of insomniacs; especially to those who are chronic hypnotic users and are drug-dependent. This paper present two methodological models, based upon the pharmacological literature, which permit the selection of such subjects for research studies. The usefulness of the models is discussed with reference to a preliminary investigation based on 10 cases, and recommendations are made both for further research and clinical practice.     

Management of intrathecal baclofen therapy for severe acquired brain injury: consensus and recommendations for good clinical practice

Although widespread in the treatment of generalised spasticity due to severe acquired brain injury, clinical use of intrathecal baclofen administered through an implanted catheter is not yet supported by full scientific evidence. The aim of the study is to provide recommendations for good clinical practice regarding intrathecal baclofen therapy. We used a modified RAND Delphi method to develop consensus-based medical guidelines, involving clinicians who use intrathecal baclofen therapy throughout Italy. The clinicians were asked 38 questions grouped in six areas (patient selection, contraindications for implant, tests prior to implant, method of implant and management of therapy, efficacy evaluation and goal setting, and management of complications). To establish consensus, 75% agreement was required in answers to every question. Consensus was reached on the second round of the Delphi process on 27/38 questions (71%), specifically those regarding identification of objectives, efficacy evaluation, and method of implant and management of therapy, whereas management of complications and contraindications for implant remained critical areas. Despite the limits of our method, a set of recommendations was drawn up for clinical practice in this sector. The study also revealed residual critical areas and indicated future lines of research necessary to reach evidence-based consensus.     

Interventions in consultation-liaison psychiatry: the development of a schema and a checklist for operationalized interventions

A literature review and pilot investigations reveal that (ward-) management consultation-liaison (C/L) psychiatry recommendations are infrequent and unsystematically used. Furthermore, the communication with the operational group as defined by Meyer and Mendelson is not sufficiently activated. The major focus of the consultation is the first contact, but follow-up is infrequent. With the exception of biologic recommendations and disposition, chart notes by psychiatric consultants do not sufficiently specify the actions to be taken by the ward staff in a general hospital. A schema for the systematic organization of the intervention was developed. A checklist of operationalized C/L interventions is reported. This combination provides a tool for the systematic use of strategic ward management and discharge recommendations. Its basic structure is currently integrated in MICRO CARES [Hammer et al, SCAMC]. The impact on clinical care, education, and research is described.     

The effects of the ketogenic diet on behavior and cognition

Multiple forms of the ketogenic diet (KD) have been successfully used to treat drug-resistant epilepsy, however its mainstream use as a first-line therapy is still limited. Further investigation into its clinical efficacy as well as the molecular basis of activity is likely to assist in the reversal of any resistance to its implementation. In this review we shall attempt to elucidate the current state of experimental and clinical data concerning the neuroprotective and cognitive effects of the KD in both humans and animals. Generally, it has been shown by many research groups that effective implementation of KD exerts strong neuroprotective effects with respect to social behavior and cognition. We will also elucidate the role of KD in the interesting relationship between sleep, epilepsy and memory. Currently available evidence also indicates that, under appropriate control, and with further studies investigating any potential long-term side effects, the KD is also a relatively safe intervention, especially when compared to traditional anti-epileptic pharmacotherapeutics. In addition, due to its neuroprotective capacity, the KD may also hold potential benefit for the treatment of other neurological or neurodegenerative disorders.     

The ketogenic diet: what has science taught us?

Despite intense and growing interest in studying the mechanisms of ketogenic diet (KD) action, and recently published studies implicating novel molecular interactions with metabolic substrates, there nevertheless remains the pragmatic and scientific challenge of sustaining continued research in this field. This is in part a consequence of limited research funding and perhaps skepticism regarding the ultimate need to understand underlying mechanisms, particularly when clinical studies have increasingly validated the efficacy of the KD and its variants. After a decade and a half of more concerted laboratory efforts to understand KD mechanisms, it would be prudent to ask - what has all this scientific research really taught us? In this regard, it is instructive to compare and contrast laboratory research in dietary approaches for epilepsy with that traditionally used to screen for potential antiepileptic drugs (AEDs). In this review, lessons learned from AED development are applied to the more recent experimental findings and approaches attempting to link metabolic changes induced by the KD to neuronal and network excitability in the brain.     

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring

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.     

Measurement issues in the use of cognitive neuroscience tasks in drug development for impaired cognition in schizophrenia: a report of the second consensus building conference of the CNTRICS initiative

This overview describes the goals and objectives of the second conference conducted as part of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. This second conference was informed by a series of online surveys and brought together basic and clinical scientists from academia and industry to address the concerns central to each field of research. Our goal was to develop recommendations for future research addressing the psychometric and practical challenges involved in translating paradigms from cognitive neuroscience into tasks that are feasible for use in the treatment discovery and development process. In this overview article, we describe the series of talks that were presentations at the conference. This article serves as an introduction to the set of articles included in this special issue that provide overviews and discussions of the issues raised and the recommendations made in these talks and in the subsequent discussions at the meeting. In addition, we describe the online surveys conducted in the month before the conference that were used to obtain suggestions from the field as to important task selection criteria and to generate initial benchmark goals for psychometric development for cognitive neuroscience tasks.     

Treatment and prevention of spontaneous intracerebral hemorrhage: comparison of EUSI and AHA/ASA recommendations

Stroke is a leading cause of death and the primary cause of permanent disability in adults in Western countries and has an enormous socioeconomic impact. Among all stroke subtypes, intracerebral hemorrhage is the deadliest form, especially in patients with intraventricular hemorrhage. In recent years, intracerebral hemorrhage has become a major focus within stroke research. The latest data from randomized controlled trials, however, have shown disappointing results. In 2006, the European Stroke Initiative published recommendations for the management of spontaneous intracerebral hemorrhage, followed by an updated recommendation by the American Heart Association/American Stroke Association in 2007. This review gives a comprehensive overview and comparison of the two recommendations. Finally, we provide an overview of ongoing clinical trials in intracerebral hemorrhage.     

Clinical Practice Guidelines for the Medical and Surgical Management of Primary Intracerebral Hemorrhage in Korea

The purpose of this clinical practice guideline (CPG) is to provide current and comprehensive recommendations for the medical and surgical management of primary intracerebral hemorrhage (ICH). Since the release of the first Korean CPGs for stroke, evidence has been accumulated in the management of ICH, such as intracranial pressure control and minimally invasive surgery, and it needs to be reflected in the updated version. The Quality Control Committee at the Korean Society of cerebrovascular Surgeons and the Writing Group at the Clinical Research Center for Stroke (CRCS) systematically reviewed relevant literature and major published guidelines between June 2007 and June 2013. Based on the published evidence, recommendations were synthesized, and the level of evidence and the grade of the recommendation were determined using the methods adapted from CRCS. A draft guideline was scrutinized by expert peer reviewers and also discussed at an expert consensus meeting until final agreement was achieved. CPGs based on scientific evidence are presented for the medical and surgical management of patients presenting with primary ICH. This CPG describes the current pertinent recommendations and suggests Korean recommendations for the medical and surgical management of a patient with primary ICH.     

Alternative diets to the classical ketogenic diet--can we be more liberal?

The ketogenic diet (KD), a high-fat, adequate protein, low-carbohydrate diet has been used since 1921 for the treatment of severe medically refractory epilepsy. In the past 15 years, the use of the KD has expanded enormously and a huge amount of clinical evidence of its efficacy is available. The classical KD is however restrictive and therefore alternative more liberal varieties of the classical KD have been developed within the last 8 years. The purpose of this report is to summarise the principles and evidence of effectiveness of the alternative ketogenic diets: Medium Chain Triglyceride (MCT)-KD, modified Atkins diet (MAD) and low glycaemic index treatment (LGIT), compared to the classical KD. The clinical evidence to date suggests that the more liberal versions of the classical KD such as MCT KD, MAD and LGIT have an efficacy close to the classical KD; however, no RCT data are available for MAD and LGIT. This evidence suggests that factors such as age, epilepsy type, lifestyle and resources are important factors in deciding which diet we should start a patient on. This report intends to summarise guidelines based on the evidence available.     

First tier measures in the treatment of intracranial hypertension in the patient with severe craniocerebral trauma. Proposal and justification of a protocol

The management of severe head injuries in general and that of high intracranial pressure (ICP) in particular are among the most challenging tasks in neurocritical care. One of the difficulties still faced by clinicians is that of reducing variability among centers when implementing management protocols. The purpose of this paper is to propose a standardized protocol for the management of high ICP after severe head injury, consistent with recently published clinical practice guidelines and other clinical evidence such as that provided by the systematic reviews of the Cochrane Collaboration. Despite significant advances in neuromonitoring, deeper insight into the physiopathology of severe brain trauma and the many therapeutic options available, standardized protocols are still lacking. Recently published guidelines provide sketchy recommendations without details on how and when to apply different therapies. Consequently, great variability exists in daily clinical practice even though different centers apply the same evidence-based recommendations. In this paper we suggest a structured protocol in which each step is justified and integrated into an overall strategy for the management of severe head injuries. The most recent data from both the preliminary and definitive results of randomized clinical trials as well as from other sources are discussed. The main goal of this article is to provide neurotraumatology intensive care units with a unified protocol that can be easily modified as new evidence becomes available. This will reduce variation among centers when applying the same therapeutic measures. This goal will facilitate comparisons in outcomes among different centers and will also enable the implementation of more consistent clinical practice in centers involved in multicenter clinical trials.     

An evidence-based approach in the treatment of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disease with diverse symptoms for which there is no curative or disease-modifying treatment available. Currently, tetrabenazine is the only drug approved for HD by a regulatory agency, and only for the treatment of chorea. In the current review, we present updated results from recent clinical trials and ongoing clinical research efforts to find effective and safe treatments for HD motor, and neuropsychiatric and cognitive symptoms. We used a systematic review approach that included data from well-designed randomised controlled trials. The authors conclude that there is weak evidence to support most of the treatment decisions in HD and thus clinicians may be guided only by expert opinion-based therapeutic recommendations. Ongoing research is considerable and is expected to have an impact in the management of HD in upcoming years.     

Clinical practice guidelines for the treatment of schizophrenia: from theory to practice

INTRODUCTION: Based on the concept of evidence-based medicine (EBM), the clinical practice guidelines (CPG) occupy an increasingly important place in the field of the treatment of schizophrenia. Although CPGs have been elaborated in a rigorous way, few of them provide the readers with tools for their use in practice. The clinician must therefore create his own method of application. This problem was encountered within the framework of a retrospective study carried out in a rehabilitation unit, where we sought to answer the question concerning the use of the CPG approach in the pharmacological treatment of schizophrenia: "to what degree do doctors, with only indirect knowledge, respect these CPGs?" METHOD: The comparative study between CPG and practical current clinic implied: (1) the choice of a pertinent CPG for the clinical framework studied, (2) the selection of measuring instruments, which allow the quantification of obvious clinical problems approached in the CPG, and (3) the development of a standardized system of comparison to determine the degree of respect of the recommendations. The Expert Consensus Guideline for the treatment of schizophrenia (ECGTS) was selected as the reference. A method of application of the ECGTS is depicted: use of standardized clinical scales; translation of the results of the clinical examination in terms of clinical problems to which the recommendations of the guideline refers; and determination of the degree of respect of the recommendations. RESULTS: In the group of 20 patients included in this study, the recommendations of the ECGTS were totally respected in 65% of the patients, and partially respected in 10%, while in 25% of the patients, they were not respected. COMMENTS: These observations suggest that the clinical approach has to be improved, mainly with regard to the treatment of psychotic and depressive symptoms. This work also showed the limits of the CPG: for example, over half of the patients presented side effects on clinical evaluation, whereas the regulation of their medication respected the recommendations of the ECGTS. CONCLUSION: The future certainly belongs to CPG, which proposes, in addition to the clinical recommendations themselves, a method to check their application in clinical practice.     

Dietary therapy is not the best option for refractory nonsurgical epilepsy

The ketogenic diet (KD) is currently a well‐established treatment for patients with medically refractory, nonsurgical epilepsy. However, despite its efficacy, the KD is highly restrictive and constitutes a treatment with serious potential adverse effects, and often with difficulties in its implementation and compliance. Patients on the KD require strict follow‐up and constant supervision by a medical team highly experienced in its management in order to prevent complications. Other alternative treatments for patients with refractory epilepsy include vagus nerve stimulation (VNS), new‐generation antiepileptic drugs (AEDs), corpus callosotomy (CC), and responsive focal cortical stimulation (RNS). In this review, we explain not only the difficulties of the KD as a therapeutic option for refractory epilepsy but also the benefits of other therapeutic strategies, which, in many cases, have proven to have better efficacy than the KD itself.     

Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet

The clinical efficacy of the ketogenic diet (KD) has now been well-documented. However, the underlying bases of KD antiepileptic efficacy are still a matter of speculation. A number of suggestions regarding underlying mechanisms have been offered, but all require rigorous testing. Development of appropriate animal model systems, and clear statement of experimentally testable hypotheses, are needed. Among the general hypotheses of interest are the following: (1) the KD alters the nature, and/or degree, of energy metabolism in the brain -- therefore altering brain excitability; (2) the KD leads to changes in cell (neuronal and perhaps glial) properties, which decrease excitability and dampen epileptiform discharge; (3) the KD induces changes in neurotransmitter function and synaptic transmission -- thus altering inhibitory-excitatory balance and discouraging hyper-synchronization; (4) the KD is associated with changes in a variety of circulating factors which act as neuromodulators that can regulate CNS excitability; and (5) the KD gives rise to alterations in brain extracellular milieu, which serve to depress excitability and synchrony. An understanding of the mechanism underlying KD antiepileptic efficacy will help us not only to optimize the clinical use of the ketogenic diet, but also to develop novel antiepileptic treatments.     

Clinical utility of exome sequencing in a pediatric epilepsy cohort

Objective

Exome sequencing (ES) has played an important role in the identification of causative variants for individuals with epilepsy and has proven to be a valuable diagnostic tool. Less is known about its clinical utility once a diagnosis is received. This study systematically reviewed the impact of ES results on clinical decision-making and patient care in a pediatric epilepsy cohort at a tertiary care medical center.

Methods

Pediatric patients with unexplained epilepsy were referred by their neurologist, and informed consent was obtained through an institutional review board–approved research ES protocol. For patients who received a genetic diagnosis, a retrospective chart review was completed of the probands and their relatives' medical records prior to and after genetic diagnosis. The following outcomes were explored: provider management recommendations, changes in care actually implemented, and anticipatory guidance provided regarding the proband's condition.

Results

Fifty-three probands met the inclusion criteria. Genetic diagnosis led to at least one provider recommendation in 41.5% families (22/53). Recommendations were observed in the following categories: medication, screening for non-neurological comorbidities/referrals to specialists, referrals to clinical research/trials, and cascade testing. Anticipatory guidance including information about molecular diagnosis, prognosis, and relevant foundations/advocacy groups was also observed.

Significance

Results demonstrate the clinical utility of ES for individuals with epilepsy across multiple aspects of patient care, including anti-seizure medication (ASM) selection; screening for non-neurological comorbidities and referrals to appropriate medical specialists; referral to reproductive genetic counseling; and access to research, information, and support resources. To our knowledge, this is the first study to evaluate the clinical utility of ES for a pediatric epilepsy cohort with broad epilepsy phenotypes. This work supports the implementation of ES as part of clinical care in this population.     

A framework for considering the ethical aspects of psychiatric research protocols

The ethics of psychiatric research has emerged as a topic of national importance. Attention to this topic has been stimulated by a number of factors, including heightened awareness of the distinct moral problems arising in the care of mental illness, the rapid development of new psychopharmaceutical agents, the emergence of evidence-based approaches in psychiatry, the expansion of clinical trials within the private mental health sector, and recent recommendations offered by the President's National Bioethics Advisory Commission (NBAC). Consequently, clinical practitioners and investigators alike will increasingly be called upon to evaluate the ethical acceptability of psychiatric research protocols encountered in their professional work. In light of this, we present a framework for considering ethical aspects of psychiatric research protocols. This framework gives emphasis to nine elements: (1) scientific issues; (2) research team issues; (3) risk and benefit in protocol design; (4) confidentiality; (5) selection, exclusion, and recruitment considerations; (6) informed consent and decisional capacity; (7) incentives; (8) institutional and peer/professional review issues; and (9) data presentation issues. Case illustrations are provided. It is hoped that enhanced knowledge of the considerations presented in this framework will ultimately improve our ability to help people with mental illness.     

Animal models of the ketogenic diet: what have we learned, what can we learn?

Despite its clinical use as a therapy for refractory epilepsy for more than 75 years, the ketogenic diet (KD) remains a therapy in search of an explanation. The mechanism of action of the KD is unclear and the optimal indications for its clinical use are incompletely defined. Animal models could help to elucidate these questions. Surprisingly, there have been very few animal studies of the KD, and those that have been performed are difficult to compare because of wide discrepancies in experimental methods. Earlier models concentrated on the effect of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals. Recent studies are beginning to examine the longer term effects of the KD and its role in epileptogenesis. Some features of clinical experience have been replicated in animal models, including the role of ketosis, elevation of seizure threshold by both classic ketogenic and medium chain triglyceride diets, better effectiveness at younger ages, and rapid reversal of the seizure protective effect when the diet is discontinued. These parallels raise hope that pertinent clinical questions can be addressed in the more controlled setting of the research laboratory. As in the clinical arena, there has been a recent resurgence of interest in pursuing basic questions related to the ketogenic diet, using techniques of modern neuroscience. Experimental approaches such as brain slice neurophysiology, genetic models, dissection of metabolic pathways, and neurohistological techniques hold much promise in the effort to understand this intriguing alternative to standard anticonvulsants.     

Symptom Validity Testing: A Critical Review

This paper provides a comprehensive review of the published literature on symptom validity tests (SVT) and, with the accompanying tables, serves as a reference to assist in their selection, interpretation, and defense. Because malingering is inherently an applied problem that frequently arises in a medico-legal context, the use of SVTs must meet certain standards. Thus, a number of methodological and theoretical weaknesses of SVT research which limit the use of SVTs as clinical tools and sources of evidence are highlighted. These criticisms incorporate recommendations which must be addressed if conclusions based on SVT data are to meet the increasingly rigorous standards for the admissibility of scientific evidence.