Expert Review of Neurotherapeutics最新文献

Introduction: Lennox Gastaut syndrome (LGS) as an electroclinical diagnosis has been utilized as a clinical entity for more than 70 years. However, with the recognition of other distinct electroclinical epilepsy syndromes, no consistent single etiology, and the variability of criteria used in clinical trials, the clinical utility of such a diagnosis has been questioned. Recently, the International League Against Epilepsy for the first time defined diagnostic criteria for epilepsy syndromes, thereby allowing consistent language and inclusion criteria to be utilized.

Areas covered: Recent diagnostic criteria for syndrome diagnosis are explored as defined by the International League Against Epilepsy, with further literature reviewed to highlight relevant features, and differential diagnosis explored.

Expert opinion: Developmental and Epileptic Encephalopathy (DEE) is an overall term that may be descriptive of many different epilepsies, most of early onset, whether electroclinically or etiologically defined, of which LGS is one. Although we have moved forward in defining an increasing number of etiologically specific syndromes, this to date remains a minority of the DEEs. Although there is progress with precision medicine targeted at specific causes, the term LGS still remains useful as a diagnosis in defining treatment options, as well as overall prognosis.

Introduction: Being an inherited neurodegenerative disease with an identifiable genetic defect, Huntington's disease (HD) is a suitable candidate for early intervention, possibly even in the pre-symptomatic stage. Our recent advances in elucidating the pathogenesis of HD have revealed a series of novel potential therapeutic targets, among which immunotherapies are actively pursued in preclinical experiments.

Areas covered: This review focuses on the potential of antibody-based treatments targeting various epitopes (of mutant huntingtin as well as phosphorylated tau) that are currently evaluated in vitro and in animal experiments. The references used in this review were retrieved from the PubMed database, searching for immunotherapies in HD, and clinical trial registries were reviewed for molecules already evaluated in clinical trials.

Expert opinion: Antibody-based therapies have raised considerable interest in a series of neurodegenerative diseases characterized by deposition of aggregated of aberrantly folded proteins, HD included. Intrabodies and nanobodies can interact with mutant huntingtin inside the nervous cells. However, the conflicting results obtained with some of these intrabodies highlight the need for proper choice of epitopes and for developing animal models more closely mimicking human disease. Approval of these strategies will require a considerable financial and logistic effort on behalf of healthcare systems.

Introduction: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-refractory seizures, including tonic/atonic 'drop' seizures, and intellectual impairment and slow spike-wave discharges on the electroencephalogram. Fenfluramine, previously prescribed as a weight-loss drug but then withdrawn, has recently been approved in the US, EU, and UK for the adjunct treatment of seizures associated with LGS.

Areas covered: The authors review the efficacy and safety findings from clinical trials of fenfluramine in LGS. The authors then discuss the evidence for adverse effects that may be of particular concern to fenfluramine, namely cardiac abnormalities, and weight loss, in the context of the use of fenfluramine for the treatment of the refractory seizures in LGS.

Expert opinion: Fenfluramine has demonstrated efficacy in reducing the frequency of seizures in LGS, notably drop seizures, in short-term and long-term clinical trials. Valvular heart disease and pulmonary hypertension have not been reported at the low doses (≤26 mg/day) used in these studies, however, data are limited. Due to its novel mechanism of action, fenfluramine may be of benefit in LGS which has not responded adequately to other antiseizure medications. However, none of these medications, including fenfluramine, achieves the ultimate goal of seizure freedom in most cases.

Introduction: Dissociative identity disorder (DID) is a treatable mental health condition that is associated with a range of psychobiological manifestations. However, historical controversy, modern day misunderstanding, and lack of professional education have prevented accurate treatment information from reaching most clinicians and patients. These obstacles also have slowed empirical efforts to improve treatment outcomes for people with DID. Emerging neurobiological findings in DID provide essential information that can be used to improve treatment outcomes.

Areas covered: In this narrative review, the authors discuss symptom characteristics of DID, including dissociative self-states. Current treatment approaches are described, focusing on empirically supported psychotherapeutic interventions for DID and pharmacological agents targeting dissociative symptoms in other conditions. Neurobiological correlates of DID are reviewed, including recent research aimed at identifying a neural signature of DID.

Expert opinion: Now is the time to move beyond historical controversy and focus on improving DID treatment availability and efficacy. Neurobiological findings could optimize treatment by reducing shame, aiding assessment, providing novel interventional brain targets and guiding novel pharmacologic and psychotherapeutic interventions. The inclusion of those with lived experience in the design, planning and interpretation of research investigations is another powerful way to improve health outcomes for those with DID.

Introduction: Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time.

Areas covered: The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components.

Expert opinion: There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.

Introduction: An aripiprazole long-acting injectable (LAI) antipsychotic is now available for gluteal administration every 2 months via two different formulations: aripiprazole lauroxil (AL) and aripiprazole monohydrate (Ari 2MRTU). These longer dosing regimens of aripiprazole LAI offer new potential benefits for patients.

Areas covered: The authors review the evidence supporting the efficacy and safety of aripiprazole LAIs given every 2 months for the treatment of schizophrenia or bipolar disorder (BD) in adults. The article culminates with the authors' expert perspectives on the subject.

Expert opinion: AL 1064 mg every 2 months has established efficacy for the treatment of schizophrenia based on pharmacokinetic bridging studies and prospective data for treatment of an acute exacerbation of schizophrenia. In an open-label trial, Ari 2MRTU showed efficacy for the treatment of schizophrenia and BD type I based on pharmacokinetic parameters (comparable to aripiprazole once-monthly 400 mg); it also showed efficacy regarding the secondary endpoints. Multiple doses of AL 1064 mg or Ari 2MRTU 960 mg are generally well tolerated, in line with the safety profile of oral aripiprazole, with the exception of the injection-site reactions. While AL may require a 1-day initiation regimen, Ari 2MRTU 960 covers all the recommended doses of oral aripiprazole (10-20 mg).

Introduction: Targeted interventions are needed to delay or prevent the onset of neurodegenerative diseases. Poor dietary habits are associated with cognitive decline, highlighting the benefits of a healthy diet with fish and polyunsaturated fatty acids (PUFAs). Intake of omega-3 PUFAs docosahexaenoic acid (DHA), α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) is linked with healthy aging, cardiovascular benefits, and reduced risk of Alzheimer's disease. Although omega-3 has health benefits, its intake is often inadequate and insufficient in modern diets. Although fish oil supplements offer an alternative source, inconsistent results from clinical trials raise questions about the factors determining their success.

Areas covered: In this this review, the authors discuss the aforementioned determining factors and highlight strategies that could enhance the effectiveness of omega-3 PUFAs interventions for dementia and cognitive decline. Moreover, the authors provide suggestions for potential future research.

Expert opinion: Factors such as diet, lifestyle, and genetic predisposition can all influence the effectiveness of omega-3 supplementation. When implementing clinical trials, it is crucial to consider these factors and recognize their potential impact on the interpretation of results. It is important to study each variable independently and the interactions between them.