Expert Review of Neurotherapeutics最新文献

Introduction: In the United States, it is reported that 1.4% of the general population commits suicide. It has been postulated that antiseizure medications (ASMs) can lead to the development of suicidal ideation and suicidal behavior; however, this risk is still very low and has yet to be precisely established.

Areas covered: This narrative review evaluates the risk of suicide-related events (SREs) in subjects taking ASMs for various neurological disorders. Screening tools for suicidal ideation and suicidal behavior are also discussed. References for this article were found using PubMed/MEDLINE.

Expert opinion: Although some ASMs can be associated with SREs, this is not yet clearly established. The mechanisms involved in suicide risk in subjects taking ASMs are multifactorial. The bidirectional relationship between depression and epilepsy, as well as other associations, should be kept in mind when interpreting any impact of ASMs in PWE. Screening for SREs, close monitoring of subjects taking ASMs are the most appropriate strategies to minimize suicide risk. More efforts should be made to achieve accurate risk stratification through prognostic models that could be applied to subjects taking ASMs. Studies exploring the association between ASMs and suicide should consider ASMs individually and control for prior SREs.

Introduction: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID).

Areas covered: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER.

Expert opinion: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

Introduction: High-grade glioma (HGG) is one of the most deadly and difficult cancers to treat. Despite intense research efforts, there has not been a significant breakthrough in treatment outcomes since the early 2000's. Anti-glioma gene therapy has demonstrated promise in preclinical studies and is under investigation in numerous clinical trials.

Areas covered: This manuscript reviews the current landscape of clinical trials exploring gene therapy treatment of HGG. Using information from clinicaltrials.gov, all trials initiated within the past 5 years (2018-2023) as well as other important trials were cataloged and reviewed. This review discusses trial details, innovative methodologies, and concurrent pharmacological interventions. The review also delves into the subtypes of gene therapy used, trends over time, and future directions.

Expert opinion: Trials are in the early stages (phase I or II), and there are reports of clinical efficacy in published results. Synergistic effects utilizing immunotherapy within or alongside gene therapy are emerging as a promising avenue for future breakthroughs. Considerable heterogeneity exists across trials concerning administration route, vector selection, drug combinations, and intervention timing. Earlier intervention in newly diagnosed HGG and avoidance of corticosteroids may improve efficacy in future trials. The results from ongoing trials demonstrate promising potential for molding the future landscape of HGG care.

Introduction: The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders.

Areas covered: This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed.

Expert opinion: Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.

Introduction: There is increased focus on the negative impact of the overprescribing of medication, specifically psychotropic medication, including anti-seizure medications (ASM), in people with Intellectual Disability (ID). This is particularly important for the older adult population, where multi-morbidity and polypharmacy are more common. ASMs are associated with psychiatric and behavioral adverse effects. Furthermore, there is growing awareness of the anticholinergic burden for older adults with epilepsy and ID and the relationship with behaviors that challenge (BtC).

Areas covered: This review defines the older adult population and outlines the relationship between epilepsy and ID. BtC is outlined in the context of the population and the relationship with ASMs. The evidence base to guide prescribing and de-prescribing for newer ASMs is also presented, including pragmatic data.

Expert opinion: Polypharmacy, particularly psychotropics, are a mortality risk factor for older adults with epilepsy and ID. Therefore, any BtC requires a holistic assessment with a multi-disciplinary approach. This includes specific consideration of all prescribed medicines in the context of polypharmacy. There should be routine reviews, at least annually, for those aged 40 years and over particularly focused on anticholinergic burden and/or polypharmacy.

Introduction: Severe pediatric traumatic brain injury (spTBI), including abusive head trauma (AHT) in young children, is a major public health problem. Long-term consequences of spTBI include a large variety of physical, neurological, biological, cognitive, behavioral and social deficits and impairments.

Areas covered: The present narrative review summarizes studies and reviews published from January 2019 to February 2024 on spTBI. Significant papers published before 2019 were also included. The article gives coverage to the causes of spTBI, its epidemiology and fatality rates; disparities, inequalities, and socioeconomic factors; critical care; outcomes; and interventions.

Expert opinion: There are disparities between countries and according to socio-economic factors regarding causes, treatments and outcomes of spTBI. AHT has an overall poor outcome. Adherence to critical care guidelines is imperfect and the evidence-base of guidelines needs further investigations. Neuroimaging and biomarker predictors of outcomes is a rapidly evolving domain. Long-term cognitive, behavioral and psychosocial difficulties are the most prevalent and disabling. Their investigation should make a clear distinction between objective (clinical examination, cognitive tests, facts) and subjective measures (estimations using patient- and proxy-reported questionnaires), considering possible common source bias in reported difficulties. Family/caregiver-focused interventions, ecological approaches, and use of technology in delivery of interventions are recommended to improve long-term difficulties after spTBI.

Introduction: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive head trauma. Historically, the diagnosis has been primarily clinical, which has hindered definitive early diagnosis and proactive intervention.

Areas covered: The authors analyze the recent advancements in early diagnosis of CTE by examining biomarkers, imaging, and clinical decision tools. They discuss the identification of neuropathologies - such as tau aggregates - through novel techniques ranging from blood sampling and to brain density scanning. The reader will walk away with a better understanding of current advancements in early detection and be better equipped to deal with encephalopathies secondary to trauma in clinical practice.

Expert opinion: Tremendous progress has been made in understanding the pathophysiology of CTE. Despite these advancements, CTE treatment is still primarily symptomatic rather than underlying disease. Future research should focus on integrating current understanding of CTE pathophysiology with treatment modalities.

Introduction: Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is a clinical entity distinct from multiple sclerosis and aquaporin-4 (AQP4+)-IgG-positive neuromyelitis optica spectrum disorder. There is a lack of evidence regarding the efficacy and safety of current treatments used for MOGAD.

Areas covered: In this article, the authors review the currently available literature on the pharmacological management of MOGAD. This article is based on an extensive search for articles including meta-analyses, clinical trials, systematic reviews, observational studies, case series and case reports.

Expert opinion: Intravenous high-dose methylprednisolone is the most common therapy for acute attack with patients having a good treatment response. In cases with poor recovery, intravenous immunoglobulins (IVIG) or plasma-exchange proved to be effective. Maintenance therapies include mycophenolate mofetil, azathioprine, IVIG, oral corticosteroids, rituximab, and interleukin-6 receptor (IL6-R) antagonists. Rituximab is the most used drug while IL6-R antagonists emerged as an effective option for people not responding to current treatments. Larger prospective studies with longer follow-ups are needed to confirm whether the blockage of the IL6-R is an effective and safe option. Since there is no evidence of major safety issues related to the new available therapies, the authors believe that waiting for disease activity to consider a possible treatment change, is an unwise approach.