Expert Review of Neurotherapeutics最新文献

Introduction: Many children are affected by social anxiety disorder (SAD). Pharmacotherapy, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may be indicated, but a clear understanding of the risks and benefits associated with these pharmacological treatments is needed.

Areas covered: This expert review explores the risks and benefits of pharmacotherapy for treating SAD in children.

Expert opinion: Pharmacotherapy may be considered as a treatment when symptoms are complex or severe or when effective psychotherapy, such as cognitive behavioral therapy (CBT), is not accessible. We recommend that clinicians collaborate closely with parents, pediatricians, and psychiatrists in the treatment planning process, while monitoring the effects of pharmacotherapy. Future research should prioritize the personalization of treatments.

Introduction: Frontotemporal dementia (FTD) encompasses a group of heterogeneous neurodegenerative disorders. Aside from genetic cases, its diagnosis is challenging, particularly in the early stages when symptoms are ambiguous, and structural neuroimaging does not reveal characteristic patterns.

Areas covered: The authors performed a comprehensive literature search through MEDLINE, Scopus, and Web of Science databases to gather evidence to aid the diagnostic process for suspected FTD patients, particularly in early phases, even in sporadic cases, ranging from established to promising tools. Blood-based biomarkers might help identify very early neuropathological stages and guide further evaluations. Subsequently, neurophysiological measures reflecting functional changes in cortical excitatory/inhibitory circuits, along with functional neuroimaging assessing brain network, connectivity, metabolism, and perfusion alterations, could detect specific changes associated to FTD even decades before symptom onset. As the neuropathological process advances, cognitive-behavioral profiles and atrophy patterns emerge, distinguishing specific FTD subtypes.

Expert opinion: Emerging disease-modifying therapies require early patient enrollment. Therefore, a diagnostic paradigm shift is needed - from relying on typical cognitive and neuroimaging profiles of advanced cases to widely applicable biomarkers, primarily fluid biomarkers, and, subsequently, neurophysiological and functional neuroimaging biomarkers where appropriate. Additionally, exploring subjective complaints and behavioral changes detected by home-based technologies might be crucial for early diagnosis.

Introduction: Dysregulated mechanistic target of rapamycin (mTOR) activity is implicated in seizure development in epilepsies caused by variants in mTOR pathway genes. Sirolimus and everolimus, allosteric mTOR inhibitors, are widely used in transplant medicine and oncology. Everolimus is approved for treating seizures in tuberous sclerosis complex (TSC), the prototype mTORopathy. Emerging evidence suggests that mTOR inhibitors could also be effective in other mTORopathies, such as DEPDC5-related epilepsy and focal cortical dysplasia type 2 (FCD2).

Areas covered: This narrative review summarizes key regulatory proteins in the mTOR cascade and outlines epilepsy syndromes linked to variants in genes encoding these proteins, particularly TSC, GATOR1-related epilepsies, and FCD2. It discusses the clinical pharmacology of mTOR inhibitors and the evidence supporting their efficacy as antiseizure medications (ASM) in mTORopathies. Lastly, potential benefits of next-generation mTOR inhibitors for CNS indications are evaluated.

Expert opinion: The therapeutic benefits of mTOR inhibitors in TSC are well-established, but their value in other mTORopathies remains uncertain. Despite targeting the underlying disease biology, their efficacy in TSC is not significantly different from other ASM, likely due in part to pharmacokinetic constraints. Next-generation mTOR inhibitors that address these limitations may offer improved response rates, but they are in the preclinical development phase.

Introduction: When a first anti-CGRP monoclonal antibody (anti-CGRP mAb) fails, switching to a different anti-CGRP mAb is an option often considered, despite the fact that this approach is not yet systemically studied.

Methods: We present the findings of a systematic review conducted according to the PRISMA recommendations on published studies - of any design - investigating the clinical outcomes after switching for any reason to different anti-CGRP mAbs.

Results: The literature search retrieved 76 records, while 19 papers were eventually reviewed. Most studies were retrospective and/or had a small sample size. A significant proportion of participants experienced an improved treatment response after switching between different anti-CGRP mAbs. Specifically, according to prospective studies' results, the median MMDs were reduced by 12.8 days after 6 months of switching, while up to 48% of episodic and 36% of the chronic migraine patients achieved a >50% response rate.

Conclusions: Switching between different anti-CGRP mAbs may be beneficial, at least for some patients, and should be considered when therapy with a first anti-CGRP mAb fails for any reason. Larger prospective studies, employing standardized protocols for switching or comparative effectiveness trials between mAbs, are anticipated to elucidate this issue further.

Introduction: Zonisamide (ZNS), is an antiseizure medication (ASM) approved by the US FDA and the European Medicines Agency (EMA) for focal-onset seizures. An oral suspension formulation has recently been introduced to improve administration for specific patient populations, particularly those with swallowing difficulties.

Areas covered: This article explores the new ZNS oral suspension, evaluating its pharmacokinetic benefits, impact on patient care, and adherence. Bioavailability studies confirm that the oral suspension is bioequivalent to ZNS capsules, though no additional clinical trials in epilepsy patients have been conducted. This review presents and discusses the oral suspension's benefits, such as ease of administration for those with swallowing difficulties and flexible dosing, while also addressing potential drawbacks, including dosing accuracy and stability issues.

Expert opinion: The ZNS oral suspension allows additional flexibility for epilepsy management, particularly for patients unable to swallow capsules. Its bioavailability and specific formulation may improve adherence and seizure control.

Introduction: Duchenne muscular dystrophy (DMD) is a rare X-linked genetic disorder caused by mutations in the dystrophin gene, leading to an almost complete absence of dystrophin, which is essential for muscle cell structure and function. This resulting muscle deterioration and fibrosis, eventually causes respiratory failure and cardiomyopathy. While there is currently no cure, existing therapies aim to prolong survival and alleviate symptoms.

Areas covered: This paper reviews current and emerging therapies for DMD, focusing on their safety and efficacy. Although corticosteroids remain the standard treatment, newly approved drugs such as exon-skipping therapies, vamorolone, delandistrogene moxeparvovec, and givinostat provide new treatment options. Additionally, future therapies, including gene therapy, stem cell treatments, and anti-fibrotic agents, show promise for clinical application.

Expert opinion: Advancements in DMD treatments have expanded patient options. While gene therapy offers potential for correcting the genetic defect and alleviating symptoms, corticosteroids remain the most cost-effective and well-researched treatment. This is partly due to the lack of compelling long-term safety and efficacy data for gene therapies. The accelerated FDA review process has enabled faster approval of new medications; however many have provided minimal clinical benefit to patients. Despite these challenges, continued drug development and innovative research offer hope to patients.

Introduction: Topiramate is a drug belonging to the second generation of antiseizure arsenal, used to treat focal onset seizures without generalization, focal-to-bilateral tonic-clonic seizures, and primary generalized tonic-clonic seizures.

Areas covered: The narrative evaluation of topiramate's clinical research that has been published in this article focuses on the medication's effectiveness and safety when used to treat primary generalized and focal-to-bilateral tonic-clonic seizures. From their founding to the present, the databases MEDLINE, SCOPUS, EBSCO, and GOOGLE SCHOLAR were searched.

Expert opinion: Topiramate treatment has the obvious benefit of being effective in treating tonic-clonic seizures; nevertheless, it may have a drawback in that up to 56% of patients discontinue therapy due to its rather poor tolerability, particularly at doses exceeding 600 mg daily. Patients are most bothered by psychiatric and cognitive side effects, and then by appetite and weight decrease. While the onset of anorexia cannot be prevented by changing the dosage regimen, psychiatric and cognitive side effects can be mitigated by slowly titrating the topiramate dose.

Introduction: Cognitive reserve (CR) is a crucial factor in explaining individual differences in the risk of Alzheimer's disease (AD) and cognitive decline. CR refers to the brain's ability to cope with pathology through compensatory mechanisms. This review examines the various methods used to measure, predict, and influence CR.

Areas covered: Based on a search of PubMed, PubMed Central, EMBASE, Scopus, and the Cochrane Library (up to 1 June 2024), this review addresses key CR proxies, highlighting their strengths and limitations. The review also explores established and emerging interventions. We critically evaluate the statistical methods used to measure CR and assess its practical application.

Expert opinion: CR plays a crucial role in delaying the onset and progression of AD. Lifestyle choices and experiences build CR and impact cognitive aging. However, practical challenges remain in applying CR in clinical settings, particularly in individuals with advanced cognitive decline. Education, while commonly used as a proxy for CR, may not fully capture its complexity. Alternatives like occupational complexity could offer more practical measures, but their application is still evolving. Addressing these limitations is key to advancing dementia prevention strategies.

Introduction: In Parkinson's disease (PD), sleep-wake problems are disease-related symptoms that occur throughout the day and have a negative impact on patients' quality of life to an extent that is equal to or greater than that of typical motor symptoms.

Areas covered: Insomnia due to fragmented sleep and excessive daytime sleepiness (EDS) worsen as PD progresses. Nighttime wearing-off and early morning-off should be considered first when fragmented sleep is reported in PD patients. If the main complaint of patients with insomnia is difficulty falling asleep, restless legs syndrome should be differentiated first. Obstructive sleep apnea causes sleep quality deterioration and fragmented sleep. For rapid eye movement sleep behavior disorder (RBD), preventative measures against sleep-related trauma are necessary. RBD has also attracted attention as a PD precursor state and as a disease progression marker that is associated with specific PD clinical subtypes. In PD patients, the sleep-wake phase may advance/delay or become irregular due to circadian dysfunction.

Expert opinion: Importantly, sleep-wake problems are core symptoms related to the pathogenesis and progression of PD, and addressing a wide range of these symptoms will improve patients' quality of life.

Introduction: We present a literature review on the clinical conundrums surrounding the differential diagnosis of restless legs syndrome (RLS, Willis-Ekbom disease), as well as conditions that can mimic RLS. An extensive literature search showed that secondary causes of RLS ranged from commonly recognized causes, such as iron deficiency anemia, to less widely noted causes, such as rheumatoid disorders and hypothyroidism. There is a controversial association with Parkinson's disease, essential tremor, and RLS, whereby RLS is proposed as a prodromal feature.

Areas covered: The clinical presentation of restless legs syndrome (RLS), a highly prevalent movement disorder usually during sleep with a circadian variation. The review highlights differences between commonly established secondary causes of RLS, RLS mimics, genetic and drug-induced RLS. A flowchart presents some key features of different and overlapping secondary RLS and mimics and genetic RLS.

Expert opinion: RLS is one of the commonest movement disorders and the International Restless Legs Syndrome Study Group has suggested five-point criteria for robust diagnosis of RLS. However, even in expert hands, diagnosis is accurate in about 85% and misdiagnosis, especially with 'RLS mimics,' appears to be high. There are wide variations in the way RLS can present, and this includes different types of secondary RLS as well as drug induced or genetic patterns of RLS. Secondary RLS is highly complex and can be associated with Parkinson's disease as well as prodromal stage of Parkinson and essential tremor. Other known causes of secondary RLS are many and include end-stage kidney disease as well as metabolic disorders to painful conditions such as rheumatic disorders and fibromyalgia and polyradiculopathy.