AIM:The following clinical trial protocol aims to investigate the additional effects of bilateral transcranial direct current stimulation (tDCS) combined with constraint-induced movement therapy (CIMT) compared to CIMT alone in children and adolescents with spastic hemiparetic cerebral palsy. METHODS:This randomized, triple-blind, controlled trial will enroll 32 participants aged 7-16 years with spastic hemiparetic cerebral palsy (MACS I-II). Participants will be allocated to CIMT with sham or active bilateral tDCS (C3-C4, 1 mA, 20 min), with electrode placement guided by transcranial magnetic stimulation mapping. The intervention will last 3 weeks (5 days/week, 3 h/day). Primary outcomes will assess upper limb use (PMAL/TMAL). Secondary outcomes include dexterity (Box and Block Test), strength (dynamometry), functional performance (PAFT), and participation (COPM, GAS). Assessments will occur post-intervention and at 1, 3, and 6 months. Implementation of outcomes and cost-effectiveness will also be evaluated. Once completed, the study team will perform intention-to-treat analyses using linear mixed-effects models. EXPECTED RESULTS:The HAND-IN trial will provide evidence on the clinical, implementation, and economic effects of combining CIMT with bilateral tDCS in children with spastic hemiparetic cerebral palsy. If effective, this approach may enhance the durability of upper limb functional gains and support the adoption of neuromodulation in pediatric neurorehabilitation.Trial Registration Number (Brazilian Clinical Trials Record- REBEC): RBR-2fczbt2 (https://ensaiosclinicos.gov.br/rg/RBR-2fczbt2). Registration on January 15, 2026.
INTRODUCTION:Pediatric-onset multiple sclerosis (POMS) is uncommon but clinically relevant, as inflammatory demyelination occurs during brain maturation. Compared with adult-onset MS, POMS is characterized by higher early relapse rate and MRI inflammatory activity, better recovery from individual relapses, yet disability milestones are reached at a younger age. Early identification is essential to avoid treatment delays, while preventing misdiagnosis of mimics. AREAS COVERED:This review summarizes the diagnostic work-up of children with a first acquired demyelinating syndrome, differential diagnosis, the role of MRI, cerebrospinal fluid (CSF) markers, antibody testing, serum neurofilament light chain, optical pathway assessment and the 2024 McDonald criteria. Early prognostic factors and therapeutic implications are discussed, including evidence supporting early high-efficacy therapies in selected children. References for this review were identified through searches of PubMed, authors' own files, abstracts presented at main congresses, from 1 January 1979 to 1 July 2026. EXPERT OPINION:Early identification of POMS requires integrated assessment of clinical presentation, MRI lesion topography, CSF findings, antibody testing, and emerging biomarkers. Although central vein sign, paramagnetic rim lesions, kappa free light chains and serum neurofilament light chain may refine stratification, pediatric validation remains incomplete. Earlier, more accurate diagnosis should support individualized treatment to preserve long-term outcomes.
INTRODUCTION:Late-onset bipolar disorder (LOBD) represents a clinically relevant but understudied subtype of bipolar. Compared with early-onset bipolar disorder, LOBD may present with distinct clinical features, increased somatic comorbidity, and potential associations with neurodegenerative and vascular processes. Specific diagnostic and therapeutic recommendations for LOBD are currently limited. AREAS COVERED:This narrative review examines the current evidence regarding epidemiology, pathophysiology, diagnostic workup, and management of LOBD. Literature was identified using PubMed to conduct a structured literature search of the MEDLINE database for articles between 2015 and 2025, and review of relevant articles. Particular attention is given to differential diagnosis with secondary mania and neurodegenerative disorders, the role of medical and neurological evaluation, and treatment considerations including pharmacological strategies, neuromodulation, psychosocial interventions, and longitudinal follow-up. EXPERT OPINION:Current evidence suggests that LOBD likely represents a heterogeneous condition with multiple underlying mechanisms, including vascular burden, neurodegenerative processes, and age-related biological vulnerability. Comprehensive somatic and cognitive assessment is essential. While treatment generally follows established bipolar disorder guidelines, careful adaptation is required due to comorbidity, polypharmacy, and age-related pharmacodynamic changes. Lithium, with its potential neuroprotective properties, may be the first-choice medication. Future research should focus on clarifying pathophysiological mechanisms and developing tailored management strategies.
INTRODUCTION:Major depressive disorder is a leading cause of disability, with a significant rate of patients responding inadequately to antidepressants, and residual symptoms, including insomnia, worsening overall outcomes. Current adjunctive options display partial efficacy and tolerability, motivating the search for different strategies. Beyond regulating the sleep-wake cycle, orexin systems are implicated in reward and cognition, and have emerged as new targets for depressive disorders. AREAS COVERED:This Drug Profile summarizes the published peer-reviewed evidence on seltorexant (JNJ-42847922; MIN-202), a selective orexin-2 receptor antagonist, for adjunctive treatment of MDD, covering its pharmacological, preclinical, and clinical profile, efficacy, safety and tolerability, head-to-head comparisons with current adjunctive treatments, regulatory status, and competitive landscape. Relevant literature was identified through structured searches of PubMed/MEDLINE and ClinicalTrials.gov (from database inception to April 2026), complemented by Google Scholar employed solely to identify conference proceedings, using combinations of terms related to seltorexant and depression. EXPERT OPINION:Seltorexant 20 mg has shown a promising antidepressant effect, particularly in patients with clinically significant insomnia, and a favorable tolerability profile. The mixed phase-3 results, the modest effect sizes, and gaps on core symptoms of depression, including anhedonia and suicidality, and on long-term safety warrant a measured positive view, pending confirmatory data.
INTRODUCTION:Chronic migraine (CM) refractory to conventional pharmacotherapy (r-CM) remains a debilitating neurological condition with limited therapeutic options. High-frequency spinal cord stimulation at 10 kilohertz (HF-SCS) has recently emerged as a distinct neuromodulatory paradigm for this patient population. Unlike traditional spinal cord stimulation, HF-SCS operates above the frequency range that generates paresthesia, thereby eliminating stimulation-induced sensation while potentially engaging unique analgesic mechanisms. AREAS COVERED:This focused narrative review synthesizes the available clinical evidence, technical considerations, and mechanistic hypotheses specifically pertaining to cervical HF-SCS for refractory chronic migraine (r-CM). The authors further provide their expert perspectives on the future of this technology as a treatment option for refractory chronic migraine. EXPERT OPINION:Current data from prospective open-label studies and retrospective case series suggest that cervical HF-SCS may reduce monthly migraine days, facilitate conversion from chronic to episodic migraine patterns in some implanted patients, and may improve headache-related disability and quality of life over at least 52 weeks of follow-up. The paresthesia-free nature of HF-SCS confers a distinct advantage for both patient tolerability and future trial design, as it permits sham-controlled methodologies that have historically been impossible with conventional neurostimulation. However, these findings remain preliminary and should be considered hypothesis-generating pending confirmation in adequately powered randomized sham-controlled trials.
INTRODUCTION:Psychosis is increasingly understood as a disorder of brain systems that are also central to sleep regulation. Indeed, sleep disturbances are both highly prevalent in psychotic disorders and are likely to contribute to the emergence and maintenance of psychotic experiences. AREAS COVERED:This narrative review, based on a comprehensive search of MEDLINE/PubMed, Embase, PsycINFO, and Web of Science (March 2026), examines the bidirectional relationship between sleep dysfunction and psychosis, the shared biological mechanisms underlying both, the utility of sleep assessment as an early warning marker for relapse, and the current gaps in sleep-targeted intervention evidence. EXPERT OPINION:Sleep dysfunction constitutes a transdiagnostic pathway to psychosis, with varying temporal profiles across diagnoses: organic and substance-induced psychoses emerge acutely over hours to days with rapid reversibility; mood- and trauma-related psychoses develop subacutely over days to weeks; schizophrenia spectrum disorders show insidious onset over years with chronic persistence. Across these presentations, disturbances in sleep continuity, architecture, and circadian regulation may act as mechanistic drivers rather than epiphenomena, interacting with disorder-specific vulnerabilities to shape the timing, severity, and course of psychosis. Translating this understanding into practice requires routine sleep-circadian assessment from the earliest clinical stages, integration of scalable interventions into transdiagnostic care pathways, and recognition of sleep as both a clinically relevant outcome and a stratification variable in future psychosis trials. This framework positions sleep-circadian dysfunction not only as a marker of risk and progression, but also as a promising modifiable target for prevention, early intervention, and relapse reduction across psychotic disorders.
INTRODUCTION:Cluster headache is an extremely painful and severely disabling primary headache disorder that, despite its profound impact on quality of life, remains underdiagnosed and undertreated. Effective management requires a structured approach across the cluster cycle, but practical, timeline-based guidance integrating established and emerging therapies is lacking. AREAS COVERED:The authors present a treatment framework organized by clinical timeline: inter-cycle period, cycle onset, active cycle, and resolution, addressing acute abortive, bridge, and prophylactic therapies with evidence quality, dosing, and monitoring. Both established synthetic agents and recently recognized biologic therapies are examined, with particular focus on anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and forward-looking targets such as PACAP and 5-HT2A. References were identified through searches of PubMed and clinical trial registries from inception to June 2026. EXPERT OPINION:Anti-CGRP monoclonal antibodies are a meaningful advance, best positioned as an adjunct to established prophylaxis rather than a replacement. PACAP-targeted therapy is a promising direction whose role in cluster headache remains to be defined. The serotonergic agent psilocybin warrants closer attention, as its early therapeutic signal merits rigorous investigation despite the legal and historical barriers constraining its study.
INTRODUCTION:Chronic cluster headache (CCH) is a very severe and disabling primary headache disorder characterized by frequent, unilateral attacks of excruciating pain accompanied by cranial autonomic symptoms without a substantial remission phase. A proportion of patients experience inadequate symptom control or intolerance to conventional therapies, highlighting the need for alternative treatment strategies. AREAS COVERED:This narrative review highlights the anatomical and physiological rationale for sphenopalatine ganglion (SPG) stimulation and summarizes the available clinical evidence regarding its efficacy in acute and preventive treatment of CCH. Furthermore, this review also evaluates SPG's safety profile. This article is based on the currently available literature including data from randomized controlled trials, long-term follow-up studies, and real-world observational reports. EXPERT OPINION:For patients with inadequate response or intolerance to traditional oral preventive options, neuromodulation is a practical alternative. There is both cohort and randomized controlled evidence establishing SPG stimulation efficacy in both acute and potentially preventive treatment of refractory cluster headache, although there is associated surgical risk with serious adverse events reported. SPG stimulation represents a promising option for carefully selected patients with refractory CCH, as an acute treatment, with a potential role in cluster headache prevention. Further controlled studies are needed to more clearly define optimal patient selection, long-term outcomes, and comparative effectiveness.
INTRODUCTION:Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established therapy for medically refractory childhood dystonia. Achieving optimal outcomes requires repeated programming by experienced multidisciplinary teams in specialized centers. Geographic distance, travel burden, and access to expertise pose major barriers to families long-term care. AREAS COVERED:This review summarizes literature and clinical experience on remote DBS programming for pediatric dystonia through March 2026 identified using targeted searches of PubMed and Embase. Telemedicine-enabled platforms allow clinicians to adjust stimulation parameters through secure interfaces while conducting real-time video assessments. Feasibility studies and early clinical applications indicate that remote programming is technically achievable, safe, and capable of delivering meaningful therapeutic adjustments without in-person visits. For children, who often require early programming, remote care can reduce travel, minimize disruption to school and family life, and facilitate therapy optimization. Challenges remain, including regulatory requirements, infrastructure needs, and development of standardized pediatric protocols. EXPERT OPINION:Remote DBS programming is a promising strategy to expand access to specialized care for children with dystonia. As telemedicine technologies, digital motor assessments, and neuromodulation platforms advance, remote programming has potential to become an integral component of long-term pediatric DBS management, improving outcomes and easing families' burden.
INTRODUCTION:Down syndrome (DS) confers a high risk of Alzheimer's disease (AD) and is a genetically determined form of AD. As such, DS provides a uniquely informative biological context in which to investigate AD initiation and progression. Defining the molecular mechanisms that link trisomy 21 to neurodegeneration has broad implications for AD biology and neurotherapeutic development. AREAS COVERED:This review summarizes findings from brain, cerebrospinal fluid, and blood-based proteomic studies, integrated with transcriptomic and multiomics analyses, to characterize molecular pathways underlying AD in DS. The literature was identified through iterative PubMed/MEDLINE searches and manual review of reference lists, considering studies available through June 2026 with no limitation to publication dates. EXPERT OPINION:Brain, lesion-specific, cerebrospinal fluid, and blood-based proteomics, interpreted alongside transcriptomic and complementary omics data, position DSAD as a network-level disorder in which amyloid and tau pathology interact with immune, vascular, metabolic, synaptic, and proteostasis pathways. This integrated proteomic framework helps define shared and subtype-specific mechanisms across DSAD, sporadic AD, and autosomal dominant AD, while supporting biological staging, patient stratification, and therapeutic target discovery.
INTRODUCTION:The most common cell type in the central nervous system (CNS), astrocytes, is also the cell type most commonly associated with the brain cancer called astrocytoma. Advances in genetic/molecular techniques led to the 2021 CNS tumor reclassifications. In this review, we will simplify the somewhat complex 2021 neuropathological diagnostic algorithm and transition into a discussion on uncommon treatment options and the biochemical basis for their applications. AREAS COVERED:Herein, the authors review the most common new CNS tumor classifications based on histological and genetic alterations. Treatment and prognosis of these tumors change as the diagnostic capabilities improve. The literature utilized to complete this manuscript was collected through www.pubmed.gov, from the years 1924-2026. The search focused on astrocytomas, neuropathology criteria, molecular/genetics of, and treatment options. EXPERT OPINION:Neuropathology is crucial for providing guidance to the neurosurgeons operating, oncologists and radiation oncologists treating, and most importantly the patients and families that go through these treatments. Neuropathology ultimately provides the most important first step in determining the treatment flow chart, thus the proper identification/diagnosis with a detailed genetic profile of the tumor enhances insight on the treatment and prognostic expectations. Our ability to better understand the genetic/molecular alterations occurring in CNS tumors leads us to better treatments and hopefully eventual cures.
INTRODUCTION:Medication-overuse headache (MOH) affects 1-2% of the population and imposes substantial burden. Corticosteroids are often used as bridge therapy during withdrawal, although their effectiveness remains uncertain. This study aims to evaluate the effectiveness of corticosteroids as a withdrawal strategy in MOH. METHODS:A systematic review with meta-analysis was conducted in accordance with PRISMA guidelines. The protocol was registered in PROSPERO (ID: 1161824). Searches were performed in PubMed, MEDLINE, EMBASE, the Cochrane Library, Web of Science, SciELO, and LILACS through June 2025. Randomized, placebo-controlled trials assessing corticosteroids during withdrawal therapy in adults with MOH were included. Random-effects meta-analyses were performed when feasible using RevMan 7.2.0. RESULTS:Of 4,483 records identified, four trials comprising 250 participants met eligibility criteria. Two studies presented high risk of bias, two raised some concerns. Considerable heterogeneity in design, dosing regimens, follow-up duration, and outcome definitions limited comparability and precluded a unified pooled analysis. Across studies, results consistently failed to show benefit. Meta-analytic findings demonstrated no advantage of corticosteroids over placebo regarding early withdrawal headache, withdrawal symptoms or reversal of medication overuse. CONCLUSION:The available evidence does not support corticosteroids as effective withdrawal therapy for MOH.
INTRODUCTION:Neuropathic pain is considered the most difficult to manage, with many patients getting inadequate relief from the current pharmacotherapy. While many drugs have been added to the regimen, Lacosamide has emerged as a promising therapeutic option. This systematic review focuses on the efficacy and safety of lacosamide in adult patients with neuropathic pain. METHODS:Databases such as PubMed, Embase, Scopus, Web of Science, and Cochrane were searched thoroughly for Randomized Controlled Trials (RCTs) published in English through November 2025. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in the included studies. RESULTS:Eight RCTs involving 976 participants with different neuropathic pain conditions met the inclusion criteria. Across the included studies, Lacosamide (200-600 mg/day) provided a modest reduction in their pain scores. However, it didn't have much of a positive impact on quality of life, limited function, adverse effects were common, and a high dropout rate was observed in several trials. CONCLUSION:Lacosamide might provide a modest analgesic benefit across multiple neuropathic conditions. But its extensive, long-term use requires more research to confirm its benefits, particularly the optimum dosing protocols.
INTRODUCTION:Migraine is a highly prevalent and disabling neurological disorder whose diagnosis remains clinical. However, overlap with secondary headache disorders represents a major diagnostic challenge, particularly in patients with atypical features or changes in headache pattern, making neuroimaging crucial in selected cases. AREAS COVERED:This review provides an updated overview of the differential diagnosis of migraine in adults, focusing on the role of clinical assessment, red flags, and neuroimaging in identifying secondary causes. A comprehensive, narrative review of the literature was conducted, integrating current guidelines and recent evidence on imaging indications and modalities. We discuss key conditions that may mimic migraine, including vascular, neoplastic, infectious, cerebrospinal fluid pressure-related, and cervicogenic disorders, highlighting their clinical and radiological features. Attention is given to the concept of pretest probability to guide imaging decisions and to the limitations of red flags in clinical practice. EXPERT OPINION:Neuroimaging should not be routinely performed in patients with typical migraine and normal neurological examination but rather tailored to the individual clinical context. An integrated approach combining clinical judgment, awareness of red flags, and targeted imaging is essential to avoid both underdiagnosis of secondary headaches and overuse of unnecessary investigations.
INTRODUCTION:Although the efficacy of fremanezumab in treating migraine has been proven in randomized controlled trials, its effectiveness is not well understood. Consequently, this study purpose was to synthesize and estimate its real-world effectiveness and safety in patients with migraine. METHODS:A systematic search of PubMed, Scopus and Web of Science was conducted from inception to November2025. Real-world studies evaluating fremanezumab effectiveness, measured by monthly migraine days (MMDs), monthly headache days (MHDs), Headache Impact Test (HIT-6) and related outcomes, including safety, were included. Random-effects meta-analyses were performed. RESULTS:One month after treatment initiation, fremanezumab reduced MMD by -5.82 days (95% CI: -6.67, -4.97), MHD by -7.30 days (95% CI: -9.72, -4.87) and HIT-6 scores by -6.84 points (95% CI: -10.30, -3.39). Approximately 50% of patients achieved a ≥ 50% reduction in MMD or MHD within 3 months, with response rates increasing progressively up to 12 months. Adverse event rates were 0.05 (95% CI: 0.02, 0.09) in 6 months and 0.07 (95% CI: 0.03, 0.12) in 12 months, with constipation being the most frequently reported event. CONCLUSION:Fremanezumab is associated with clinically significant reductions in migraine frequency, disability and acute medication used in real-world settings, with a favorable safety profile. PROSPERO:CRD42021266322.
INTRODUCTION:Although effective acute migraine therapies are available, unmet treatment needs such as nausea, vomiting, or delayed gastric emptying remain. STS101 is a novel dihydroergotamine (DHE) nasal powder designed to treat acute migraine with a simple single. AREAS COVERED:A targeted PubMed and ClinicalTrials.gov search was performed from database inception through October 2025 using the keywords "STS101," "dihydroergotamine," "migraine," and "intranasal powder." Eligible sources included English-language clinical studies, trial registry records, regulatory documents, and relevant conference abstracts addressing STS101 formulation, pharmacokinetics, efficacy, safety, and/or regulatory development. Data from Phase 1 pharmacokinetic trials, the Phase 3 EMERGE and SUMMIT randomized controlled trials, and the ASCEND long-term safety study are discussed. EXPERT OPINION:The pivotal efficacy trials did not meet their 2-hour co-primary endpoints. Later time-point analyses suggested possible clinical benefit, including higher rates of pain freedom and most bothersome symptom freedom from 3 to 48 hours. STS101 may be useful for some patients who prefer a non-oral intranasal rescue option or have had inadequate responses to triptans, gepants or other DHE forms of administration. Its clinical role will likely depend on how clinicians weigh its delivery platform, DHE pharmacology, tolerability, and place relative to other available intranasal options.
