Despite traditional workups, accurate diagnosis of patients who are classified under cryptogenic stroke with underrecognized etiologies is very challenging. Accurate diagnosis is important for timely and optimized treatment modalities, disease progression monitoring, and proper treatment assessment. This review highlights the limitations regarding the diagnosis of ischemic stroke with underrecognized etiologies and discusses the novel technologies that can shape the future diagnosis with personalized medicine approach. The current article is based on English language research articles selected from PubMed, EMBASE, Scopus, Web of Science search using the following search terms: embolic stroke of undetermined source, cryptogenic stroke, atrial cardiopathy, PFO closure, cancer-associated stroke, wearable devices, multiomics, stroke and artificial intelligence. Soon, extended diagnostic workups, multiomics, wearable and implantable technologies, and novel imaging techniques will become more common in routine diagnosis of ischemic stroke. The integration of novel technologies supported by artificial intelligence will transform stroke management with rapid and precise diagnosis and individualized treatment strategies. This will put future diagnosis in the hands of patients and the gradual integration of the novel technologies may provide real-time, patient-specific stroke management options.

ABSTRACT Introduction Restless Legs Syndrome (RLS) is a sensorimotor disorder linked to brain iron deficiency and dopaminergic dysfunction. Increasing evidence suggests that alterations in adenosine signaling may represent the missing link connecting dopaminergic and glutamatergic abnormalities. The ‘adenosine hypothesis’ proposes that brain iron deficiency induces a hypoadenosinergic state, primarily through adenosine A1 receptor downregulation, resulting in cortical hyperexcitability, hyperarousal, and periodic limb movements. Areas covered This critical perspective examines experimental, neurophysiological, and clinicaldata supporting the adenosine hypothesis of RLS. Findings from animal models demonstrate altered A1/A2A receptor balance in cortico-striatal terminals, promoting glutamatergic hyperactivity. In particular, neurophysiological studies further support the adenosine hypothesis, highlighting a pattern of cortical hyperexcitability and impaired inhibitory control in RLS. In this context, preliminary clinical trials with dipyridamole, an equilibrative nucleoside transporter inhibitor that enhances extracellular adenosine, showed symptomatic improvement, supporting adenosinergic enhancement as a therapeutic approach. Expert opinion The adenosine hypothesis provides an integrative framework uniting dopaminergic, glutamatergic, and iron-related mechanisms in RLS. Targeting adenosine transmission could complement existing therapies and mitigate augmentation. Future research should prioritize receptor-selective ligands, multimodal biomarkers, and controlled trials to translate this hypothesis into mechanism-based neurotherapeutic strategies.

ABSTRACT Introduction Parkinson’s disease (PD) exhibits distinct phenotypes with specific pathophysiological features. Their definition is essential to inform therapeutic choices and trials design. Areas covered We searched in September 2025 PubMed/MEDLINE, Scopus, and Web of Science to review current PD stratifications strategies based on clinical, tissue and imaging biomarkers, highlighting their specific strengths and limitations. We provide an overview on the proposed pathophysiological mechanisms underlying distinct phenotypes and the open challenges in the field. Expert opinion Subtyping of PD based on clinical phenotype is rapidly evolving, driven by advances in understanding its pathological mechanisms and clinical heterogeneity. Identifying distinct PD phenotypes is essential to deliver personalized care and optimize clinical trial design, particularly for disease-modifying therapies. Neurotransmitter-based subtyping (cholinergic/noradrenergic/serotonergic) provides a biologically grounded framework that partially overlaps with anatomical models such as the brain-first/body-first distinction. However, validity of such models is also controversial, especially in more advanced stages of PD where many pathways merge. Integrating multimodal data, including clinical/imaging/biomarker/genetic measures, is crucial to improve stratification accuracy and account for comorbidities/copathology. Future progress relies on hypothesis-supervised data-driven approaches, longitudinal validation, and globally inclusive cohorts to achieve robust, biologically informed, and clinically meaningful PD subtyping.

ABSTRACT Introduction The ketogenic diet as a potential treatment for Alzheimer’s disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis. Areas covered In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search. Expert opinion More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.

ABSTRACT Introduction Migraine is among the most disabling neurological disorders worldwide and preventive treatment remains a cornerstone for reducing disease burden. Recent advances in mechanism-based therapies have positioned calcitonin gene-related peptide (CGRP) and its main receptor as central targets for migraine prophylaxis. Areas covered This updated narrative overview summarizes the pharmacological profile, clinical efficacy, safety and regulatory status of rimegepant, integrating evidence published through 2025 and highlighting emerging real-world and clinical trends. Relevant literature was identified through searches in PubMed/MEDLINE and Scopus (last search: 19 November 2025) using predefined combinations of terms related to rimegepant and migraine. The review also examines emerging concepts such as situational prevention, potential combination approaches with traditional or novel preventives and exploratory use in other CGRP-mediated headache disorders. Expert opinion Rimegepant represents a significant addition to migraine prophylaxis by offering a flexible and well-tolerated option that bridges acute and preventive care. Its role may expand through rational combinations and investigation in other headache disorders. Persistence and long-term safety require careful monitoring, and reimbursement frameworks will determine its future clinical adoption.

ABSTRACT Introduction Multiple system atrophy is a sporadic α-synucleinopathy, characterized by parkinsonism, cerebellar and pyramidal signs combined in different ways, in association with autonomic failure. In absence of disease-modifying therapies, management is directed toward symptomatic treatment and maintenance of function. Areas covered This review critically appraises current evidence, highlights novel therapeutic strategies, and provides guidance for clinical practice and future research directions. A literature search without date restrictions was conducted using PubMed to identify published studies relevant to this review. Motor symptom interventions are primarily levodopa-based, yielding partial and transient responses, especially in MSA-P, whereas dopaminergic agonists, MAO-B inhibitors, amantadine, and device-aided therapies provide a limited or short-lived benefit. Physiotherapy, occupational therapy, and multidisciplinary rehabilitation are integral to motor symptoms management. Non-motor symptoms management target autonomic failure (neurogenic orthostatic hypotension, urinary/sexual dysfunction, etc.), gastrointestinal dysmotility and sleep disorders (REM sleep Behavior Disorder, stridor, etc.), using a stepwise combination of lifestyle measures, pharmacological agents and device-aided interventions. Expert opinion Management of MSA remains largely symptomatic. Multimodal treatment and integration of rehabilitative and non-pharmacological strategies are critical, while ongoing trials in neuroprotection and neuromodulation represent key avenues to improve long-term outcomes.

ABSTRACT Introduction Fibromyalgia is a chronic pain syndrome characterized by widespread nociplastic pain, fatigue, sleep disturbances, and mood symptoms. Conventional treatments often yield limited benefits, prompting interest in noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS). Areas covered This review synthesizes evidence from 31 randomized controlled trials (RCTs) evaluating the efficacy, safety, and tolerability of tDCS in fibromyalgia. A systematic search of Embase and Medline were conducted without date or language restrictions. Most studies assessed anodal tDCS targeting the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC), with outcomes spanning pain, global symptom burden, psychological symptoms, fatigue, and sleep quality. Ten of 14 sham-controlled trials reported significant pain reductions with M1 stimulation. Seven trials showed improvements in overall symptom severity (FIQ/FIQR), though most did not meet the minimal clinically important difference. Outcomes for fatigue, sleep, and mood were less consistent and often underreported. Expert opinion While tDCS appears safe and effective for fibromyalgia-related pain, variability in protocols and limited reporting of non-pain outcomes hinder broader conclusions. As an adjunctive therapy, its role may be enhanced through protocol standardization, longer-term follow-up, and combination strategies such as pairing with repetitive transcranial magnetic stimulation (rTMS) to address the full spectrum of fibromyalgia symptoms.

ABSTRACT Background Serotonin Reuptake Inhibitors (SRIs) are the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), but they are effective in only 40–60% of the patients. We performed meta-analyses of predictors of resistance to SRIs in OCD. Methods The systematic review was conducted as per PRISMA guidelines and registered in PROSPERO (ID: CRD42024568797). Multiple random-effects meta-analyses were performed for each predictor, depending on the type of the predictor variable and the outcome (continuous vs categorical). Pooled outcomes were reported as odds ratios (OR), mean differences (MD), standardized mean differences (SMD), Fisher’s r-to-z transformed correlation coefficient, along with their 95% confidence intervals (CI). Results Out of 10,688 studies screened, 46 met our eligibility criteria, including a total of N = 4860 subjects. Analysis of categorical outcomes showed that earlier age at onset (SMD = 1.9 [0.79–2.99]), longer duration of illness (SMD = 2.78 [0.77–4.79]), greater OCD severity at baseline (MD = 2.50 [1.53–3.46]), poorer insight (OR = 0.24 [0.08–0.68]), contamination obsessions (OR = 0.61 [0.43–0.85]), and comorbid tics (OR = 0.44 [0.29–0.67]) predicted non-response to SRIs. Baseline OCD severity (Z = 0.56 [0.21–0.92]), poorer insight (SMD = 1.33 [0.42–1.33]), and presence of comorbid tics (SMD = 0.67 [0.01–1.36]) predicted poor response in continuous outcome analyses. Conclusions Baseline severity, insight, and comorbid tics were consistent predictors of poor treatment response.

ABSTRACT Background This study compared the efficacy and safety/tolerability of atogepant versus rimegepant as preventive migraine treatments in Japanese patients using anchored matching-adjusted indirect comparisons (MAICs). Methods Three placebo-controlled trials were included: RELEASE and PROGRESS (atogepant), and BHV3000-309 (rimegepant). Efficacy outcomes included change from baseline in mean monthly migraine days (MMDs) and mean monthly acute medication use days (MUDs). Quality-of-life endpoints included Migraine-Specific Quality-of-Life Questionnaire (MSQ) v2.1 Role Function-Restrictive (RFR) domain score, Migraine Disability Assessment (MIDAS) total score, and EQ visual analog scale (EQ-VAS) score. Safety/tolerability outcomes included treatment-emergent adverse events (AEs) and AEs leading to treatment discontinuation. Results Atogepant demonstrated a statistically significant greater reduction from baseline in mean MMDs (mean difference [MD]: 1.33; 95% confidence interval [CI]: −2.48, −0.18) and monthly acute MUDs (MD: ‑1.97; 95% CI: −3.06, −0.87) versus rimegepant across 12 weeks; and a statistically significant greater improvement from baseline in MSQ v2.1 RFR domain score at Week 12 (MD: 4.80; 95% CI: 0.15, 9.45). No significant differences were identified for other endpoints. Conclusions In these MAICs, atogepant was associated with statistically significant greater reductions in MMDs and monthly acute MUDs, and greater improvements in MSQ v2.1 RFR domain scores versus rimegepant in Japanese patients with migraine.