Background Stress hyperglycemia (SHG) is associated with worse clinical outcomes in minor ischemic stroke. Hemorrhagic transformation (HT) represents a potential mechanism mediating this association, but clear characterization of this relationship is lacking. We therefore aimed to investigate whether HT mediates the effect of SHG on functional outcomes in patients with minor stroke. Methods This was a prospective international cohort study (5 comprehensive stroke centers, Italy/United Kingdom). Individuals presenting with National Institutes of Health Stroke Scale ≤5, prestroke modified Rankin Scale ≤1, and without large vessel occlusion between January 2022 and December 2023 were included. SHG was assessed ≤24 hours using the glucose‐to‐glycated hemoglobin ratio. HT ≤7 days was classified in hemorrhagic infarction and parenchymal hematoma. Causal mediation was used to estimate SHG effect on modified Rankin Scale ≥2 at 3 months mediated by HT. Effect modification of age, diabetes, C‐reactive protein, and intravenous thrombolysis was explored. Results There were 1316 patients included (mean age 69.6±12.7 years, 837 men [63.6%]). Higher glucose‐to‐glycated hemoglobin ratio quartiles were associated with modified Rankin Scale ≥2 (adjusted odds ratio [OR], 1.72 [95% CI, 1.24–2.40]; P=0.001) and HT severity (adjusted OR, 2.32 [95% CI, 1.43–3.76]; P=0.001). A significant proportion (14.8%) of the SHG effect on mRS was mediated by HT (average causal mediation effect, 0.014 [95% CI, 0.003–0.030]; P=0.006). Effect modification was found for younger age (≈60 years old), higher C‐reactive protein (≈7 mg/L), and absence of diabetes, but not for intravenous thrombolysis use. Conclusions In patients with minor stroke, HT significantly mediated the effect of SHG on unfavorable outcome. The mediating effect of HT was greater in patients either ≈60 years old, without diabetes, or with high baseline C‐reactive protein levels. These initial results might inform patient selection for future interventional studies.

AIMS:AQP4 is involved in regulating brain water homeostasis and in the function of the glymphatic system. In iNPH there is an altered parenchymal expression of AQP4, contributing to glymphatic dysfunction. This study aimed to test AQP4 and AQP1 levels in cerebrospinal fluid from iNPH, NOT-NPH, and control subjects to evaluate their diagnostic utility and their correlation with clinical parameters. METHODS:CSF samples were collected from probable iNPH patients during the Tap test (TT). Patients who responded to the TT or with a Rout ≥ 12 mmHg/mL/min, performed ventriculoperitoneal shunting (VPS); patients with a negative response to the TT and with a Rout < 12 mmHg/mL/min did not perform surgery (NOT-iNPH group). Ten CSF samples from healthy Controls were collected from our biobank. We conducted an ELISA test to measure levels of Aquaporin 1 and Aquaporin 4. Clinical parameters were collected before and after the TT. A total of 16 iNPH patients, 10 NOT-iNPH patients, and 10 controls were involved in this study. RESULTS:AQP1 levels were higher in iNPH versus NOT-NPH and controls (p < 0,005); AQP4 levels were similar in the three groups. In iNPH patients only, there was a significant correlation between AQP4 CSF levels and MDS-UPDRS-III (r 0.76, p < 0.001), TUG (Time Up-and-Go) (r 0.58, p < 0.05), and MMSE (r - 0.55, p = 0.05). CONCLUSIONS:AQP-4 CSF levels may correlate with the severity of Parkinsonian signs in iNPH patients, while AQP1 CSF levels may reflect the downregulation of CSF production.

The optimal anesthetic strategy during mechanical thrombectomy (MT) for acute ischemic stroke (AIS) remains debated. While general anesthesia (GA) and non-GA approaches are widely used, the impact of emergency conversion (EC) from non-GA to GA is unclear. We evaluated outcomes of patients undergoing EC compared with those managed with primary GA or non-GA. We conducted a multicenter observational study of consecutive anterior circulation large vessel occlusion patients with pre-stroke modified Rankin Scale (mRS) ≤ 2 treated with MT between January 2022 and December 2023 across three centers. Patients were categorized as GA, non-GA, or EC. Inverse probability weighting (IPW) with multivariable adjustment was applied. The primary outcome was 90-day mRS shift; secondary outcomes included pneumonia and 3-month mortality. Among 669 patients, 399 (59.6%) underwent GA, 188 (28.1%) non-GA, and 82 (12.3%) EC. No significant differences were observed in 90-day functional outcomes for EC versus GA (adjusted common OR [acOR] 0.74; 95% CI, 0.48–1.14; p = 0.170) or EC versus non-GA (acOR 0.70; 95% CI, 0.40–1.20; p = 0.193). Compared with EC, non-GA patients had lower pneumonia risk (acOR 0.17; 95% CI, 0.07–0.45; p = 0.001), while GA was associated with reduced 3-month mortality (acOR 0.48; 95% CI, 0.28–0.85; p = 0.011). Emergency conversion was not linked to worse functional outcomes compared with GA or non-GA. However, EC was associated with higher pneumonia risk relative to non-GA and increased mortality compared with GA. Larger prospective studies are warranted to clarify the impact of EC during MT.

Essential blepharospasm (BEB) is a focal dystonia characterized by abnormal brainstem excitability and impaired inhibitory control within trigeminal–facial circuits. Botulinum toxin type A (BoNT-A) is the established first-line treatment, primarily acting at the neuromuscular junction. However, whether BoNT-A also modulates central brainstem circuits in BEB patients remains unclear, and dedicated neurophysiological studies have yielded conflicting results. To investigate whether BoNT-A modulates brainstem interneuronal excitability in BEB using the blink reflex recovery cycle and to correlate clinical outcomes with neurophysiological results. Thirteen patients with BEB underwent neurophysiological and clinical evaluation before (T0) and one month after (T1) BoNT-A treatment. The blink reflex recovery cycle was assessed at interstimulus intervals (ISIs) of 200, 300, 500, and 1000 ms. Clinical severity was assessed using the BSPSS, JRS, and BDS scales. The R2 amplitude ratio showed a statistically significant decrease after treatment across all ISIs (all p ≤ 0.001), indicating reduced brainstem interneuronal excitability. All clinical scales demonstrated statistically significant improvement after treatment (BSPSS, JRS, BDS; all p < 0.001). This pilot study provides preliminary evidence that BoNT-A treatment may reduce brainstem interneuronal excitability in BEB patients, as evidenced by a substantial and consistent decrease in R2 amplitude ratios of the blink reflex recovery cycle. These findings are consistent with a central modulatory effect of BoNT-A beyond its established peripheral action. Larger controlled studies are warranted to confirm these results.

The diagnostic landscape for idiopathic normal-pressure hydrocephalus is intricate, and there is a pressing need for accurate and cost-effective methods. Because of the lack of accurate diagnostic and prognostic quantitative biomarkers, the frequent presence of comorbidities, and the limited understanding of the pathophysiology of the disorder, only a minority of patients receive disease-specific treatment. While traditional neuroimaging offers insights, its isolated diagnostic precision can be enhanced. Emerging quantitative methods analyzing cortical thickness based on standard T1-weighted brain MR images offer new diagnostic possibilities. We analyzed 294 patients referred to our clinic from January 2015 until December 2022. After the exclusion criteria, the final sample consisted of 100 possible iNPH patients. Of these, 71 underwent ventriculoperitoneal shunt surgery, while 29 did not qualify post-evaluation. Cortical thickness was assessed using an advanced deep-learning neuroimaging pipeline. For predictive modeling, we employed a comprehensive set of Machine Learning algorithms, including Distributed Random Forests, Extremely Randomized Trees, Generalized Linear Model with Regularization, Gradient Boosting Machines, Extreme Gradient Boosting machines, and a fully connected multi-layer Artificial Neural Network. These algorithms were strategically combined into a Super Learner ensemble approach to harness their collective predictive power. Among patients with negative CSFTT outcomes or subpar VPS surgery responses, distinct cortical variations emerged, particularly in the caudal middle frontal, rostral middle frontal, superior frontal, and superior parietal regions. Our Super Learner model, integrating CSF dynamics and cortical thickness data, achieved a 90% positive predictive value, signifying a tangible advancement over traditional measures. Analyzing preoperative cortical thickness emerges as a viable strategy for streamlining therapeutic decisions for potential iNPH patients. Future endeavors should focus on large-scale multicentric studies to further delineate specific cortical thickness patterns, potentially enhancing the prediction accuracy for VPS surgery outcomes.

anti-CGRP monoclonal antibodies (anti-CGRP mAbs) represent a highly effective prophylactic treatment for chronic migraineurs, but for some subjects they are ineffective. We aimed to determine if OnabotulinumtoxinA (BoNT/A) treatment may be helpful in these cases. We collected data from fourteen chronic migraineurs who attended our Headache Center and who did not benefit from anti-CGRP mAbs treatment. After anti-CGRP mAbs failure, these patients underwent at least one BoNT/A treatment according to the PREEMPT protocol. We then compared the variation in headache days (DOH), pain intensity (NRS), and symptomatic medication intake (ADI) before and after anti-CGRP mAbs therapy and before and after BoNT/A treatment: we confirmed that the interruption of anti-CGRP mAbs treatment had actually been due to a lack of benefit in terms of DOH (19.21 ± 7.58 days and 20.29 ± 8.32 days; p = 0.74), NRS (7.64 ± 0.75 vs 7.57 ± 1.01; p = 0.85) and ADI (42.86 ± 52.74 vs 45.64 ± 52.82; p = 0.79). All patients started BoNT/A therapy after discontinuing anti-CGRP mAbs. After a period without treatment, therapy with BoNT/A caused a significant reduction in DOH (23.86 ± 6.97 vs. 11.36 ± 10.10, p = 0.010), ADI (47.07 ± 51.19 vs. 20.50 ± 21.42, p = 0.010) and NRS (8.07 ± 1.00 vs. 6.64 ± 1.60, p = 0.014), improving clinical conditions in patients non-responders to anti-CGRP mAbs. It is not well established on which basis pharmacological resistance to anti-CGRP mAbs develops in such refractory patients. Still, these data may point towards a mechanism of pain relief that could not be solely related to CGRP pathways activity, thus being a good rescue therapy in resistant headache management, although further data are needed. Our preliminary results suggest that BoNT/A may be a promising salvage therapy option when anti-CGRP mAbs are ineffective, but evidence requires confirmation from basic research and in larger, uncontrolled, prospective studies in chronic migraineurs.

Background. The association between malnutrition and poor outcomes in stroke patients has, to date, been evaluated using composite scores derived from laboratory measurements. However, Bioelectrical Impedance Analysis (BIA) and its advanced application, Bioelectrical Impedance Vector Analysis (BIVA), offer a non-invasive, cost-efficient, and rapid alternative. These methods enable precise assessment of body composition, nutritional status, and hydration levels, making them valuable tools in the clinical evaluation of stroke patients. Objective. This study aimed to compare the ordinal distribution of modified Rankin Scale (mRS) scores at 90 days following an acute ischemic stroke, stratifying patients based on their nutritional status at the time of Stroke Unit admission, as determined by the Bioelectrical Impedance Vector Analysis (BIVA) malnutrition parameter. Methods. We conducted a single-centre prospective observational study on all consecutive patients admitted for acute ischemic stroke to our Stroke Unit between 1 April 2024, and 30 September 2024. We applied the IPW (Inverse Probability Weighting) statistical technique and ordinal logistic regression to compare mRS scores in malnourished and non-malnourished patients. Results. Overall, our study included 195 patients with ischemic stroke assessed using BIVA. Of these, 37 patients (19%) were malnourished. After IPW, we found that malnourished patients had significantly lower rates of favorable 90-day functional outcomes (cOR 3.34, 95% CI 1.74-6.41; p = 0.001). Even after accounting for relevant covariates, malnutrition remained an independent predictor of unfavorable outcomes (acOR 2.79, 95% CI 1.37-5.70; p = 0.005), along with NIHSS score at admission (acOR 1.19, 95% CI 1.11-1.28; p < 0.001), intravenous thrombolysis (acOR 0.28, 95% CI 0.15-0.52; p < 0.001), absolute lymphocyte count (cOR 1.01, 95% CI 1.00-1.02; p = 0.027), and albumin concentration (cOR 0.82, 95% CI 0.75-0.89; p < 0.001). Conclusions. Malnutrition, assessed through Bioelectrical Impedance Vector Analysis (BIVA) at the time of admission to the Stroke Unit, is associated with worse clinical outcomes at 90 days following the ischemic cerebrovascular event.

Background: Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in pain transmission and modulation, and implicated in migraine pathophysiology. Due to the vasodilatory action of CGRP, anti-CGRP drugs, while ameliorating migraine, may increase hypertension, a major risk factor for cerebrovascular diseases. Although most studies support the safety of this class of drugs, the use of anti-CGRP drugs in some individuals has been associated with elevated blood pressure. Case Presentation: We report a case of a cerebral hemorrhage in a patient treated with an anti-CGRP monoclonal antibody and a poorly controlled blood pressure. Discussion: Migraine is associated with increased cerebrovascular risk and hypertension, and anti-CGRP therapies could potentially contribute to acute hypertensive episodes, possibly increasing the risk of complications, including cerebral hemorrhage, in vulnerable individuals. Conclusions: Limited evidence links anti-CGRP therapies to hypertension. Pending additional data, caution is recommended when prescribing these drugs, especially in patients with cardiovascular risk factors.

Background: Recently, research on the pathogenesis of multiple sclerosis (MS) has focused on the role of B lymphocytes and the possibility of using specific drugs, such as Ocrelizumab and Rituximab, directed toward these cells to reduce inflammation and to slow disease progression. Objective: We aimed to evaluate the effect of Ocrelizumab/Rituximab on laboratory immune parameters and identify the predictors of treatment responses. Methods: A retrospective single-center study was conducted among patients who received infusion therapy with an anti-CD20 drug to treat MS. Results: A total of 64 patients met the inclusion criteria, with 277 total cycles of therapy studied. Compared with the baseline values, anti-CD20 infusions resulted in absolute-value and percentage decreases in B lymphocyte levels and increased the absolute and percentage levels of NK cells 3 and 5 months after therapy (p < 0.001). After multivariate logistic regression analysis, a reduced percentage level of NK cells 3 months after infusion could predict disease activity 6 months after Ocrelizumab/Rituximab administration (p = 0.041). Conclusions: Lower percentage levels of NK cells 3 months after anti-CD20 infusion correlate with the presence of disease activity 6 months after therapy, confirming a possible protective role of NK cells in MS.

INTRODUCTION:Restless legs syndrome (RLS) is a sensory-motor sleep disorder that affects up to 13% of adults in the Western world and 2-4% of children. It impairs night sleep with an impact on daily performances and life quality. Thus, moderate-to-severe RLS requires pharmacological treatment. AREAS COVERED:In the present review, which is based on PubMed searches with no time limits, the authors discuss the recommended pharmacotherapy for RLS in addition to other emerging treatment options. The authors provide coverage to the current recommendations for both adults and pediatric patients with RLS. EXPERT OPINION:Current evidence suggests removing all causes of secondary RLS, including iron deficiency, chronic renal failure, drugs, and treating other sleep disorders that may worsen symptoms. Also, intermittent RLS should be addressed with behavioral measures and on-demand therapy. For chronic persistent RLS, α2δ calcium channel ligands are a first-line pharmacological approach, whereas dopamine agonists are associated with increased risk and should be spared. When RLS is refractory to first-line treatment, polytherapy, or opioid monotherapy should be considered. Nonetheless, some patients may not reach sustained symptom relief. Further research is needed to better understand the pathophysiology of RLS and to develop newer more effective drugs.

Aims: The aim of this study is to assess the sleep quality and daytime sleepiness improvement in chronic migraineurs after 6 months of a 2:1 KD (ketogenic diet) and LGID (low-glycemic-index diet). Methods: Twenty-six patients underwent 2:1 KD (11 patients) and LGID (15 patients). PSQI (Pittsburgh sleep quality index) and ESS (Epworth sleepiness scale) were administered at the baseline and the 3-month and 6-month follow-up. MIDAS (Migraine Disability Assessment), HIT-6 (Headache Impact Test 6), migraine frequency (migraine days per month), migraine intensity, BMI (Body Mass Index), FM (Fat Mass), and FFM (Fat-Free Mass) were also assessed. Results: PSQI (F1.544, 38.606 = 7.250; p = 0.004), ESS (F1.988, 49.708 = 9.938; p < 0.001), HIT-6 (F1.432, 35.805 = 12.693; p < 0.001), migraine frequency (F1.522, 38.041 = 23.070; p < 0.001), migraine intensity (F1.949, 48.721 = 18.798; p < 0.001), BMI (F1.274, 31.857 = 38.191; p < 0.001), and FM (F1.245, 31.134 = 45.487; p < 0.001) improved significantly. The MIDAS (F1.005, 25.121 = 3.037; p = 0.093) and the FMM (F1.311, 32.784 = 1.741; p = 0.197) did not improve significantly. The ESS (p = 0.712) and PSQI (p = 0.776) data at 3-month and 6-month follow-ups did not differ significantly, as well as for migraine frequency, migraine intensity, BMI, FM, and HIT-6. A mild correlation emerged between the mean FM and mean ESS reduction during the 6 months (r = 0.497, p = 0.010). Conclusions: Six months of LGID and 2:1 KD can improve sleep quality and daytime sleepiness in patients with chronic migraine. The effectiveness on migraine, sleep quality, and daytime sleepiness does not differ significantly between the 3-month and 6-month follow-up periods.

Auriculotemporal neuralgia is a rare facial pain disorder with no therapeutic evidence for refractory cases. We described a male patient with right auriculotemporal neuralgia, refractory to anesthetic nerve blocks and botulinum toxin type A injections, who was successfully treated with pulsed radiofrequency without adverse events. Pulsed radiofrequency may be an effective and safe treatment for refractory auriculotemporal neuralgia.

Trigeminal neuralgia is a neuropathic pain syndrome responsive to botulinum toxin type A therapy. This review had the goal of analyzing the different studies published from 2002 to January 2024 to better define the techniques and the types of botulinum toxin type A used, the doses, the injection routes, and the different populations of trigeminal neuralgia patients treated. We considered only articles in which the therapy was administered to humans to treat trigeminal neuralgia. Case reports, case series, open-label, retrospective, and RCT studies were considered. The research was conducted on MEDLINE and the keywords included (trigeminal neuralgia) and (botulinum). Thirty-five articles were considered suitable for this review. Botulinum toxin type A was shown to be an effective therapy for TN pain in all the articles analyzed, albeit there is a lack of standardization in methods and outcomes. The techniques, the doses, and the injection approaches were very heterogeneous among the studies. Only two botulinum toxin type A formulations have been used in this setting: onabotulinumtoxinA and lanbotulinumtoxinA. There were 300 patients treated with onabotulinumtoxinA and 760 treated with lanbotulinumtoxinA overall (in 42 patients, the formulation was not specified). The distinction between etiological and clinical types of TN has been made by only a small portion of the studies. The main adverse event was transient facial asymmetry. Botulinum toxin type A is indeed a promising therapy that is clearly effective for trigeminal neuralgia. OnabotulinumtoxinA is the most common formulation used in Western countries; however, the meager sample of TN patients treated, and the lack of standardization are not sufficient for this therapy to be approved by the FDA or EMA. Indeed, more studies with standardized methods and larger samples are needed for this purpose.

Numb chin syndrome is a rare pain disorder characterized by decreased sensation and paresthesia in the territory of the mental nerve. Neuropathic pain is sometimes described in this setting, and the most common treatments include oral analgesics, gabapentinoids, and carbamazepine; however, botulinum toxin type A has never been used in this setting. We describe a case of bilateral numb chin syndrome, secondary to Burkitt lymphoma, associated with refractory and persistent burning neuropathic pain, effectively treated twelve times with subcutaneous Botulinum toxin type A (BoNT/A) injections. The procedure was well tolerated, but the patient reported incomplete mouth closure of minimal entity. BoNT/A could be a safe and effective therapy for neuropathic pain associated with numb chin syndrome.

Introduction: Mechanical thrombectomy (MT) is the standard treatment for acute ischemic stroke (AIS) due to anterior large vessel occlusion (LVO). Despite successful recanalization, some patients remain disabled after 3 months. Mechanisms that can cause futile recanalization (FR) are still largely unknown. We investigated if stress hyperglycemia might be associated with FR. Patients and methods: This is a retrospective analysis of consecutive patients with successful recanalization treated in four participating centers between January 2021 and December 2022. According to the modified Rankin scale (mRS) status at 3 months, patients were divided into two groups: FR, if mRS score >2, and useful recanalization (UR), if mRS score ⩽2. Stress hyperglycemia was estimated by the glucose-to-glycated hemoglobin ratio (GAR) index. Results: A total of 691 subjects were included. At 3 months, 403 patients (58.3%) were included in the FR group, while the remaining 288 patients (41.7%) were included in the UR group. At the multivariate analysis, variables independently associated with FR were the following: age (OR 1.04, 95% CI 1.02–1.06, p < 0.001), GAR index (OR 1.08, 95% CI 1.03–1.14, p = 0.003), NIHSS at admission (OR 1.16, 95% CI 1.11–1.22; p < 0.001), and procedure length (OR 1.01, 95% CI 1.00–1.02; p = 0.009). We observed that the model combining age, GAR index, NIHSS at admission, and procedure length had good predictive accuracy (AUC 0.78, 95% CI 0.74–0.81). Conclusions: Stress hyperglycemia predicts FR in patients with successful recanalization after MT. Further studies should explore if managing stress hyperglycemia may reduce futile recanalization. Additionally, we recommend paying close attention to AIS patients with a GAR index greater than 24.8 who exhibit a high risk of FR.

INTRODUCTION:The drug most frequently used for thrombolysis in cases of acute ischemic stroke (AIS) is alteplase. However, there is moderate-to-high-quality evidence that tenecteplase has similar or higher efficacy and safety. With improved pharmacokinetic properties over alteplase, tenecteplase could be a significant advantage in treating AIS.AREAS COVERED:After conducting an extensive search on Scopus and PubMed, this manuscript reviews and compares the pharmacokinetic properties of alteplase and tenecteplase. Additionally, it provides information on pharmacodynamics, clinical efficacy, safety, tolerability, and drug-drug interactions.EXPERT OPINION:The pharmacokinetic profile of alteplase and tenecteplase is derived from studies in patients with acute myocardial infarction. Thanks to its pharmacokinetic properties, tenecteplase is the drug closest to being the ideal fibrinolytic for AIS. Its longer half-life enables a single-bolus administration, which is particularly useful in emergencies. Tenecteplase has proven to have a good efficacy and safety profile in randomized clinical trials. Although we are awaiting the results of the ongoing phase 3 randomized clinical trials, we believe that tenecteplase has the potential to revolutionize the treatment of AIS through thrombolysis.