Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Serum tau protein elevation in migraine: a cross-sectional case-control study.

BACKGROUND: Migraine is a disorder associated with neuropeptide release, pain and inflammation. Tau protein has recently been linked to inflammatory diseases and can be influenced by neuropeptides such as CGRP, a key neurotransmitter in migraine. Here, we report serum concentrations of total-tau protein in migraine patients and healthy controls. METHODS: In this cross-sectional study, interictal blood samples from n = 92 patients with episodic migraine (EM), n = 93 patients with chronic migraine (CM), and n = 42 healthy matched controls (HC) were studied. We assessed serum total-tau protein (t-tau) and for comparison neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L (UCH-L1) concentrations using the Neurology 4-plex kit, on a single molecule array HD-X Analyzer (Quanterix Corp Lexington, MA). Matched serum/cerebrospinal fluid (CSF) samples were used for post-hoc evaluations of a central nervous system (CNS) source of relevant findings. We applied non-parametric tests to compare groups and assess correlations. RESULTS: Serum t-tau concentrations were elevated in EM [0.320 (0.204 to 0.466) pg/mL] and CM [0.304 (0.158 to 0.406) pg/mL] patients compared to HC [0.200 (0.114 to 0.288) pg/mL] (p = 0.002 vs. EM; p = 0.025 vs. CM). EM with aura [0.291 (0.184 to 0.486 pg/mL); p = 0.013] and EM without aura [0.332 (0.234 to 0.449) pg/mL; p = 0.008] patients had higher t-tau levels than HC but did not differ between each other. Subgroup analysis of CM with/without preventive treatment revealed elevated t-tau levels compared to HC only in the non-prevention group [0.322 (0.181 to 0.463) pg/mL; p = 0.009]. T-tau was elevated in serum (p = 0.028) but not in cerebrospinal fluid (p = 0.760). In contrast to t-tau, all proteins associated with cell damage (NfL, GFAP, and UCH-L1), did not differ between groups. DISCUSSION: Migraine is associated with t-tau elevation in serum but not in the CSF. Our clinical study identifies t-tau as a new target for migraine research.

A phase 3, randomised, placebo-controlled study of erenumab for the prevention of chronic migraine in patients from Asia: the DRAGON study.

ABSTACT: BACKGROUND: DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study. METHODS: DRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18-65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD. RESULTS: At baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was - 8.2 days for erenumab and - 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: - 1.57 [95%CI: - 2.83, - 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (- 5.34 vs - 4.66) and mMIDAS scores (- 14.67 vs - 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo). CONCLUSION: DRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials. TRIAL REGISTRATION: NCT03867201.

Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial.

BACKGROUND: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. METHODS: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15-35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. FINDINGS: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p<0·0001) and in the bimagrumab 700 mg group 2·8 kg [2·2]; p<0·0001) but not in the bimagrumab 70 mg group (0·6 kg [SD 2·2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. INTERPRETATION: Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. FUNDING: Novartis Pharma.

Fatal intracranial haemorrhage in a hypertensive patient with atrial fibrillation and coronavirus disease 2019.

We present a case of a fatal cerebral haemorrhage in an 82-year-old male patient with coronavirus disease 2019 (COVID-19), who was taking prophylactic oral anticoagulation because of atrial fibrillation (rivaroxaban 20 mg q.d. for two years). On admission, the patient was deeply comatose, mechanically ventilated, with tachycardia up to 150 bpm, high blood pressure >210/120 mmHg and a body temperature >39°C. A computed tomography scan of the head showed a large intracerebral haemorrhage located in the deep structures of the right hemisphere, with a mass effect and bleeding to the ventricles. Rivaroxaban was discontinued at admission. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but he did not have typical symptoms of pneumonia. In the following days, the patient's neurological condition did not improve, and a fever of up to 40°C and abnormal coagulation parameters remained resistant to pharmacotherapy. The patient developed multi-system organ failure and died on day 8. Here, we review the recent literature and discuss the possible association of SARS-CoV-2-mediated endothelial injury and cardiovascular disorders with cerebrovascular complications. We postulate that anti-inflammatory treatment in COVID-19 and the stabilisation of endothelium functions can be particularly important in patients with pre-existing cardiovascular conditions.

Effectiveness of 6-Week Nordic Walking Training on Functional Performance, Gait Quality, and Quality of Life in Parkinson's Disease.

Background and objectives: Motor rehabilitation improves physical mobility and quality of life in Parkinson's disease (PD). As specialized rehabilitation is expensive and resource-consuming, there is a need for simpler, cost-effective methods. The purpose of the study was to determine whether Nordic Walking (NW) training may support the management of motor disability in PD. Materials and Methods: Forty patients (median age 64.0 years, range 50-75 years) with idiopathic PD, Hoehn and Yahr stages II-III, were randomly assigned to NW or standard rehabilitation (SR) programs, comprising twelve rehabilitation sessions conducted bi-weekly throughout the 6-week study period. Results: Median Unified Parkinson's Disease Rating Scale part III scores were significantly reduced with NW, by 8.5, and with SR, by 6.0 points (both p < 0.001), with significantly greater improvement with NW than with SR (p = 0.047). Gait quality and balance control, measured using the Dynamic Gait Index, improved with NW by a median of 8.0 and with SR by 5.5 points (both p < 0.001), with slightly greater improvement with NW, compared to the SR group (p = 0.064). Quality of life, assessed using the Parkinson's Disease Questionnaire (PDQ-39), improved with NW by a median of 15 and with SR by 12 points, p = 0.001 and p = 0.008, respectively. Conclusions: The 6-week Nordic Walking program improves functional performance, quality of gait, and quality of life in patients with PD and has comparable effectiveness to standard rehabilitation.

Multiple sclerosis: oral health, behaviours and limitations of daily oral hygiene - a questionnaire study.

CLINICAL RATIONALE FOR THE STUDY: Neurological deficits and progressing disability in patients with multiple sclerosis (MS) may hamper daily oral hygiene, but their relations with oral problems have not yet been clearly determined. AIM OF THE STUDY: The aim of this study was to identify the most significant dental problems and limitations of daily oral hygiene in Polish patients with MS. MATERIAL AND METHODS: 199 patients with diagnosed MS (median age 37 years) treated in the neurological outpatient clinic were interviewed using a paper-based questionnaire. They provided answers on oral health, behaviours and the limitations of their daily oral hygiene. Clinical information regarding symptoms, MS phenotype, relapses, medication and degrees of disability was based on medical records. RESULTS: The most frequent symptoms were dry mouth (43.2%) and bleeding from gums (28.1%). Dry mouth was more frequent in patients with secondary-progressive MS (SPMS) than relapsing-remitting MS (65.4% vs 41.3%, p = 0.023). Patients with bleeding from gums had had MS for a longer duration (median 6 vs 4 years, p = 0.002). Difficulties in daily oral hygiene were more frequent in patients with SPMS (24.0% vs 8.1%; p = 0.016). Greater proportions of patients with muscle weakness of limbs, imbalance or pain brushed their teeth irregularly. Frequent (i.e. at least every six months) visits to the dentist's surgery were uncommon in patients with SPMS (12.0% vs 39.7%, p = 0.010). CONCLUSIONS AND CLINICAL IMPLICATIONS: Dry mouth and bleeding from gums are more frequent in patients with longer lasting and more advanced types of MS. Daily oral hygiene and oral health self-control is limited in patients with MS, mainly due to motor deficits, balance problems and pain, and this becomes worse with disease duration. To minimise the burden of the disease, patients with MS require better education and improvement in their awareness regarding proper oral health control, such as the use of electric toothbrushes. In addition, patients with chronic and progressive disability from multiple sclerosis may benefit from better organised access to dental care.

Brain morphometric analysis predicts decline of intelligence quotient in children with sickle cell disease: A preliminary study.

PURPOSE: For children with sickle cell disease (SCD) and at low risk category of stroke, we aim to build a predictive model to differentiate those with decline of intelligence-quotient (IQ) from counterparts without decline, based on structural magnetic-resonance (MR) imaging volumetric analysis. MATERIALS AND METHODS: This preliminary prospective cohort study included 25 children with SCD, homozygous for hemoglobin S, with no history of stroke and transcranial Doppler mean velocities below 170cm/s at baseline. We administered the Kaufman Brief Intelligence Test (K-BIT) to each child at yearly intervals for 2-4 years. Each child underwent MR examination within 30 days of the baseline K-BIT evaluation date. We calculated K-BIT change rates, and used rate of change in K-BIT to classify children into two groups: a decline group and a non-decline group. We then generated predictive models to predict K-BIT decline/non-decline based on regional gray-matter (GM) volumes computed from structural MR images. RESULTS: We identified six structures (the left median cingulate gyrus, the right middle occipital gyrus, the left inferior occipital gyrus, the right fusiform gyrus, the right middle temporal gyrus, the right inferior temporal gyrus) that, when assessed for volume at baseline, are jointly predictive of whether a child would suffer subsequent K-BIT decline. Based on these six regional GM volumes and the baseline K-BIT, we built a prognostic model using the K* algorithm. The accuracy, sensitivity and specificity were 0.84, 0.78 and 0.86, respectively. CONCLUSIONS: GM volumetric analysis predicts subsequent IQ decline for children with SCD.

Sickle cell anemia: intracranial stenosis and silent cerebral infarcts in children with low risk of stroke.

PURPOSE: Children with sickle cell anemia (SCA), who have mean blood flow velocities <170 cm/s in the terminal internal carotid (tICA) or middle cerebral (MCA) arteries on transcranial Doppler ultrasonography (TCD), are considered to be at low risk of stroke. The prevalence of intracranial stenosis, which raises the risk of stroke, is not known in these children. Here, we estimated the prevalence of stenosis and explored its association with silent cerebral infarcts determined based on Magnetic Resonance (MR) scans. PATIENTS/METHODS: We studied prospectively a cohort of 67 children with SCA without prior clinically overt stroke or TIA (median age 8.8 years; range limits 2.3-13.1 years; 33 females) and with TCD mean velocity <170 cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries. RESULTS: In 7 children (10.5%, 95% CI: 4.9-20.3%) we found 10 stenoses, including 4 with isolated left tICA stenosis and 3 with multiple stenoses. We found silent infarcts in 26 children (37.7%, 95% CI: 27.2-49.5%). The median number of infarcts in an affected child was 2 (range limits: 1-9), median volume of infarcts was 171 mm(3) (range limits: 7-1060 mm(3)), and median infarct volume in relation to total brain volume was 0.020% (range limits: 0.001-0.101%). The number and volume of infarcts were significantly higher in children with arterial stenosis (both p=0.023). CONCLUSIONS: The prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170 cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts.

Brain ischemia in patients with intracranial hemorrhage: pathophysiological reasoning for aggressive diagnostic management.

Patients with intracranial hemorrhage have to be managed aggressively to avoid or minimize secondary brain damage due to ischemia, which contributes to high morbidity and mortality. The risk of brain ischemia, however, is not the same in every patient. The risk of complications associated with an aggressive prophylactic therapy in patients with a low risk of brain ischemia can outweigh the benefits of therapy. Accurate and timely identification of patients at highest risk is a diagnostic challenge. Despite the availability of many diagnostic tools, stroke is common in this population, mostly because the pathogenesis of stroke is frequently multifactorial whereas diagnosticians tend to focus on one or two risk factors. The pathophysiological mechanisms of brain ischemia in patients with intracranial hemorrhage are not yet fully elucidated and there are several important areas of ongoing research. Therefore, this review describes physiological and pathophysiological aspects associated with the development of brain ischemia such as the mechanism of oxygen and carbon dioxide effects on the cerebrovascular system, neurovascular coupling and respiratory and cardiovascular factors influencing cerebral hemodynamics. Consequently, we review investigations of cerebral blood flow disturbances relevant to various hemodynamic states associated with high intracranial pressure, cerebral embolism, and cerebral vasospasm along with current treatment options.

Acute intracranial in-stent thrombosis after angioplasty of middle cerebral artery symptomatic stenosis: a case report.

INTRODUCTION: Intracranial atherosclerotic disease is one of the major risk factors of ischemic stroke. Percutaneous transluminal angioplasty with stent deployment may be effective for the treatment of symptomatic intracranial stenosis, however its value is yet to be determined. High possibility of serious periprocedural complications, such as acute in-stent thrombosis or stroke, narrows the current recommendations for this treatment to patients with high-grade stenosis (>70%), and to experienced neurointerventional centers. CASE REPORT: We present a 44-year-old male with symptomatic high-grade stenosis of the M1 segment of left middle cerebral artery, treated with percutaneous transluminal angioplasty with stenting. The procedure was complicated with acute in-stent thrombosis treated with intra-arterial thrombolysis, which resulted in a nondisabling stroke. CONCLUSIONS: The procedure-related stroke in this patient was probably caused by middle cerebral artery perforator ostium occlusion with balloon predilatation and transient in-stent thrombosis related to insufficient antiplatelet pretreatment. Exhausted cerebrovascular reserve due to long-lasting high-grade intracranial stenosis should also be considered as a factor contributing to ischemic complications.

Sickle cell disease and transcranial Doppler imaging: inter-hemispheric differences in blood flow Doppler parameters.

BACKGROUND AND PURPOSE: to establish reference values of interhemispheric differences and ratios of blood flow Doppler parameters in the terminal internal carotid artery, middle cerebral artery, and anterior cerebral artery in children with sickle cell anemia. METHODS: fifty-seven out of 74 recruited children (mean age, 7.8 ± 3.4 years; range limits, 3-14 years), who were free of neurological deficits and intracranial narrowing detectable by MRA and had flow velocities <170 cm/s by conventional transcranial Doppler ultrasound, underwent transcranial color-coded duplex ultrasonography. Reference limits of flow parameters corrected and uncorrected for the angle of insonation were estimated using tolerance intervals, with P=0.90 for all possible data values from 95% of a population. RESULTS: reference limits for left-to-right differences in cm/s in the mean angle-corrected and uncorrected flow velocities were -56 to 53 and -72 to 75 for middle cerebral artery, -49 to 57 and -81 to 91 for anterior cerebral artery, and -55 to 64 and -73 to 78 for terminal internal carotid artery, respectively. Respective reference limits for left-to-right velocity ratios were 0.31 to 1.84 and 0.38 to 1.75 for middle cerebral artery, 0.48 to 2.99 and 0.46 to 2.89 for anterior cerebral artery, and 0.61 to 2.56 and 0.56 to 2.23 for terminal internal carotid artery. CONCLUSIONS: the study provides reference limits of interhemispheric differences and ratios of blood flow Doppler parameters that may be helpful in identification of intracranial arterial narrowing in children with sickle cell disease undergoing ultrasound screening for stroke prevention.

Decompressive hemicraniectomy in ischaemic stroke.

BACKGROUND AND PURPOSE: Hemispheric ischaemic stroke complicated by oedema is associated with high mortality. The results of randomized studies showed that decompressive hemicraniectomy performed in this group of patients could be beneficial. First experiences with implementation of hemi-craniectomy in patients with brain infarct in our stroke centre are presented. MATERIAL AND METHODS: Between August 2007 and July 2008, four patients with hemispheric brain infarcts complicated by malignant oedema underwent decompressive hemicraniectomy within 72 hours from symptoms onset. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Clinical outcome was assessed 3, 6 and 12 months after the event using the modified Rankin scale (mRS). RESULTS: In the first patient, the neurosurgical procedure included only decompressive hemicraniectomy, whereas in the other three duraplasty was performed additionally. The first patient died 23 days after the stroke onset due to acute respiratory failure. Another died at four months after the event, due to infectious complications. The remaining two patients presented severe functional disability 12 months after the procedure (mRS score 4). CONCLUSIONS: Decompressive surgery with duraplasty can be a life-saving procedure for patients with brain oedema. To our knowledge, the presented cases are among the first reported cases of hemispheric ischaemic stroke treated with decompressive hemicraniectomy in Poland. Extended follow-up with a larger group of patients is necessary to assess long-term outcome.

Middle cerebral artery vasospasm: transcranial color-coded duplex sonography versus conventional nonimaging transcranial Doppler sonography.

OBJECTIVE: To prospectively compare accuracies of transcranial color-coded duplex sonography (TCCS) and transcranial Doppler sonography (TCD) in the diagnosis of middle cerebral artery (MCA) vasospasm. DESIGN: Prospective blinded head-to-head comparison TCD and TCCS methods using digital subtraction angiography (DSA) as the reference standard. SETTING: Department of Radiology in a tertiary university health center in a metropolitan area. PATIENTS: Eighty-one consecutive patients (mean age, 53.9 +/- 13.9 years; 48 women). The indication for DSA was subarachnoid hemorrhage in 71 patients (87.6%), stroke or transient ischemic attack in five patients (6.2%), and other reasons in five patients (6.2%). INTERVENTIONS: The MCA was graded as normal, narrowed <50%, and >50% using DSA. The accuracy of ultrasound methods was estimated by total area (Az) under receiver operator characteristic curve. To compare sensitivities of ultrasound methods, McNemar's test was used with mean velocity thresholds of 120 cm/sec for the detection of less advanced, and 200 cm/sec for the more advanced MCA narrowing. MEASUREMENTS AND MAIN RESULTS: Angiographic MCA narrowing 50% in 10 of 135 arteries. Accuracy of TCCS was insignificantly higher than that of TCD in the detection of 50% narrowing, total Az for mean velocity being 0.83 +/- 0.05, 0.77 +/- 0.05, and 0.95 +/- 0.02, 0.86 +/- 0.08, respectively. Sensitivity of TCCS at commonly used threshold of 120 cm/sec for less advanced MCA spasm was significantly better than that of TCD at similar specificity, 55% vs. 39%, p = 0.038, whereas at a threshold of 200 cm/sec used for more advanced spasm, sensitivities and specificities of both methods were not different. CONCLUSION: The accuracy of TCCS and TCD is similar, but TCCS is more sensitive than TCD in the detection of MCA spasm. Sensitivity of both techniques in the detection of mild and more advanced spasm using 120 cm/sec and 200 cm/sec thresholds, respectively, is poor; however, a larger sample is required to increase precision of our sensitivity estimates.

Perfusion computed tomography in prediction of functional outcome in patients with acute ischaemic stroke.

PURPOSE: To determine the value of perfusion computed tomography (CT) in prediction of the clinical course and late functional outcome in patients with acute ischaemic stroke who had unremarkable initial brain CT examination. MATERIAL AND METHODS: Single slice perfusion CT was performed in 55 consecutive patients (27 women, mean age 67 +/- 11 years) with acute ischaemic stroke within 6 hours (median 2.26 hours) from onset of symptoms. Values of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) obtained from affected hemisphere were compared to respective values in non-affected hemisphere (relative parameters). Initial neurological deficits were estimated using NIH Stroke Scale (NIHSS) score and correlated with perfusion CT values, employing Spearman rank correlation coefficient (r). Values of perfusion CT parameters in prediction of functional outcome were determined by comparing against scores on modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) after three months of onset of stroke. RESULTS: All perfusion CT parameters significantly correlated with initial neurological deficit. The highest correlation with the NIHSS was found for relative CBF, which correlated better than absolute CBF (rCBF r = 0.69; CBF r = 0.50, P < 0.001). In prediction of favourable outcome (mRS

Carotid artery diameter in men and women and the relation to body and neck size.

BACKGROUND AND PURPOSE: To explore relationships among gender, body size, neck size, and the diameters of the common carotid artery (CCA) and internal carotid artery (ICA). METHODS: Using multivariate regression, the best predictors of sonographic diameters of CCA and ICA were determined based on age, height, weight, body mass index, body surface area, neck circumference, neck length, and blood pressure. RESULTS: Measurements were obtained in 500 consecutive patients (age 52+/-15 years; 61% women). Mean diameters of ICA (4.66+/-0.78 mm) and CCA (6.10+/-0.80 mm) in women were significantly smaller than in men: 5.11+/-0.87 mm and 6.52+/-0.98 mm, respectively. Sex significantly influenced the diameters after controlling for body size, neck size, age, and blood pressure. CONCLUSIONS: Carotid arteries are smaller in women even after adjusting for body and neck size, age, and blood pressure.