Performance of Different Risk Scores for the Detection of Atrial Fibrillation Among Patients With Cryptogenic Stroke.

BACKGROUND: Atrial fibrillation (AF) is a frequent underlying cause of cryptogenic stroke (CS) and its detection can be increased using implantable cardiac monitoring (ICM). We sought to evaluate different risk scores and assess their diagnostic ability in identifying patients with CS with underlying AF on ICM. METHODS: Patients with CS, being admitted to a single tertiary stroke center between 2017 and 2022 and receiving ICM, were prospectively evaluated. The CHA2DS2-VASc, HAVOC, Brown ESUS-AF, and C2HEST scores were calculated at baseline. The primary outcome of interest was the detection of AF, which was defined as at least 1 AF episode on ICM lasting for 2 consecutive minutes or more. The diagnostic accuracy measures and the net reclassification improvement were calculated for the 4 risk scores. Stroke recurrence was evaluated as a secondary outcome. RESULTS: A total of 250 patients with CS were included, and AF was detected by ICM in 20.4% (n=51) during a median monitoring period of 16 months. Patients with CS with AF detection were older compared with the rest (P=0.045). The median HAVOC, Brown ESUS-AF, and C2HEST scores were higher among the patients with AF compared with the patients without AF (all P<0.05), while the median CHA2DS2-VASc score was similar between the 2 groups. The corresponding C statistics for CHA2DS2-VASc, HAVOC, Brown ESUS-AF, and C2HEST for AF prediction were 0.576 (95% CI, 0.482-0.670), 0.612 (95% CI, 0.523-0.700), 0.666 (95% CI, 0.587-0.746), and 0.770 (95% CI, 0.699-0.839). The C2HEST score presented the highest diagnostic performance based on C statistics (P<0.05 after correction for multiple comparisons) and provided significant improvement in net reclassification for AF detection (>70%) compared with the other risk scores. Finally, stroke recurrence was documented in 5.6% of the study population, with no difference regarding the 4 risk scores between patients with and without recurrent stroke. CONCLUSIONS: The C2HEST score was superior to the CHA2DS2-VASc, HAVOC, and Brown ESUS-AF scores for discriminating patients with CS with underlying AF using ICM.

Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis.

BACKGROUND: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy-related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. METHODS: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I2-statistics. RESULTS: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%-84%]; I2=82%), focal neurological deficits 55% ([95% CI, 40%-70%]; I2=82%), encephalopathy 54% ([95% CI, 39%-68%]; I2=43%), seizures 37% ([95% CI, 27%-49%]; I2=65%), headache 31% ([95% CI, 22%-42%]; I2=58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%-100%]; I2=44%), lobar cerebral microbleeds 96% ([95% CI, 92%-99%]; I2=25%), gadolinium enhancing lesions 54% ([95% CI, 42%-66%]; I2=62%), cortical superficial siderosis 51% ([95% CI, 34%-68%]; I2=77%) and lobar macrohemorrhage 40% ([95% CI, 11%-73%]; I2=88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%-53%]; I2=76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. CONCLUSIONS: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.

Rehabilitation on cerebellar ataxic patients with multiple sclerosis: A systematic review.

Multiple Sclerosis (MS) is a chronic inflammatory, autoimmune disease of the Central Nervous System with a vast spectrum of clinical phenotypes. A major aspect of its clinical presentation is cerebellar ataxia where physiotherapy and treatment modalities play a significant role on its management. This systematic review aims to investigate the physiotherapeutic rehabilitation techniques regarding the management of cerebellar ataxia due to MS and secondary to stratify each protocol as part of a multi structural personalized rehabilitation approach based on the gravity of the symptoms. A Pubmed Medline, Scopus and Web of Science research was performed using the corresponding databases. The results were screened by the authors in pairs. In our study, six (6) non-pharmacological interventional protocols, 3 Randomized Controlled Trials and 3 pilot studies, were included with a total of 145 MS patients. Physiotherapeutic techniques, such as NDT-Bobath, robotic and visual biofeedback re-education protocols and functional rehabilitation techniques were included. In most cases cerebellar ataxic symptoms were decreased post-treatment. The overall quality of the studies included was of moderate level (level B). Rehabilitation in cerebellar ataxia due to MS should be based on multicentric studies with the scope of adjusting different types of treatments and physiotherapeutic techniques based on the severity of the symptom.

Prevalence of Clinical and Neuroimaging Markers in Cerebral Amyloid Angiopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. METHODS: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I2 statistics. RESULTS: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%-60%]; I2=93%), cortical superficial siderosis (49% [95% CI, 38%-59%]; I2=95%), dementia or mild cognitive impairment (50% [95% CI, 35%-65%]; I2=97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%-61%]; I2=98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%-67%]; I2=97%), lacunar infarcts (30% [95% CI, 25%-36%]; I2=78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%-67%]; I2=88%) and basal ganglia (21% [95% CI, 2%-51%]; I2=98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%-65%]; I2=91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01-2.46]; I2=47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P=0.03) and transient focal neurological episodes (57% versus 17%; P=0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. CONCLUSIONS: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings.

CADASIL in Greece: Mutational spectrum and clinical characteristics based on a systematic review and pooled analysis of published cases.

BACKGROUND: Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece. METHODS: After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece. RESULTS: We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations). CONCLUSIONS: The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered.

Classical Cerebrospinal Fluid Biomarkers in Dementia with Lewy Bodies.

The use and interpretation of diagnostic cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders, such as Dementia with Lewy bodies (DLB), represent a clinical challenge. According to the literature, the composition of CSF in DLB patients varies. Some patients present with reduced levels of amyloid, others with full Alzheimer Disease CSF profile (both reduced amyloid and increased phospho-tau) and some with a normal profile. Some patients may present with abnormal levels of a-synuclein. Continuous efforts will be required to establish useful CSF biomarkers for the early diagnosis of DLB. Given the heterogeneity of methods and results between studies, further validation is fundamental before conclusions can be drawn.

Prevalence, Characteristics, and Outcomes of Undetermined Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

Background and Purpose: There are scarce data regarding the prevalence, characteristics and outcomes of intracerebral hemorrhage (ICH) of undetermined (unknown or cryptogenic) etiology. We sought to determine the prevalence, radiological characteristics, and clinical outcomes of undetermined ICH. Methods: Systematic review and meta-analysis of studies involving patients with spontaneous ICH was conducted to primarily assess the prevalence and clinical-radiological characteristics of undetermined ICH. Additionally, we assessed the rates for ICH secondary to hypertensive arteriopathy and cerebral amyloid angiopathy. Subgroup analyses were performed based on the use of (1) etiology-oriented ICH classification, (2) detailed neuroimaging, and (3) Boston criteria among patients with cerebral amyloid angiopathy related ICH. We pooled the prevalence rates using random-effects models, and assessed the heterogeneity using Cochran Q and I2 statistics. Results: We identified 24 studies comprising 15 828 spontaneous ICH patients (mean age, 64.8 years; men, 60.8%). The pooled prevalences of hypertensive arteriopathy ICH, undetermined ICH, and cerebral amyloid angiopathy ICH were 50% (95% CI, 43%­58%), 18% (95% CI, 13%­23%), and 12% (95% CI, 7%­17% [P<0.001 between subgroups]). The volume of ICH was the largest in cerebral amyloid angiopathy ICH (24.7 [95% CI, 19.7­29.8] mL), followed by hypertensive arteriopathy ICH (16.2 [95% CI, 10.9­21.5] mL) and undetermined ICH (15.4 [95% CI, 6.2­24.5] mL). Among patients with undetermined ICH, the rates of short-term mortality (within 3 months) and concomitant intraventricular hemorrhage were 33% (95% CI, 25%­42%) and 38% (95% CI, 28%­48%), respectively. Subgroup analysis demonstrated a higher rate of undetermined ICH among studies that did not use an etiology-oriented classification (22% [95% CI, 15%­29%]). No difference was observed between studies based on the completion of detailed neuroimaging to assess the rates of undetermined ICH (P=0.62). Conclusions: The etiology of spontaneous ICH remains unknown or cryptogenic among 1 in 7 patients in studies using etiology-oriented classification and among 1 in 4 patients in studies that avoid using etiology-oriented classification. The short-term mortality in undetermined ICH is high despite the relatively small ICH volume.

Implantable Cardiac Monitoring in the Secondary Prevention of Cryptogenic Stroke.

OBJECTIVE: In this study, we sought to evaluate the impact of implantable cardiac monitoring (ICM) in the prevention of stroke recurrence after a cryptogenic ischemic stroke or transient ischemic attack (TIA). METHODS: We evaluated consecutive patients with cryptogenic ischemic stroke or TIA admitted in a comprehensive stroke center during an 8-year period. We compared the baseline characteristics and outcomes between patients receiving conventional cardiac monitoring with repeated 24-hour Holter-monitoring during the first 5 years in the outpatient setting and those receiving continuous cardiac monitoring with ICM during the last 3 years. Associations on the outcomes of interest were further assessed in multivariable regression models adjusting for potential confounders. RESULTS: We identified a total of 373 patients receiving conventional cardiac monitoring and 123 patients receiving ICM. Paroxysmal atrial fibrillation (PAF) detection was higher in the ICM cohort compared to the conventional cardiac monitoring cohort (21.1% vs 7.5%, p < 0.001). ICM was independently associated with an increased likelihood of PAF detection during follow-up (hazard ratio [HR] = 1.94, 95% confidence interval [CI] = 1.16-3.24) in multivariable analyses. Patients receiving ICM were also found to have significantly higher rates of anticoagulation initiation (18.7% vs 6.4%, p < 0.001) and lower risk of stroke recurrence (4.1% vs 11.8%, p = 0.013). ICM was independently associated with a lower risk of stroke recurrence during follow-up (HR = 0.32, 95% CI = 0.11-0.90) in multivariable analyses. INTERPRETATION: ICM appears to be independently associated with a higher likelihood of PAF detection and anticoagulation initiation after a cryptogenic ischemic stroke or TIA. ICM was also independently related to lower risk of stroke recurrence in our cryptogenic stroke / TIA cohort. ANN NEUROL 2020;88:946-955.

Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis.

OBJECTIVE: Although statin pretreatment (SP) is associated with better outcomes in patients with acute cerebral ischemia after an ischemic stroke/transient ischemic attack, data on the underlying mechanism of this beneficial effect are limited. APPROACH AND RESULTS: We sought to evaluate the potential association between SP and microembolic signal (MES) burden in acute cerebral ischemia because of large artery atherosclerosis (LAA). We prospectively evaluated consecutive patients with first-ever acute cerebral ischemia because of LAA in 3 tertiary stroke centers over a 2-year period. All patients underwent continuous 1-hour transcranial Doppler monitoring of the relevant vessel at baseline (≤24 hours). SP was recorded and dichotomized as high dose or low-to-moderate dose. SP was documented in 43 (41%) of 106 LAA patients (mean age, 65.4±10.3 years; 72% men; low-to-moderate dose, 32%; high dose, 8%). There was a significant (P=0.022) dose-dependent effect between SP and MES prevalence: no SP (37%), SP with low-to-moderate dose (18%), and SP with high dose (0%). Similarly, a significant (P=0.045) dose-dependent effect was documented between SP and MES burden: no SP (1.1±1.8), SP with low-to-moderate dose (0.7±1.6), and SP with high dose (0±0). In multivariable logistic regression analysis adjusting for demographics, vascular risk factors, location of LAA, stroke severity, and other prevention therapies, SP was associated with lower likelihood of MES presence (odds ratio, 0.29; 95% confidence interval, 0.09-0.92; P=0.036). In addition, SP was found also to be independently related to higher odds of functional improvement (common odds ratio, 3.33; 95% confidence interval, 1.07-10.0; P=0.037). CONCLUSIONS: We found that SP in patients with acute LAA is related with reduced MES presence and lower MES burden with an apparently dose-dependent association.

Plasma Glial Fibrillary Acidic Protein in the Differential Diagnosis of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Plasma GFAP (glial fibrillary acidic protein) has recently emerged as a potential biomarker for the differentiation of acute intracerebral hemorrhage (ICH) from acute ischemic stroke (AIS). We prospectively assessed the diagnostic accuracy of GFAP in the differential diagnosis of ICH. METHODS: Consecutive patients presenting to the emergency department within 6 hours from symptom onset were evaluated. All patients underwent extensive diagnostic work-up and were classified according to discharge diagnosis in AIS, ICH, subarachnoid hemorrhage, and stroke mimics. GFAP was also measured in healthy volunteers (controls). Baseline stroke severity was evaluated using National Institutes of Health Stroke Scale. Receiver operating characteristic curve analysis was used to identify the optimal cutoff point for the differentiation between subgroups. Correlation analyses of GFAP plasma concentrations with baseline National Institutes of Health Stroke Scale and onset to sampling time were performed with the nonparametric Spearman rank test and fractional polynomial regression, respectively. RESULTS: Our study population consisted of 270 individuals (AIS: 121, ICH: 34, stroke mimics: 31, subarachnoid hemorrhage: 5, controls: 79). No differences on baseline stroke severity and onset to sampling time were detected between AIS and ICH. Higher median plasma GFAP values were documented in ICH compared with AIS, stroke mimics, and controls (P<0.001). Receiver operating characteristic analysis highlighted a cutoff value of 0.43 ng/mL as the optimal threshold for the differentiation between ICH and AIS (sensitivity: 91%, specificity: 97%). No association was detected between plasma GFAP concentrations and baseline stroke severity for both AIS (P=0.515) and ICH (P=0.387). In the fractional polynomial analysis, the association between GFAP concentration and onset to sampling time was best described by a J-shaped curve for AIS and an inverted U-shaped curve for ICH, with a peak at 2 hours. CONCLUSIONS: Plasma GFAP seems to be a sensitive and specific biomarker for the differentiation of ICH from both AIS and other acute neurological disorders, with the optimal diagnostic yield being present in the second hour from symptom onset.

Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: A systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: Patent foramen ovale (PFO) can be detected in up to 43% of patients with cryptogenic cerebral ischemia undergoing investigation with transesophageal echocardiography (TEE). The diagnostic value of transthoracic echocardiography (TTE) in the detection of PFO in patients with cryptogenic ischemic stroke or transient ischemic attack has not been compared with that of transcranial Doppler (TCD) using a comprehensive meta-analytical approach. METHODS: We performed a systematic literature review to identify all prospective observational studies of patients with cryptogenic cerebral ischemia that provided both sensitivity and specificity measures of TTE, TCD, or both compared to the gold standard of TEE. RESULTS: Our literature search identified 35 eligible studies including 3,067 patients. The pooled sensitivity and specificity for TCD was 96.1% (95% confidence interval [CI] = 93.0-97.8%) and 92.4% (95% CI = 85.5-96.1%), whereas the respective measures for TTE were 45.1% (95% CI = 30.8-60.3%) and 99.6% (95% CI = 96.5-99.9%). TTE was superior in terms of higher positive likelihood ratio values (LR+ = 106.61, 95% CI = 15.09-753.30 for TTE vs LR+ = 12.62, 95% CI = 6.52-24.43 for TCD; p = 0.043), whereas TCD demonstrated lower negative likelihood values (LR- = 0.04, 95% CI = 0.02-0.08) compared to TTE (LR- = 0.55, 95% CI = 0.42-0.72; p < 0.001). Finally, the area under the summary receiver operating curve (AUC) was significantly greater (p < 0.001) in TCD (AUC = 0.98, 95% CI = 0.97-0.99) compared to TTE studies (AUC = 0.86, 95% CI = 0.82-0.89). INTERPRETATION: TCD is more sensitive but less specific compared to TTE for the detection of PFO in patients with cryptogenic cerebral ischemia. The overall diagnostic yield of TCD appears to outweigh that of TTE.

Neuropsychological profiles comparison between Multiple Sclerosis patients and Multiple Sclerosis patients with overlapping features of Systemic Lupus Erythematosus.

AIM: Multiple sclerosis (MS) and Systemic Lupus Erythematosus (SLE) are autoimmune disorders that may lead to cognitive impairment. This study aimed to compare the neuropsychological profiles of patients with MS, and MS and coexisting SLE features. METHODS: We included a total of 90 participants, divided into 3 groups: 30 patients with clinically definite relapsing remitting MS, 30 with coexisting MS and incomplete SLE (overlap group) and 30 healthy controls (HC). All participants underwent neuropsychological assessment with the Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Selective Reminding Test (SRT). RESULTS: Both groups scored lower on the MoCA compared to the HC (p < .001). The overlap group showed the lowest performance on the SDMT and PASAT compared to the other two groups (p < .01), while the MS group scored similarly to the HC in the PASAT (p > .05). Regarding the learning rate and long-term recall, the overlap group had lower scores compared to both the MS and HC (p < .001), but it outperformed both groups in the retention efficacy score (p < .001). The MS group did not differ significantly from the HC in these memory domains (p > .05). CONCLUSION: The overlap group exhibited a broader range of impairments, including slower processing speed, decreased working memory, reduced learning rate, and long-term retrieval deficits. Their retention ability remained intact. The coexistence of MS with SLE pathology had additive impacts on cognitive function.

Blood Pressure Variability in Acute Stroke: A Narrative Review.

The management of blood pressure variability (BPV) in acute stroke presents a complex challenge with profound implications for patient outcomes. This narrative review examines the role of BPV across various stages of acute stroke care, highlighting its impact on treatment strategies and prognostic considerations. In the prehospital setting, while guidelines lack specific recommendations for BP management, emerging evidence suggests a potential link between BPV and outcomes. Among ischaemic stroke patients who are ineligible for reperfusion therapies, BPV independently influences functional outcomes, emphasising the need for individualised approaches to BP control. During intravenous thrombolysis and endovascular therapy, the intricate interplay between BP levels, recanalisation status, and BPV is evident. Striking a balance between aggressive BP lowering and avoiding hypoperfusion-related complications is essential. Intracerebral haemorrhage management is further complicated by BPV, which emerges as a predictor of mortality and disability, necessitating nuanced BP management strategies. Finally, among patients with acute subarachnoid haemorrhage, increased BPV may be correlated with a rebleeding risk and worse outcomes, emphasizing the need for BPV monitoring in this population. Integration of BPV assessment into clinical practice and research protocols is crucial for refining treatment strategies that are tailored to individual patient needs. Future studies should explore novel interventions targeting BPV modulation to optimise stroke care outcomes.

CSF and plasma biomarkers in cerebral amyloid angiopathy: A single-center study and a systematic review/meta-analysis.

INTRODUCTION: There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [ß-amyloids (Aß42 and Aß40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD). PATIENTS AND METHODS: A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively. RESULTS: We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aß42 levels [RoM: 0.47; 95% CI: 0.36-0.62; p < 0.0001], Aß40 levels [RoM: 0.70; 95% CI: 0.63-0.79; p < 0.0001] and the ratio Aß42/Aß40 [RoM: 0.62; 95% CI: 0.39-0.98; p = 0.0438] differentiated CAA from HC. CSF Aß40 levels [RoM: 0.73; 95% CI: 0.64-0.83; p = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; p = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; p = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; p < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; p < 0.0001, respectively]. Plasma Aß42 [RoM: 1.14; 95% CI: 0.89-1.45; p = 0.2079] and Aß40 [RoM: 1.07; 95% CI: 0.91-1.25; p = 0.3306] levels were comparable between CAA and HC. CONCLUSIONS: CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aß40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.

Clinical significance of small nerve fiber involvement in the early diagnosis and treatment of patients with Fabry disease.

INTRODUCTION: Peripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available. METHODS: We conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN). RESULTS: Twenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered. CONCLUSION: Our results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

IL-6 Serum Levels in COVID-19 Patients With Vertigo.

Introduction Dizziness and vertigo represent well-established symptoms of COVID-19. An overexpression of cytokines, a condition often described with the term "cytokine storm" or "hypercytokinemia", is a key characteristic of SARS-Cov-2 infection and plays a pivotal role in disease progression and prognosis. Among them, IL-6 is of major importance.  Purpose The purpose of this study is to investigate any probable IL-6 serum titer difference in COVID-19 patients with vertigo (V+) or without vertigo (V-) admitted to the COVID-19 internal medicine departments of Attikon University Hospital, Athens, Greece, within 12 months. Methods The sample consisted of 52 COVID-19 patients who were diagnosed between January 1, 2020, and December 31, 2020. Of those, 31 reported vertigos during their admission (V+), while the remaining 21 COVID-19 patients did not complain of such symptoms (V-). Results Higher IL-6 serum levels post-COVID-19 infections lead to higher incidence rates of vertigo symptoms (p<.005), regardless of gender and age (p.005).

Impaired cerebral autoregulation in Fabry disease: A case-control study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls. METHODS: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated. RESULTS: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities. CONCLUSIONS: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.

Quality metrics in the management of acute stroke in Greece during the first 5 years of Registry of Stroke Care Quality (RES-Q) implementation.

Introduction: Establishment of a prospective stroke registry may promote the documentation and improvement of acute stroke care. We present the status of stroke management in Greece using the Registry of Stroke Care Quality (RES-Q) dataset. Methods: Consecutive patients with acute stroke were prospectively registered in RES-Q registry by contributing sites in Greece during the years 2017-2021. Demographic and baseline characteristics, acute management, and clinical outcomes at discharge were recorded. Stroke quality metrics, with a specific interest in the association between acute reperfusion therapies and functional recovery in ischemic stroke patients are presented. Results: A total of 3590 acute stroke patients were treated in 20 Greek sites (61% men, median age 64 years; median baseline NIHSS 4; 74% ischemic stroke). Acute reperfusion therapies were administered in almost 20% of acute ischemic stroke patients, with a door to needle and door to groin puncture times of 40 and 64 min, respectively. After adjustment for contributing sites, the rates of acute reperfusion therapies were higher during the time epoch 2020-2021 compared to 2017-2019 (adjusted OR 1.31; 95% CI 1.04-1.64; p < 0.022; Cochran-Mantel-Haenszel test). After propensity-score-matching, acute reperfusion therapies administration was independently associated with higher odds of reduced disability (one point reduction across all mRS scores) at hospital discharge (common OR 1.93; 95% CI 1.45-2.58; p < 0.001). Conclusions: Implementation and maintenance of a nationwide stroke registry in Greece may guide the stroke management planning, so that prompt patient transportation, acute reperfusion therapies, and stroke unit hospitalization become more widely accessible, improving the functional outcomes of stroke patients.

Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients.

Background: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation dose in COVID-19. Objective: We aim to systematically assess the currently available data regarding the effects of different dosing regimens of low molecular weight heparin and/or fondaparinux (LMWH/F) on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases. Design: We conducted a living systematic review and meta-analysis on the effects of different LMWH/F doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. Data Sources and Methods: MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database, and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH/F among confirmed COVID-19 cases. Results: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between LMWH/F and mortality during the following comparisons: (1) no LMWH/F versus any LMWH/F; (2) prophylactic versus higher than prophylactic LMWH/F; (3) prophylactic versus therapeutic LMWH/F; (4) intermediate versus therapeutic LMWH/F; and (5) lower than therapeutic versus therapeutic LMWH/F. Mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19-3.39). However, this effect was mostly driven by observational data. No associations were detected between the intensity of LMWH/F and the risk of thrombotic and hemorrhagic events, except the lower risk for hemorrhage in patients on prophylactic compared to higher LMWH/F doses. Conclusion: The risk for all-cause mortality was higher in patients receiving prophylactic LMWH/F compared to those on an intermediate dose of LMWH/F, based on observational data. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies. Registration: The study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771).