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1.  Observational Study Assessing Demographic, Economic and Clinical Factors Associated with Access and Utilization of Health Care Services of Patients with Multiple Sclerosis under Treatment with Interferon Beta-1b (EXTAVIA) 
PLoS ONE  2014;9(11):e113933.
Multiple sclerosis (MS) results in an extensive use of the health care system, even within the first years of diagnosis. The effectiveness and accessibility of the health care system may affect patients' quality of life. The aim of the present study was to evaluate the health care resource use of MS patients under interferon beta-1b (EXTAVIA) treatment in Greece, the demographic or clinical factors that may affect this use and also patient satisfaction with the health care system. Structured interviews were conducted for data collection. In total, 204 patients (74.02% females, mean age (SD) 43.58 (11.42) years) were enrolled in the study. Analysis of the reported data revealed that during the previous year patients made extensive use of health services in particular neurologists (71.08% visited neurologists in public hospitals, 66.67% in private offices and 48.53% in insurance institutes) and physiotherapists. However, the majority of the patients (52.45%) chose as their treating doctor private practice neurologists, which may reflect accessibility barriers or low quality health services in the public health system. Patients seemed to be generally satisfied with the received health care, support and information on MS (84.81% were satisfied from the information provided to them). Patients' health status (as denoted by disease duration, disability status and hospitalization needs) and insurance institute were found to influence their visits to neurologists. Good adherence (up to 70.1%) to the study medication was reported. Patients' feedback on currently provided health services could direct these services towards the patients' expectations.
PMCID: PMC4242657  PMID: 25419842
2.  Reperfusion Therapies of Acute Ischemic Stroke: Potentials and Failures 
Over the past 20 years, clinical research has focused on the development of reperfusion therapies for acute ischemic stroke (AIS), which include the use of systemic intravenous thrombolytics (alteplase, desmoteplase, or tenecteplase), the augmentation of systemic intravenous recanalization with ultrasound, the bridging of intravenous with intra-arterial thrombolysis, the use of multi-modal approaches to reperfusion including thrombectomy and thromboaspiration with different available retrievers. Clinical trials testing these acute reperfusion therapies provided novel insight regarding the comparative safety and efficacy, but also raised new questions and further uncertainty on the field. Intravenous alteplase (tPA) remains the fastest and easiest way to initiate acute stroke reperfusion treatment, and should continue to be the first-line treatment for patients with AIS within 4.5 h from onset. The use of tenecteplase instead of tPA and the augmentation of systemic thrombolysis with ultrasound are both novel therapeutical modalities that may emerge as significant options in AIS treatment. Endovascular treatments for AIS are rapidly evolving due to technological advances in catheter-based interventions and are currently emphasizing speed in order to result in timely restoration of perfusion of still-salvageable, infarcted brain tissue, since delayed recanalization of proximal intracranial occlusions has not been associated with improved clinical outcomes. Comprehensive imaging protocols in AIS may enable better patient selection for endovascular interventions and for testing multi-modal combinatory strategies.
PMCID: PMC4217479  PMID: 25404927
reperfusion therapies; stroke; cerebral ischemia; sonothrombolysis; thrombolysis; intravenous; intra-arterial
3.  Comparative efficacy of different acute reperfusion therapies for acute ischemic stroke: a comprehensive benefit–risk analysis of clinical trials 
Brain and Behavior  2014;4(6):789-797.
Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit–risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset-to-treatment time (OTT).
A comprehensive literature search was conducted to identify all available published, peer-reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit-to-risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0–1) or functional independence (BRR2, mRS score: 0–2) at 3 months divided by the percentage of patients who died during the same period.
A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria. IV therapy with tenecteplase (TNK) was found to have the highest BRRs (BRR1 = 5.76 and BRR2 = 6.82 for low-dose TNK; BRR1 = 5.80 and BRR2 = 6.87 for high-dose TNK), followed by sonothrombolysis (BRR1 = 2.75 and BRR2 = 3.38), while endovascular thrombectomy with MERCI retriever was found to have the lowest BRRs (BRR1 range, 0.31–0.65; BRR2 range, 0.52–1.18). A second degree negative polynomial correlation was detected between favorable functional outcome and OTT (R2 value: 0.6419; P < 0.00001) indicating the time dependency of clinical efficacy of all reperfusion therapies.
Intravenous thrombolysis (IVT) with TNK and sonothrombolysis have the higher BRR among investigational reperfusion therapies. The combination of sonothrombolysis with IV administration of TNK appears a potentially promising therapeutic option deserving further investigation.
PMCID: PMC4178251  PMID: 25365799
Acute stroke; analysis; benefit-to-risk ratio; reperfusion therapies
4.  Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment 
Stroke; a journal of cerebral circulation  2013;44(10):10.1161/STROKEAHA.113.001576.
Background and Purpose
Statins reduce stroke risk when initiated months after TIA/stroke and reduce early vascular events in acute coronary syndromes, possibly via pleiotropic plaque-stabilisation. Few data exist regarding acute statin use in TIA. We aimed to determine if statin pre-treatment at TIA onset modified early stroke risk in carotid stenosis.
We analyzed data from 2770 TIA patients from 11 centres, 387 with ipsilateral carotid stenosis. ABCD2 score, abnormal DWI, medication pre-treatment, and early stroke were recorded.
In patients with carotid stenosis, 7-day stroke risk was 8.3% (95% confidence interval [CI] 5.7–11.1) compared with 2.7% [CI 2.0–3.4%] without stenosis (p<0.0001) (90-day risks 17.8% and 5.7% [p<0.0001]). Among carotid stenosis patients, non-procedural 7-day stroke risk was 3.8% [CI 1.2–9.7%] with statin treatment at TIA onset, compared to 13.2% [CI 8.5–19.8%] in those not statin pre-treated (p=0.01) (90-day risks 8.9% versus 20.8% [p=0.01]). Statin pre-treatment was associated with reduced stroke risk in carotid stenosis patients (OR for 90-day stroke 0.37, CI 0.17–0.82), but not non-stenosis patients (OR 1.3, CI 0.8–2.24) (p for interaction 0.008). On multivariable logistic regression, the association remained after adjustment for ABCD2 score, smoking, antiplatelet treatment, recent TIA, and DWI hyperintensity (adjusted p for interaction 0.054).
In acute symptomatic carotid stenosis, statin pre-treatment was associated with reduced stroke risk, consistent with findings from randomized trials in acute coronary syndromes. These data support the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke. Randomized trials addressing this question are required.
PMCID: PMC3871879  PMID: 23908061
Transient ischaemic attack; carotid stenosis; statin
5.  Comparative efficacy of different acute reperfusion therapies for acute ischemic stroke: a comprehensive benefit–risk analysis of clinical trials 
Brain and Behavior  2014;10.1002/brb3.279.
Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit–risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset‐to‐treatment time (OTT).
A comprehensive literature search was conducted to identify all available published, peer‐reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit‐to‐risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0–1) or functional independence (BRR2, mRS score: 0–2) at 3 months divided by the percentage of patients who died during the same period.
A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria. IV therapy with tenecteplase (TNK) was found to have the highest BRRs (BRR1 = 5.76 and BRR2 = 6.82 for low‐dose TNK; BRR1 = 5.80 and BRR2 = 6.87 for high‐dose TNK), followed by sonothrombolysis (BRR1 = 2.75 and BRR2 = 3.38), while endovascular thrombectomy with MERCI retriever was found to have the lowest BRRs (BRR1 range, 0.31–0.65; BRR2 range, 0.52–1.18). A second degree negative polynomial correlation was detected between favorable functional outcome and OTT (R2 value: 0.6419; P < 0.00001) indicating the time dependency of clinical efficacy of all reperfusion therapies.
Intravenous thrombolysis (IVT) with TNK and sonothrombolysis have the higher BRR among investigational reperfusion therapies. The combination of sonothrombolysis with IV administration of TNK appears a potentially promising therapeutic option deserving further investigation.
PMCID: PMC4178251  PMID: 25365799
Acute stroke; analysis; benefit‐to‐risk ratio; reperfusion therapies
6.  Acute Stroke Imaging Research Roadmap II 
PMCID: PMC4040226  PMID: 23860298
7.  Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry 
There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention.
Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology.
A total of 78 AF patients (mean age 71 ± 9years; 54% men; 81% IS, 19% TIA; median CHADS2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2–5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 ± 5 months (range 1–18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria (n = 1) and rectal bleeding (n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%).
Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation.
PMCID: PMC3994923  PMID: 24790645
atrial fibrillation; dabigatran etexilate; secondary prevention; stroke; transient ischemic attack
8.  Adherence to a Mediterranean diet and risk of incident cognitive impairment 
Neurology  2013;80(18):1684-1692.
We sought to determine the relationship of greater adherence to Mediterranean diet (MeD) and likelihood of incident cognitive impairment (ICI) and evaluate the interaction of race and vascular risk factors.
A prospective, population-based, cohort of individuals enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 2003–2007, excluding participants with history of stroke, impaired cognitive status at baseline, and missing data on Food Frequency Questionnaires (FFQ), was evaluated. Adherence to a MeD (scored as 0–9) was computed from FFQ. Cognitive status was evaluated at baseline and annually during a mean follow-up period of 4.0 ± 1.5 years using Six-item-Screener.
ICI was identified in 1,248 (7%) out of 17,478 individuals fulfilling the inclusion criteria. Higher adherence to MeD was associated with lower likelihood of ICI before (odds ratio [lsqb]OR[rsqb] 0.89; 95% confidence interval [lsqb]CI[rsqb] 0.79–1.00) and after adjustment for potential confounders (OR 0.87; 95% CI 0.76–1.00) including demographic characteristics, environmental factors, vascular risk factors, depressive symptoms, and self-reported health status. There was no interaction between race (p = 0.2928) and association of adherence to MeD with cognitive status. However, we identified a strong interaction of diabetes mellitus (p = 0.0134) on the relationship of adherence to MeD with ICI; high adherence to MeD was associated with a lower likelihood of ICI in nondiabetic participants (OR 0.81; 95% CI 0.70–0.94; p = 0.0066) but not in diabetic individuals (OR 1.27; 95% CI 0.95–1.71; p = 0.1063).
Higher adherence to MeD was associated with a lower likelihood of ICI independent of potential confounders. This association was moderated by presence of diabetes mellitus.
PMCID: PMC3716473  PMID: 23628929
9.  Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case–control studies 
Chronic cerebrospinal venous insufficiency (CCSVI) has recently been implicated in the pathogenesis of multiple sclerosis (MS). This comprehensive meta-analysis of case–control studies investigates the association of CCSVI with MS.
Through Medline, EMBASE and Cochrane database searches, case–control ultrasound studies comparing CCSVI frequency among patients with MS and healthy controls were identified.
We identified 19 eligible studies including 1250 patients with MS and 899 healthy controls. The pooled analysis showed that CCSVI was associated with MS [odds ratio (OR) 8.35; 95% confidence interval (CI) 3.44–20.31; p < 0.001) with considerable heterogeneity across studies (I2 = 80.1%). This association was substantially attenuated in sensitivity analyses excluding studies that were carried out by the group that originally described CCSVI, included investigators who had also been involved in publications advocating endovascular procedures for CCSVI treatment, or were conducted in Italy. Our most conservative sensitivity analysis combining different exclusion criteria yielded no association of CCSVI with MS (OR 1.35; 95% CI 0.62–2.93; p = 0.453) without any heterogeneity (I2 = 0%).
There is considerable heterogeneity across different case–control studies evaluating the association of CCSVI and MS. The greatest factor contributing to this heterogeneity appears to be the involvement of investigators in other publications supporting endovascular procedures as a novel MS treatment.
PMCID: PMC3932766  PMID: 24587827
chronic cerebrospinal venous insufficiency; meta-analysis; multiple sclerosis; ultrasound
10.  Statins and cerebral hemodynamics 
HMG-CoA reductase inhibitors (statins) are associated with improved stroke outcome. This observation has been attributed in part to the palliative effect of statins on cerebral hemodynamics and cerebral autoregulation (CA), which are mediated mainly through the upregulation of endothelium nitric oxide synthase (eNOS). Several animal studies indicate that statin pretreatment enhances cerebral blood flow after ischemic stroke, although this finding is not further supported in clinical settings. Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA.
PMCID: PMC3494001  PMID: 22929438
cerebral autoregulation; cerebral hemodynamics; cerebral vasomotor reactivity; HMG-CoA reductase inhibitors; statins
11.  The role of remote ischemic preconditioning in the treatment of atherosclerotic diseases 
Brain and Behavior  2013;3(6):606-616.
Remote ischemic preconditioning (RIPC) is the application of a transient and brief ischemic stimulus to a distant site from the organ or tissue that is afterward exposed to injury ischemia, and has been found to reduce ischemia–reperfusion injury (IRI) in various animal models. RIPC appears to offer two distinct phases of endothelial IRI protection, which are presumably mediated through neuronal and humoral pathways.
We conducted a comprehensive literature review on the available published data about the potential effect of RIPC in patients undergoing IRI in one or more vital organs.
Our search highlighted 24 randomized clinical trials about the effect of RIPC on variable clinical settings (abdominal aortic aneurysm repair, open heart surgery, percutaneous coronary intervention, living donor renal transplantation, coronary angiography, elective decompression surgery, carotid endarterectomy, recent stroke, or transient ischemic attack combined with intracranial carotid artery stenosis). Most of the trials focused on postoperative cardiac or renal function after RIPC with conflicting results. Preconditioning protocols, age limits, comorbidities, and concomitant drug use varied significantly across trials, and therefore no firm conclusions can be drawn using the available data. However, no severe local adverse events were observed in any patient undergoing limb or arm preconditioning.
RIPC is a safe and well-tolerated procedure that may constitute a potentially promising innovative treatment in atherosclerotic diseases. Large, multicenter, randomized clinical trials are required to determine an optimal protocol for the RIPC procedure, and to evaluate further the potential benefits of RIPC in human ischemic injury.
PMCID: PMC3868166  PMID: 24363964
Aortic aneurysm; atherosclerosis; coronary artery disease; ischemic stroke; peripheral arterial disease; remote ischemic preconditioning
12.  The Argatroban and tPA Stroke Study: final results of a pilot safety study 
Background and Purpose
Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tPA in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion.
During standard dose IV tPA, a 100μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage (sICH) or parenchymal hemorrhage-type 2 (PH-2). Recanalization was measured at 2 and 24 hours by transcranial Doppler (TCD) or CT angiography.
Sixty-five patients were enrolled (45% men, mean age 63±14 years, median NIHSS = 13). The median (IQR) time tPA to Argatroban bolus was 51 (38, 60) minutes. Target anticoagulation was reached at a median (IQR) of 3 (2, 7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%, 95% CI 1.7–15.0). Of these, 3 were symptomatic (4.6%, 95% CI 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2 hour monitoring period, TCD recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%).
The combination of Argatroban and IV tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions, and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted.
PMCID: PMC3289043  PMID: 22223235
Anticoagulation; acute stroke; thrombolysis; Argatroban; thrombin-inhibition
13.  Association of Ultrasonographic Parameters with Subclinical White-Matter Hyperintensities in Hypertensive Patients 
Background and Purpose. Cerebral white matter hyperintensities (WMHs) are regarded as typical MRI expressions of small-vessel disease (SVD) and are common in hypertensive patients. Hypertension induces pathologic changes in macrocirculation and in microcirculation. Changes in microcirculation may lead to SVD of brain and consequently to hypertensive end-organ damage. This damage is regarded the result of interactions between the macrovascular and microvascular levels. We sought to investigate the association of cerebral WMHs with ultrasonographic parameters of cerebral macrocirculation evaluated by carotid duplex ultrasound (CDU) and transcranial doppler (TCD). Subjects and Methods. The study was prospective, cross-sectional and consecutive and included hypertensive patients with brain MRI with WMHs. Patients underwent CDU and TCD. The clinical variables recorded were demographic characteristics (age, gender, race) and vascular risk factors (hypertension, diabetic mellitus, hypercholesterolemia, current smoking, and body mass index). Excluded from the study were patients with history of clinical stroke (including lacunar stroke and hemorrhagic) or transient ischemic attack (either hemispheric or ocular), hemodynamically significant (>50%) extra- or intracranial stenosis, potential sources of cardioembolism, and absent transtemporal windows. WMHs were quantified with the use of a semiquantitative visual rating method. Ultrasound parameters investigated were (1) common carotid artery (CCA) diameter and intima-media thickness, (2) blood flow velocity in the CCA and internal carotid artery (ICA), and (3) blood flow velocity and pulsatility index of middle cerebral artery (MCA). Results. A total of 52 patients fulfilled the study inclusion criteria (mean age 71.4 ± 4.5 years, 54% men, median WMH-score: 20). The only two ultrasound parameters that were independently associated with WMH score in multivariate linear regression models adjusting for demographic characteristics and vascular risk factors were increased mean common carotid artery (CCA) diameter (beta = 0.784, SE = 0.272, P = 0.006, R2 = 23.9%) and increased middle cerebral artery pulsatility index (MCA-PI; beta = 0.262, SE = 0.110, P = 0.025, R2 = 9.0%). Among all ultrasound parameters the highest AUC (areas under the receiver operating characteristic curve) were documented for MCA-PI (AUC = 0.82, 95% CI = 0.68−0.95, P < 0.001) and mean CCA diameter (AUC = 0.80, 95% CI = 0.67−0.92, P < 0.001). Conclusions. Our study showed that in hypertensive individuals with brain SVD the extent of structural changes in cerebral microcirculation as reflected by WMHs burden is associated with the following ultrasound parameters of cerebral macrocirculation: CCA diameter and MCA-PI.
PMCID: PMC3463900  PMID: 23056917
14.  Mild cognitive impairment: effect of education on the verbal and nonverbal tasks performance decline 
Brain and Behavior  2012;2(5):620-627.
We sought to longitudinally evaluate the potential association of educational level with performance on verbal and nonverbal tasks in individuals with mild cognitive impairment (MCI). We evaluated patients with MCI, age >50 years, no medication intake, absent vascular risk factors, and no lesions on brain magnetic resonance imaging (MRI). Each patient underwent a clinical assessment packet and a series of neuropsychological tests of the language and constructional praxis subtests of Cambridge Cognitive Examination (CAMGOG) and the Boston naming test (BNT), at baseline, 6 months, and 12 months. Educational levels were defined taking into account the total years of education, the school level, and diplomas. MCI patients with low education level showed a stepwise reduction in scores of naming objects (NO; P = 0.009), definition (DF; P = 0.012), language (LT; P = 0.021), constructional praxis (CD; P = 0.022), confrontation naming skills (BXB; P = 0.033), phonemic help (BFB; P = 0.041), and BNT (P = 0.002). Analysis of covariance, controlling for baseline scores, showed that education was associated with NO score (P = 0.002), DF score (P = 0.005), LT (P = 0.008), CD score (P = 0.008), BXB score (44.36 ± 1.84, P = 0.0001), BFB (P = 0.022), and BNT (P = 0.004). Our findings indicate that education appeared to affect verbal and nonverbal task performance in MCI patients. Despite the fact that higher educated patients are more acquainted with the tasks, slower deterioration in consecutive follow-up examinations could be explained by the cognitive reserve theory. The potential association of this protective effect with delayed onset of symptoms deserves further investigation.
PMCID: PMC3489814  PMID: 23139907
Cognitive reserve; mild cognitive impairment; nonverbal; verbal
15.  Real-Time Hemodynamic Assessment of Downstream Effects of Intracranial Stenoses in Patients with Orthostatic Hypoperfusion Syndrome 
Arterial flow velocity changes on transcranial Doppler can reflect changes in cerebral flow during position-induced ischemia if obtained during short-term monitoring of positional changes.
Subjects and Methods
Our multicenter group monitored symptomatic and asymptomatic arteries in patients with recurrent neurological deficits during positional changes and documented intracranial arterial stenosis. Bilateral posterior cerebral and middle cerebral arteries were monitored dependent on clinical symptom localization. The symptomatic artery was monitored distal to the intracranial stenosis, and mean flow velocities (MFV) were recorded at different body positions. The symptomatic artery relative MFV ratio was defined as the ratio of symptomatic artery MFV in the asymptomatic position – MFV in the symptomatic position/MFV in the asymptomatic position.
Sixteen patients underwent transcranial Doppler monitoring: mean age 62 ± 19 years, 11 (69%) men, 6 (40%) with transient ischemic attacks. Ten patients (63%) had posterior and 6 anterior circulation symptoms. Patients developed neurological symptoms while standing up (63%) and/or sitting (44%), walking (13%) or during neck extension (6%). Symptomatic artery MFV dropped by ≥25% from the resting to the symptomatic position in all patients except for one. The mean symptomatic artery MFV relative ratio was higher compared with the mean asymptomatic artery MFV relative ratio: 0.5 ± 0.28 versus −0.02 ± 0.1 (p = 0.001, Wilcoxon test). The symptomatic artery relative ratio of >0.25 had a 94% sensitivity and 100% specificity for predicting neurological symptom development during testing (κ = 0.9, p < 0.001).
A significant reduction in intracranial flow velocity distal to an intracranial stenosis can identify patients whose symptoms can worsen with positional changes. These patients may prove a target for interventional revascularization techniques.
PMCID: PMC3014861  PMID: 20693790
Intracranial arterial stenosis; Arterial flow velocity; Hypoperfusion
16.  There is No Association between Cardiovascular Autonomic Dysfunction and Peripheral Neuropathy in Chronic Hemodialysis Patients 
Background and Purpose
The potential association between the severity of autonomic dysfunction and peripheral neuropathy has not been extensively investigated, with the few studies yielding inconsistent results. We evaluated the relationship between autonomic dysfunction and peripheral neuropathy in chronic hemodialysis patients in a cross-sectional study.
Cardiovascular autonomic function was assessed in 42 consecutive patients with chronic renal failure treated by hemodialysis, using a standardized battery of 5 cardiovascular reflex tests. Symptoms of autonomic dysfunction and of peripheral neuropathy were evaluated using the Autonomic Neuropathy Symptom Score (ANSS) and the Neuropathy Symptoms Score. Neurological deficits were assessed using the Neuropathy Disability Score. Conduction velocities along the sensory and motor fibers of the sural and peroneal nerves were measured. Thermal thresholds were documented using a standardized psychophysical technique.
Parasympathetic and sympathetic dysfunction was prevalent in 50% and 28% of cases, respectively. Peripheral neuropathy was identified in 25 cases (60%). The prevalence of peripheral neuropathy did not differ between patients with impaired (55%) and normal (75%) autonomic function (p=0.297; Fisher's exact test). The electrophysiological parameters for peripheral nerve function, neuropathic symptoms, abnormal thermal thresholds, age, gender, and duration of dialysis did not differ significantly between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were more likely to have an abnormal ANSS (p=0.048). The severity of autonomic dysfunction on electrophysiological testing was positively correlated with ANSS (r=0.213, p=0.036).
The present data indicate that although cardiovascular autonomic dysfunction is prevalent among patients with chronic renal failure, it is not associated with the incidence of peripheral neuropathy.
PMCID: PMC2950919  PMID: 20944815
autonomic dysfunction; hemodialysis; neuropathy; cardiovascular reflexes
17.  Validity and Reliability of the Greek Version of the Multiple Sclerosis International Quality-of-Life Questionnaire 
Background and Purpose
There are no data regarding psychometrically validated, health-related quality-of-life instruments designed specifically for patients with multiple sclerosis (MS) in Greece. Recently, the MS International Quality-of-Life questionnaire (MusiQoL), a multidimensional, self-administered questionnaire, which is available in 14 languages (including Greek), has been validated using a large international sample. We investigated the validity and reliability of the Greek version of the MusiQoL.
Consecutive patients with different types and severities of MS were recruited from two tertiary-care centers in Greece. All patients completed the MusiQoL, the Short-Form-36 quality-of-life questionnaire (SF-36), and a symptom checklist at baseline and 21±7 days (mean±SD) later. Data regarding sociodemographic status, MS history, and functional outcome were also collected prospectively. Construct validity, internal consistency, reproducibility, and external consistency were tested.
A total of 92 patients was evaluated. The construct validity was confirmed in terms of satisfactory item-internal consistency correlations and scaling success (87.5-100%) of item-discriminant validity. The dimensions of the MusiQoL exhibited high internal consistency (Cronbach's alpha: 0.63-0.96), and reproducibility was satisfactory (intraclass correlation coefficients: 0.69-0.99). External validity testing indicated that the MusiQoL correlated significantly with all SF-36 dimension scores (Spearman's correlation: 0.43-0.76).
The Greek version of the MusiQoL appears to be a valid and reliable instrument for measuring quality of life in Greek MS patients.
PMCID: PMC2806539  PMID: 20076798
epilepsy; quality of life; questionnaire; Greece
18.  A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke 
Background and Purpose
Ultrasound transiently expands perflutren-lipid microspheres (µS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated µS with systemic tissue plasminogen activator (tPA).
Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL µS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours.
Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. µS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, µS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of µS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456.
Perflutren µS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further µS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.
PMCID: PMC2707058  PMID: 18356546
microspheres; thrombolysis; stroke; occlusion; transcranial Doppler
19.  Role of Multimodal Evaluation of Cerebral Hemodynamics in Selecting Patients with Symptomatic Carotid or Middle Cerebral Artery Steno-occlusive Disease for Revascularization 
The circle of Willis provides collateral pathways to perfuse the affected vascular territories in patients with severe stenoocclusive disease of major arteries. The collateral perfusion may become insufficient in certain physiological circumstances due to failed vasodilatory reserve and intracranial steal phenomenon, so-called ‘Reversed-Robinhood syndrome’. We evaluated cerebral hemodynamics and vasodilatory reserve in patients with symptomatic distal internal carotid (ICA) or middle cerebral artery (MCA) severe steno-occlusive disease.
Diagnostic transcranial Doppler (TCD) and TCD-monitoring with voluntary breath-holding according to a standard scanning protocol were performed in patients with severe ICA or MCA steno-occlusive disease. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. Patients with exhausted vasomotor reactivity and intracranial steal phenomenon during breath-holding were further evaluated by 99technetiumm-hexamethyl propylene amine oxime single photon emission computed tomography (HMPAO-SPECT) with acetazolamide challenge.
Sixteen patients (age 27–74 years, 11 men) fulfilled our TCD criteria for exhausted vasomotor reactivity and intracranial steal phenomenon during the standard vasomotor testing by breath holding. Acetazolamide-challenged HMPAO-SPECT demonstrated significant hypoperfusion in 12 patients in affected arterial territories, suggestive of failed vasodilatory reserve. A breath-holding index of ≤0.3 on TCD was associated with an abnormal HMPAO-SPECT with acetazolamide challenge. TCD findings of a breath holding index of ≤0.3 and intracranial steal during the procedure were determinants of a significant abnormality on HMPAO-SPECT with acetazolamide challenge.
Multimodal evaluation of cerebral hemodynamics in symptomatic patients with severe steno-occlusive disease of the ICA or MCA is helpful in the identification and quantification of failed vasodilatory reserve. This approach may be useful in selecting patients for possible revascularization procedures.
PMCID: PMC3317325  PMID: 22518232
Transcranial Doppler; cerebrovascular reserve; acetazolamide challenge; single photon emission computed tomography; revascularization
20.  Cerebral Hemodynamics in Acute Stroke: Pathophysiology and Clinical Implications 
The capacity of the brain to regulate its blood flow in order to meet metabolic demands and to compensate for acute and chronic changes in cerebral perfusion pressure (cerebral autoregulation) is an essential protecting mechanism against cerebral ischemia.
We reviewed existing data on methods of assessing cerebral blood flow and autoregulation.
Cerebral autoregulation is mechanistically complex and depends on myogenic, neuronal, endothelial, and metabolic factors. There are numerous methods of estimating cerebrovascular reserve (CVR) non-invasively including Positive Emission Tomography (gold standard), Transcranial Doppler ultrasound, dynamic contrast-enhanced perfusion Magnetic Resonance Imaging, Single-Photon Emission Computed Tomography and Xenon Computed Tomography. Since each of these techniques has its advantages and disadvantages, selection of a specific method for CVR testing depends on availability, acquired experience in interpreting the study, required precision, and cost. Cerebral autoregulation may be impaired in patients with symptomatic or asymptomatic carotid stenosis or occlusion and is associated with a higher risk of stroke or transient ischemic attack (TIA) ipsilateral to the carotid artery disease.
Assessment of CVR can help stratify patients based on their risk of stroke or TIA and select patients who may benefit from revascularization therapies. Cerebral vasoreactivity testing may be useful to evaluate cerebral autoregulation after revascularization procedures as a surrogate endpoint of vascular events related to hypoperfusion or hyperperfusion.
PMCID: PMC3317296  PMID: 22518224
Regional cerebral blood flow; autoregulation; cerebral ischemia; cerebral blood volume; cerebral perfusion pressure
21.  Ultrasound Enhanced Thrombolysis: Applications in Acute Cerebral Ischemia 
Intravenous tissue plasminogen activator (TPA) improves patient chances to recover from stroke by inducing mostly partial recanalization of large intracranial thrombi. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. The international multi-center CLOTBUST trial showed that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming multi-disciplinary experimental research conducted worldwide for the past 30 years.
In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared to 8% who received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, subject for a pivotal trial. However, different results were achieved in a small TRUMBI trial and another study that used Transcranial Color-Coded Duplex Sonography (TCCD). Adverse bio-effects of mid-KHz (300) ultrasound promote bleeding, including brain areas not-affected by ischemia while exposure to multi-frequency / multi-element duplex ultrasound resulted in a trend towards higher risk of hemorrhagic transformations.
To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single beam 2 MHz TCD with perflutren-lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter). Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.
PMCID: PMC2686927  PMID: 19513336
TPA; Transcranial Doppler; Stroke; Thrombolysis; Outcomes
22.  Intraoperative radial nerve injury during coronary artery surgery – report of two cases 
Peripheral nerve injury and brachial plexopathy are known, though rare complications of coronary artery surgery. The ulnar nerve is most frequently affected, whereas radial nerve lesions are much less common accounting for only 3% of such intraoperative injuries.
Case presentations
Two 52- and 50-year-old men underwent coronary artery surgery. On the first postoperative day they both complained of wrist drop on the left. Neurological examination revealed a paresis of the wrist and finger extensor muscles (0/5), and the brachioradialis (4/5) with hypoaesthesia on the radial aspect of the dorsum of the left hand. Both biceps and triceps reflexes were normoactive, whereas the brachioradialis reflex was diminished on the left. Muscles innervated from the median and ulnar nerve, as well as all muscles above the elbow were unaffected. Electrophysiological studies were performed 3 weeks later, when muscle power of the affected muscles had already begun to improve. Nerve conduction studies and needle electromyography revealed a partial conduction block of the radial nerve along the spiral groove, motor axonal loss distal to the site of the lesion and moderate impairment in recruitment with fibrillation potentials in radial innervated muscles below the elbow and normal findings in triceps and deltoid. Electrophysiology data pointed towards a radial nerve injury in the spiral groove. We assume external compression as the causative factor. The only apparatus attached to the patients' left upper arm was the sternal retractor, used for dissection of the internal mammary artery. Both patients were overweight and lying on the operating table for a considerable time might have caused the compression of their left upper arm on the self retractor's supporting column which was fixed to the table rail 5 cm above the left elbow joint, in the site where the radial nerve is directly apposed to the humerus.
Although very uncommon, external compression due to the use of a self retractor during coronary artery surgery can affect – especially in obese subjects – the radial nerve within the spiral groove leading to paresis and should therefore be included in the list of possible mechanisms of radial nerve injury.
PMCID: PMC1697803  PMID: 17147818

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