The Role of White Matter Damage in the Risk of Periprocedural Diffusion-Weighted Lesions after Carotid Artery Stenting.

BACKGROUND: White matter hyperintensities (WMH) are a common finding in aged individuals affected by carotid artery disease and are a risk factor for first-ever and recurrent stroke. We investigated if white matter damage increases the risk of brain microembolism during carotid artery stenting (CAS), as evaluated by the appearance of new areas of restricted diffusion on diffusion-weighted images (DWI). METHODS: We evaluated 47 patients with severe internal carotid artery (ICA) stenosis undergoing CAS, comparing preprocedural clinical, ultrasound and radiological characteristics. WMH volume was computed on FLAIR images before CAS. After CAS, the DWI scan was looked over for areas of restricted diffusion (DWI lesions). A first univariate analysis was adopted to compare groups according to the occurrence of DWI lesions. Then, the variable DWI lesion was modelled by means of a logistic regression model. RESULTS: Seventeen patients developed at least 1 DWI lesion after CAS. Compared with non-DWI, DWI patients were more commonly treated in the left ICA (p = 0.007) and had a more severe WMH damage (p = 0.027). Indeed, the risk of a DWI lesion was higher in left versus right stenosis (OR = 9.0, 95% CI 1.9-42.7, p = 0.005) and increased for each log-unit of WMH lesion load (OR = 7.05, 95% CI 1.07-46.49, p = 0.042). A WMH lesion load of at least 5.25 cm3 had a 50% probability of occurrence of a new DWI lesion. CONCLUSIONS: Treated side and preexisting white matter damage are risk conditions for brain microembolism during CAS. This should be taken into account to optimize severe carotid artery disease management.

Cortical ischemic lesion burden measured by DIR is related to carotid artery disease severity.

BACKGROUND: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. METHODS: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). RESULTS: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). CONCLUSIONS: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored.

Acute hyperglycemia reduces cerebrovascular reactivity: the role of glycemic variability.

CONTEXT: Cerebral vasomotor reactivity (CVR) is reduced in patients with diabetes mellitus (DM), and glucose variability (GV) might be responsible for cerebrovascular damage. OBJECTIVE: Studying patients with insulin resistance without DM, we explored the role of GV in impairing CVR. PATIENTS: We studied 18 metabolic syndrome (MS) patients without DM, 9 controls (C), and 26 patients with DM. MAIN OUTCOME MEASURES: Groups were compared in terms of CVR, GV, and 24-hour blood pressure. To evaluate the impact of acute hyperglycemia on CVR, a hyperglycemic clamp was performed in MS patients and controls. RESULTS: Baseline CVR was reduced in DM vs C and MS (C vs DM = 20.2, 95% CI = 3.5-36.9, P = .014; and MS vs DM = 22.2, 95% CI = 8.6-35.8, P = .001), but similar between MS and C (MS vs C = 2.0, 95% CI = -14.7 to 18.7, P = .643). During acute hyperglycemia, CVR fell in MS and C to values comparable to DM. GV progressively increased from C to MS to DM. In MS, CVR at 120 minutes and GV displayed a negative correlation (r = -0.48, P = .043), which did not change after controlling for mean 24-hour systolic and diastolic blood pressure. In MS, the CVR reduction was significantly correlated to GV (r = 0.55, P = .02). CONCLUSIONS: GV is increased in patients with MS but without DM and is the major predictor of CVR reduction induced by acute hyperglycemia, possibly representing the earliest cause of cerebrovascular damage in DM.

Diffusion-weighted lesions after carotid artery stenting are associated with cognitive impairment.

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

Lack of correlation between cerebral vasomotor reactivity and flow-mediated dilation in subjects without vascular disease.

Cerebral vasomotor reactivity (CVR) represents the capability of cerebral vessels to modify their caliber in response to a stimulus. Impaired CVR is associated with an increased risk for ischemic events in patients with carotid disease. Endothelial dysfunction is considered an important pathogenic factor for atherosclerosis and can be noninvasively assessed by flow-mediated vasodilation (FMD) evaluation. We aimed to evaluate both CVR and FMD in patients without histories of vascular disease in order to define a possible correlation. FMD was measured as brachial artery flow and diameter changes induced by transient ischemia. CVR to hypercapnia was assessed in all subjects by means of a breath-holding test and, in 20 subjects, by an additional CO(2) inhalation test. In 30 healthy volunteers (60% women, mean age 56 ± 6 years), CVR and FMD did not appear to be correlated (p = 0.444). A strong association between CO(2)-induced CVR and breath-holding index was observed (p < 0.001). CVR and FMD represent 2 different modalities that evaluate vasomotor function. According to our data, they did not appear to correlate, probably due to physiologic differences between cerebral and peripheral vascular districts and the vasodilatory stimulus used. The carbon dioxide-induced CVR and breath-holding index appeared to be significantly associated.

Cerebral hemodynamics and systemic endothelial function are already impaired in well-controlled type 2 diabetic patients, with short-term disease.

OBJECTIVE: Impaired cerebral vasomotor reactivity (VMR) and flow-mediated dilation (FMD) were found in selected subgroups of type 2 diabetes mellitus (T2DM) patients with long-term disease. Our study aimed to evaluate cerebral hemodynamics, systemic endothelial function and sympatho-vagal balance in a selected population of well-controlled T2DM patients with short-term disease and without cardiac autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS: Twenty-six T2DM patients with short-term (4.40±4.80 years) and well-controlled (HbA1C = 6.71±1.29%) disease, without any complications, treated with diet and/or metformin, were consecutively recruited. Eighteen controls, comparable by sex and age, were enrolled also. RESULTS: FMD and shear rate FMD were found to be reduced in T2DM subjects with short-term disease (8.5% SD 3.5 and 2.5 SD 1.3, respectively) compared to controls (15.4% SD 4.1 and 3.5 SD 1.4; p<.001 and p<.05). T2DM patients also displayed reduced VMR values than controls (39.4% SD 12.4 vs 51.7%, SD 15.5; p<.05). Sympatho-vagal balance was not different in T2DM patients compared to healthy subjects. FMD and shear rate FMD did not correlate with VMR in T2DM patients or in controls (p>.05). CONCLUSIONS: In well-controlled T2DM patients with short-term disease cerebral hemodynamics and systemic endothelial function are altered while autonomic balance appeared to be preserved.

Primary sensory and motor cortex activities during voluntary and passive ankle mobilization by the SHADE orthosis.

This study investigates cortical involvement during ankle passive mobilization in healthy subjects, and is part of a pilot study on stroke patient rehabilitation. Magnetoencephalographic signals from the primary sensorimotor areas devoted to the lower limb were collected together with simultaneous electromyographic activities from tibialis anterior (TA). This was done bilaterally, on seven healthy subjects (aged 29 ± 7), during rest, left and right passive ankle dorsiflexion (imparted through the SHADE orthosis, O-PM, or neuromuscular electrical stimulation, NMES-PM), and during active isometric contraction (IC-AM). The effects of focussing attention on ankle passive movements were considered. Primary sensory (FS(S1)) and motor (FS(M1)) area activities were discriminated by the Functional Source Separation algorithm. Only contralateral FS(S1) was recruited by common peroneal nerve stimulation and only contralateral FS(M1) displayed coherence with TA muscular activity. FS(M1) showed higher power of gamma rhythms (33-90 Hz) than FS(S1). Both sources displayed higher beta (14-32 Hz) and gamma powers in the left than in the right hemisphere. Both sources displayed a bilateral reduction of beta power during IC-AM with respect to rest. Only FS(S1) beta band power reduced during O-PM. No beta band modulation was observed of either source during NMES-PM. Mutual FS(S1)-FS(M1) coherence in gamma2 band (61-90 Hz) showed a slight trend towards an increase when focussing attention during O-PM. Somatosensory and motor counterparts of lower limb cortical representations were discriminated in both hemispheres. SHADE was effective in generating repeatable dorsiflexion and inducing primary sensory involvement similarly to voluntary movement.

Is there a role of near-infrared spectroscopy in predicting the outcome of patients with carotid artery occlusion?

BACKGROUND: Transcranial Doppler (TCD) studies demonstrated that cerebral vasomotor reactivity (VMR) can predict the outcome of carotid artery occlusion (CAO). Near-infrared spectroscopy (NIRS) is a non-invasive optical method for assessing hemoglobin (Hb) oxygenation parameters. The purpose of this study was to evaluate the role of NIRS parameters as prognostic markers of stroke occurrence in patients with CAO. METHODS: Sixty-five patients (46 men, mean age 68.8 years) with CAO were enrolled. Forty-two patients had previous cerebrovascular events (15 TIA, 27 minor stroke), the remaining 23 were asymptomatic. All subjects underwent simultaneous TCD and NIRS examination at rest and after hypercapnia. All patients completed follow-up (median, 36 months). RESULTS: During follow-up, 11 strokes occurred. Cerebral VMR measured by TCD had a prognostic role in stroke occurrence (p=0.042). The increase in Hb oxygen saturation detected by NIRS during hypercapnia predicted the occurrence of new cerebrovascular events, although without an overt significance (p=0.058). Hb oxygen saturation at rest, however, failed to be of prognostic value (p=0.65). CONCLUSIONS: NIRS is potentially useful in monitoring cerebral oxygenation; however, at present NIRS does not effectively predict the outcomes of stroke or vascular death in patients with CAO. This study does confirm the primary role of TCD VMR in the outcome of carotid disease.

Neuronal functionality assessed by magnetoencephalography is related to oxidative stress system in acute ischemic stroke.

The hypoxic brain damage induced by stroke is followed by an ischemia-reperfusion injury modulated by oxidative stress. Magnetoencephalographic (MEG) recording of rest and evoked cortical activities is a sensitive method to analyse functional changes following the acute ischemic damage. We aimed at investigating whether MEG signals are related to oxidative stress compounds in acute stroke. Eighteen stroke patients and 20 controls were enrolled. All subjects underwent MEG assessment to record background activity and somatosensory evoked responses (M20 and M30) of rolandic regions, neurological examination assessed by National Institute of Health Stroke Scale (NIHSS) and plasmatic measurement of copper, iron, zinc, ceruloplasmin, transferrin, total peroxides and Total Anti-Oxidant Status. Magnetic Resonance was performed to estimate the lesion site and volume. Delta power and M20 equivalent current dipole (ECD) strength in the affected hemisphere (AH) correlated with NIHSS scores (respectively, rho=.692, p=.006 and rho=-.627, p=.012) and taken together explained 67% of NIHSS variability (p=.004). Higher transferrin and lower peroxides levels correlated with better clinical status (respectively, rho=-.600, p=.014 and rho=.599, p=.011). Transferrin also correlated with AH M20 ECD strength (rho=.638 p=.014) and inversely with AH delta power (rho=-.646 p=.023) and the lesion volume, especially in cortico-subcortical stroke (p=.037). Our findings strengthen MEG reliability in honing the evaluation of neuronal damage in acute ischemic stroke also demonstrating an association between the MEG parameters most representing the clinical status and the oxidative stress compounds. Our results meet at a possible protective role of transferrin in limiting the oxidative damage in acute stroke.

Hemoglobin oxygen saturation as a marker of cerebral hemodynamics in carotid artery occlusion: an integrated transcranial doppler and near-infrared spectroscopy study.

Cerebral hemodynamics play a pivotal role in stroke pathogenesis. Transcranial Doppler (TCD) studies demonstrated the importance of cerebral vasomotor reactivity (VMR) on the outcome of carotid artery occlusion (CAO). So far, positron emission tomography represents the best technique for detecting both hemodynamic and metabolic aspects of cerebral perfusion adaptive processes in cerebrovascular patients. Near-infrared spectroscopy (NIRS) is a new method allowing for a non-invasive assessment of cerebral blood flow and hemoglobin (Hb) oxygenation parameters.A recent TCD and NIRS study demonstrated that patients with symptomatic CAO had lower VMR values measured by TCD and lower oxygen saturation (oxygen%) increases detected by NIRS than asymptomatic ones. The parameters were obtained simultaneously after CO(2) inhalation. The present study aims to investigate if Hb oxygen % could represent also at rest a marker of hemodynamic status in carotid disease.Thirty-five symptomatic and 17 asymptomatic patients with CAO underwent a simultaneous examination by means of TCD and NIRS at rest condition and during CO(2) reactivity test. Symptomatic patients presented with oxygen% values at rest higher (p = 0.001) and VMR values lower (p < 0.001) than asymptomatic subjects. According to a logistic model, for each unitary VMR increase, the odds of being symptomatic decreases of about 10% (OR = 0.9, p = 0.001); for each unitary increase of oxygen% at baseline, this odd increases of about 23% (OR = 1.23, p = 0.031). In addition to TCD VMR values, oxygen hemoglobin saturation at rest detected by NIRS can discriminate symptomatic from asymptomatic patients with CAO. NIRS can add an important contribution to explain pathophysiological mechanisms of stroke occurrence.

Transient athetosis induced by tiagabine.

Movement disorders have been reported with use of different antiepileptic drugs (AEDs). We report a 32-year-old woman, affected by a symptomatic focal drug-resistant epilepsy and a mild hemiparesis, with acute athetoid movements, transiently linked to increasing tiagabine (TGB) therapy. To our knowledge, no other cases of acute athetosis related to TGB have been reported to date. However, we cannot rule out the possibility that involuntary movements were induced by an interaction between TGB and concomitant AEDs, in particular phenobarbital (PB), possibly by increasing GABAergic transmission. We hypothesize that the presence of a static encephalopathy may have influenced the kind of extrapyramidal side effect induced by TGB in our patient, leading to athetosis.

Transcranial Doppler and near-infrared spectroscopy can evaluate the hemodynamic effect of carotid artery occlusion.

BACKGROUND AND PURPOSE: Cerebral hemodynamic and metabolic changes can compensate for the decrease in cerebral blood flow occurring in patients with carotid occlusive disease. At present, a complete assessment of the cerebral adaptive status is only possible with positron-emission tomography. Near-infrared spectroscopy (NIRS) is a noninvasive technique that, providing a real time assessment of fluctuations in cerebral hemoglobin, has been used to estimate the cerebral blood volume and to measure cerebral vasomotor reactivity (VMR). Moreover, NIRS technology, by allowing the absolute measurement of absorption and scattering coefficients of brain, can determine the oxyhemoglobin and deoxyhemoglobin concentrations in situ in the blood stream. METHODS: In order to evaluate different aspects of the cerebral hemodynamic status, 27 subjects with symptomatic and asymptomatic carotid artery occlusion and 30 healthy subjects underwent a simultaneous examination by means of transcranial Doppler (TCD), able to reliably detect collateral circulation and VMR, and NIRS at rest condition and during CO2 reactivity test. RESULTS: The main finding of this study was the demonstration of a difference between asymptomatic and symptomatic patients in terms of mean flow velocity increase (52.4% versus 21.0%; P<0.001) estimated by TCD and of hemoglobin saturation increase measured by NIRS (6.8% versus 3.8%; P=0.015). CONCLUSIONS: The opportunity to perform NIRS and TCD simultaneously provides useful information about both hemodynamic and metabolic cerebral adaptive status in patients with occlusive disease in a simple, noninvasive, and reliable way.