Vittorio Di Piero

Detection of Carotid Adventitial Vasa Vasorum and Plaque Vascularization With Ultrasound Cadence Contrast Pulse Sequencing Technique and Echo-Contrast Agent

Background and Purpose— Adventitial vasa vasorum and plaque vascularization have been established as predictors of unstable atheromasic lesions in cerebro- and cardiovascular patients. Ultrasound contrast agents provide reliable information on tissue perfusion and microcirculation. We used contrast ultrasound duplex scanning to identify carotid plaque vascularization. Methods— Contrast carotid duplex scanning was performed in 23 patients with plaques of different degree of stenosis and echogenicity. Results— Plaque vascularization was detected in the fibrous and fibro-fatty tissue and not observed in the calcific nor in the necrotic and hemorrhagic tissue. Constantly, a small vessel was observed under ulcerations. Conclusions— Carotid contrast ultrasound imaging appears to be an emerging technique for identifying plaque angiogenesis. Further studies are needed to clarify the role of plaque angiogenesis for assessing cerebrovascular risk and to monitor effects of therapies aimed to plaque remodelling.

A cerebral blood flow study on tonic pain activation in man

&NA; This study examined brain areas involved in tonic pain perception. Cerebral blood flow was assessed by dynamic Xenon‐133 inhalation single‐photon emission tomography (SPET) in 7 healthy right‐handed male volunteers undergoing the cold pressor test (CPT). In single experimental sessions, each subject was scanned twice, once in the resting state and once while immersing the left hand in freezing water (0°C ± 1). Immersion of the hand induced severe pain (visual analogue scale: 6.9 ± 1.9) in all subjects. After correction for pCO2, cerebral blood flow was analyzed by placing a template of square regions of interest (ROIs) over 5 selected tomographic slices. Relative to the resting‐state values, during the CPT, flow determinations revealed a 7–8% regional blood flow increase in the contralateral frontal lobe and bilateral temporal regions and a 15% flow increase in a ROI located over the primary sensorimotor cortex in the tomogram at 80 mm above the orbito‐meatal line (corresponding to the cortical somatotopic representation of the hand) contralateral to the stimulated side. The tonic pain induced by the CPT thus appears to activate the contralateral frontal and bilateral temporal regions and more prominently, the primary sensorimotor cortex. This pattern of activation suggests that tonic painful stimuli activate the cortex partly via complex circuits and partly via direct somatosensory pathways.

Correlates of leukoaraiosis and ventricular enlargement on magnetic resonance imaging: A study in normal elderly and cerebrovascular patients

Several studies have repeatedly demonstrated that leukoaraiosis as well as ventricular enlargement are common findings in normal elderly and in stroke patients, although there is no general consensus on prevalence rate as well as on their clinical correlations. It is also controversial whether white matter changes and ventricular enlargement are reciprocally related. In this study we investigated the prevalence and extent of white matter hyperintensities and the degree of ventricular enlargement on magnetic resonance imaging in 50 normal elderly individuals (mean age 62.1 ± 7.3 years) and in 50 consecutive chronic ischemic stroke patients (mean age 66.1 ± 7.7 years). All subjects underwent extensive clinical assessment. White matter hyperintensities were graded from 0 to 3 on a semi‐quantitative scale, while bifrontal horn, bicaudate, and third ventricle ratio indices were used as measures of brain atrophy. Hypertension, diabetes, alcohol consumption, cardiac disease, carotid pathology occurred significantly more often in patients than in controls. Prevalence rates of white matter hyperintensities were 30% in controls and 82% in patients. Patients had significantly larger ventricular indices than controls. Significant univariate correlations for the extent of white matter hyperintensities were found with age, sex, hypertension, cardiac disease, carotid pathology, diabetes, history of stroke and ventricular enlargement. Age, sex, cardiac disease, alcohol habit, cerebrovascular disease and extent of white matter hyperintensities correlated with severity of ventricular enlargement. Multivariate regression analysis identified age, hypertension and history of stroke as independent predictors of white matter hyperintensities, while history of stroke, age and alcohol consumption were found as the only independent predictors of ventricular enlargement Separate analysis between periventricular, subcortical or deep white matter hyperintensities and each of the three ventricular indices failed to show a significant association after adjustment for clinical and demographic factors. We suggest that leukoaraiosis and ventricular enlargement are independent pathological processes associated with different risk factors in addition to age and stroke disease.

Clinical, Cognitive, and Neurophysiologic Correlates of Short-Term Treatment with Carbamazepine, Oxcarbazepine, and Levetiracetam in Healthy Volunteers

BACKGROUND The adverse effects of the antiepileptic drugs (AEDs) originally developed are well known, while those of the newer AEDs remain unclear. OBJECTIVE To investigate clinical, cognitive, and neurophysiologic effects of carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. METHODS A double-blind crossover study was conducted in 10 volunteers. Eight-day treatment with carbamazepine, oxcarbazepine, levetiracetam, or placebo was administered in random order. Drug doses were titrated gradually to the daily target doses on day 7: carbamazepine 800 mg, oxcarbazepine 1200 mg, and levetiracetam 1500 mg. At baseline and at the end of each treatment period, participants underwent cognitive and neurophysiologic assessment. A washout period of 14 days between treatment periods was conducted. RESULTS More adverse events were self-reported with carbamazepine (63%) than the other treatments (oxcarbazepine 12%, levetiracetam 20%, placebo 5%; p < 0.001 between the 4 groups). Carbamazepine induced the greatest motor slowing (p = 0.002), followed by oxcarbazepine (p = 0.01). Levetiracetam left baseline motor speed unchanged. All AEDs increased attention span from baseline values as shown on the Stroop test. Quantitative electroencephalogram (EEG) analysis showed that carbamazepine significantly increased the delta–theta power and reduced the frequency of alpha rhythm; oxcarbazepine induced smaller changes than carbamazepine. Levetiracetam did not change any EEG measurements. On color visually evoked potential (VEP) tests, carbamazepine induced a constant slowing of P1 latency, while oxcarbazepine induced changes only after the blue–black pattern. All color VEP measures for volunteers receiving levetiracetam were almost unchanged. CONCLUSIONS After short-term treatment in healthy volunteers, carbamazepine induced major clinical and neurophysiologic changes. Oxcarbazepine was better tolerated than carbamazepine. Levetiracetam interfered least with clinical and neurophysiologic test results.

Monitoring After the Acute Stage of Stroke A Prospective Study

Background and Purposes— In the early stage of stroke, the occurrence of neurologic and medical complications is associated with clinical deterioration. Previous studies were focused on the first week after stroke onset. The aim of this study was to evaluate the impact of complications on clinical outcome in patients with stroke in the early subacute stage. Methods— We prospectively evaluated the influence on the outcome of complications feasible (MC) and not feasible for monitoring (NMC) in all patients with stroke admitted consecutively in our subacute stroke unit. Patients were divided into three classes according to stroke severity evaluated by the National Institutes of Health Stroke Scale score. A change in the National Institutes of Health Stroke Scale score group from admission to discharge was considered clinically significant. Results— We included 261 patients. Sixty percent of patients had complications (105 MC, 118 NMC). Hyperthermia (OR=14.12; 95% CI: 6.01 to 33.20), urinary infections (OR=4.92; 95% CI: 2.19 to 11.04), hypertension (OR=2.86; 95% CI: 1.21 to 6.76), hypoxia (OR=15.75; 95% CI: 6.73 to 36.84), and neuroradiologic damage progression (OR=58.31; 95% CI, 19.48 to 174.55) were associated with a change to a more severe class at discharge and with a higher risk of mortality. Conclusions— A high percentage of patients can develop both MC and NMC during this subacute stage of stroke. The occurrence of complications influences outcome and raises the question about the need for a prolonged stay in a dedicated ward for patients with stroke.

Tonic pain: a SPET study in normal subjects and cluster headache patients

Abstract Whether the pathogenesis of cluster headache (CH) is peripheral or central is still matter of debate. An involvement of central structures related to pain perception and modulation, which also causes an alteration of the physiological pattern of pain perception in CH, has been hypothesized. We investigated the pattern of brain response to pain in normal subjects and CH patients by evaluating the cerebral blood flow (CBF) changes using an experimental model of tonic aching pain stimulation, the cold water pressor test (CWPT). CBF was assessed quantitatively by the Xe‐133 inhalation method and single photon emission tomography (SPET), at rest and during CWPT, as previously described (Di Piero et al., 1994). CWPT was performed in 12 volunteers and in seven patients with CH. All the CH patients had a left‐sided headache and were studied in a headache‐free phase out of the cluster period. During CWPT, volunteers showed a significant CBF increase in the contralateral primary sensorimotor (P<0.001), frontal (P<0.01) and temporal (P<0.002) regions and thalamus (P<0.01) and in the ipsilateral temporal (P<0.005) and anterior cingulate (P<0.01) regions. During left‐hand stimulation (ipsilateral to the headache side) by CWPT in CH patients, CBF changes were significantly lower than those observed in volunteers in the contralateral primary sensorimotor region (P<0.0005) and thalamus region (P<0.01). There were no significant differences in the brain response observed during the stimulation of the hand contralateral to the headache side. In conclusion, in a headache‐free phase out of the cluster period, the pattern of cerebral activation during tonic pain stimulation of the hand ipsilateral to the headache side is critically modified in CH patients in areas which are probably involved in the detection of the stimulus intensity. This modification may reflect a marker of a biological modification of the pain conveyance system. The fact that it is also present out of the active period of the disease, suggests a possible involvement of central tonic pain mechanisms in the pathogenesis of CH.

Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine

BackgroundPreventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing.ObjectiveTo study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention.MethodsWe recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy.ResultsIn HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication intake significantly decreased during the treatment period compared to pre-treatment baseline (all p < 0.05), and this benefit persisted on average 4.8 weeks after the end of tDCS.ConclusionsAnodal tDCS over the visual cortex is thus able to increase habituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs, who on average lack habituation interictally. Moreover, 2 weekly sessions of anodal tDCS had a significant preventive anti- migraine effect, proofing the concept that the low preactivation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation. The therapeutic results indicate that a larger sham-controlled trial using the same tDCS protocol is worthwhile.

MRI Findings in Lymphomatosis Cerebri: Description of a Case and Revision of the Literature

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma; we report a case of LC mainly involving the brainstem and cerebellum. This diagnosis should be considered in patients presenting with diffuse white matter disease, and a subacute clinical history of cognitive deficits, ataxic gait, and personality changes. We present our findings along with a review of the neuroradiological literature.

Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials.

ABSTRACT Nitroglycerin (NTG), a NO donor, induces an attack in migraine patients approximately 4–6 h after administration. The causative mechanisms are not known, but the long delay leaves room for a central effect, such as a change in neuronal excitability and synaptic transmission of various CNS areas involved in pain and behaviour including trigeminal nucleus caudalis and monoaminergic brain stem nuclei. To explore the central action of NTG, we have studied its effects on amplitude and habituation of the nociceptive blink reflex (nBR) and the visual evoked potential (VEP) before, 1 h and 4 h after administration of NTG (1.2 mg sublingual) or placebo (vehicle sublingual) in two groups of 10 healthy volunteers. We found a significant decrease in nBR pain and reflex thresholds both 1 and 4 h post‐NTG. At the 4 h time point R2 latency was shorter (p = 0.04) and R2 response area increased (p < 0.01) after NTG but not after placebo. Habituation tended to become more pronounced after both NTG and placebo administration. There was a significant amplitude increase in the 5th VEP block (p = 0.03) at 1 h after NTG and in the 1st block (p = 0.04) at 4 h. VEP habituation was replaced by potentiation at both delays after NTG; the change in habituation slope was significant at 1 h (p = 0.02). There were no significant VEP changes in subjects who received sublingual placebo. In conclusion, we found that in healthy subjects sublingual NTG, but not its vehicle, induces changes in a trigeminal nociceptive reflex and an evoked cortical response which are comparable to those found immediately before and during an attack of migraine. These changes could be relevant for the attack‐triggering effect of NTG in migraineurs.

Common carotid artery intima-media thickness determinants in a population study.

Common carotid artery (CCA) intima‐media thickness (IMT) is considered an atherosclerosis risk marker. Thickening of the intima‐media complex is accelerated by vascular risk factors, in particular, by age and elevated blood pressure. Nonetheless, it also reflects intimal hyperplasia and intimal fibrocellular hypertrophy provoked by nonatherosclerotic mechanisms such as tensile wall stress. The aims of our study were to investigate the relationship between CCA IMT and the presence of vascular risk factors and to correlate CCA IMT with the degree of distal internal carotid artery (ICA) stenosis and the proximal CCA resistive index (RI), representative of wall stress.