Bimanual motor skill learning and robotic assistance for chronic hemiparetic stroke: a randomized controlled trial.

Using robotic devices might improve recovery post-stroke, but the optimal way to apply robotic assistance has yet to be determined. The current study aimed to investigate whether training under the robotic active-assisted mode improves bimanual motor skill learning (biMSkL) more than training under the active mode in stroke patients. Twenty-six healthy individuals (HI) and 23 chronic hemiparetic stroke patients with a detectable lesion on MRI or CT scan, who demonstrated motor deficits in the upper limb, were randomly allocated to two parallel groups. The protocol included a two-day training on a new bimanual cooperative task, LIFT-THE-TRAY, under either the active or active-assisted modes (where assistance decreased in a pre-determined stepwise fashion) with the bimanual version of the REAplan® robotic device. The hypothesis was that the active-assisted mode would result in greater biMSkL than the active mode. The biMSkL was quantified by a speed-accuracy trade-off (SAT) before (T1) and immediately after (T2) training on days 1 and 2 (T3 and T4). The change in SAT after 2 days of training (T4/T1) indicated that both HI and stroke patients learned and retained the bimanual cooperative task. After 2 days of training, the active-assisted mode did not improve biMSkL more than the active mode (T4/T1) in HI nor stroke patients. Whereas HI generalized the learned bimanual skill to different execution speeds in both the active and active-assisted subgroups, the stroke patients generalized the learned skill only in the active subgroup. Taken together, the active-assisted mode, applied in a pre-determined stepwise decreasing fashion, did not improve biMSkL more than the active mode in HI and stroke subjects. Stroke subjects might benefit more from robotic assistance when applied "as-needed." This study was approved by the local ethical committee (Comité d'éthique médicale, CHU UCL Namur, Mont-Godinne, Yvoir, Belgium; Internal number: 54/2010, EudraCT number: NUB B039201317382) on July 14, 2016 and was registered with ClinicalTrials.gov (Identifier: NCT03974750) on June 5, 2019.

Preserved motor skill learning in acute stroke patients.

Recovery is dynamic during acute stroke, but whether new motor skills can be acquired with the paretic upper limb (UL) during this recovery period is unknown. Clarifying this unknown is important, because neurorehabilitation largely relies on motor learning. The aim was to investigate whether, during acute stroke, patients achieved motor skill learning and retention with the paretic UL. Over 3 consecutive days (D1-D3), 14 patients practiced with their paretic UL the CIRCUIT, a motor skill learning task with a speed/accuracy trade-off (SAT). A Learning Index (LI) was used to quantify normalised SAT changes in comparison with baseline. Spontaneous motor recovery was quantified by another task without SAT constraint (EASY), by grip force (GF), and the Box and Blocks test (BBT). In patients, CIRCUIT LI improved 98% ± 66.2 (mean ± SD). This improvement was similar to that of young healthy individuals (n = 30) who trained with a slightly different protocol for 3 consecutive days (83.8% ± 58.8%). Generalisation of SAT gains to an untrained circuit was observed in both groups. From D1 to D3, stroke patients improved their performance on EASY, while changes in GF and BBT were heterogeneous. During acute stroke, patients retained SAT gains for a motor skill learned with the paretic UL in a manner similar to that of healthy individuals. These results demonstrate acute stroke patients achieved motor skill learning and retention that exceeded paretic UL improvements explained by spontaneous recovery.

Learning a Bimanual Cooperative Skill in Chronic Stroke Under Noninvasive Brain Stimulation: A Randomized Controlled Trial.

Background. Transcranial direct current stimulation (tDCS) has been suggested to improve poststroke recovery. However, its effects on bimanual motor learning after stroke have not previously been explored. Objective. We investigated whether dual-tDCS of the primary motor cortex (M1), with cathodal and anodal tDCS applied over undamaged and damaged hemispheres, respectively, improves learning and retention of a new bimanual cooperative motor skill in stroke patients. Method. Twenty-one chronic hemiparetic patients were recruited for a randomized, double-blinded, cross-over, sham-controlled trial. While receiving real or sham dual-tDCS, they trained on a bimanual cooperative task called CIRCUIT. Changes in performance were quantified via bimanual speed/accuracy trade-off (Bi-SAT) and bimanual coordination factor (Bi-Co) before, during, and 0, 30, and 60 minutes after dual-tDCS, as well as one week later to measure retention. A generalization test then followed, where patients were asked to complete a new CIRCUIT layout. Results. The patients were able to learn and retain the bimanual cooperative skill. However, a general linear mixed model did not detect a significant difference in retention between the real and sham dual-tDCS conditions for either Bi-SAT or Bi-Co. Similarly, no difference in generalization was detected for Bi-SAT or Bi-Co. Conclusion. The chronic hemiparetic stroke patients learned and retained the complex bimanual cooperative task and generalized the newly acquired skills to other tasks, indicating that bimanual CIRCUIT training is promising as a neurorehabilitation approach. However, bimanual motor skill learning was not enhanced by dual-tDCS in these patients.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis.

OBJECTIVE: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). METHODS: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2-4, 5-10, and >10 CMBs), using random effects models. RESULTS: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2-12.6 vs 1.1%, 95% CI 0.5-1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1-3 years): OR 3.1 (95% CI 1.4-6.8; p = 0.006), 4.3 (95% CI 1.8-10.3; p = 0.001), and 3.4 (95% CI 1.4-8.3; p = 0.007) for 2-4, 5-10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1-15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. CONCLUSIONS: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.

OBJECTIVE: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. METHODS: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. RESULTS: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. INTERPRETATION: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders.

Increased functional connectivity one week after motor learning and tDCS in stroke patients.

Recent studies using resting-state functional magnetic resonance imaging (rs-fMRI) demonstrated that changes in functional connectivity (FC) after stroke correlate with recovery. The aim of this study was to explore whether combining motor learning to dual transcranial direct current stimulation (dual-tDCS, applied over both primary motor cortices (M1)) modulated FC in stroke patients. Twenty-two chronic hemiparetic stroke patients participated in a baseline rs-fMRI session. One week later, dual-tDCS/sham was applied during motor skill learning (intervention session); one week later, the retention session started with the acquisition of a run of rs-fMRI imaging. The intervention+retention sessions were performed once with dual-tDCS and once with sham in a randomized, cross-over, placebo-controlled, double-blind design. A whole-brain independent component analysis based analysis of variance (ANOVA) demonstrated no changes between baseline and sham sessions in the somatomotor network, whereas a FC increase was observed one week after dual-tDCS compared to baseline (qFDR <0.05, t63=4.15). A seed-based analysis confirmed specific stimulation-driven changes within a network of motor and premotor regions in both hemispheres. At baseline and one week after sham, the strongest FC was observed between the M1 and dorsal premotor cortex (PMd) of the undamaged hemisphere. In contrast, one week after dual-tDCS, the strongest FC was found between the M1 and PMd of the damaged hemisphere. Thus, a single session of dual-tDCS combined with motor skill learning increases FC in the somatomotor network of chronic stroke patients for one week.

Neural substrates underlying motor skill learning in chronic hemiparetic stroke patients.

Motor skill learning is critical in post-stroke motor recovery, but little is known about its underlying neural substrates. Recently, using a new visuomotor skill learning paradigm involving a speed/accuracy trade-off in healthy individuals we identified three subpopulations based on their behavioral trajectories: fitters (in whom improvement in speed or accuracy coincided with deterioration in the other parameter), shifters (in whom speed and/or accuracy improved without degradation of the other parameter), and non-learners. We aimed to identify the neural substrates underlying the first stages of motor skill learning in chronic hemiparetic stroke patients and to determine whether specific neural substrates were recruited in shifters versus fitters. During functional magnetic resonance imaging (fMRI), 23 patients learned the visuomotor skill with their paretic upper limb. In the whole-group analysis, correlation between activation and motor skill learning was restricted to the dorsal prefrontal cortex of the damaged hemisphere (DLPFCdamh: r = -0.82) and the dorsal premotor cortex (PMddamh: r = 0.70); the correlations was much lesser (-0.16 < r > 0.25) in the other regions of interest. In a subgroup analysis, significant activation was restricted to bilateral posterior parietal cortices of the fitters and did not correlate with motor skill learning. Conversely, in shifters significant activation occurred in the primary sensorimotor cortexdamh and supplementary motor areadamh and in bilateral PMd where activation changes correlated significantly with motor skill learning (r = 0.91). Finally, resting-state activity acquired before learning showed a higher functional connectivity in the salience network of shifters compared with fitters (qFDR < 0.05). These data suggest a neuroplastic compensatory reorganization of brain activity underlying the first stages of motor skill learning with the paretic upper limb in chronic hemiparetic stroke patients, with a key role of bilateral PMd.

Neural substrates underlying stimulation-enhanced motor skill learning after stroke.

Motor skill learning is one of the key components of motor function recovery after stroke, especially recovery driven by neurorehabilitation. Transcranial direct current stimulation can enhance neurorehabilitation and motor skill learning in stroke patients. However, the neural mechanisms underlying the retention of stimulation-enhanced motor skill learning involving a paretic upper limb have not been resolved. These neural substrates were explored by means of functional magnetic resonance imaging. Nineteen chronic hemiparetic stroke patients participated in a double-blind, cross-over randomized, sham-controlled experiment with two series. Each series consisted of two sessions: (i) an intervention session during which dual transcranial direct current stimulation or sham was applied during motor skill learning with the paretic upper limb; and (ii) an imaging session 1 week later, during which the patients performed the learned motor skill. The motor skill learning task, called the 'circuit game', involves a speed/accuracy trade-off and consists of moving a pointer controlled by a computer mouse along a complex circuit as quickly and accurately as possible. Relative to the sham series, dual transcranial direct current stimulation applied bilaterally over the primary motor cortex during motor skill learning with the paretic upper limb resulted in (i) enhanced online motor skill learning; (ii) enhanced 1-week retention; and (iii) superior transfer of performance improvement to an untrained task. The 1-week retention's enhancement driven by the intervention was associated with a trend towards normalization of the brain activation pattern during performance of the learned motor skill relative to the sham series. A similar trend towards normalization relative to sham was observed during performance of a simple, untrained task without a speed/accuracy constraint, despite a lack of behavioural difference between the dual transcranial direct current stimulation and sham series. Finally, dual transcranial direct current stimulation applied during the first session enhanced continued learning with the paretic limb 1 week later, relative to the sham series. This lasting behavioural enhancement was associated with more efficient recruitment of the motor skill learning network, that is, focused activation on the motor-premotor areas in the damaged hemisphere, especially on the dorsal premotor cortex. Dual transcranial direct current stimulation applied during motor skill learning with a paretic upper limb resulted in prolonged shaping of brain activation, which supported behavioural enhancements in stroke patients.

White matter perivascular spaces are related to cortical superficial siderosis in cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: We set out to investigate whether MRI-visible centrum semiovale perivascular spaces (CSO-PVS), a potential biomarker of impaired interstitial fluid drainage in sporadic cerebral amyloid angiopathy, is associated with cortical superficial siderosis (cSS), reflecting recurrent hemorrhage from severe leptomeningeal and superficial cortical vascular amyloid. METHODS: Retrospective multicenter cohort study of possible/probable cerebral amyloid angiopathy according to the Boston criteria. PVS were rated in basal ganglia and CSO (CSO-PVS) on axial T2-weighted sequences, using a validated 4-point visual rating scale and were classified as high (score>2) or low degree (score≤2) for prespecified analyses. Independent risk factors for high CSO-PVS degree were investigated in logistic regression. RESULTS: The final cohort consisted of 138 cerebral amyloid angiopathy patients (mean age, 71.8 years; 95% confidence interval, 70.2-73.4 years; 52.2% men). High CSO-PVS degree was present in 61.2% of cases. The prevalence of any cSS, and disseminated cSS (involving >3 sulci), was higher in patients with high versus low CSO-PVS degree (for any cSS 45.9% versus 13.5%; P<0.00005; for disseminated cSS 31.8% versus 0%; P<0.00005). In multivariable logistic regression analysis, cSS presence (odds ratio, 4.78; 95% confidence interval, 1.64-13.87; P=0.004) was an independent predictors of high CSO-PVS degree. We found no associations between basal ganglia PVS and cSS. CONCLUSIONS: High degree of CSO-PVS is highly prevalent in sporadic cerebral amyloid angiopathy and is related to cSS. Our findings suggest that severe leptomeningeal and cortical vascular amyloid (causing cSS) is related to impaired interstitial fluid drainage from cerebral white matter, although determining the causal direction of this relationship requires prospective studies.

Single session of dual-tDCS transiently improves precision grip and dexterity of the paretic hand after stroke.

BACKGROUND: After stroke, deregulated interhemispheric interactions influence residual paretic hand function. Anodal or cathodal transcranial direct current stimulation (tDCS) can rebalance these abnormal interhemispheric interactions and improve motor function. OBJECTIVE: We explored whether dual-hemisphere tDCS (dual-tDCS) in participants with chronic stroke can improve fine hand motor function in 2 important aspects: precision grip and dexterity. METHODS: In all, 19 chronic hemiparetic individuals with mild to moderate impairment participated in a double-blind, randomized trial. During 2 separate cross-over sessions (real/sham), they performed 10 precision grip movements with a manipulandum and the Purdue Pegboard Test (PPT) before, during, immediately after, and 20 minutes after dual-tDCS applied simultaneously over the ipsilesional (anodal) and contralateral (cathodal) primary motor cortices. RESULTS: The precision grip performed with the paretic hand improved significantly 20 minutes after dual-tDCS, with reduction of the grip force/load force ratio by 7% and in the preloading phase duration by 18% when compared with sham. The dexterity of the paretic hand started improving during dual-tDCS and culminated 20 minutes after the end of dual-tDCS (PPT score +38% vs +5% after sham). The maximal improvements in precision grip and dexterity were observed 20 minutes after dual-tDCS. These improvements correlated negatively with residual hand function quantified with ABILHAND. CONCLUSIONS: One bout of dual-tDCS improved the motor control of precision grip and digital dexterity beyond the time of stimulation. These results suggest that dual-tDCS should be tested in longer protocols for neurorehabilitation and with moderate to severely impaired patients. The precise timing of stimulation after stroke onset and associated training should be defined.

Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy.

OBJECTIVE: To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA). METHODS: European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders. RESULTS: During a median follow-up time of 24 months (interquartile range 9-44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%-27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%-28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%-76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%-95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ≥ 2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05-6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35-7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline. CONCLUSIONS: Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.

Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy.

OBJECTIVE: We investigated the prevalence and clinical-radiologic associations of cortical superficial siderosis (cSS) in patients with probable cerebral amyloid angiopathy (CAA) compared to those with intracerebral hemorrhage (ICH) not attributed to CAA. METHODS: We conducted a retrospective multicenter cohort study of 120 patients with probable CAA and 2 comparison groups: 67 patients with either single lobar ICH or mixed (deep and lobar) hemorrhages; and 22 patients with strictly deep hemorrhages. We rated cSS, ICH, white matter changes, and cerebral microbleeds. RESULTS: cSS was detected in 48 of 120 (40%; 95% confidence interval [CI]: 31.2%-49.3%) patients with probable CAA, 10 of 67 (14.9%; 95% CI: 7.4%-25.7%) with single lobar ICH or mixed hemorrhages, and 1 of 22 (4.6%; 95% CI: 0.1%-22.8%) patients with strictly deep hemorrhages (p < 0.001 for trend). Disseminated cSS was present in 29 of 120 (24%; 95% CI: 16.8%-32.8%) patients with probable CAA, but none of the other patients with ICH (p < 0.001). In probable CAA, age (odds ratio [OR]: 1.09; 95% CI: 1.03-1.15; p = 0.002), chronic lobar ICH (OR: 3.94; 95% CI: 1.54-10.08; p = 0.004), and a history of transient focal neurologic episodes (OR: 11.08; 95% CI: 3.49-35.19; p < 0.001) were independently associated with cSS. However, cSS occurred in 17 of 48 patients with probable CAA (35.4%; 95% CI: 22.2%-50.5%) without chronic lobar ICH. CONCLUSIONS: cSS (particularly if disseminated) is a common and characteristic feature of CAA. Chronic lobar ICH is an independent risk factor for cSS, but the causal direction and mechanism of association are uncertain. Hemorrhage into the subarachnoid space, independent of previous (chronic) lobar ICH, must also contribute to cSS in CAA. Transient focal neurologic episodes are the strongest clinical marker of cSS.

Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study.

BACKGROUND AND PURPOSE: Small vessel disease (mainly hypertensive arteriopathy and cerebral amyloid angiopathy (CAA)) is an important cause of spontaneous intracerebral haemorrhage (ICH), a devastating and still poorly understood stroke type. Enlarged perivascular spaces (EPVS) are a promising neuroimaging marker of small vessel disease. Based on the underlying arteriopathy distributions, we hypothesised that severe centrum semiovale EPVS are more common in lobar ICH attributed to CAA than other ICH. We evaluated EPVS prevalence, severity and distribution, and their clinical-radiological associations. METHODS: Retrospective multicentre cohort study of 121 ICH patients. Clinical information was obtained using standardised forms. Basal ganglia and centrum semiovale EPVS on T2-weighted MRI (graded 0-4 (>40 EPVS)), white-matter changes, cerebral microbleeds (CMBs) and lacunes were rated using validated scales. RESULTS: Patients with probable or possible CAA (n=76) had a higher prevalence of severe (>40) centrum semiovale EPVS compared with other ICH patients (35.5% vs 17.8%; p=0.041). In logistic regression age (OR: 1.43; 95% CI 1.01 to 2.02; p=0.045), deep CMBs (OR: 3.27; 95% CI 1.27 to 8.45; p=0.014) and mean white-matter changes score (OR: 1.29; 95% CI 1.17 to 1.43; p<0.0001) were independently associated with increased basal ganglia EPVS severity; only age was associated with increased centrum semiovale EPVS severity (OR: 1.50; 95% CI 1.08 to 2.10; p=0.017). CONCLUSIONS: EPVS are common in ICH. Different mechanisms may account for EPVS according to their anatomical distribution. Severe centrum semiovale EPVS may be secondary to, and indicative of, CAA with value as a new neuroimaging marker. By contrast, basal ganglia EPVS severity is associated with markers of hypertensive arteriopathy.

Risk and benefit of statins in stroke secondary prevention.

Statin is now recommended in secondary prevention after stroke or transient ischemic attacks to reduce the risk of a new stroke or major cardiovascular events. However, some issues about the extent of the benefit in some stroke patients and the risk of cerebral hemorrhage remain debated. This review shows that statins are significantly effective in decreasing the risk of further strokes despite an increase in the risk of brain hemorrhage. A significant benefit was observed in men and women, in aged patients and possibly to a greater extent in patients with carotid artery stenosis. Intensive statin therapy lowering the LDL-cholesterol beyond the cut-off value of 1.8 mmol/L (70 mg/dl) seems to be more effective than less intensive treatment and without an increased risk of side effects. Overall, statins are well tolerated. Further prospective studies should clarify whether the effect is of the same magnitude in small vessel disease and how to select the patients to reduce the risk of cerebral hemorrhage.

Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis.

BACKGROUND AND PURPOSE: Transient focal neurological episodes (TFNE) are recognized in cerebral amyloid angiopathy (CAA) and may herald a high risk of intracerebral hemorrhage (ICH). We aimed to determine their prevalence, clinical neuroimaging spectrum, and future ICH risk. METHODS: This was a multicenter retrospective cohort study of 172 CAA patients. Clinical, imaging, and follow-up data were collected. We classified TFNE into: predominantly positive symptoms ("aura-like" spreading paraesthesias/positive visual phenomena or limb jerking) and predominantly negative symptoms ("transient ischemic attack-like" sudden-onset limb weakness, dysphasia, or visual loss). We pooled our results with all published cases identified in a systematic review. RESULTS: In our multicenter cohort, 25 patients (14.5%; 95% confidence interval, 9.6%-20.7%) had TFNE. Positive and negative symptoms were equally common (52% vs 48%, respectively). The commonest neuroimaging features were leukoaraiosis (84%), lobar ICH (76%), multiple lobar cerebral microbleeds (58%), and superficial cortical siderosis/convexity subarachnoid hemorrhage (54%). The CAA patients with TFNE more often had superficial cortical siderosis/convexity subarachnoid hemorrhage (but not other magnetic resonance imaging features) compared with those without TFNE (50% vs 19%; P=0.001). Over a median period of 14 months, 50% of TFNE patients had symptomatic lobar ICH. The meta-analysis showed a risk of symptomatic ICH after TFNE of 24.5% (95% confidence interval, 15.8%-36.9%) at 8 weeks, related neither to clinical features nor to previous symptomatic ICH. CONCLUSIONS: TFNE are common in CAA, include both positive and negative neurological symptoms, and may be caused by superficial cortical siderosis/convexity subarachnoid hemorrhage. TFNE predict a high early risk of symptomatic ICH (which may be amenable to prevention). Blood-sensitive magnetic resonance imaging sequences are important in the investigation of such episodes.

Brain activations underlying different patterns of performance improvement during early motor skill learning.

BACKGROUND/INTRODUCTION: Motor learning plays a central role in daily life and in neurorehabilitation. Several forms of motor learning have been described, among which motor skill learning, i.e. reaching a superior level of performance (a skill) through a shift of the speed/accuracy trade-off. During the first stage of learning a visuomotor skill, we observed differential patterns of evolution of the speed/accuracy trade-off in normal subjects. Half of the subjects rapidly achieved successful motor skill learning with an early shift of the speed/accuracy trade-off leading to a superior level of performance (shift pattern). The other subjects attained only minimal global improvement due to a converse evolution of speed and accuracy (i.e. a respect of the speed/accuracy trade-off: fit pattern). Functional magnetic resonance imaging (fMRI) was used to explore the neural substrates underlying these differential patterns during the first stage of motor skill learning in normal subjects. METHODS: Twenty right-handed normal subjects performed an implicit visuomotor learning task with their non-dominant hand. The task ("circuit game") consisted in learning to navigate a pointer along a circuit as quickly and accurately as possible using a fMRI-compatible mouse. Velocity, accuracy, and performance indexes were used to characterise the motor learning pattern (shift/fit) and to perform fMRI correlation analysis in order to find the neural substrate associated with the shift and fit patterns during early motor skill learning. RESULTS: Nine subjects showed a fit pattern (fitters), and eleven, a shift pattern ("shifters"). fMRI analyses at whole group level (ANOVA) and at sub-group level demonstrated that the supplementary motor area (SMA) was more activated in "shifters" than in the "fitters" groups and that the BOLD activation within the SMA correlated significantly with the on-line shift of the speed/accuracy trade-off in the "shifters" group. CONCLUSION: Despite identical instructions and experimental conditions, during the first stage of motor skill learning normal subjects spontaneously adopted different patterns that can be differentiated based on distinct fMRI activation patterns. In this implicit visuomotor task, the SMA proper was the key area underlying the achievement of early successful motor skill learning, i.e. on-line shift of the speed/accuracy trade-off.

Granulomatous meningitis due to rheumatoid arthritis.

Meningoencephalitis is a rare but aggressive complication of rheumatoid arthritis (RA). The most common complications of RA occur in the severe and chronic stages of the disease. Only a few cases have been reported in the literature. The symptoms are usually nonspecific, and arthralgia may be missing. Brain MRI and CSF analysis are useful to guide the diagnosis. However, a biopsy is required to demonstrate the existence of granulomatous lesions and the lack of mycobacterium infection. Early detection is essential to prevent neurological complications. Treatment consists of intravenous high doses of corticoid followed by oral tapered doses associated with immunosuppressive therapy. The present case is remarkable by the presence of granulomatous lesions in the lung and meninges and the dramatic improvement after immunosuppressive therapy.

Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study.

Subclinical acute ischaemic lesions on brain magnetic resonance imaging have recently been described in spontaneous intracerebral haemorrhage, and may be important to understand pathophysiology and guide treatment. The underlying mechanisms are uncertain. We tested the hypothesis that ischaemic lesions are related to magnetic resonance imaging markers of the severity and type of small-vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy) in a multicentre, cross-sectional study. We studied consecutive patients with intracerebral haemorrhage from four specialist stroke centres, and age-matched stroke service referrals without intracerebral haemorrhage. Acute ischaemic lesions were assessed on magnetic resonance imaging (<3 months after intracerebral haemorrhage) using diffusion-weighted imaging. White matter changes and cerebral microbleeds were rated with validated scales. We investigated associations between diffusion-weighted imaging lesions, clinical and radiological characteristics. We included 114 patients with intracerebral haemorrhage (39 with clinically probable cerebral amyloid angiopathy) and 47 age-matched controls. The prevalence of diffusion-weighted imaging lesions was 9/39 (23%) in probable cerebral amyloid angiopathy-related intracerebral haemorrhage versus 6/75 (8%) in the remaining patients with intracerebral haemorrhage (P = 0.024); no diffusion-weighted imaging lesions were found in controls. Diffusion-weighted imaging lesions were mainly cortical and were associated with mean white matter change score (odds ratio 1.14 per unit increase, 95% confidence interval 1.02-1.28, P = 0.024) and the presence of strictly lobar cerebral microbleeds (odds ratio 3.85, 95% confidence interval 1.15-12.93, P = 0.029). Acute, subclinical ischaemic brain lesions are frequent but previously underestimated after intracerebral haemorrhage, and are three times more common in cerebral amyloid angiopathy-related intracerebral haemorrhage than in other intracerebral haemorrhage types. Ischaemic brain lesions are associated with white matter changes and cerebral microbleeds, suggesting that they result from an occlusive small-vessel arteriopathy. Diffusion-weighted imaging lesions contribute to the overall burden of vascular-related brain damage in intracerebral haemorrhage, and may be a useful surrogate marker of ongoing ischaemic injury from small-vessel damage.