Early brain imaging predictors of post-stroke spasticity.

BACKGROUND: Post-stroke spasticity is a major factor disturbing rehabilitation and functional recovery in stroke survivors. Clinical predictors of post-stroke spasticity have often been discussed, but brain image predictors for spasticity have been insufficiently researched. The aim of this study was to use magnetic resonance imaging data to identify early brain imaging predictors for potential development of spasticity after stroke. METHODS: Consecutive patients admitted to a stroke unit were screened prospectively over 22 months. Patients with first-ever supratentorial ischaemic stroke were included in the study. Standardized clinical assessments for post-stroke spasticity were prospectively performed within 7 days and at 3 months. Brain imaging data (3 Tesla magnetic resonance imaging (3T MRI)) were collected at the baseline and evaluated. RESULTS: Brain imaging data from 103 stroke patients were collected in the hyperacute phase (< 7 days after stroke onset). A total of 23 patients developed post-stroke spasticity. The volumes of brain lesions involving motor network areas were significantly larger in patients with post-stroke spasticity compared with those without post-stroke spasticity (p < 0.01). Supratentorial lesion of < 0.5 cm3 were not associated with risk of post-stroke spasticity, except when the internal capsule and striatum was affected. CONCLUSION: Lesions involving motor network areas are considered to be a precondition of post-stroke spasticity. There is, however, a low risk of developing post-stroke spasticity with < 0.5 cm3 volumes of supratentorial brain lesions involving motor network areas. Larger volume brain lesions involving motor network areas, e.g. > 3 cm3, were significantly more common in patients with post-stroke spasticity. Pure cortical lesions has no risk of post-stroke spasticity in stroke survivors.

Early clinical predictors of post stroke spasticity.

Background and Purpose: Up to 40% of stroke patients with paresis develop post-stroke spasticity (PSS), which induces difficult complications including pain, contracture, posture disorder. The most important factor for PSS management is its early initiation, so that early recognition of PSS is required in clinical practice.Methods: This prospective observational cohort study was conducted with a high standard of PSS assessment and a comprehensive protocol investigating possible predictive factors to identify early predictors of PSS already in the acute phase following stroke (<7 days). PSS was assessed with the Resistance to Passive movement Scale (REPAS) for major joint movements in upper- and lower limbs, based on Ashworth scale, within 7 days following stroke and after 3 months. Binary logistic regression analysis with significant clinical parameters was applied with 95% of confidence intervals (CI) to find predictors of PSS.Results: Of 145 consecutive first-ever stroke patients, 34 patients (23.4%) exhibited PSS. The Modified Rankin Scale (MRS), National Institutes of Health Stroke Scale (NIHSS), and Mini-Mental State Examination (MMSE) were revealed as strong clinical predictors of PSS. The combination of an MRS >2 (Odds Ratio (OR): 56.538, 95% CI: 17.150-186.394), NIHSS >2 (OR: 57.137, 95% CI:15.685-208.142) and MMSE <27 (OR: 6.133, 95% CI:2.653-14.178) showed positive predictive (95.2%) value for prediction of PSS (sensitivity 94.4%, specificity 93.3%).Conclusions: Besides evaluating PSS itself with a reliable and valid rating scale the common clinical scales in stroke units practice (NIHSS, MRS, MMSE) allow early identification of patients at high risk for PSS.

GLM analysis of time resolved NIRS data of motor activation during different motor tasks.

The hemodynamic response to motor activation was investigated by time-resolved NIRS in healthy subjects and patients with unilateral impairment in motor ability. Healthy subjects performed a simple and a complex finger movement task, patients a handgrip task. A General Linear Model approach (GLM) was applied during NIRS data processing. In general, compared to the integral (continuous wave signal), higher significance of activation was found for the variance signal that selectively represents changes in the deep compartment. A discussion of GLM results with respect to task complexity and difficulty is provided.

Laminar infarcts in clinical routine: a prospective analysis in standard stroke unit patients.

The present study aimed to investigate prospectively the frequency of laminar infarcts (LI) within a standard stroke unit population. Laminar infarcts follow neuroanatomical borders rather than the vascular architecture. The LI are rarely noticed in clinical routine because they are typically not detected by computed tomography. As there is a lack of systemic studies about this specific infarct pattern, little is known about their frequency, clinical characteristics or pathophysiological mechanisms. Consecutive acute ischemic stroke unit patients were prospectively enrolled during a 12 month period. The LI were defined as ischemic lesions following the gyral anatomy of the cerebral cortex. The clinical assessment included a standardized questionnaire, clinical syndromes and standard diagnostic results. There were 491 consecutive ischemic stroke patients enrolled (243 female, mean age 75 ± 12 years). The MRI revealed no laminar lesion crossing vascular territories and 28 patients with LI non-crossing vascular territories (7 %). According to the TOAST classification, 61 % of LI were classified as stroke of undetermined etiology (TOAST V) including 46 % with completed evaluation (TOAST Vb). In contrast to these findings, only 20 % of the whole study cohort with non-laminar infarcts were classified as TOAST V. The results indicate that LI are rare. In clinical routine, patients with LI require particular attention. Within the TOAST classification, this specific infarct pattern seems to be underrepresented.

Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial.

BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702.

Secondary prevention after minor stroke and TIA - usual care and development of a support program.

BACKGROUND: Effective methods of secondary prevention after stroke or TIA are available but adherence to recommended evidence-based treatments is often poor. The study aimed to determine the quality of secondary prevention in usual care and to develop a stepwise modeled support program. METHODS: Two consecutive cohorts of patients with acute minor stroke or TIA undergoing usual outpatient care versus a secondary prevention program were compared. Risk factor control and medication adherence were assessed in 6-month follow-ups (6M-FU). Usual care consisted of detailed information concerning vascular risk factor targets given at discharge and regular outpatient care by primary care physicians. The stepwise modeled support program additionally employed up to four outpatient appointments. A combination of educational and behavioral strategies was employed. RESULTS: 168 patients in the observational cohort who stated their openness to participate in a prevention program (mean age 64.7 y, admission blood pressure (BP): 155/84 mmHg) and 173 patients participating in the support program (mean age 67.6 y, BP: 161/84 mmHg) were assessed at 6 months. Proportions of patients with BP according to guidelines were 50% in usual-care and 77% in the support program (p<0.01). LDL<100 mg/dl was measured in 62 versus 71% (p = 0.12). Proportions of patients who stopped smoking were 50 versus 79% (p<0.01). 72 versus 89% of patients with atrial fibrillation were on oral anticoagulation (p = 0.09). CONCLUSIONS: Risk factor control remains unsatisfactory in usual care. Targets of secondary prevention were met more often within the supported cohort. Effects on (cerebro-)vascular recurrence rates are going to be assessed in a multicenter randomized trial.

Clinical characterization of symptomatic microangiopathic brain lesions.

BACKGROUND: Microangiopathic brain lesions can be separated in diffuse lesions - leukoaraiosis - and focal lesions - lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. METHODS: Sixty-four consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood, and urine parameters. RESULTS: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, mini mental score examination, mental examination) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy, and a higher National Institutes of Health Stroke Scale increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. CONCLUSIONS: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts.

Non-invasive simultaneous recording of neuronal and vascular signals in subacute ischemic stroke.

In acute focal cerebral ischemia blood flow and neuronal activity change dramatically. A better understanding of the pathophysiological interactions of these two important parameters is limited owing to the lack of noninvasive techniques to simultaneously measure these parameters in humans. In this feasibility study, we used DC-magnetoencephalography and near-infrared spectroscopy to find out whether blood flow and neuronal activity as well as neurovascular coupling can be analyzed in patients suffering from subacute ischemic stroke. In a simple motor test condition, six patients with subacute ischemic stroke performed self-paced finger movements (30-s periods of movement, separated by 30-s periods of rest; for a total of 15 min). Combined DC-magnetoencephalography and near-infrared spectroscopy were recorded over the affected and unaffected hemispheres. As a control group, four healthy subjects were investigated. In four out of six patients, the time courses of both signals closely followed the motor task cycles revealing significant differences between movement and rest periods. The vascular signal reached a maximum 1-5 s later than the neuronal signals. This proof-of-principle study demonstrates that it has become feasible to simultaneously and noninvasively monitor neuronal and vascular signal changes in patients in the subacute state of ischemic stroke.

Cross-correlation of motor activity signals from dc-magnetoencephalography, near-infrared spectroscopy, and electromyography.

Neuronal and vascular responses due to finger movements were synchronously measured using dc-magnetoencephalography (dcMEG) and time-resolved near-infrared spectroscopy (trNIRS). The finger movements were monitored with electromyography (EMG). Cortical responses related to the finger movement sequence were extracted by independent component analysis from both the dcMEG and the trNIRS data. The temporal relations between EMG rate, dcMEG, and trNIRS responses were assessed pairwise using the cross-correlation function (CCF), which does not require epoch averaging. A positive lag on a scale of seconds was found for the maximum of the CCF between dcMEG and trNIRS. A zero lag is observed for the CCF between dcMEG and EMG. Additionally this CCF exhibits oscillations at the frequency of individual finger movements. These findings show that the dcMEG with a bandwidth up to 8 Hz records both slow and faster neuronal responses, whereas the vascular response is confirmed to change on a scale of seconds.

Magnetoencephalography discriminates modality-specific infraslow signals less than 0.1 Hz.

DC-magnetoencephalography (DC-MEG) technique has been refined and allows to record cortical activity in the infraslow frequency range less than 0.1 Hz noninvasively. Important questions however, remained, especially, how specific these infraslow activations can be recorded and whether different activations, for example, motor versus acoustic, can be separated. To clarify these questions, in the present DC-MEG study, cortical infraslow activity was investigated intraindividually in response to different activation modalities, that is, motor versus acoustic: in 13 individuals, 30-s periods of finger movement or listening to concert music, were interleaved for 60 min. DC-MEG was capable to resolve intermodal differences concerning the relative amplitudes, field patterns, and source localizations. These results clarify that DC-MEG allows to identify and to discriminate modality-specific infraslow cortical neuronal signals.

Differential infraslow (<0.1 Hz) cortical activations in the affected and unaffected hemispheres from patients with subacute stroke demonstrated by noninvasive DC-magnetoencephalography.

BACKGROUND AND PURPOSE: Sustained mass depolarization of neurons, termed cortical spreading depolarization, is one electrophysiological correlate of the ischemic injury of neurons. Cortical spreading depolarizations spread in the gray matter at a rate of approximately 3 mm/min and are associated with large infraslow extracellular potential changes (<0.05 Hz). Moreover, smaller infraslow potential changes accompany functional activation and might help to assess neuronal repair after stroke. The objective of the present pilot study was to investigate whether it is feasible to apply noninvasive near-DC-magnetoencephalography to detect and monitor infraslow field changes in patients with acute stroke. METHODS: A simple motor condition was used to induce physiological cortical infraslow field changes. Five patients in a subacute state after ischemic stroke performed self-paced simple finger movements (30-second periods of finger movements, always separated by 30-second periods of rest, for a total of 15 minutes). Near-DC-magnetoencephalography signals were recorded over the contralateral primary motor cortex for the affected and unaffected hemisphere, respectively. RESULTS: In all patients, the time courses of the contralateral cortical field amplitudes in the infraslow frequency range followed closely the motor task cycles revealing statistically significant differences between finger movement and rest periods. In 4 of 5 patients, infraslow field amplitudes were significantly stronger over the unaffected hemisphere compared with the affected hemisphere. CONCLUSIONS: This study demonstrates that cortical infraslow activity can be recorded noninvasively in patients in the subacute state after ischemic stroke. It is suggested that near-DC-magnetoencephalography is a promising tool to also detect cortical spreading depolarization noninvasively.

Increased prevalence of microangiopathic brain lesions among siblings of patients with lacunar stroke. A prospective multicenter study.

BACKGROUND: Family and twin studies suggest predisposing genetic factors in stroke. Lacunar infarcts represent a homogeneous phenotype, which is a prerequisite for genetic analyses. Applying an affected sib -pair analysis, we prospectively assessed the prevalence of microangiopathic brain lesions (MBL) and associated risk factors among siblings of patients with lacunar stroke. METHODS: Index patients fulfilled clinical criteria of a lacunar stroke in combination with a corresponding MBL on CT or MRI. Siblings were characterized as affected if MBL demonstrated on MRI. The prevalence of MBL was compared with population prevalence data extracted from other studies. RESULTS: From 784 patients screened, 81 index patients with lacunar stroke and 97 siblings were recruited, of which 42% were identified as affected. Compared with data from unselected historical controls and stratified by age groups, prevalence was between 2 and 5 times higher. CONCLUSIONS: Our results indicate that genetic stroke studies are feasible even in subtypes of ischemic stroke. The high prevalence of MBL among siblings of patients with lacunar infarct might suggest a familial aggregation. However, due to the small sample size these results need to be interpreted with caution and require confirmation by planned genetic analyses.

Dynamics of cortical neurovascular coupling analyzed by simultaneous DC-magnetoencephalography and time-resolved near-infrared spectroscopy.

Functional magnetic resonance imaging (fMRI) visualizes activated brain areas with a high spatial resolution. The activation signal is determined by the local change of cerebral blood oxygenation, blood volume and blood flow which serve as surrogate marker for the neuronal signal itself. Here, the complex coupling between these parameters and the electrophysiologic activity is characterized non-invasively in humans during a simple motor task using simultaneously DC-magnetoencephalography (DC-MEG), for the detection of neuronal signals, and time-resolved near-infrared spectroscopy (trNIRS), for cortical metabolic/vascular responses: over the left primary motor cortex hand area of healthy subjects DC-fields and trNIRS parameters followed closely the 30 s motor task cycles, i.e., finger movements of the right hand alternating with rest. In subjects showing a sufficient signal-to-noise ratio the analysis of variance of photon time of flight proved that the task-related trNIRS changes originated from the cortex. While onset and relaxation started simultaneously, trNIRS signals reached 50% of the maximum level 1-4 s later than the DC-MEG-signals. The non-invasive 'dual' setup helps to characterize simultaneously the two complementary aspects of the 'hemodynamic inverse problem', i.e., the coupling of neuronal and vascular/metabolic signals, in healthy subjects and provides a new analysis perspective for pathophysiological coupling concepts in diverse diseases, e.g., in stroke, hypertension and Alzheimer's disease.

Combined MEG and EEG methodology for non-invasive recording of infraslow activity in the human cortex.

OBJECTIVE: Periinfarct depolarisation and spreading depression represent key mechanisms of neuronal injury after stroke. Changes in cortical electrical potentials and magnetic fields in the very low frequency range are relevant parameters to characterize these events, which up to now have only been recorded invasively. In this study, we proved whether a non-invasive combined MEG/EEG recording technique is able to quantitatively monitor cortical infraslow activity in humans. METHODS: We used repetitive very slow and slow right finger movements as a physiological motor activation paradigm to induce cortical infraslow activity. Infraslow fields were recorded over the left hemisphere using a modulation-based MEG technique. EEG was performed using 16 standard Ag-Cl electrodes that covered the left motor cortex. RESULTS: We recorded stable focal motor-related infraslow magnetic field changes in seven out of seven subjects. We also found correlating infraslow electrical potential changes in three out of seven subjects. Slow finger movements generated significantly stronger field and potential changes than very slow movements. CONCLUSIONS: This study demonstrates the technical feasibility of combined non-invasive electrical potential and magnetic field measurements to localize and quantitatively monitor physiological, low amplitude, infraslow cortical activity in humans. This specific combination of simultaneous recording techniques allows to benefit from the specific physical advantages of each method. SIGNIFICANCE: This combined non-invasive MEG-EEG methodology is able to provide important information on infraslow neuronal activity originating from tangentially and radially oriented sources. Moreover, this dual approach has the potential to separate neuronal from non-neuronal DC-sources, e.g., radially to the head orientated DC-currents across the skin/scalp/skull/dura occurring during cerebral hypercapnia or hypoxia.

Recording of focal direct current (DC) changes in the human cerebral cortex using refined non-invasive DC-EEG methodology.

A non-invasive DC electroencephalographic (DC-EEG) method was developed to record and analyze focal low-frequency (<0.1 Hz) DC changes in the human cerebral cortex. A simple repetitive finger-movement task was used as a physiological activation paradigm. DC-EEG amplitudes were recorded using a custom-made DC amplifier with automatic offset correction. A total of 16 standard Ag/AgCl electrodes covered the left primary motor cortex. In three of six subjects, reliable focal motor-related DC-EEG shifts over the hand cortex were monitored. This study demonstrates that refined DC-EEG recording and data analysis procedures allow non-invasive recording of low-frequency and low-amplitude focal cortical changes in humans. An important clinical perspective of this technology is the detection of stroke-associated cortical DC activity.

Tonic neuronal activation during simple and complex finger movements analyzed by DC-magnetoencephalography.

Functional neuroimaging techniques map neuronal activation indirectly via local concomitant cortical vascular/metabolic changes. In a complementary approach, DC-magnetoencephalography measures neuronal activation dynamics directly, notably in a time range of the slow vascular/metabolic response. Here, using this technique neuronal activation dynamics and patterns for simple and complex finger movements are characterized intraindividually: in 6/6 right-handed subjects contralateral prolonged (30 s each) complex self-paced sequential finger movements revealed stronger field amplitudes over the pericentral sensorimotor cortex than simple movements. A consistent lateralization for contralateral versus ipsilateral finger movements was not found (4/6). A subsequent sensory paradigm focused on somatosensory afferences during the motor tasks and the reliability of the measuring technique. In all six subjects stable sustained neuronal activation during electrical median nerve stimulation was recorded. These neuronal quasi-tonic activation characteristics provide a new non-invasive neurophysiological measure to interpret signals mapped by functional neuroimaging techniques.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis.

BACKGROUND: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. OBJECTIVE: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. MATERIALS AND METHODS: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. RESULTS AND DISCUSSION: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF. CONCLUSION: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

Delayed occlusion after internal carotid artery dissection under heparin.

Internal carotid artery dissection (ICAD) is a frequent etiology of stroke in the young. Immediate anticoagulation with unfractionated heparin is the most frequent treatment. A theoretical side effect of unfractionated heparin is an increase in the intramural hematoma resulting in hemodynamic cerebral infarction. We studied 20 patients with ICAD. All patients were immediately treated with unfractionated heparin. Activated partial thromboplastin time (aPTT) ratios were measured twice daily. We prospectively monitored the course of ICAD with repeated ultrasound in hospital. Unexpectedly, delayed ICA occlusion was noted in 5 patients under treatment. One of these developed a watershed infarct. We then analyzed the aPTT ratios over the first 6 days after diagnosis. Patients with delayed occlusion had significantly higher aPTT ratios (2.6 +/- 0.4 vs. 2.0 +/- 0.5, p < 0.05). Within the limits of a partially retrospective design, our study seems to support the notion that unfractionated heparin can increase the intramural hematoma. Our findings further justify a randomized clinical trial to resolve the anticoagulant/antiplatelet debate.

Neurovascular coupling analyzed non-invasively in the human brain.

Most functional brain imaging methods detect neuronal activations indirectly through the accompanying neurovascular response. Here, we demonstrate that a novel methodological approach, the combination of DC-magnetoencephalography (DC-MEG) and near-infrared spectroscopy (NIRS), allows non-invasive assessment of the dynamics of neurovascular coupling in the human brain: detecting directly slow neuronal processes (with time constants of 30s), DC-MEG revealed, even in unaveraged recordings, sustained neuronal activations at pericentral hand cortices contralateral to repetitive finger movements; these were accompanied by the ensuing local vascular response showing similar dynamical features as quantified by simultaneously recorded NIRS. This non-invasive approach opens a new avenue for the understanding of neurovascular coupling during physiological tasks as well as in diseases involving slow neuronal depolarization shifts and alterations of blood flow, such as stroke or migraine.