Bruno-Marcel Mackert

Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit

Objective: To determine the extent that demographics, clinical characteristics, comorbidities, and complications contribute to the risk of in-hospital mortality and morbidity in acute stroke. Methods: Data of consecutive patients admitted to 14 stroke units cooperating within the Berlin Stroke Register were analyzed. The association of demographics, clinical characteristics, comorbidities, and complications with the risk of in-hospital death and poor outcome at discharge was assessed, and independent attributable risks were calculated, applying average sequential attributable fractions. Results: In a 3-year period, 16,518 consecutive patients with ischemic or hemorrhagic stroke were documented. In-hospital mortality was 5.4%, and 45.7% had a poor outcome (modifed Rankin Scale score ≥3). In patients with length of stay (LOS) ≤7 days, 37.5% of in-hospital deaths were attributed to stroke severity, 23.1% to sociodemographics (age and prestroke disability), and 28.9% to increased intracranial pressure (iICP) and other complications. In those with LOS >7 days, age and stroke severity accounted for 44.1%, whereas pneumonia (12.2%), other complications (12.6%), and iICP (8.3%) contributed to one-third of in-hospital deaths. For poor outcome, attributable risks were similar for prestroke disability, stroke severity, pneumonia, and other complications regardless of the patients LOS. Conclusions: Approximately two-thirds of early death and poor outcome in acute stroke is attributed to nonmodifiable predictors, whereas main modifiable factors are early complications such as iICP, pneumonia, or other complications, on which stroke unit treatment should focus to further improve the prognosis of acute stroke.

dc Magnetoencephalography: Direct measurement in a magnetically extremely-well shielded room

Direct measurement of slow brain activity in the range of seconds is reported. The measurements were made by superconducting quantum interference devices operating in a magnetically extremely well-shielded room. Directly measured dc magnetoencephalography (MEG) reveals that sustained fields of the brain rise with a sharp slope immediately after motor stimulation, whereas their relaxation to the resting level is slower and is delayed by several seconds. These features of sustained brain activity could not be resolved by modulated dc MEG which was applied earlier to study these phenomena.

DC-magnetoencephalography and time-resolved near-infrared spectroscopy combined to study neuronal and vascular brain responses

The temporal relation between vascular and neuronal responses of the brain to external stimuli is not precisely known. For a better understanding of the neuro-vascular coupling changes in cerebral blood volume and oxygenation have to be measured simultaneously with neuronal currents. With this motivation modulation dc-magnetoencephalography was combined with multi-channel time-resolved near-infrared spectroscopy to simultaneously monitor neuronal and vascular parameters on a scale of seconds. Here, the technique is described, how magnetic and optical signals can be measured simultaneously. In a simple motor activation paradigm (alternating 30 s of finger movement with 30 s of rest for 40 min) both signals were recorded non-invasively over the motor cortex of eight subjects. The off-line averaged signals from both modalities showed distinct stimulation related changes. By plotting changes in oxy- or deoxyhaemoglobin as a function of magnetic field a characteristic trajectory was created, which was similar to a hysteresis loop. A parametric analysis allowed quantitative results regarding the timing of coupling: the vascular signal increased significantly slower than the neuronal signal.

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.

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.

Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia - The PREDICT study.

Stroke-associated pneumonia is a frequent complication after stroke associated with poor outcome. Dysphagia is a known risk factor for stroke-associated pneumonia but accumulating evidence suggests that stroke induces an immunodepressive state increasing susceptibility for stroke-associated pneumonia. We aimed to confirm that stroke-induced immunodepression syndrome is associated with stroke-associated pneumonia independently from dysphagia by investigating the predictive properties of monocytic HLA-DR expression as a marker of immunodepression as well as biomarkers for inflammation (interleukin-6) and infection (lipopolysaccharide-binding protein). This was a prospective, multicenter study with 11 study sites in Germany and Spain, including 486 patients with acute ischemic stroke. Daily screening for stroke-associated pneumonia, dysphagia and biomarkers was performed. Frequency of stroke-associated pneumonia was 5.2%. Dysphagia and decreased monocytic HLA-DR were independent predictors for stroke-associated pneumonia in multivariable regression analysis. Proportion of pneumonia ranged between 0.9% in the higher monocytic HLA-DR quartile (≥21,876 mAb/cell) and 8.5% in the lower quartile (≤12,369 mAb/cell). In the presence of dysphagia, proportion of pneumonia increased to 5.9% and 18.8%, respectively. Patients without dysphagia and normal monocytic HLA-DR expression had no stroke-associated pneumonia risk. We demonstrate that dysphagia and stroke-induced immunodepression syndrome are independent risk factors for stroke-associated pneumonia. Screening for immunodepression and dysphagia might be useful for identifying patients at high risk for stroke-associated pneumonia.

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.

The Randomized Controlled STRAWINSKI Trial: Procalcitonin-Guided Antibiotic Therapy after Stroke

Background Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. Aims This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. Methods In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). Results In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45–1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). Conclusion PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients.

Magnetoneurography: theory and application to peripheral nerve disorders.

Magnetoneurography (MNG) is a non-invasive method to trace and visualize three-dimensionally the propagation path of compound action currents (CAC) along peripheral nerves. The basic physical and physiological principle is the mapping of extremely weak magnetic fields generated by the intraaxonal longitudinal ion flows of evoked nerval CAC using SQUID sensors (Superconducting Quantum Interference Devices). During recent years, MNG protocols have been established which allow for a non-invasive spatiotemporal tracing of impulse propagation along peripheral nerves in humans and in particular along proximal nerve segments in a clinical setting. Thereby, the three-dimensional path, the local nerve conduction velocity, the length and strength of the CAC de- and repolarization phase have been reconstructed. First recordings in patients demonstrated that the method is sensitive enough to detect and to localize nerve conduction anomalities along nerve roots, as, e.g. caused by lumbosacral disc herniation. This review on MNG will focus on those studies which provide data from humans and thereby reveal perspectives for its future clinical applications.

Characterization of motor and somatosensory function for stroke patients

In a pilot study, stroke patients with a lesion related to the motor system were studied using magnetoencephalography (MEG) and electromyography (EMG). The patients performed sustained finger movements for 30 s followed by 30 s of rest and 20 repetitions of this sequence in total. Task-related cortical signals derived from MEG were observed here at very different frequency scales. Slow signals below 0.1 Hz were extracted by independent component analysis and are associated with the sustained activation of the motor cortex, the dcMEG motor activation. MEG-EMG coupling phenomena in the 10-30 Hz range were analyzed using the imaginary part of coherency and are attributed to cortico-muscular coupling driving the muscles. Additionally a signal from the somatosensory cortex due to an electrical stimulation at the wrist, the N20m, was recorded as a physiological marker. Field maps and time series associated with the three types of signals are presented for one patient and one control subject as the signal quality of the patient data was not sufficient to achieve a group result. The feasibility of a comprehensive electrophysiological measuring and analysis procedure of the motor function for stroke research is demonstrated by the results.