Christoph Drenckhahn

Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial

Background Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients. Methods Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance. Findings On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections. Interpretation PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections. Trial Registration Controlled-Trials.com ISRCTN74386719

Correlates of spreading depolarization in human scalp electroencephalography

It has been known for decades that suppression of spontaneous scalp electroencephalographic activity occurs during ischaemia. Trend analysis for such suppression was found useful for intraoperative monitoring during carotid endarterectomy, or as a screening tool to detect delayed cerebral ischaemia after aneurismal subarachnoid haemorrhage. Nevertheless, pathogenesis of such suppression of activity has remained unclear. In five patients with aneurismal subarachnoid haemorrhage and four patients with decompressive hemicraniectomy after malignant hemispheric stroke due to middle cerebral artery occlusion, we here performed simultaneously full-band direct and alternating current electroencephalography at the scalp and direct and alternating current electrocorticography at the cortical surface. After subarachnoid haemorrhage, 275 slow potential changes, identifying spreading depolarizations, were recorded electrocorticographically over 694 h. Visual inspection of time-compressed scalp electroencephalography identified 193 (70.2%) slow potential changes [amplitude: −272 (−174, −375) µV (median quartiles), duration: 5.4 (4.0, 7.1) min, electrocorticography–electroencephalography delay: 1.8 (0.8, 3.5) min]. Intervals between successive spreading depolarizations were significantly shorter for depolarizations with electroencephalographically identified slow potential change [33.0 (27.0, 76.5) versus 53.0 (28.0, 130.5) min, P = 0.009]. Electroencephalography was thus more likely to display slow potential changes of clustered than isolated spreading depolarizations. In contrast to electrocorticography, no spread of electroencephalographic slow potential changes was seen, presumably due to superposition of volume-conducted electroencephalographic signals from widespread cortical generators. In two of five patients with subarachnoid haemorrhage, serial magnetic resonance imaging revealed large delayed infarcts at the recording site, while electrocorticography showed clusters of spreading depolarizations with persistent depression of spontaneous activity. Alternating current electroencephalography similarly displayed persistent depression of spontaneous activity, and direct current electroencephalography slow potential changes riding on a shallow negative ultraslow potential. Isolated spreading depolarizations with depression of both spontaneous electrocorticographic and electroencephalographic activity displayed significantly longer intervals between successive spreading depolarizations than isolated depolarizations with only depression of electrocorticographic activity [44.0 (28.0, 132.0) min, n = 96, versus 30.0 (26.5, 51.5) min, n = 109, P = 0.001]. This suggests fusion of electroencephalographic depression periods at high depolarization frequency. No propagation of electroencephalographic depression was seen between scalp electrodes. Durations/magnitudes of isolated electroencephalographic and corresponding electrocorticographic depression periods correlated significantly. Fewer spreading depolarizations were recorded in patients with malignant hemispheric stroke but characteristics were similar to those after subarachnoid haemorrhage. In conclusion, spreading depolarizations and depressions of spontaneous activity display correlates in time-compressed human scalp direct and alternating current electroencephalography that may serve for their non-invasive detection.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Increased Extracellular K+ Concentration Reduces the Efficacy of N-methyl-d-aspartate Receptor Antagonists to Block Spreading Depression-Like Depolarizations and Spreading Ischemia

Background and Purpose— Spreading depression (SD)-like depolarizations may augment neuronal damage in neurovascular disorders such as stroke and traumatic brain injury. Spreading ischemia (SI), a particularly malignant variant of SD-like depolarization, is characterized by inverse coupling between the spreading depolarization wave and cerebral blood flow. SI has been implicated in particular in the pathophysiology of subarachnoid hemorrhage. Under physiological conditions, SD is blocked by N-methyl-d-aspartate receptor (NMDAR) antagonists. However, because both SD-like depolarizations and SI occur in presence of an increased extracellular K+ concentration ([K+]o), we tested whether this increase in baseline [K+]o would reduce the efficacy of NMDAR antagonists. Methods— Cranial window preparations, laser Doppler flowmetry, and K+-sensitive/reference microelectrodes were used to record SD, SD-like depolarizations, and SI in rats in vivo; microelectrodes and intrinsic optical signal measurements were used to record SD and SD-like depolarizations in human and rat brain slices. Results— In vivo, the noncompetitive NMDAR antagonist dizocilpine (MK-801) blocked SD propagation under physiological conditions, but did not block SD-like depolarizations or SI under high baseline [K+]o. Similar results were found in human and rat neocortical slices with both MK-801 and the competitive NMDAR antagonist D-2-amino-5-phosphonovaleric acid. Conclusions— Our data suggest that elevated baseline [K+]o reduces the efficacy of NMDAR antagonists on SD-like depolarizations and SI. In conditions of moderate energy depletion, as in the ischemic penumbra, or after subarachnoid hemorrhage, NMDAR inhibition may not be sufficient to block these depolarizations.

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

A Time-Domain NIR Brain Imager Applied in Functional Stimulation Experiments

We developed a time-domain brain imager that is based on picosecond diode lasers, a multimode fiber switch and multi-channel time-correlated single photon counting. It allows to record time-resolved diffuse reflectance for 16 source-detector pairs within typically 1 s. Data analysis was based on the evaluation of moments of measured distributions of times of flight of photons. To show the relevance of these moments for achieving depth selectivity, three-dimensional sensitivities of integral, mean time of flight and variance to absorption changes were calculated using a perturbation approach based on the diffusion equation for photon density for a homogeneous semi-infinite medium. It turned out that variance is almost exclusively sensitive to deep layers, whereas the integral reflects changes in deep as well as in superficial layers. The lateral resolution of the imager was demonstrated by a phantom experiment. Results of a motor stimulation experiment on a healthy volunteer strongly suggest that variance reveals mainly the cerebral activation whereas the integral may additionally contain significant systemic contributions.

Spreading ischemia after aneurysmal subarachnoid hemorrhage.

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization associated with net influx of cations and water. Prolonged SDs facilitate neuronal death. SD induces tone alterations in cerebral resistance arterioles, leading to either transient hyperperfusion (physiological neurovascular coupling) in healthy tissue or hypoperfusion (inverse neurovascular coupling = spreading ischemia) in tissue at risk for progressive damage. Spreading ischemia has been shown experimentally in an animal model replicating the conditions present following aneurysmal subarachnoid hemorrhage (aSAH), in animal models of the ischemic core and penumbra following middle cerebral artery occlusion, and in patients with aSAH. In animals, spreading ischemia produced widespread cortical necrosis. In patients, spreading ischemia occurred in temporal correlation with ischemic lesion development early and late after aSAH. We briefly review important features of SD and spreading ischemia following aSAH.

A validation study of the use of near-infrared spectroscopy imaging in primary and secondary motor areas of the human brain.

The electroencephalographically measured Bereitschafts (readiness)-potential in the supplementary motor area (SMA) serves as a signature of the preparation of motor activity. Using a multichannel, noninvasive near-infrared spectroscopy (NIRS) imager, we studied the vascular correlate of the readiness potential. Sixteen healthy subjects performed a self-paced or externally triggered motor task in a single or repetitive pattern, while NIRS simultaneously recorded the task-related responses of deoxygenated hemoglobin (HbR) in the primary motor area (M1) and the SMA. Right-hand movements in the repetitive sequence trial elicited a significantly greater HbR response in both the SMA and the left M1 compared to left-hand movements. During the single sequence condition, the HbR response in the SMA, but not in the M1, was significantly greater for self-paced than for externally cued movements. Nonetheless, an unequivocal temporal delay was not found between the SMA and M1. Near-infrared spectroscopy is a promising, noninvasive bedside tool for the neuromonitoring of epileptic seizures or cortical spreading depolarizations (CSDs) in patients with epilepsy, stroke, or brain trauma because these pathological events are associated with typical spatial and temporal changes in HbR. Propagation is a characteristic feature of these events which importantly supports their identification and characterization in invasive recordings. Unfortunately, the present noninvasive study failed to show a temporal delay during self-paced movements between the SMA and M1 as a vascular correlate of the readiness potential. Although this result does not exclude, in principle, the possibility that scalp-NIRS can detect a temporal delay between different regions during epileptic seizures or CSDs, it strongly suggests that further technological development of NIRS should focus on both improved spatial and temporal resolution. This article is part of a Special Issue entitled Status Epilepticus.

Excitotoxicity and Metabolic Changes in Association With Infarct Progression

Background and Purpose— We investigated to what extent excitotoxicity and metabolic changes in the peri-infarct region of patients with malignant hemispheric stroke are associated with delayed infarct progression. Methods— In 18 patients with malignant hemispheric stroke, 2 microdialysis probes were implanted within the peri-infarct tissue at a distance of 5 and 15 mm to the infarct. Precise probe placement was achieved by intraoperative laser speckle imaging. Glutamate, glucose, pyruvate, and lactate levels were monitored for 5 days after surgery. Delayed infarct progression was determined from serial MRI on the day after surgery and after the monitoring period. Results— Initial stroke volume ranged from 122 to 479 cm3 with a median of 295 cm3. Nine of 18 patients (50%) had delayed infarct progression (median, 44 cm3; range, 19–93 cm3). In these patients, glucose and individual pyruvate levels were significantly lower when compared with patients without infarct progression, whereas glutamate and the lactate–pyruvate ratio were significantly elevated in patients with infarct progression early after surgery (12–36 hours) at the 15-mm microdialysis probe location. Lactate was elevated but without difference between groups. Conclusions— Excitotoxic or metabolic impairment was associated with delayed infarct progression and could serve as a treatment target.

Complications in Aneurysmal Subarachnoid Hemorrhage Patients With and Without Subdural Electrode Strip for Electrocorticography.

Purpose: Patients with aneurysmal subarachnoid hemorrhage (aSAH) frequently develop secondary noninfectious and infectious complications with an important impact on clinical course and outcome. In this study, we report on the rate of typical extracranial and intracranial complications in 30 prospectively enrolled patients with severe aSAH who received a linear subdural recording strip for continuous electrocorticography to detect ictal epileptiform events and spreading depolarizations. Methods: The group was compared with 30 retrospectively included patients with aSAH who had not received a subdural recording strip, but were treated during the same period. The control group was matched according to an aSAH grading system, sex, and establishment of external ventricular drainage, but could not be matched according to aneurysm treatment and focal brain lesions such as initial intracerebral hemorrhages. Results: No evidence was found that procedures of the electrocorticography study led to clinically relevant complications. In particular, the subdural strip did not lead to local damage of brain tissue or any increased rate of meningitis/ventriculitis. The median score on the modified Rankin Scale on day 15 was the same in both groups. Minor differences between both groups are explained by the limitations in the study design. Conclusions: Our study suggests that neuromonitoring with a subdural recording strip for up to 15 days can be safely performed in patients with aSAH.