Oliver W. Sakowitz

Spreading depolarizations occur in human ischemic stroke with high incidence

Cortical spreading depression (CSD) and periinfarct depolarization (PID) have been shown in various experimental models of stroke to cause secondary neuronal damage and infarct expansion. For decades it has been questioned whether CSD or PID occur in human ischemic stroke. Here, we describe CSD and PID in patients with malignant middle cerebral artery infarction detected by subdural electrocorticography (ECoG).

Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke

BACKGROUND Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain. METHODS We randomly assigned 112 patients 61 years of age or older (median, 70 years; range, 61 to 82) with malignant middle-cerebral-artery infarction to either conservative treatment in the intensive care unit (the control group) or hemicraniectomy (the hemicraniectomy group); assignments were made within 48 hours after the onset of symptoms. The primary end point was survival without severe disability (defined by a score of 0 to 4 on the modified Rankin scale, which ranges from 0 [no symptoms] to 6 [death]) 6 months after randomization. RESULTS Hemicraniectomy improved the primary outcome; the proportion of patients who survived without severe disability was 38% in the hemicraniectomy group, as compared with 18% in the control group (odds ratio, 2.91; 95% confidence interval, 1.06 to 7.49; P=0.04). This difference resulted from lower mortality in the surgery group (33% vs. 70%). No patients had a modified Rankin scale score of 0 to 2 (survival with no disability or slight disability); 7% of patients in the surgery group and 3% of patients in the control group had a score of 3 (moderate disability); 32% and 15%, respectively, had a score of 4 (moderately severe disability [requirement for assistance with most bodily needs]); and 28% and 13%, respectively, had a score of 5 (severe disability). Infections were more frequent in the hemicraniectomy group, and herniation was more frequent in the control group. CONCLUSIONS Hemicraniectomy increased survival without severe disability among patients 61 years of age or older with a malignant middle-cerebral-artery infarction. The majority of survivors required assistance with most bodily needs. (Funded by the Deutsche Forschungsgemeinschaft; DESTINY II Current Controlled Trials number, ISRCTN21702227.).

Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients?

ObjectiveTo analyze the time course and changes of cerebral microdialysis parameters after aneurysmal subarachnoid hemorrhage (SAH) in respect to the clinical course (asymptomatic, delayed, and acute ischemic neurologic deficits) to evaluate the method of bedside microdialysis in these patients. DesignProspective, controlled study during a 3-yr period. SettingNeurosurgical intensive care unit at a primary level university hospital, supervised and staffed by members of both the department of neurosurgery and the department of anesthesiology and intensive care medicine. PatientsNinety-seven patients (51 females/21 males; 52 ± 13 yrs; World Federation of Neurological Surgeons Scale grades 0–5) after aneurysmatic SAH. Measurements and Main ResultsA microdialysis catheter (CMA 100) was inserted into the region most likely to be affected by vasospasm directly after aneurysm clipping, connected to a pump, and perfused with Ringer solution (0.3 &mgr;L/min). The dialysates were collected hourly and analyzed at the bedside for glucose, lactate, lactate-pyruvate ratio, glutamate, and glycerol (CMA 600). Patients were classified according to clinical presentation as being asymptomatic or having acute (AIND) or delayed (DIND) ischemic neurologic deficits. DIND patients (n = 18) had significantly higher lactate and glutamate concentrations on days 1–8 post-SAH and a higher lactate-pyruvate ratio on days 3–8 post-SAH compared with asymptomatic patients (n = 57;p < .025). Glucose and glycerol levels did not differ in asymptomatic and DIND patients. AIND patients (n = 22) had the worst metabolic pattern: the extracellular glucose concentration was low, whereas the lactate, lactate-pyruvate ratio, glutamate, and glycerol levels were significantly elevated compared with asymptomatic and DIND patients. In 83% of the DIND patients, the changes in metabolites indicative of cerebral ischemia preceded the onset of symptomatic vasospasm. All DIND patients clinically improved in their Glasgow Coma Scale scores with induced hypertension, intentional hypervolemia, and/or hemodilution therapy (p = .01). ConclusionCerebral bedside microdialysis is a safe and promising technique for monitoring (impending) regional cerebral ischemia. The dialysate changes can indicate early the onset of delayed neurologic deterioration and are in good accordance with the clinical course of SAH patients. In the future, this technique may be used to monitor the efficacy of the intensive care therapy of these patients.

Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study

BACKGROUND Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. METHODS We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. FINDINGS Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. INTERPRETATION Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. FUNDING US Army CDMRP PH/TBI research programme.

Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions

How does infarction in victims of stroke and other types of acute brain injury expand to its definitive size in subsequent days? Spontaneous depolarizations that repeatedly spread across the cerebral cortex, sometimes at remarkably regular intervals, occur in patients with all types of injury. Here, we show experimentally with in vivo real-time imaging that similar, spontaneous depolarizations cycle repeatedly around ischaemic lesions in the cerebral cortex, and enlarge the lesion in step with each cycle. This behaviour results in regular periodicity of depolarization when monitored at a single point in the lesion periphery. We present evidence from clinical monitoring to suggest that depolarizations may cycle in the ischaemic human brain, perhaps explaining progressive growth of infarction. Despite their apparent detrimental role in infarct growth, we argue that cycling of depolarizations around lesions might also initiate upregulation of the neurobiological responses involved in repair and remodelling.

Wavelet Transform in the analysis of the frequency composition of evoked potentials

This technical paper deals with the application of the Wavelet Transform to the study of evoked potentials. In particular, Wavelet Transform gives an optimal time-dependent frequency decomposition of the evoked responses, something difficult to be achieved with previous methods such as the Fourier Transform. We describe in detail the protocol for implementing the decomposition based on the Wavelet Transform and apply it to two different types of evoked potentials. In the first case we study alpha responses in pattern visual evoked potentials and in the second case, we study gamma responses to bimodal (auditory and visual) stimulation. Although in this study we focus on methodological issues, we briefly discuss physiological implications of the present time-frequency analysis. Furthermore, we show examples of the better performance of the wavelet decomposition in comparison with Fourier-based methods.

Acute Focal Neurological Deficits in Aneurysmal Subarachnoid Hemorrhage Relation of Clinical Course, CT Findings, and Metabolite Abnormalities Monitored With Bedside Microdialysis

Background and Purpose— We sought (1) to identify early metabolic markers for the development of (ir)reversible neurological deficits and cerebral infarction in subarachnoid hemorrhage (SAH) patients by using the microdialysis technique and (2) to evaluate the influence of intracerebral hemorrhage (ICH) on microdialysis parameters. Methods— We performed a prospective study of 44 SAH patients with acute focal neurological deficits (AFND) occurring acutely with SAH (due to ICH) or directly after surgery (due to clip stenosis, thromboembolism, or early edema). Fifty-one nonischemic SAH patients served as a control group. A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. The microdialysates were analyzed hourly for extracellular glucose, lactate, lactate/pyruvate ratio, glutamate, and glycerol with a bedside analyzer. Microdialysis-related CT findings were evaluated for the presence of ICH and cerebral infarction. Reversibility of neurological symptoms after 4 weeks and 6- and 12-month outcomes were assessed. Results— In patients with AFND, cerebral metabolism was severely disturbed when microdialysis started compared with controls (P <0.005). Infarction on CT was associated with pathological microdialysis parameters (P <0.002) and development of a fixed deficit (P <0.003), while the presence of ICH alone was not. A secondary neurological deterioration of AFND patients (n=11) was reflected by preceding (0 to 20 hours) changes of microdialysate concentrations. Conclusions— In the presence of ICH, pathological microdialysis values may indicate reversible tissue damage. Extreme microdialysis values and pathological microdialysis concentrations that further deteriorate 2-fold are highly indicative of the development of cerebral infarction and permanent neurological deficits. Therefore, the analysis of relative changes of microdialysis parameters is crucial for the detection of ischemia in SAH patients.

Preliminary Evidence That Ketamine Inhibits Spreading Depolarizations in Acute Human Brain Injury

Background and Purpose— Spreading depolarizations, characterized by large propagating, slow potential changes, have been demonstrated with electrocorticography in patients with cerebral hemorrhage and ischemic stroke. Whereas spreading depolarizations are harmless under normal conditions in animals, they cause or augment damage in the ischemic brain. A fraction of spreading depolarizations is abolished by N-methyl-d-aspartate receptor antagonists. Summary of Case— In 2 patients with severe acute brain injury (traumatic and spontaneous intracranial hemorrhage), spreading depolarizations were inhibited by the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine. This restored electrocorticographic activity. Conclusions— These anecdotal electrocorticographic findings suggest that ketamine has an inhibitory effect on spreading depolarizations in humans. This is of potential interest for future neuroprotective trials.

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.

Impaired Cerebral Vasomotor Activity in Spontaneous Intracerebral Hemorrhage

Background and Purpose— Impairment of cerebrovascular autoregulation may promote secondary brain injury in acute brain insults. Until now, only limited data are available on autoregulation in patients with spontaneous intracerebral hemorrhage. In the current study, we aimed to investigate cerebrovascular reactivity and its significance for outcome in spontaneous intracerebral hemorrhage. Methods— We continuously recorded mean arterial pressure, intracranial pressure, and cerebral perfusion pressure for mean 95 hours in 20 patients with spontaneous intracerebral hemorrhage. The moving correlation coefficient between mean arterial pressure and intracranial pressure (pressure reactivity index), an index of cerebral vasoreactivity, was calculated from the available artifact-free monitoring time (mean, 50.4 hours). Results— In the univariate analysis pressure reactivity index (r=0.66; P=0.002), hemorrhage volume (r=0.62; P=0.007), cerebral perfusion pressure (r=−0.71; P=0.001), mean arterial pressure (r=−0.61; P=0.005), and hematoma growth (r=0.53; P=0.02) significantly correlated with National Institutes of Health Stroke Scale Score at discharge. In a multivariate stepwise linear regression model, pressure reactivity index remained the only independent predictor of outcome (&bgr;=0.659; P=0.004). In the subgroup of patients with pressure reactivity index greater than a functional threshold of >0.2, the correlation between mean cerebral perfusion pressure and outcome remained significant (r=−0.73; P=0.0102), whereas National Institutes of Health Stroke Scale Score at discharge did not correlate with cerebral perfusion pressure in patients with pressure reactivity index <0.2 (r=−0.05; P=0.9078). Conclusions— We found evidence for impaired cerebral vasomotor activity as measured by pressure reactivity index in patients with spontaneous intracerebral hemorrhage. We suggest that impaired cerebrovascular reactivity contributes to poor outcome in intracerebral hemorrhage patients. This effect may be mediated by fluctuations in cerebral perfusion.