Status epilepticus (SE) is accompanied by complex pathophysiologic changes, most of which are undetectable by standard clinical examination and imaging techniques alone, which are currently employed in the intensive care unit (ICU) setting. Invasive neuromonitoring including intracortical and subdural electroencephalography, partial brain tissue oxygen tension (PbtO2), cerebral blood flow (CBF), and cerebral microdialysis allows assessments of changes in focal and global cerebral physiology associated with ictal activity. This information can potentially be combined with current techniques to provide integrated pathophysiologic end points measured at the brain tissue into SE treatment concepts. There are no studies or clinical trials to support this approach, but the following review summarizes the conceptual framework and supportive literature for this approach.
The underlying pathophysiology of status epilepticus (SE) remains mostly invisible to the clinician in the intensive care unit (ICU) setting. In animal studies associated hemodynamic and brain neurochemical changes have been well described. In the last decade, bedside invasive neuromonitoring techniques allow the assessments of changes in focal and global cerebral physiology associated with ictal activity on the tissue level in humans. Recent studies demonstrate that laboratory research insufficiently replicates the complexity of the human condition. Herein we summarize the current knowledge gained from human studies integrating cortical electrographic and brain tissue metabolic and hemodynamic information into the current pathophysiologic concept of SE in humans. With increasing experience gained by the use of extended neuromonitoring, we are more and more able to understand associated hemodynamic and brain neurochemical changes in patients with SE. In the future, this information can potentially provide integrated pathophysiologic end points into SE treatment concepts.
Surface EEG Combined with Invasive Neuromonitoring
Continuous scalp electroencephalography (EEG) monitoring is commonly used in comatose patients, revealing a high incidence of nonconvulsive seizures (NCSz) and nonconvulsive status epilepticus (NCSE) in medical and neurologic/neurosurgical ICU patients (Claassen et al., 2004; Oddo et al., 2009). Few studies correlated surface EEG findings with intracranial measurements of brain physiology. Seizure-associated brief episodes of brain tissue hypoxia have been known for many years from patients with temporal lobe epilepsy (Dymond & Crandall, 1976). Similarly, blood flow changes typically visualized using imaging techniques are used in clinical practice to characterize seizure onset (Salek-Haddadi et al., 2006; Roche-Labarbe et al., 2008). After traumatic brain injury (TBI) increases in intracranial pressure and brain chemistry (i.e., lactate pyruvate ratio) have been reported (Vespa et al., 2007). Recently, one small study did not find an association of partial brain tissue hypoxia (based on nursing records of PbtO2 drops below 20 mm Hg) with scalp-recorded NCSz (Park et al., 2011). However, the authors' objective was to determine if PbtO2 measurements could be used to detect nonconvulsive seizures with adequate sensitivity and specificity to alert clinicians. Their study demonstrated both that EEG is required to diagnose seizures and that interpreting of multimodality measurements requires access to high-density, nonstationary monitoring data.
Intracortical Mini Depth-Electrode Combined with Invasive Neuromonitoring
In the ICU setting, surface EEG monitoring is commonly artifact contaminated, which is a major obstacle for automated seizure detection. Recently, a new method of invasive EEG monitoring, a mini depth-electrode, was placed in the cortex of 16 patients with brain injury through a burr hole. Intracortical seizures were detected in 10 patients, and only half had a surface (scalp EEG) correlate. The phenomenon of neurovascular coupling has been well described in animal studies and represents increased oxygen supply through cerebral blood flow augmentation to metabolically active neurons (Roy & Sherrington, 1890; Bahar et al., 2006; Schwartz, 2007; Geneslaw et al., 2011; Zhao et al., 2011). A recent report using invasive neuromonitoring techniques in a patient with frequent seizures after cardiac arrest showed drops in PbtO2 despite increases in CBF associated with cortical electrographic seizures (Ko et al., 2011). This observation supports the notion that at times and possibly particularly in acutely brain-injured patients the metabolic demand inflicted by the seizure activity outmatches the substrate supply via increased cerebral blood flow. In a study of 48 comatose subarachnoid hemorrhage (SAH) patients with surface and cortical EEG monitoring, compensatory mechanisms involving increased CBF were only observed in patients with scalp seizures with a delay of 10 min, whereas increases in mean arterial blood pressure leading to an increase in cerebral perfusion pressure were seen rapidly following seizure onset (Claassen et al., 2013). These findings were most prominent for seizures detected not only on the depth electrode but also on the scalp, suggesting that the amount of involved brain tissue is important for this phenomenon in humans. Animal work further suggests that vasodilation may be seen only in actively seizing brain, whereas surrounding brain tissue will have vasoconstriction (Zhao et al., 2011). These observations, however, require a spatial resolution that will be difficult to achieve in humans with existing technology.
As mentioned earlier, compensatory vasodilatory mechanisms may still be insufficient, especially in patients with brain injury where repetitive seizures, SE, and cortical spreading depolarizations are common. The increased metabolic demand reflected in the cerebral metabolic rate of oxygen (CMRO2) (Zhao et al., 2011) may result in an imbalance between energy supply and demand. Associated metabolic changes of increased cerebral glutamate, glycerol, higher lactate/pyruvate ratio, and decreased cerebral glucose levels have been described previously in humans in both surface-detected and intracortical-detected seizures using cerebral microdialysis (During & Spencer, 1993; Vespa et al., 1998, 2007; Pan et al., 2008; Ko et al., 2011; Pan et al., 2012; Schiefecker et al., 2012). The sensitivity of this invasive method in detecting seizure/SE–associated brain metabolic changes is currently limited by the sampling time of at least 20 min. In line with that, profound metabolic changes were not observed in the series of 48 comatose SAH patients following seizures detected on scalp or intracortical EEG; however, the authors did not report cerebral glutamate levels (Claassen et al., 2013). Only baseline cerebral glucose levels were lower in intracortical-detected seizures that typically did not evolve to detectable seizures on scalp EEG, suggesting that glucose may be fundamental as an energy supply to allow progression of seizures. Newer methods of cerebral microdialysis may overcome these limitations and provide near real-time metabolic information of the seizing brain (Bhatia et al., 2006; Nandi & Lunte, 2009).
Subdural Strip Electrodes
Continuous electrocorticography (ECoG) is another important tool of invasive neuromonitoring and was recently reinvented as a research tool in severely brain injured patients (Lauritzen et al., 2011). Cortical spreading depolarizations are frequent in patients with acute brain injury including SAH, TBI, and malignant hemispheric stroke and associated with poor outcome in TBI patients (Dreier et al., 2006; Dohmen et al., 2008; Hartings et al., 2011; Lauritzen et al., 2011). Although more research is needed, the detection of spreading convulsions in SAH patients and their association with electrographic seizures in ECoG recordings, secondary neuronal injury, and posthemorrhagic seizures suggests a pathophysiologic role of cortical spreading depolarizations (CSD) in the initiation of seizures, evolution to SE, and postinjury epilepsy (Dreier et al., 2006, 2012; Dohmen et al., 2008; Fabricius et al., 2008; Hartings et al., 2011; Lauritzen et al., 2011). Scalp EEG may not be sufficiently sensitive in detecting single spreading depolarizations and depressions of spontaneous activity in humans, but when CSDs occur in clusters, slow potential changes may be detected on surface EEG (Drenckhahn et al., 2012).
In addition to routine biochemical monitoring (glucose, lactate, pyruvate, glutamate, glycerol), in vivo brain microdialysis permits sampling of other stable biochemical compounds in the extracellular fluid of the human brain that pass the dialysis membrane. This technique provides the possibility of further investigate on neuronal excitability (glutamate) (Balosso et al., 2009), and associated inflammatory responses (interleukin 1 [IL-6], tumor necrosis factor alpha [TNFα]) in patients with repetitive seizures or SE as previously shown in patients with SAH and TBI (Sarrafzadeh et al., 2010; Helmy et al., 2011). Moreover, it provides a method of measuring interstitial concentrations of various drugs (i.e., antiepileptic drugs) (Lindberger et al., 2001, 2002; Rambeck et al., 2006) and even performing quantitative pharmacokinetic studies (Hammarlund-Udenaes, 2000; Wei et al., 2009). These methods are currently limited by the variable recovery rate (Tisdall et al., 2006; Helmy et al., 2009); however, new approaches may overcome some existing limitations and may provide techniques to monitor drug metabolism and even allow the delivery of low molecular-weight drugs into the extracellular compartment in future. Lastly, multimodal neuromonitoring devices may prove beneficial to guide decisions about intensity and duration of therapy in patients with SE, that is, to titrate sedatives in order to achieve the optimal level of sedation, ensure sufficient energy supply (glucose, oxygen) to the vulnerable brain tissue, and evaluate the optimal time to titrate patients with SE from sedatives drugs (Helbok et al., 2012). Future trials are conceivable that would utilize multimodality monitoring end points to guide treatment intensity and duration.
On a meta level these preliminary observations illustrate the complexity of acute human brain injury and the major limitations of directly translating existing seizure models to humans. With increasing experience gained by the use of extended neuromonitoring we are more and more able to understand associated hemodynamic and brain neurochemical changes in patients with status epilepticus. Trials based on hypotheses that originate from pathophysiologic observations made in the acute human brain injury model will likely lead to treatment trials with a higher chance of positive outcome than those that directly translate observations made in the animal laboratory that insufficiently replicate the complexity of the human condition.
None of the authors has any conflict of interest to disclose.
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