Segment Cd is Congruent to Segment Hz
Author manuscript; available in PMC 2017 Sep one.
Published in final edited course equally:
Electroencephalographic Periodic Discharges and Frequency-Dependent Encephalon Tissue Hypoxia in Astute Brain Injury
oneDepartment of Neurology, Columbia University, New York, NY, United states
iSection of Neurology, Columbia Academy, New York, NY, USA
J. Michael Schmidt
1Department of Neurology, Columbia University, New York, NY, The states
oneSection of Neurology, Columbia University, New York, NY, USA
Cristina M Falo
1Department of Neurology, Columbia Academy, New York, NY, Usa
1Department of Neurology, Columbia University, New York, NY, USA
aneDepartment of Neurology, Columbia University, New York, NY, United states
1Department of Neurology, Columbia University, New York, NY, U.s.a.
iDepartment of Neurology, Columbia University, New York, NY, USA
E. Sander Connolly
2Department of Neurosurgery, Columbia University, New York, NY, The states
1Section of Neurology, Columbia University, New York, NY, USA
Periodic discharges (PDs) that practise non come across seizure criteria, also known equally the ictal-interictal continuum (IIC), are pervasive on EEG following acute encephalon injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown.
To determine whether distinct PD patterns can exist identified that, like to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing encephalon injury.
Design, Setting, and Participants
This prospective cohort study included 90 asleep patients with high-class spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), fractional pressure of oxygen in interstitial brain tissue (PbtO2) and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a unmarried tertiary intendance center. The retrospective analysis was performed from September 1, 2014, to May one, 2016, with a hypothesis that the outcome on brain tissue oxygenation was primarily dependent on the belch frequency.
Chief Outcomes and Measures
Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between hateful multimodality monitoring information and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping.
Of the 90 patients included in the study (26 men and 64 women; hateful [SD] age, 55 [fifteen] years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings but. Frequencies of PDs ranged from 0.five to 2.5 Hz. Median PbtO2 was 23 mmHg without PDs compared to xvi mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were meaning for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of loftier-frequency PD onset (≥ 2.0 Hz) and PbtO2 reduction (median normalized PbtO2 decreased past 25% 5–10 min later onset). Increased regional CBF of 21.0 mL/100g/min for 0 Hz, 25.ix mL/100g/min for 1.0 Hz, 27.five mL/100g/min for 1.five Hz, and 34.seven mL/100g/min for ii.0 Hz and increased global cerebral perfusion pressure level of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.five Hz, and 67.8 mm Hg for iii.0 Hz were seen for college PD frequencies.
Determination and Relevance
These data give some back up to consider redefining the continuum betwixt seizures and PDs, suggesting that additional damage afterward acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood period increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may exist inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms.
Periodic discharges, acute brain injury, EEG, multimodality monitoring
With the increasing use of continuous electroencephalography (EEG) in neurologic and nonneurologic intensive care units (ICUs), EEG phenomena of unclear significance are detected more than frequently.1–4
Among these phenomena, periodic discharges (PDs) are virtually common.5
The prevalence of PDs ranges in medical and surgical ICU cohorts from 17% to 29% of asleep patients, even later exclusion of patients with neurological abnormalities.6,7
In neurologic ICUs with more than liberal utilise of continuous EEG, prevalence ranges from 17% to as many as xl% of patients.8–10
Invasive multimodality monitoring (MMM) in comatose patients with spontaneous subarachnoid hemorrhage (SAH) has revealed that electrographic seizures may exist associated with a decrease in partial pressure of oxygen in interstitial brain tissue (PbtO2), metabolic crisis, height of intracranial pressure, and a delayed increase in regional cerebral blood catamenia (CBF).11,12
These pathophysiologic changes during seizures are consistent with a large torso of work generated across different experimental seizure models.13–15
In humans with acute encephalon injury, electrographic seizure burden worsens clinical outcomes16,17, which in conjunction with the aforementioned physiologic alterations that occur during seizures provide a rationale for treating electrographic seizures.
In comparing, the physiological changes of the brain during PDs are poorly understood. Whether PDs are associated with unfavorable brain tissue changes such as metabolic crisis with tissue hypoxia remains unclear. In comatose patients with acute encephalon injuries, PDs have been interpreted every bit an epiphenomenon18
and a harm-causing complication of acute brain injury.4
In a purely descriptive approach, PDs accept been classified as being role of an
ictal interictal continuum
(IIC), a term that has become widely used.2,19
Uncertainty near the significance and underlying pathophysiological changes associated with PDs is reflected in varying local recommendations, with some centers aggressively administering antiseizure medications in response to PD detection and others favoring a watch-and-wait exercise.twenty,21
Here we test the hypothesis that distinct IIC patterns can be identified and are similar to electrographic seizures in that they cause brain tissue hypoxia and may therefore atomic number 82 to additional brain injury. We hypothesized that this effect on brain tissue oxygenation was primarily dependent on discharge frequency (higher-frequency discharges causing more than metabolic stress that is not compensated for adequately after acute brain injury compared to lower-frequency discharges). In a secondary analysis, we explored the spatial characteristics of discharges (hypothesizing that generalized discharges cause more damage than lateralized ones). To exam these hypotheses, we analyzed prospectively collected intracortical (depth) EEG (dEEG) and surface (scalp) EEG (sEEG) recordings with information obtained from MMM (PbtO2 and regional CBF) in patients with high-grade nontraumatic SAH.
A more detailed description of the written report can exist constitute in eMethods one in the Supplement. Information were collected as part of the ongoing prospective SAH Outcomes Project study. All patients with poor-grade (Hunt and Hess grades 4–5; range, 1–5, with higher scores indicating greater disease severity22) SAH patients admitted to the neurologic ICU at Columbia University Medical Center, New York, New York, from June one, 2006, to September 1, 2014, who underwent invasive MMM following an institutional protocol were included in the study.11,23
Patients underwent invasive brain monitoring when the Glasgow Coma Score was no higher than 8 (range, 3–15, with higher scores indicating greater wakefulness) at ICU admission and when no anticipated improvement of consciousness, clinical deterioration, and/or death was expected for at least 48 hours.11
This study was approved by the institutional review lath of Columbia University Medical Middle. Patient representatives provided written informed consent.
According to a previously described institutional protocol, invasive neuromonitoring includes measurements of intracranial pressure, PbtO2, regional CBF, and dEEG.23,24
Details are available in eMethods 1 of the Supplement and take been published previously.11
The sEEG recordings were obtained co-ordinate to the international 10–20 electrode organization.
Full general Management
Medical and surgical management followed the guidelines gear up forth past the American Centre Association.25
Multimodality monitoring followed the guidelines of the Neurocritical Intendance Society and the European Society of Intensive Care Medicine, too as local guidelines.22, 26–28
Independent of initial EEG findings, patients were given intravenous phenytoin sodium for 1 week after hemorrhage. Thereafter, antiseizure medication therapy was discontinued unless seizures were detected on sEEG recordings. Isolated seizures detected past sEEG recordings were typically treated with levetiracetam, and status epilepticus was treated with midazolam infusion.29
Periodic discharges were non deemed seizures and not treated with antiseizure medications. However, patients were maintained on an antiseizure medication regimen if PDs occurred during the start 7 days afterward admission and continued across that time, in order to prevent transition to seizure activity. Findings on dEEG recordings did not alter the antiseizure regimen.23
Information collection for the prospective outcomes database and digital physiological information have been described previously.11,thirty
The data collection procedure is summarized in the eMethods i in the Supplement.
EEG Monitoring and Nomenclature
Continuous EEG recordings were rated after visual inspection by two experienced EEG clinicians (J.Due west. and J.C.) blinded to the clinical course of patients.11
Rating was performed separately for sEEG and dEEG recordings according to published criteria.three
Studies performed later the publication of these criteria have shown fantabulous interrater agreement regarding seizure detection and satisfactory interrater understanding regarding identification of PDs.31,32
Therefore, in the nowadays study, classification followed agreement between the 2 master raters, and in cases of disagreement, the terminal rating was determined past a tertiary clinician (Thou.R.) who acted as a tiebreaker.
Classification of PDs
Frequencies were chosen ranging from 0 Hz (no PDs) to a maximum of 2.5 Hz. Periodic discharges of 3.0 Hz or higher were considered seizures by convention.3
Examples of coded EEG frequencies are shown (Fig. 1). In cases of PDs at different frequencies, the predominant PD frequency for a given minute was chosen. In addition to PDs, the presence or the absence of seizures was coded for each EEG minute following previously reported methods.xi
Periodic discharges on the sEEG were classified according to criteria set forth by the American Clinical Neurophysiology Society Standardized Disquisitional Care EEG Terminology3,31, using the main terms
bilateral independent. Accordingly, for each EEG minute that contained PDs, we code these as unilateral left- or right- sided PDs; bilateral independent and generalized PDs after visual inspection. Unilaterality was defined equally unilateral or bilateral synchronous (but predominantly unilateral) PDs in focal, regional and hemispheric distribution. Bilateral independent PDs included 2 or more independent and bilaterally present PD patterns in focal, regional or hemispheric distribution. In our report, bilateral contained PDs likewise included multifocal bilateral asynchronous patterns. Generalized PDs were divers as bilateral, bisynchronous, and symmetric patterns, even when occurring in a restricted field (eastward.g. bifrontal). Triphasic waves were categorized equally generalized discharges.three
4 examples of periodic discharge frequencies on dEEG in four patients
The concluding coded PD frequency was determined according to the predominant frequency because the entire minute PDs were independent in. The segments shown hither exhibit PD-frequencies of approximately 0.5 Hz (A), 1 Hz (B), 1.5 Hz (C), 2.5 Hz (D). PDs shown in B, C, and D had no consistent correlate on sEEG. Abbreviations: dEEG, Depth/Intracortical EEG; sEEG, Surface/Scalp EEG; PD, Periodic Discharge; Hz, Hertz
Data training and all analyses were performed using R software (version three.0.ii; R Project). For each of the physiological measures, we defined a filter to remove the most common artifacts, based on clinical knowledge about their onset, time class, and morphologic features. Details on the data filtering procedure and an example are bachelor in eFigure i in the Supplement.
Data were analyzed from September 1, 2014, to May ane, 2016. Data are represented as frequencies, median (interquartile range), or means (SD). Differences betwixt patient groups were tested using the Mann-Whitney examination or the Chi-Square test, as appropriate. P<0.05 was ready as the threshold of statistical significance using a two-tailed
test. All other statistical analyses were performed using nonparametric bootstrapping, which sampled the median 500 times with replacement, as implemented in the R parcel “kicking”. We determined the 2.v% to 97.5% CI for weather condition of interest and classified the difference between 2 conditions as meaning if their CIs were nonoverlapping.33
To examine the association of PD frequencies and physiological variables, we chose the 0-Hz condition every bit a reference. For the purposes of the change signal analysis, we chose the time from 10 and 5 minutes preceding the PD frequency change as the baseline.
During the study period, 666 patients with spontaneous SAH were admitted to Columbia Academy Medical Center, 204 of whom had a Glasgow Coma Score on admission of eight or lower and were potential candidates. Amidst these, 90 patients were included in the study (26 men and 64 women; mean [SD] age, 55 [fifteen] years) (Table 1), and 114 were excluded, well-nigh frequently for anticipated comeback of the Glasgow Blackout Score or decease within 48 hours. Additional characteristics of the study cohort are described in eMethods 2 in the Supplement. Baseline characteristics of patients included and excluded in the nowadays study were overall comparable (eTable in the Supplement).
Tabular array 1
mean (SD) or n (%)
|Age||Female person n (%)||Caucasian|
|55 +−15||64 (71)||27 (thirty)|
median (IQR) or mean (SD)
APACHE Two Score
||SAH Sum Score||IVH Sum Score|
|4 [4–5]||22 +− 7||19 +− ten||four +− 4|
|Global Cerebral Edema||43 (46)|
|Aneurysm Clipping||Aneurysm Coiling|
|53 (60)||24 (28)|
n (%) or median (IQR)
|Worst Chase&Hess score inside first 24 hours of SAH|
|49 (59)||5 [4–five]|
Functional Result at 3 months
median (IQR) or n (%)
|Modified Rankin||Dead or severely disabled|
|5 [3–6]||56 (62)|
70-ii patients (80%) had sEEG and dEEG recordings; the remaining 18 patients (xx%) had sEEG recordings merely. The mean (SD) EEG time per patient was 104 (69) hours. Of the 90 patients included in the report, 53 (59%) had PDs on sEEG or dEEG recordings or both. Twenty-one patients (23%) had PDs visible on only dEEG recordings and 32 (36%) had PDs visible on sEEG recordings. 20-one patients (23%) had generalized PDs; 21 (23%), right-sided PDs; xv (17%), left-sided PDs; and 9 (10%), bilateral PDs. Twenty-two patients (24%) had more than ane type of surface PD (e.g. generalized and lateralized PDs). Twenty-ix patients (32%) had lateralized PDs occurring but on i side throughout the recording (due east.yard., only left-sided, never right-sided). 20-8 patients (31%) had seizures, which were only visible on dEEG recordings in 19 (68%). All simply one patient with seizures on the sEEG and/or dEEG recordings also had PDs on sEEG and/or dEEG recordings.
PD Frequency and MMM Variables
The hateful duration of single PD episodes in patients who had PDs on dEEG recordings were 1110 minutes for a frequency of 0 Hz, 51 minutes for 0.5 Hz, 14 minutes for 1.0 Hz, 24 minutes for 1.5 Hz, 23 minutes for 2.0 Hz, 10 minutes for 2.v Hz, and xviii minutes for three.0 Hz. In patients who had PDs on dEEG recordings, the mean (SD) number of changes between frequencies per hour beyond patients was 0.73 (1.20). Probabilities of transition from one frequency to another are shown in eFigure 2 in the Supplement. Changes in PD frequencies by and large are small (0.5 and 1.0 Hz), but large changes can occur when PD runs stop. For example, the probability of going from a frequency of 3.0 Hz to 0 Hz is most 0.4 (everyman entry on the left cavalcade in eFigure ii in the Supplement).
Frequencies of PDs on dEEG recordings were correlated with the MMM variables (Fig. 2). This assay was conducted with and without episodes that also fulfilled seizure criteria, which yielded comparable results. Median PbtO2 (Fig. 2A) was significantly lower at 14.4 mm Hg for a PD frequency of 2.v Hz and 14.7 mm Hg for a PD frequency of 3.0 Hz when compared with PbtO2 at 0 Hz (23.iv mm Hg). Median regional CBF values (Fig. 2B) were higher at 25.9 mL/100g/min for a PD frequency of 1.0 Hz, 27.5 mL/100g/min for a PD frequency of i.5 Hz, and 34.seven mL/100g/min for a PD frequency of ii.0 Hz when compared with median regional CBF of 21.0 mL/100g/min for a PD frequency of 0 Hz, but this difference was not statistically pregnant. No patient had higher-frequency PDs (>2.0 Hz) and simultaneous regional CBF measurements. Median cerebral perfusion pressure level was increased at frequencies higher than 0 Hz and reduced at 3.0 Hz (Fig. 2C), but neither the initial increase nor the drop at 3.0 Hz reached statistical significance. Intracranial force per unit area did not appear to systematically change at 9.half-dozen mm Hg for a PD frequency of 0 Hz, 8.6 mm Hg for a PD frequency of 0.5 Hz, 8.four mm Hg for a PD frequency of 1.0 Hz, 9.0 mm Hg for a PD frequency of 1.five Hz, seven.eight mm Hg for a PD frequency of 2.0 Hz, 9.iii mm Hg for a PD frequency of 2.five Hz, and 10.v mm Hg for a PD frequency of iii.0 Hz.
Frequency of periodic discharges (PDs) on dEEG and multimodality monitoring parameters
A, Brain oxygen, B-C, Local and global cognitive blood flow, D, Intracranial Force per unit area. Frequency of 0 corresponds to absence of PDs. Values represent medians with interquartile ranges (25–75). Meaning differences to respective values at 0 Hz revealed by bootstrapping (500 repetitions) are marked with an asterisk. Abbreviations: dEEG, Depth/Intracortical EEG; PbtO2, Interstitial Fractional Brain Oxygen Tension; rCBF, Regional Cerebral Claret Menstruum; CPP, Cerebral Perfusion Pressure; ICP, Intracranial Pressure
Brain oxygen at PD-Frequency Change Points
Next we investigated whether the reduction of PbtO2 at a PD frequency of at least 2.0 Hz (high-frequency periodic discharges on dEEG) could exist retraced in the time window surrounding high-frequency PD onset. For this purpose, we included in the analysis all patients with loftier-frequency PDs and plotted PbtO2 time courses starting 10 minutes before until 15 minutes after onset of high frequency PDs (Fig. 3).xi
High frequency PD onsets, that were preceded by a lower PD frequency were included if the change in frequency was one.0 Hz or greater (e.g. increase from ane.5 to 2.5 Hz, just not from 1.5 to two.0 Hz). We institute that PbtO2 values began to decrease approximately 5 minutes before the onset of high-frequency PDs. Bootstrapping revealed significant reductions of PbtO2 in the 5- to ten-infinitesimal window afterwards high-frequency PD onset compared to PbtO2 v to 10 minutes before the episodes.
Interstitial brain oxygen (PbtO2) at the onset of high frequency periodic discharges (≥2.0 Hz)
Episodes: n= 27 in north= viii patients. PbtO2 normalized to maximum. Pregnant differences of respective time points in comparison with PbtO2 at v–10 min before high frequency PD onset revealed by bootstrapping (500 repetitions) are marked with an asterisk.
PbtO2 and Distribution of PDs on sEEG
Regardless of anatomical distribution, PbtO2 was lower at high PD frequencies (Fig. 4A). To explore the association of anatomical localization of PDs on sEEG and PbtO2 values, nosotros combined lateralized (right- and left-sided) PDs and generalized and bilateral PD distributions, respectively (Fig. 4B and C). Low-frequency (0.five–i.5 Hz) generalized PDs had lower PbtO2 when compared with low-frequency LPDs. No apparent PbtO2 difference was institute between high-frequency (≥2.0Hz) lateralized PDs and high-frequency generalized PDs.
Interstitial brain oxygen tension in relation to surface EEG periodic discharges
A, PbtO2 in relation to all PDs on sEEG categorized according to discharge frequency. B, PbtO2 in relation to low frequency PDs (0.5–1.5 Hz) categorized according to lateralized (right or left) and generalized PD distribution on sEEG. Lateralized PDs: n= 14 patients, generalized PDs: n=9 patients. C, PbtO2 in relation to high frequency PDs (2.0–2.5 Hz) categorized according to lateralized (right or left) and generalized PD distribution on sEEG. Laterlized PDs: due north= five patients, Generalized PDs: n=5 patients. Abbreviations: PbtO2, Interstitial brain oxygen; sEEG, Scalp/surface EEG; PDs, Periodic Discharges
This study is the showtime, to our cognition, in humans to anchor PDs in a framework of existent-fourth dimension brain physiologal changes using sEEG and dEEG recordings in combination with invasive monitoring of PbtO2 and regional CBF. Past analyzing a large annotated EEG data set, the nowadays study establishes the belch frequency as the central characteristic that allows discrimination between potentially harmful and likely beneficial PDs. Our findings suggest a PD frequency range of compensated brain metabolism where elevated CBF sufficiently matches the increased oxygen demand (0.five–2 Hz) and a higher PD frequency range (>two.0 Hz) of metabolic decompensation where encephalon oxygen levels decrease, indicating tissue hypoxia. Brain physiological changes above this decompensation threshold resemble those seen in seizures, with the clinical implication that high-frequency PDs after acute brain injury may be interpreted and managed every bit seizures.
Findings on dEEG Recordings
The hypothesis of a decompensation threshold is supported by 2 findings. First, brain tissue oxygen levels decrease at high PD frequencies with a critical threshold of greater than 2 per second. 2nd, local CBF and cerebral perfusion pressure as an indicator of global brain perfusion increment with all PDs just do non increase further with frequencies above 2.0 Hz, suggesting a compensatory perfusion response with a limit.
We plant a close temporal association between the onset of high-frequency PDs and the reduction of PbtO2. This finding suggests a possible causal association between high-frequency PDs and interstitial brain oxygen reduction. Interestingly, we found a subtract in brain tissue oxygenation preceding PD frequency changes that, although statistically nonsignificant, raises the possibility that the electrographic changes could be reflecting rather than causing metabolic breakdown. A conceivable scenario is that brief episodes of hypoxia trigger PDs, which in plow perpetuate a hypermetabolic state and thus hypoxia, resulting in a fell cycle betwixt hypoxia and PDs. However, the electrographic changes may be purely secondary, with further investigation needed to determine whether they cause additional hypermetabolic and hypoxic changes.
Certainly, whether PDs are the crusade or the effect of tissue hypoxia cannot be sufficiently addressed using this exploratory written report design. The alterations of brain tissue physiological changes seen with the onset of high-frequency PDs, including the oxygen decrease that precedes high-frequency PDs, are coinciding with the physiologic changes seen in electrographic seizures.11
During seizures, tissue deoxygenation is common, may precede the onset of spontaneous seizure activeness, and is oftentimes reversible later cessation of seizures
34–37. Nevertheless, seizures –unlike PDs – accept more convincingly been shown to worsen clinical outcome16,17, which provides a rationale to treat seizures, although the underlying pathophysiological changes may not be completely understood. Whether treatment of high-frequency PDs is beneficial remains speculative at this point, and indeed controversy remains regarding whether and how to treat EEG seizure patterns in this setting. Future interventional trials targeting high-frequency PDs or interventions aimed at underlying conditions leading to PDs may advance our understanding further.38–39
Based on our study results alone, we are not in a position to recommend changing treatment of PDs. Our written report may rather advise that the injury potential of high-frequency PDs should be investigated and possibly be a target for clinical trials investigating the benefits of handling. With respect to terminology, the physiological resemblance of loftier-frequency PDs and seizures provides some support to consider recategorization of some of the patterns within the IIC based on PD frequency. Notably, in the present study, we were careful to exclude not only classic seizures only also very high-frequency PDs (3 per 2nd or more) because these have been categorized as seizures previously.1,3
Including these patterns in the analysis but strengthened the observations.
Our study does not establish whether PDs influence clinical outcome. Withal, because PDs are very mutual EEG phenomena in acute encephalon injury, we need to clarify their physiological significance before embarking on big randomized controlled trials on PDs or electrographic seizures. We must know whether sure types of PDs have to exist regarded every bit seizures. Failure to correctly differentiate betwixt benign and malignant EEG patterns is bound to derange study results and may lead to type II errors.
Findings on sEEG Recordings
Findings on sEEG were consequent with the findings on dEEG recordings; withal, they largely remained descriptive and statistically nonsignificant. The lack of statistical power likely reflects the relatively lower prevalence of PDs, and in particular fewer loftier-frequency PDs, detected with sEEG recordings in comparing with dEEG recordings. Although virtually all patients with PDs on sEEG recordings had a correlate on dEEG recordings, almost one-quarter of patients with PDs on dEEG recordings had no correlate on sEEG recordings. This lack of power forced united states to use a lower frequency cutoff to qualify for high-frequency PDs (>1.5 Hz). Again, lower PbtO2 was seen with college-frequency PDs compared with lower frequencies. Depression-frequency PDs were only associated with encephalon tissue hypoxia when discharges were generalized, whereas PbtO2 drops were seen for generalized and lateralized PDs at college frequencies. These sEEG information propose that the damaging effect of PDs may be based on an interaction between the frequency and spatial distribution of the discharges. Still, these preliminary surface EEG observations need to be replicated in a larger data gear up. Statistically robust reproduction of our dEEG results using sEEG data would be particularly interesting from a clinical standpoint, because centers increasingly take access to sEEG, whereas the use of dEEG remains express to few highly specialized centers.
Triphasic waves were categorized as generalized PDs according to recent guidelines, which may have systematically influenced our analysis on sEEG PDs.3
However, in our data fix, we did not detect whatsoever triphasic waves at frequencies of greater than 2.0 Hz, and the ones at a frequency of 2.0 Hz were rare.
Our written report results do not clearly demonstrate a role for sEEG recordings in the detection of PDs. Regarding feasibility and safety, generating more sEEG data in diverse patient populations will be nonproblematic. Depth EEG recordings on the other hand, despite having a similar safety profile as other MMM techniques, will likely remain restricted to patients with severe neurological affliction in whom the take chances-benefit ratio of intracortical electrode insertion is ethically justifiable.twoscore
Pathophysiologic Changes Associated with PDs
Although association studies in critically ill patients have linked the occurrence of PDs to the occurrence of nonconvulsive seizures and condition epilepticus41,42
likewise as increased mortality and worse functional outcome,43,44
few studies explored pathophysiological changes associated with PDs. Differences in the PD patterns studied and varying definitions may explicate some of the inconsistencies of the reported findings. For these reasons, we strictly adhered to the enquiry terminology as defined past the American Clinical Neurophysiology Society that is not only widely used for enquiry but is increasingly used for clinical purposes.3
A recent case serial suggests that encephalon tissue hypermetabolism may be seen on positron emission tomography scanning in patients with IIC.45
Magnetic resonance imaging studies take revealed vasogenic and cytotoxic edema in some patients with PDs that are similar to those seen in patients with seizures.46
Functional magnetic resonance imaging in patients with idiopathic generalized epilepsy has revealed increased CBF associated with elevated cognitive metabolic rate of oxygen consumption during interictal epileptiform discharges.47
In contrast, instance reports on stimulus-induced rhythmic, periodic, or ictal discharges48,49
suggest that this subtype of IIC may non be associated with an increase in regional CBF as visualized past unmarried-photon emission estimator tomography. A recent study past Vespa and coworkers12
reported metabolic crises on intraparenchymal microdialysis at times of electrographic seizures after traumatic brain injury. Their report included some patients with PDs every bit an ictal blueprint, just did not include a separate analysis focusing on PDs lonely.
Nosotros studied patients with SAH who had a loftier burden of brain injury and were selected to undergo invasive brain monitoring, which may reflect on the generalizability of the results. A selection bias analysis among patients with loftier-grade SAH was conducted and revealed no major differences between patients selected to undergo MMM compared with those who were eligible but not selected.
The fact that all cohort patients were gravely ill and limited in number entailed that analyses investigating associations between PDs and clinical outcomes were bound to lack statistical power. At three months of follow-up, 36 of our patients (40%) were dead and 20 (22%) had a modified Rankin Calibration score of 5 (range, 0 [no symptoms] to 6 [death]). A comparing betwixt patients with unfavorable (modified Rankin Scale score, 4–6) and favorable (modified Rankin Scale score, 0–3) outcomes showed simply a pregnant difference in admission Hunt and Hess scores between both groups, but did not show differences in other well-established predictors of outcome in patients with SAH (i.due east. Acute Physiology and Chronic Health Evaluation II score, aneurysmal rebleeding, patient age) or in the prevalence of high-frequency PDs, which illustrates the lack of statistical power. Future studies are needed to test whether high-frequency PDs influence clinical outcomes and whether interventions targeting high-frequency PDs may improve outcomes.
An inherent limitation of virtually enquiry in man participants, in contrast to inquiry in fauna models, is that injury patterns are not standardized and that experimental conditions are poorly controlled. In particular, the interaction between high-frequency PDs and hypoxia may get more conclusive if studied in animal models. Causality can also exist explored using causal inference methods, but are challenging to explore in datasets with low-frequency events such as transitions betwixt low- and loftier- frequency PDs.l
The difficulties of standardized PD detection and classification past visual diagnosis accept been pointed out previously.31,33
The length of EEG recordings in our cohort varied depending on clinical necessity, and twenty% of our cohort did not undergo dEEG recordings. Furthermore, encephalon-blood flow measures are technically challenging, leading to limited regional CBF data with many recording breaks. This situation is reflected in the fact that no simultaneous regional CBF recordings and high-frequency PDs were available in our information set up. Moreover, we did not include information on medication data, which may affect EEG patterns. At our institution, patients with loftier-course SAH routinely receive intravenous phenytoin during the first week after admission, which is non standard at other institutions. Generalizations to other acute encephalon injuries such as traumatic brain injury should be made with caution as pathophysiological background changes associated with this primary injury may determine the interaction between PDs and the measured brain physiology. The fact that findings on dEEG recordings could not clearly be reproduced using sEEG recordings impedes the immediate clinical applicability of our study results since most centers do not routinely use intracortical EEG technology.
Despite these limitations, our study provides a starting bespeak for prospective trials in which potential confounders can be controlled.
Our study suggests that PDs, which largely constitute EEG patterns of unclear significance, are associated with frequency-dependent changes of the underlying brain tissue physiology in patients with acute encephalon injury. We describe a frequency threshold above which physiological changes resemble those seen during electrographic seizures, such as increased regional CBF and decreased brain tissue oxygenation. This finding redefines the distinction between seizures and PDs. Our study provides a rationale to conduct prospective interventional trials to test the hypotheses that patients with PD frequencies of more 2 per second benefit from antiseizure medication and that low-frequency PDs may not exert harmful effects on encephalon tissue.
We thank the patients and relatives for their willingness to participate in our research study.
This publication was supported by the Deutsche Forschungsgemeinschaft (Enquiry Fellowship Wi 4300/1-ane, J.Westward.), the DANA foundation (JC, JMS), the NLM of the NIH under Honor Number R01LM011826 (JC), and NIH grant K01 ES026833 (SP). The content is solely the responsibleness of the authors and does non necessarily represent the official views of the NIH.
Conflict OF INTEREST DISCLOSURES
Dr. Claassen reported receiving honoraria from serving on the Informational Board of Actelion for report development.
Drs. Witsch and Claassen had total access to all the information in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Report concept and pattern: Witsch, Frey, Claassen
Acquisition, analysis, or estimation of data: All authors
Drafting of the manuscript: Witsch, Frey, Claassen
Critical revision of the manuscript for important intellectual content: Witsch, Frey, Schmidt, Roh, Reznik, Connolly, Claassen
Statistical analysis: Frey, Witsch, Schmidt, Claassen
Administrative, technical, or fabric support: Velazquez, Falo
Study supervision: Claassen
Function OF THE FUNDERS
The funding sources had no part in the blueprint and behave of the written report; collection, management, analysis, or interpretation of the information; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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Segment Cd is Congruent to Segment Hz