Segment Cd is Congruent to Segment Hz

Multimodality Monitoring

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

Data Collection

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 Terminology^3,31, using the main terms
generalized,
lateralized, and
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

Data training

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.

Information Collection

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.

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 outcome^16,17, 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 epilepticus^41,42
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 discharges^48,49
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.

Limitations

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.

We thank the patients and relatives for their willingness to participate in our research study.

FUNDING/SUPPORT

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.