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Abstract

Seizures are common after severe traumatic brain injury (TBI), with rates in the acute period approaching 5% with seizure prophylaxis in historical clinical trials. Post-traumatic seizures (PTS) are divided into categories: immediate PTS occur prior to resuscitation, typically in the field; early PTS occur from resuscitation to 7 days post-trauma; and late PTS occur thereafter. The relationship between immediate and early PTS, as well as their risk factors, are not well studied in modern cohorts. We performed a secondary analysis of a prospective database of severe TBI patients, defined as a post-resuscitation Glasgow Coma Scale ≤8, from a single institution. For the 579 patients included, rates of immediate and early PTS were 1.6% and 3.8%, respectively. We were unable to identify any clinical correlates for immediate seizures. In contrast, early PTS were associated with age (odds ratio [OR] 1.5; 95% confidence interval [CI]: 1.1–2.0; p < 0.01), hypoxia (3.3, 95% CI: 1.2–8.5; p = 0.02), and subdural hematoma (SDH) (2.8, 95% CI: 1.0–2.8; p = 0.04) in multivariable modeling. Patients with early PTS had higher rates of status epilepticus than those with immediate PTS (45% [n = 10/22] vs. 0% [n = 0/9]; p = 0.03). This supports the notion of immediate PTS, which typically occur in the field and may not reliably be deciphered from pathological posturing responses, as an entity distinct from early PTS. Status epilepticus was highly morbid, associated with a 70% mortality rate. Our previously identified markers may help risk-stratify patients who may warrant longer monitoring with continuous electroencephalography to detect and treat early PTS and corresponding status epilepticus risk.

Introduction

Post-traumatic seizures (PTS) are independently associated with poor outcomes after traumatic brain injury (TBI).^1,2 PTS are divided into two categories: early PTS occur within 7 days of trauma and late PTS occur after 7 days. In historical clinical trials, nearly 14% of patients have early PTS,³ which is associated with mortality, longer hospital length of stay, and non-home discharge.⁴ Continuous electroencephalography (EEG) improves surveillance for early PTS, especially for those without an obvious clinical correlate.^5,6 Randomized clinical trials, meta-analysis, and guidelines demonstrated that prophylaxis with anti-seizure medication (ASM) for early PTS is highly effective in reducing the rate to <5%.^3,7–9 Late PTS, also known as post-traumatic epilepsy, doubles the rate of unfavorable outcomes by 2 years and increases the risk of unexpected mortality by a factor of 30.^2,10,11

In addition to early PTS within 7 days of trauma, some literature advocates for a subcategory named “immediate PTS,” defined as PTS occurring at the time of the trauma and prior to rescucitation.^12,13 Immediate PTS may be a distinct clinical entity from traditionally defined early PTS in that they are likely provoked by the acute physical impact of the TBI, as opposed to downstream biological processes including neural inflammation, blood–brain barrier disruption, cortical irritability from intracerebral hemorrhage, and cytotoxic edema causing cell death.^13,14 In the pre-hospital setting, immediate PTS are difficult to distinguish from pathological posturing reflexes and other non-ictal phenomena. Although early PTS are associated with late PTS, immediate PTS may not confer additional risk for late PTS.^4,11,14–17

Despite the rich literature surrounding early and immediate PTS, most studies include historical cohorts of patients from the 1990s or earlier.^3,14,17–19 The past 20 years have seen dramatic changes in the care of severe TBI, including increased utilization of specialized neurocritical multidisciplinary care and acute neurosurgical interventions.^8,20,21 To characterize the clinical importance of early PTS in the current era of neurocritical care, we evaluated a large, prospective database of severe TBI patients to identify the rate and risk factors for early PTS. We further explored differences between immediate and early PTS.

Methods

The University of Pittsburgh Human Research Protection Office approved this study (STUDY19030228) with consent obtained from subject's legal representatives. We followed ethical standards for responsible research on human subjects and the Helsinki Declaration of 1975. We followed the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE).²² Data and analysis methods are available to qualified researchers upon request.

Study cohort

We performed a secondary analysis of a prospective database of severe TBI patients, defined as a post-resuscitation Glasgow Coma Scale (GCS) ≤8.²³ All patients were admitted to a single level one trauma center between November 2002 and December 2019. Our database has previously been described and excludes patients with age >80, imminent brain death (GCS 3 with bilaterally fixed and dilated pupils), penetrating injury, or pregnancy.^23–25 We additionally excluded all patients who had a pre-trauma history of seizures, regardless of etiology.

Most clinical data, as well as outcomes, were prospectively collected. A trained neuropsychologist collected the Glasgow Outcomes Scale (GOS) at 3 months post-trauma in the outpatient clinic or based on mortality records: 1 = death, 2 = persistent vegetative state, 3 = severe disability, 4 = moderate disability, and 5 = low disability. A board-eligible neurosurgeon (M.P.) collected missing data, including all radiographic data, when available through a retrospective chart review.

Major extracranial injury was defined as any body system, except the nervous, with an Abbreviated Injury Scale ≥4.²⁶ Hypotension was any blood pressure of <90 mm Hg systolic or <60 mm Hg diastolic in the pre-hospital setting or during resuscitation. Hypoxia was an oxygen saturation <88%, partial pressure of arterial oxygen of ≤75 mm Hg, or significant clinical concern for hypoxia by the treating healthcare team.

Seizure data

We have previously described our technique for recording early and late PTS.^11,27 Briefly, we defined a seizure as any clinical event or electrographic activity deemed a seizure by the treating healthcare team or epileptologist, respectively. Patients were treated with a 7-day course of phenytoin or fosphenytoin for seizure prophylaxis. If available, continuous EEG was performed from after admission to the intensive care unit until return of consciousness or 5 days after post-injury. A neurologist board certified in either epilepsy or clinical neurophysiology interpreted all EEGs.

For this project, we defined three mutually exclusive categories of PTS: 1.

Immediate seizure: any seizure in the pre-hospital setting

Early seizure: any from resuscitation through 7 days post-trauma

Late seizure: any seizure after 7 days post-trauma (also known as post-traumatic epilepsy)^1,11

Statistical analysis

We summarized baseline characteristics and compared patients with immediate PTS, early PTS, and no PTS using descriptive statistics. It is of note that although patients could have both immediate and early PTS, none did in our cohort. For normally distributed variables, we used two-sided heteroskedastic t tests and, for categorical variables, a χ² or Fisher's exact test as appropriate. For all comparisons, we compared the seizure group (i.e., immediate PTS and early PTS) to the no seizure group, which served as a baseline. The only exception was comparing rates of status epilepticus during the first 7 days between those with immediate and those with early PTS, as those without seizures by definition did not have status epilepticus. We used Firth's logistical regression combined with forward selection to identify independent predictors of PTS. We used Firth's regression because it uses a penalized likelihood-based method to account for rare outcomes (e.g., <5%).²⁸ We removed any highly colinear variables and evaluated the likelihood ratio to ensure that our model did not lose explanatory power. For all analysis, we used R (R Foundation for Statistical Computing, Vienna, Austria).

Results

Out of 579 patients with severe TBI included in our study, 9 (1.6%) had immediate PTS and 22 (3.8%) had early PTS (Fig. S1). No patient had both immediate and early PTS. There was insufficient evidence for any significant associations of immediate PTS with clinical variables (all p > 0.20). Early PTS were associated with a different distribution of GCS motor scores, higher rates of decompressive hemicraniectomy (DHC), and subdural hematoma (SDH) (all p < 0.01; Table 1). For outcomes, both immediate PTS and early PTS were associated with 3-month GOS distributions similar to those for subjects without PTS (p > 0.25). Unlike immediate PTS, early PTS were associated with an increased risk for mortality (62% in early PTS vs. 40% without early PTS; p = 0.04; Fig. 1).

FIG. 1.

Associations with early post-traumatic seizures (PTS). (A) Clinical variables and outcomes associated with early or immediate PTS. Some significant variables, such as age and Glasgow Coma Scale (GCS) score, are not included. Bars represent standard errors. (B) Odds ratios for variables included in the multivariable model.

Table 1.

Characteristics Associated With Early and Immediate Post-Traumatic Seizures

Characteristic	All (n = 548)	Early (n = 22)	p value	Immediate (n = 9)	p value
Age (SD)	40 ± 17	51 ± 19	0.01	37 ± 24	0.75
Sex (male)	79% (435/548)	82% (18/22)	0.99	78% (7/9)	0.99
Pupil reactivity
Reactive	65% (339/521)	86% (19/22)	0.12	89% (8/9)	0.48
One reactive	10% (52/521)	0% (0/22)		0% (0/9)
Unreactive	25% (130/521)	14% (3/22)		11% (1/9)
GCS Motor
1	31% (170/545)	36% (8)	<0.01	44% (4/9)	0.62
2	9% (47/545)	0% (0)		11% (1/9)
3	9% (48/545)	14% (3)		0% (0/9)
4	17% (96/545)	18% (4)		0% (0/9)
5	32% (173/545)	14% (3)		44% (4/9)
6	2% (11/545)	18% (4)		0% (0/9)
Major extracranial injury	18% (90/514)	10% (2/21)	0.55	0% (0/8)	0.36
Hypoxia	16% (85/525)	33% (7/21)	0.07	0% (0/7)	0.60
Hypotension	26% (132/515)	19% (4/21)	0.50	0% (0/8)	0.21
Depressed skull fracture	15% (77/530)	5% (1/22)	0.34	22% (2/9)	0.62
DHC	31% (172/548)	59% (13/22)	<0.01	44% (4/9)	0.47
LOS (IQR)	18 (8-27)	12 (7-18)	0.19	13 (12-16)	0.38
ICU LOS (IQR)	14 (7-20)	12 (7-16)	0.39	12 (10-13)	0.52
SDH	47% (249/530)	82% (18/22)	<0.01	44% (4/9)	0.99
EDH	10% (52/527)	10% (2/21)	0.99	0% (0/7)	0.99
tSAH	81% (427/527)	95% (20/21)	0.15	71% (5/7)	0.62
IVH	22% (118/529)	5% (1/22)	0.06	22% (2/9)	0.99
Midline shift	39% (192/493)	57% (12/21)	0.10	3/7 (43%)	0.99
Status epilepticus	-	45% (10/22)	-	0% (0/9)	0.03
GOS 3 months
1	40% (198/494)	62% (13/21)	0.27	25% (2/8)	0.73
2	6% (28/494)	0% (0/21)		0% (0/8)
3	35% (173/494)	19% (4/21)		50% (4/8)
4	15% (75/494)	19% (4/21)		25% (2/8)
5	4% (20/494)	0% (0/21)		0% (0/8)
Mortality 3 months	40% (198/494)	62% (13/21)	0.04	25% (2/8)	0.49

P value columns refer to comparisons between all patients and those with early seizures or immediate seizures, respectively. For presence of status epilepticus, p value applies to a comparison between those with early and immediate seizures. Length of stay variables are median with interquartile ranges. For cells with missing data, the number of patients with available data is also listed after the dash. Bold indicates significance (p < 0.05).

SD, standard deviation; GCS, Glasgow Coma Scale; DHC, decompressive hemicraniectomy; LOS, length of stay; ICU, intensive care unit; IQR, interquartile range; SDH, subdural hematoma; EDH, epidural hematoma; tSAH, traumatic subarachnoid hemorrhage; IVH, intraventricular hemorrhage; GOS, Glasgow Outcomes Scale.

These associations remained stable in multivariable modeling (Table 2). Age (by decade; OR 1.5; 95% CI: 1.1–2.0; p < 0.01), hypoxia (OR 3.3, 95% CI: 1.2–8.5; p = 0.02), and SDH (2.8, 95% CI: 1.0–2.8; p = 0.04) were associated with early PTS. We removed DHC from the multivariable model because of high collinearity with SDH.

Table 2.

Characteristics With Multivariable Association With Early Post-Traumatic Seizures (PTS)

Predictor	Odds ratio	95% CI	p value
Age (decade)	1.5	1.1-2.0	<0.01
Hypoxia	3.3	1.2-8.5	0.02
IVH	0.3	0.1-1.2	0.08
SDH	2.8	1.0-9.2	0.04

We developed a logistical regression model using forward selection. Age is by decade. We were unable to identify any risk factors for immediate PTS. Addition of any other feature to this model did not significantly improve explained variance (p > 0.10). Bold indicates significance.

CI, confidence interval; IVH, intraventricular hemorrhage; SDH, subdural hemorrhage.

The overall rate of status epilepticus was 1.7%. Patients with early PTS were significantly more likely to progress to status epilepticus than those with immediate PTS (45% [n = 10/22] vs. 0% [n = 0/9]; p = 0.03). Seventy percent (7/10) of patients with early status epilepticus had died within 3 months, compared with 40% (198/494) of patients without early PTS (p = 0.06). This was similar to the rates of mortality after immediate seizure (25%, 2/8; p = 0.06). No (0/10) patients with early status epilepticus had favorable outcomes by 3 months post-trauma (GOS 4–5).

Discussion

In a prospective database of severe TBI patients on seizure prophylaxis, both early (3.8%) and immediate (1.6%) PTS were uncommon and were associated with markers of more severe TBI. Both recent and historical trials of seizure prophylaxis have found similar rates of PTS, typically ∼3% for early PTS.^3,4,12,19 In the present study, we found a higher rate of status epilepticus (1.7%) for early PTS compared with a recent large, multi-institutional cohort (0.2%).⁴ That study used billing codes to capture seizure and status epilepticus occurrence, which may substantially underestimate rates.²⁹ Coupled with the higher rates of status epilepticus in our study, the associations we identified with early PTS (age, SDH, hypoxia) may help risk stratify patients. Other groups have found SDH to be highly predictive of early PTS.³⁰ Although risk stratification likely would not guide seizure prophylaxis decisions, it could guide patient selection for monitoring with long-term continuous EEG.^31,32

In our practice, we strive to place all severe TBI patients on continuous EEG for 3–5 days post-trauma. Although continuous EEG use is associated with improved outcomes in critically ill patients, this resource is limited by machine and reader availability and high costs.³³ In situations when there is limited continuous EEG availability, we use the risk factors identified in this study to guide both decision to use EEG and length of EEG usage.

We found an association between older age and early PTS (mean age 51 years with early PTS and 40 years without PTS). This was one of the strongest associations we found on both univariable and multivariable analysis, with p < 0.01 for all. Our finding mirrors prior literature showing that older age is also associated with early PTS in mild TBI.³⁴ This is contrary to associations with late PTS (i.e., post-traumatic epilepsy), in which younger age is correlated with increased risk for epilepsy.^11,12 The mechanisms for this is unclear. As in post-traumatic epilepsy, epilepsy overall occurs more frequently in younger populations, with stroke, infection, and cancer being common causes of late-onset epilepsy. Older individuals have altered pharmacokinetic absorption of ASM and worse tolerance of side effects.³⁵

We found several other variables associated with early PTS. Hypoxia, which is uncommon in our data set (< 20% overall), was not significant on univariable analysis (p = 0.07) but was significant on multivariable analysis (p = 0.03). Hypoxia is strongly associated with injury severity or difficulties with resuscitation in the field. More severe injuries, such as those requiring DHC, are associated with PTS in both our study and several others.^12,36 Intraventricular hemorrhage (IVH), which had a negative association with early PTS, did not meet our pre-specified cutoff (p < 0.05) for statistical significance on either univariable (p = 0.06) or multivariable (p = 0.08) analysis. Although the mechanisms for IVH protecting against early PTS are unclear, primary non-traumatic IVH rarely presents with seizures.³⁷

Although immediate PTS were rare even in our large data set, our findings support the notion of immediate PTS being a distinct entity from early PTS. Unlike early PTS, we were unable to find any correlations between immediate PTS and admission clinical information. Occurring in the field, immediate PTS may not be reliably deciphered from pathological posturing responses. Immediate PTS may have a different physiological mechanism occurring in the hyperacute phase from the trauma, as compared with PTS that occur within the 1st week despite seizure prophylaxis.³⁸ Early PTS were associated with mortality, whereas immediate PTS had no association with outcomes. Importantly, no patient with immediate PTS progressed to status epilepticus, whereas nearly one half with early PTS went into status epilepticus. This provides support for our hypothesis that immediate PTS is an entity distinct from early PTS.

Our study has several limitations. Our retrospective collection of some seizure data may underestimate the true incidence. Additionally, even though all our EEG readers were board certified in epilepsy or clinical neurophysiology, the inter-rater reliability of electrographic seizures without clinical correlation can be low. Despite these limitations, our rates were similar to those in previous reports from other recent prospective databases.^3,19

Even though our database included 579 patients with severe TBI, the rarity of early and immediate PTS limited our statistical power to evaluate other associations, including other markers of injury severity. In particular, we highlight that only 9 (1.6%) of patients had immediate PTS based on our definition. Therefore, multi-institutional collaborations and other epidemiological methods may be needed to further characterize the clinical importance of immediate PTS and evaluate other associations with early or immediate PTS.

Although we highlight that these characteristics indicating risk for early PTS could be used to prioritize the use of the limited resource of continuous EEG, future work is needed to evaluate that proposal prospectively. In addition to these characteristics, EEG-based features can meaningfully guide the duration of continuous EEG monitoring.^27,39

Conclusion

In our large, prospective database of 579 patients with severe TBI, rates of early seizures were low; 3.8% of patients had early PTS and 1.6% of patients had immediate PTS. Early PTS were associated with objective markers of injury severity including SDH, DHC, and hypoxia. These markers may help stratify risk of patients who may warrant longer monitoring with continuous EEG to avoid, detect, and treat status epilepticus which, in turn, was associated with a 70% mortality rate. Although the number of patients with immediate PTS in our large data set was low, we did not observe meaningful clinical associations with immediate PTS, suggesting that early PTS may differ from immediate PTS.

Transparency, Rigor, and Reproducibility Summary

This study was not registered formally. For our database, data have been collected continuously over several decades. The authors (M.P., J.F.C., J.E., W.T.K.) discussed and created a pre-specified analysis plan. We followed this plan without deviation. J.E., W.T.K. are, respectively, masters and PhD level statisticians. No power or sample size calculation occurred. We used the entire database available to us. All subjects are accounted for in the Consolidated Standards of Reporting Trials (CONSORT) diagram. Data and code are available to qualified researchers upon request.

Footnotes

Authors' Contributions

Matthew Pease: conceptualization, methodology, formal analysis, data curation, writing – original draft, writing – review and editing. Jonathan Elmer: conceptualization, methodology, formal analysis, writing – original draft, writing – review and editing. Arka N. Mallela: conceptualization, data curation, writing – review and editing. Jorge Gonzalez-Martinez: conceptualization; writing – review and editing. David O. Okonkwo: conceptualization, data curation, writing – review and editing. Flora Hammond: conceptualization, writing – review and editing. Sergiu Abramovici: conceptualization, writing – review and editing. James F. Castellano: conceptualization, data curation, writing – original draft, writing – review and editing. Wesley T. Kerr: methodology, formal analysis, writing – original draft, writing – review and editing.

Funding Information

We did not receive funding for this study specifically. Dr. Kerr's research time was supported by the Susan S. Spencer award, funded by the American Academy of Neurology, American Brain Foundation, Epilepsy Foundation, and the American Epilepsy Society.

Author Disclosure Statement

Dr. Gonzalez-Martinez accepts consulting fees from Zimmer Biomet. Dr. Castellano accepts consulting fees from Neuro One Medical Technologies. Dr. Kerr writes review articles for Medlink Neurology; is a paid consultant for SK Life Sciences, Biohaven Pharmaceuticals, and Epitel; and has collaborative or data use agreements with Eisai, Janssen, Radius Health, UCB, GlaxoSmithKline (GSK), and Jazz Pharmaceuticals. The remaining authors have no conflicts of interest to disclose.

Supplementary Material

Abbreviations Used

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Supplementary Material

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Early Post-Traumatic Seizures After Severe Traumatic Brain Injury

Abstract

Introduction

Methods

Study cohort

Seizure data

Statistical analysis

Results

Discussion

Conclusion

Transparency, Rigor, and Reproducibility Summary

Footnotes

Authors' Contributions

Funding Information

Author Disclosure Statement

Supplementary Material

Abbreviations Used

References

Supplementary Material