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Postinfectious inflammation in cerebrospinal fluid is associated with nonconvulsive seizures in subarachnoid hemorrhage patients
Epilepsy Research 169 (2021) 106504
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Postinfectious inflammation in cerebrospinal fluid is associated with nonconvulsive seizures in subarachnoid hemorrhage patients Fei Tian a, *, 1, Jin Liang b, 1, Gang Liu a, Xue Zhang b, Zengyan Cai b, Hongzhi Huo b, Erqing Chai b a b
Neuro-ICU / Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China Cerebrovascular Disease Center / Department of Neurosurgery, People’s Hospital of Gansu Province, Lanzhou, Gansu, 730000, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Cerebrospinal fluid Infection Inflammation Nonconvulsive seizures Severe Subarachnoid hemorrhage
Purpose: It was unclear how nonconvulsive seizures (NCS) occurred after subarachnoid hemorrhage (SAH). The aim of this prospective observational study was to determine the association between cerebrospinal fluid post infectious inflammation and NCS in patients with SAH. Methods: Demographics and parameters were retrieved from pooled data of all SAH patients monitored by continuous electroencephalography (cEEG) in our Stroke-Intensive Care Unit (Stroke-ICU) over six years period. Patients were divided into two groups (NCS group and non-NCS group). According to clinical and cerebrospinal fluid (CSF) parameters, a logistic regression model was used to analyze the association between CSF inflam mation and NCS. Results: The data of 143 SAH patients were analyzed (25 patients with NCS and 118 patients with non-NCS). Median age was 53 years (min – max: 19 years – 90 years). 4.8 % SAH patients were accompanied with NCS. Among these 25 NCS patients, only 2 (8%) had complete control of EEG discharges. After confounders correction, logistic regression analysis showed: SAH patients with older age [P = 0.003, OR = 1.193, 95 %CI (1.062–1.341)], intracranial infections [P = 0.000, OR = 171.939, 95 %CI (18.136–1630.064)] and higher increased modified Fisher Scale (mFS) [P = 0.003, OR = 8.884, 95 %CI (2.125–37.148)] were more likely to develop NCS; furthermore, a high level of CSF interleukin-6 (IL-6) was an independent risk factor for NCS [P = 0.000, OR = 1.015, 95 %CI (1.010–1.020)], with a threshold of 164.9 pg/mL (sensitivity = 0.84, specificity = 0.96). Compared with non-NCS patients, NCS patients were more likely to have poor Glasgow outcome scale (GOS) (1–3) at 3 months after discharge (88 %). Conclusions: SAH patients with NCS were associated with poor neurological prognosis. With the increase of age and mFS, these patients were more likely to develop NCS. As an intracranial infective mark, a high level of CSF IL-6 was an independent risk factor for NCS. For brain protection of severe brain injury after SAH, we should focus on the increasingly important role of inflammatory response.
1. Introduction Subarachnoid hemorrhage (SAH) is a severe brain injury character ized by high mortality and morbidity (Rincon et al., 2013). In patients with SAH, the incidence of nonconvulsive seizures (NCS) is approxi mately 3–13 % (Kondziella et al., 2015). Our previous study confirmed that NCS secondary to severe brain injury (SBI-NCS) was an electro physiological marker predicting poor neurological outcome (Tian et al., 2013), which was in accordance with previous literature reports (Little et al., 2007). Unfortunately, therapy with antiepileptic drugs (AEDs) and
even anesthetics for SBI-NCS is frustrating; these drugs not only fail to terminate NCS but also cause severe respiratory and circulatory depression (Tian et al., 2013; Dennis et al., 2002; Marchi et al., 2015). How this NCS phenomenon occurs is unclear (Brenner, 2002). It is certain that interventions targeting the pathogenetic mechanism may be more effective. Infection can cause status epilepticus (SE), and this infection-induced SE easily develops into NCS (Dubey et al., 2017; Zelano et al., 2014; Chateauneuf et al., 2017). Inflammatory responses play an important role in this pathological process. Clinical and animal experimental
* Corresponding author at: No. 45, Changchun Avenue, Xicheng District, Beijing, 100053, China. E-mail address: [email protected] (F. Tian). 1 Fei Tian and Jin Liang contributed equally to this paper. https://doi.org/10.1016/j.eplepsyres.2020.106504 Received 9 March 2020; Received in revised form 15 October 2020; Accepted 9 November 2020 Available online 12 November 2020 0920-1211/© 2020 Elsevier B.V. All rights reserved.
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Epilepsy Research 169 (2021) 106504
studies have shown that SE causes inflammatory reactions, which further aggravates SE to evolve into NCS, forming a vicious cycle (Avdic et al., 2018; Kubota et al., 2016). Therefore, there might be a causal link between postinfectious inflammation, SE and NCS. Therefore, we intended to explore possible causes for the occurrence of NCS in patients with severe SAH through possible correlations among infection, inflammation and NCS. Combined with clinical signs and ce rebral spinal fluid (CSF) infectious and inflammatory indicators, we hope to provide clues regarding the mechanisms underlying SBI-NCS.
cytology, procalcitonin (PCT), and interleukin-6 (IL-6) until the symp toms improved (usually a duration of 7–14 days). 2.7. NCS treatment protocol SAH patients with NCS were given intravenous AEDs immediately after confirmatory cEEG reading. Given the actual conditions in China (no lorazepam and phenytoin intravenous formulation), the controversy regarding NCS termination, and with reference to the initial treatment for convulsive status epilepticus (Brophy et al., 2017), diazepam was intravenously injected at 0.2 mg/kg and could be repeated once. No further antiepileptic treatment was given.
2. Methods 2.1. Patients and study design
2.8. Analysis
A prospective observational method was used. Data for SAH patients admitted to the Cerebrovascular Disease Center of People’s Hospital of Gansu Province from August 2013 to March 2019 were analyzed. The study was approved by the Institutional Review Board of the hospital. Legal relatives of patients with consciousness disorders signed informed consent. A prognostic assessment method was used by graduate students who were blind to patients’ baseline characteristics and finally analyzed by another experienced expert for accuracy.
The following measures were recorded and analyzed: NCS in SAH patients; ② NCS termination after diazepam injection; ③ improvement in patient consciousness dysfunction after NCS termination; ④ clinical etiological causes of NCS; ⑤ laboratory indicators of NCS in SAH pa tients (CSF cytology, biochemistry, PCT, maximal IL-6 value); ⑥ length of stay in the Stroke-ICU; and ⑦ neurological function outcome at 3 months after discharge.
2.2. Inclusion criteria
2.9. Statistical analysis
The following inclusion criteria were used: patients were ≥18 years old; ② patients met the diagnostic criteria of SAH (Connolly et al., 2012): sudden severe headache, with or without nausea, vomiting, photophobia, disturbance of consciousness, meningeal irritation sign, SAH confirmation by head computerized tomography (CT) scan or lumbar puncture CSF test, intracranial aneurysm confirmed by CT angiography (CTA) or cerebral angiography.
SPSS 22.0 was used for statistical analysis. A t-test or nonparametric test was performed for quantitative data. The chi-square test or Fisher’s exact-test was performed on categorical data. Variables with significant differences in univariate analyses were included in logistic regression analysis. Odds ratios (ORs) and 95 % confidence intervals were calcu lated. P < 0.05 indicated that the difference was statistically significant.
2.3. Exclusion criteria
3. Results
The following exclusion criteria were used: dying patients with unstable vital signs and bilaterally fixed dilated pupils; ② patients with severe water, electrolyte, acid-base balance disorder or suffering from hypoglycemic coma; ③ pregnant women and breast-feeding puerpera.
3.1. Patient baseline data A total of 536 SAH patients were continuously enrolled. Eleven pa tients died rapidly within 48 h after admission or abandoned treatment in the care of their relatives. A total of 525 patients were admitted to the Stroke-ICU for monitoring and treatment, among which 382 patients regained consciousness within 48 h or cEEG was not performed. The remaining 143 patients received cEEG monitoring: 25 patients with NCS and 118 patients without NCS (Fig. 1).
2.4. Treatment protocol for SAH Following an initial CTA or cerebral angiography examination, the neurosurgeon decided on interventional aneurysm embolization or aneurysm clipping. After the operation, the patients were transferred to the Stroke-ICU for basic life support (Diringer et al., 2011).
3.2. NCS and termination There were 4.8 % paitents with NCS among 525 SAH patients (Fig. 2, A, B and C). Among these 25 NCS patients, only 2 (8 %) showed com plete control over the EEG epileptic discharges after intravenous administration of diazepam, and the other 23 patients had recurrence of EEG epileptic discharges within 0.2 − 2 h. There was no consciousness recovery in any patient after diazepam intravenously injections.
2.5. EEG monitoring The international standard for scalp electrode number and place ment is the 10–20 system with a minimum of 16 electrodes. The patients with consciousness impairment for at least 48 h (48 h) after aneurysm clipping or interventional embolization were monitored by bedside continuous electroencephalography (cEEG) for 2 h every day: lowfrequency filter: 0.5 Hz; high-frequency filter: 70 Hz; sensitivity: 70 microvolt/cm; and sampling frequency: 256 Hz. Partially referring to the Salzburg consensus standard definition for nonconvulsive status epilepticus (Kaplan, 2007), we defined NCS as follows: epileptic discharge frequency >2.5 Hz; ②epileptic discharge frequency ≤2.5 Hz, or rhythmic delta/theta activity (>0.5 Hz) with mild clinical episodes or typical spatiotemporal evolution trends.
3.3. Comparison between NCS and non-NCS patients There were no significant differences in the underlying etiologies (hypertension, diabetes, hyperlipidemia, hyperhomocysteinemia), aneurysm diameter, or surgical methods (endovascular intervention or surgery) between the two groups. Univariate analysis showed that there were significant differences in gender, age, Hunt-Hess score (HHS), modified Fisher scale (mFS), Glasgow coma score (GCS), cerebral hemorrhage, hydrocephalus, lateral ventricle drainage, decompression craniectomy, fever, intracranial infection, Stroke-ICU length of stay, and Glasgow outcome score (GOS) at 3 months after discharge between the two groups (P < 0.05) (Table 1).
2.6. Laboratory assay All SAH patients received CSF decompressive drainage every 2 days after surgery; meanwhile, CSF specimens were tested for biochemistry, 2
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Fig. 1. Research flow chart.
3.4. NCS etiologies
4.1. NCS and termination
Because of the gender collection deviation (only 1 NCS patient was female), possible risk factors for NCS, such as age, GCS, HHS, mFS, intracerebral hemorrhage, hydrocephalus, lateral ventricular drainage, decompression craniectomy, fever, and intracranial infection, were included in the multivariate logistic regression equation. Logistic regression analysis results were as follows: SAH patients with older age [P = 0.003, OR = 1.193, 95 % CI (1.062–1.341)], intracranial infections [P = 0.000, OR = 171.939, 95 % CI (18.136–1630.064)] and higher increased mFS [P = 0.003, OR = 8.884, 95 % CI (2.125–37.148)] were more likely to develop NCS (Table 2).
Our study confirmed a 4.8 % occurrence rate of NCS in hostitalized SAH patients, which was greater than that reported in previous studies (2.8 %− 3.5 %). (Little et al., 2007; Dennis et al., 2002). This may be related to patient inclusion criteria, cEEG monitoring duration, etc. There are no reports on the NCS termination rate after SAH. Our exploratory research found that NCS control in SAH patients was not ideal, and relapse was common. This phenomenon is consistent with our previous research on encephalitic patients (Tian et al., 2013). Thus, doctors in the Stroke-ICU should be alerted that the termination of NCS induced by severe SAH may be intractable. This EEG NCS presentation may be a direct result of severe cortical dysfunction caused by brain damage rather than simple epileptic discharges.
3.5. NCS and CSF postinfectious inflammation Univariate analysis showed that the levels of protein, white blood cell (WBC) total count (neutrophilic leukocytosis), glucose (Glu), IL-6 and PCT in CSF were significantly different between the NCS and nonNCS patients. However, when we included all these variables in the logistic regression equation, only a higher CSF IL-6 level was an inde pendent risk factor for NCS occurrence [P = 0.000, OR = 1.015, 95 % CI (1.010–1.020)], with a threshold of 164.9 pg/mL (sensitivity = 0.84; specificity = 0.96) (Fig. 3).
4.2. NCS risk factors The factors associated with NCS in SAH patients included gender, age, Hunt-Hess score, mFS, GCS, cerebral hemorrhage, hydrocephalus, lateral ventricular drainage, decompression craniectomy, fever, intra cranial infection, Stroke-ICU length of stay and GOS at 3 months. After correction for gender, we found that patients with increased age and higher mFS with a complication of intracranial infection were more likely to develop NCS. This is consistent with previous studies on risk factors related to the prognosis of SAH (Lawton and Vates, 2017). Why did NCS occur in these patients? The reasons may be as follows: the older they were, the greater the decline in brain function in these pa tients who were already vulnerable to ischemia and hypoxia attacks (Leppik, 2018); ② increased mFS in SAH patients suggested severe brain damage (Pegoli et al., 2015); and ③ intracranial infection indicated a severe intracranial inflammatory response (Zelano et al., 2014). The synergistic effects of the above factors could damage the stability of the cerebral cortex neural network, reduce the threshold for seizure attacks in the brain, destroy the integrity of descending conduction pathways, and finally cause NCS.
3.6. Neurological prognosis Compared with the non-NCS patients, the patients with NCS were more likely to have poor GOS scores (GOS: 1–3) at 3 months after discharge (88 %) (Fig. 4). 4. Discussion In this study, the occurrence rate of NCS in severe SAH patients was 4.8 %, and the termination rate of NCS by intravenous diazepam in jection was only 8 %; with increases in patient age, NCS was more likely to occur with intracranial infection and higher mFS scores; increased IL6 levels in the CSF (≥164.9 pg/mL) was an independent risk factor for NCS; a severe SAH patient with NCS was more likely to have an unfa vorable neurological outcome (GOS 1–3: 88 %).
4.3. NCS and CSF inflammatory response After correction for CSF PCT, Glu, protein, and WBC total counts, our study confirmed that an increase in CSF IL-6 (≥164.9 pg/mL) was an independent risk factor for NCS in the SAH patients. This is a very 3
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Fig. 2. A~C: a 56-year-old SAH coma patient with nonconvulsive seizures. This patient showed EEG slow wave background (A) before continuous epileptic dis charges appeared (B), after diazepam intravenously injection, epileptic discharges disappeared and slow background reappeared (C). EEG epileptic discharges in this severe coma SAH patient became nontypical, but still showed apparent evolution tendency (slow wave backgroud abruptly became fast activities in most of the montages).
4
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Table 1 Patient baseline characteristics. Characteristics
NCS N = 25
non-NCS n = 118
Pvalue
Male, n (%) Age, median (IQR) Hypertension, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Hyperhomocysteinemia, n (%) Hunt-Hess score, n (%)
24 (96) 60 (58–66) 15 (60.0) 6 (24.0) 22 (88.0) 16 (64.0) 3, 5 (20.0) 4, 20 (80.0) 5, 0 (0) 2, 0 (0) 3, 14 (56.0) 4, 11 (44.0) 25 (100.0) 9 (8–11) I (16) (64.0) S (9) (36.0)
0.000 0.000 0.271 0.222 1.000 0.065 0.000
25 (100) 13 (52.0) 3 (12.0) 25 (100) 14 (56.0) 3 (12.0) 29 (21–35)
46 (39) 51 (45–58) 54 (45.8) 16 (13.6) 101 (85.6) 96 (81.4) 3, 99 (83.9) 4, 16 (13.6) 5, 3 (2.5) 2, 88 (74.6) 3, 20 (16.9) 4, 10 (8.5) 80 (67.8) 10 (9–11) I (91) (77.1) S (26) (22.0) I + S (1) (0.8) 79 (66.9) 17 (14.4) 7 (5.9) 62 (52.5) 13 (11.1) 7 (5.9) 7 (5–15)
3 (12.0)
95 (80.5)
0.000
24 (96.0) 21 (84.0) 20 (80) 7 (28) 260 (245–280)
85 (72.0) 5 (4.2) 75 (63.6) 18 (15.3) 250 (240–271)
0.018 0.000 0.161 0.149 0.239
467 (311–509)
101 (78–122)
0.000
299.5 (240.4–400.8) 0.393 (0.323–0.429) 1.08 (0.90–1.20) 1.80 (1.60–2.25)
23.4 (6.2–34.0)
0.000
0.294 (0.090–0.361) 0.50 (0.44–0.60) 2.90 (2.68–3.10)
0.000
mFS, n (%) GCS≤12, n (%) AD (mm), median (IQR) Intervention / Surgery (I/S), n (%) LVD, n (%) DC, n (%) DCI, n (%) Hydrocephalus, n (%) CH, n (%) DVT, n (%) Stroke ICU LOS (day), median (IQR) GOS 4~5 at 3 month after discharge, n (%) Fever, n (%) Intracranial infection, n (%) Pneumonia, n (%) Urinary infection, n (%) CSF pressure (mmHg), median (IQR) CSF WBC (×106/L), median (IQR) CSF IL-6 (pg/mL), median (IQR) CSF PCT (ug/L), median (IQR) CSF protein (g/L), median (IQR) CSF Glu (mmol/L), median (IQR)
Fig. 3. The ROC curve for IL-6.
0.000 0.000 0.814 0.312 0.000 0.000 0.380 0.000 0.000 0.380 0.000
Fig. 4. Compared with non-NCS, patients with NCS were more likely to have poor score (GOS:1~3) at 3 months after discharge (88 %).
0.000
2015; Avdic et al., 2019). Why did NCS occur in severe SAH patients with increased CSF IL-6? SAH causes severe brain damage, prompting the release of inflammatory mediators, including IL-6 (Chaudhry et al., 2017). ② By a variety of signal transduction pathways in the brain, these proinflammatory mediators reduce the intensity of inhibitory post synaptic potentials, and therefore, excitatory postsynaptic potentials dominate and lead to abnormal discharges in the cerebral cortex (Claassen et al., 2014; Rana and Musto, 2018; Van et al., 2018). Our study further confirmed the correlation between NCS and inflammatory responses from the perspective of infection and the CSF inflammatory response.
0.000
Abbreviations: IQR interquartile range; NCS nonconvulsive seizures; mFS modified Fisher score; GCS Glasgow coma score; ; Iintervention; ; Ssurgery; LVD lateral ventricular drainage; DC decompressive craniectomy; DCI delayed ce rebral ischemia; CH cerebral hemorrhage; DVT deep venous thrombosis; LOS length of stay; AD aneurysm diameter; GOS Glasgow outcome score; CSF cere brospinal fluid; WBC white blood cell; Glu glucose; PCT procalcitonin; IL-6 interleukin-6. Table 2 Logistic regression analysis for clinical etiologies in NCS patients. Characteristics
Odd ratio
95 % CI
Age Intracranial infection Modified Fisher score
1.193 171.939 8.884
1.062–1.341 18.136–1630.064 2.125–37.148
4.4. NCS and neurological outcome Our study found that these patients with NCS were more likely to have intracranial infection (84 %), worse mFS (44 %), older age (me dian: 60), and higher levels of CSF IL-6 (≥164.9 pg/mL). All these fac tors together led to poor neurological prognosis.
interesting phenomenon. IL-6 is a pro-inflammatory cytokine secreted by mast cells, osteoblasts, vascular smooth muscle cells and other cells. The expression of IL-6 increases rapidly when body tissues are damaged or infected, and it is involved in the regulation of the inflammatory response (Tanaka et al., 2014). Several clinical studies have found evi dence of increased IL-6 expression in blood or cerebrospinal fluid in patients with refractory epilepsy (Uludag et al., 2015, 2013; Jun et al., ´mez et al., 2018; Alapirtti et al., 2018). In addition, 2018; Mercado-Go increased IL-6 expression has been shown to be associated with epilepsy in animal studies (Zhang et al., 2019; Drion et al., 2018; Gouveia et al.,
4.5. Limitation of the study The study included 536 SAH patients, but only 25 NCS patients (4.7 %) were detected by the cEEG method, so the NCS sample size was low; the time-consuming collection period (greater than 5 years), strict cEEG monitoring standards (consciousness disturbance for at least 48 h postsurgery) and only 2 h cEEG monitoring every day (short duration) were all influential factors. Additionally, this study was not a clinical interventional study, and we were unable to examine the potential 5
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benefit from NCS complete termination. Therefore, we expect multi center and larger sample research studies to support these results.
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5. Conclusions Severe SAH patients with NCS were associated with poor neurolog ical prognosis and suffered from noneffective epileptic discharge con trol. With increasing age and mFS, these patients were more likely to develop NCS. As an intracranial infection marker, a high level of CSF IL6 was an independent risk factor for NCS. Regarding brain protection against severe brain injury after SAH, we should focus on the increas ingly important role of the inflammatory response. Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have declared that they had no competing interests. Acknowledgments I wish to thank my mentor, professor Yingying Su, for her guidance on the inspiration and direction for the study. References Alapirtti, T., Lehtim¨ aki, K., Nieminen, R., M¨ akinen, R., Raitanen, J., Moilanen, E., M¨ akinen, J., Peltola, J., 2018. The production of IL-6 in acute epileptic seizure: a video-EEG study. J. Neuroimmunol. 316, 50–55. Avdic, U., Ahl, M., Chugh, D., Ali, I., Chary, K., Sierra, A., Ekdahl, C.T., 2018. Nonconvulsive status epilepticus in rats leads to brain pathology. Epilepsia 59 (5), 945–958. ¨ Avdic, U., Ahl, M., Oberg, M., Ekdahl, C.T., 2019. Immune profile in blood following non-convulsive epileptic seizures in rats. Front. Neurol. 10, 701. Brenner, R.P., 2002. Is it status? Epilepsia 43 (Suppl 3), 103–113. Brophy, G.M., Bell, R., Claassen, J., Alldredge, B., Bleck, T.P., Glauser, T., Laroche, S.M., Riviello Jr., J.J., Shutter, L., Sperling, M.R., Treiman, D.M., Vespa, P.M., 2017. Neurocritical care society status epilepticus guideline writing committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit. Care 17 (1), 3–23. Chateauneuf, A.L., Moyer, J.D., Jacq, G., Cavelot, S., Bedos, J.P., Legriel, S., 2017. Superrefractory status epilepticus: epidemiology, early predictors, and outcomes. Intensive Care Med. 43 (10), 1532–1534. Chaudhry, S.R., Stoffel-Wagner, B., Kinfe, T.M., Güresir, E., Vatter, H., Dietrich, D., Lamprecht, A., Muhammad, S., 2017. Elevated systemic IL-6 levels in patients with aneurysmal subarachnoid hemorrhage is an unspecific marker for Post-SAH complications. Int. J. Mol. Sci. 18 (12) pii: E2580. Claassen, J., Albers, D., Schmidt, J.M., De Marchis, G.M., Pugin, D., Falo, C.M., Mayer, S. A., Cremers, S., Agarwal, S., Elkind, M.S., Connolly, E.S., Dukic, V., Hripcsak, G., Badjatia, N., 2014. Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann. Neurol. 75 (5), 771–781. Connolly Jr., E.S., Rabinstein, A.A., Carhuapoma, J.R., Derdeyn, C.P., Dion, J., Higashida, R.T., Hoh, B.L., Kirkness, C.J., Naidech, A.M., Ogilvy, C.S., Patel, A.B., Thompson, B.G., Vespa, P., American Heart Association Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, 2012. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 43 (6), 1711–1737. Dennis, L.J., Claassen, J., Hirsch, L.J., Emerson, R.G., Connolly, E.S., Mayer, S.A., 2002. Nonconvulsive status epilepticus after subarachnoid hemorrhage. Neurosurgery 51 (5), 1136–1143.
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Postinfectious inflammation in cerebrospinal fluid is associated with nonconvulsive seizures in subarachnoid hemorrhage patients Fei Tian a, *, 1, Jin Liang b, 1, Gang Liu a, Xue Zhang b, Zengyan Cai b, Hongzhi Huo b, Erqing Chai b a b
Neuro-ICU / Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China Cerebrovascular Disease Center / Department of Neurosurgery, People’s Hospital of Gansu Province, Lanzhou, Gansu, 730000, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Cerebrospinal fluid Infection Inflammation Nonconvulsive seizures Severe Subarachnoid hemorrhage
Purpose: It was unclear how nonconvulsive seizures (NCS) occurred after subarachnoid hemorrhage (SAH). The aim of this prospective observational study was to determine the association between cerebrospinal fluid post infectious inflammation and NCS in patients with SAH. Methods: Demographics and parameters were retrieved from pooled data of all SAH patients monitored by continuous electroencephalography (cEEG) in our Stroke-Intensive Care Unit (Stroke-ICU) over six years period. Patients were divided into two groups (NCS group and non-NCS group). According to clinical and cerebrospinal fluid (CSF) parameters, a logistic regression model was used to analyze the association between CSF inflam mation and NCS. Results: The data of 143 SAH patients were analyzed (25 patients with NCS and 118 patients with non-NCS). Median age was 53 years (min – max: 19 years – 90 years). 4.8 % SAH patients were accompanied with NCS. Among these 25 NCS patients, only 2 (8%) had complete control of EEG discharges. After confounders correction, logistic regression analysis showed: SAH patients with older age [P = 0.003, OR = 1.193, 95 %CI (1.062–1.341)], intracranial infections [P = 0.000, OR = 171.939, 95 %CI (18.136–1630.064)] and higher increased modified Fisher Scale (mFS) [P = 0.003, OR = 8.884, 95 %CI (2.125–37.148)] were more likely to develop NCS; furthermore, a high level of CSF interleukin-6 (IL-6) was an independent risk factor for NCS [P = 0.000, OR = 1.015, 95 %CI (1.010–1.020)], with a threshold of 164.9 pg/mL (sensitivity = 0.84, specificity = 0.96). Compared with non-NCS patients, NCS patients were more likely to have poor Glasgow outcome scale (GOS) (1–3) at 3 months after discharge (88 %). Conclusions: SAH patients with NCS were associated with poor neurological prognosis. With the increase of age and mFS, these patients were more likely to develop NCS. As an intracranial infective mark, a high level of CSF IL-6 was an independent risk factor for NCS. For brain protection of severe brain injury after SAH, we should focus on the increasingly important role of inflammatory response.
1. Introduction Subarachnoid hemorrhage (SAH) is a severe brain injury character ized by high mortality and morbidity (Rincon et al., 2013). In patients with SAH, the incidence of nonconvulsive seizures (NCS) is approxi mately 3–13 % (Kondziella et al., 2015). Our previous study confirmed that NCS secondary to severe brain injury (SBI-NCS) was an electro physiological marker predicting poor neurological outcome (Tian et al., 2013), which was in accordance with previous literature reports (Little et al., 2007). Unfortunately, therapy with antiepileptic drugs (AEDs) and
even anesthetics for SBI-NCS is frustrating; these drugs not only fail to terminate NCS but also cause severe respiratory and circulatory depression (Tian et al., 2013; Dennis et al., 2002; Marchi et al., 2015). How this NCS phenomenon occurs is unclear (Brenner, 2002). It is certain that interventions targeting the pathogenetic mechanism may be more effective. Infection can cause status epilepticus (SE), and this infection-induced SE easily develops into NCS (Dubey et al., 2017; Zelano et al., 2014; Chateauneuf et al., 2017). Inflammatory responses play an important role in this pathological process. Clinical and animal experimental
* Corresponding author at: No. 45, Changchun Avenue, Xicheng District, Beijing, 100053, China. E-mail address: [email protected] (F. Tian). 1 Fei Tian and Jin Liang contributed equally to this paper. https://doi.org/10.1016/j.eplepsyres.2020.106504 Received 9 March 2020; Received in revised form 15 October 2020; Accepted 9 November 2020 Available online 12 November 2020 0920-1211/© 2020 Elsevier B.V. All rights reserved.
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studies have shown that SE causes inflammatory reactions, which further aggravates SE to evolve into NCS, forming a vicious cycle (Avdic et al., 2018; Kubota et al., 2016). Therefore, there might be a causal link between postinfectious inflammation, SE and NCS. Therefore, we intended to explore possible causes for the occurrence of NCS in patients with severe SAH through possible correlations among infection, inflammation and NCS. Combined with clinical signs and ce rebral spinal fluid (CSF) infectious and inflammatory indicators, we hope to provide clues regarding the mechanisms underlying SBI-NCS.
cytology, procalcitonin (PCT), and interleukin-6 (IL-6) until the symp toms improved (usually a duration of 7–14 days). 2.7. NCS treatment protocol SAH patients with NCS were given intravenous AEDs immediately after confirmatory cEEG reading. Given the actual conditions in China (no lorazepam and phenytoin intravenous formulation), the controversy regarding NCS termination, and with reference to the initial treatment for convulsive status epilepticus (Brophy et al., 2017), diazepam was intravenously injected at 0.2 mg/kg and could be repeated once. No further antiepileptic treatment was given.
2. Methods 2.1. Patients and study design
2.8. Analysis
A prospective observational method was used. Data for SAH patients admitted to the Cerebrovascular Disease Center of People’s Hospital of Gansu Province from August 2013 to March 2019 were analyzed. The study was approved by the Institutional Review Board of the hospital. Legal relatives of patients with consciousness disorders signed informed consent. A prognostic assessment method was used by graduate students who were blind to patients’ baseline characteristics and finally analyzed by another experienced expert for accuracy.
The following measures were recorded and analyzed: NCS in SAH patients; ② NCS termination after diazepam injection; ③ improvement in patient consciousness dysfunction after NCS termination; ④ clinical etiological causes of NCS; ⑤ laboratory indicators of NCS in SAH pa tients (CSF cytology, biochemistry, PCT, maximal IL-6 value); ⑥ length of stay in the Stroke-ICU; and ⑦ neurological function outcome at 3 months after discharge.
2.2. Inclusion criteria
2.9. Statistical analysis
The following inclusion criteria were used: patients were ≥18 years old; ② patients met the diagnostic criteria of SAH (Connolly et al., 2012): sudden severe headache, with or without nausea, vomiting, photophobia, disturbance of consciousness, meningeal irritation sign, SAH confirmation by head computerized tomography (CT) scan or lumbar puncture CSF test, intracranial aneurysm confirmed by CT angiography (CTA) or cerebral angiography.
SPSS 22.0 was used for statistical analysis. A t-test or nonparametric test was performed for quantitative data. The chi-square test or Fisher’s exact-test was performed on categorical data. Variables with significant differences in univariate analyses were included in logistic regression analysis. Odds ratios (ORs) and 95 % confidence intervals were calcu lated. P < 0.05 indicated that the difference was statistically significant.
2.3. Exclusion criteria
3. Results
The following exclusion criteria were used: dying patients with unstable vital signs and bilaterally fixed dilated pupils; ② patients with severe water, electrolyte, acid-base balance disorder or suffering from hypoglycemic coma; ③ pregnant women and breast-feeding puerpera.
3.1. Patient baseline data A total of 536 SAH patients were continuously enrolled. Eleven pa tients died rapidly within 48 h after admission or abandoned treatment in the care of their relatives. A total of 525 patients were admitted to the Stroke-ICU for monitoring and treatment, among which 382 patients regained consciousness within 48 h or cEEG was not performed. The remaining 143 patients received cEEG monitoring: 25 patients with NCS and 118 patients without NCS (Fig. 1).
2.4. Treatment protocol for SAH Following an initial CTA or cerebral angiography examination, the neurosurgeon decided on interventional aneurysm embolization or aneurysm clipping. After the operation, the patients were transferred to the Stroke-ICU for basic life support (Diringer et al., 2011).
3.2. NCS and termination There were 4.8 % paitents with NCS among 525 SAH patients (Fig. 2, A, B and C). Among these 25 NCS patients, only 2 (8 %) showed com plete control over the EEG epileptic discharges after intravenous administration of diazepam, and the other 23 patients had recurrence of EEG epileptic discharges within 0.2 − 2 h. There was no consciousness recovery in any patient after diazepam intravenously injections.
2.5. EEG monitoring The international standard for scalp electrode number and place ment is the 10–20 system with a minimum of 16 electrodes. The patients with consciousness impairment for at least 48 h (48 h) after aneurysm clipping or interventional embolization were monitored by bedside continuous electroencephalography (cEEG) for 2 h every day: lowfrequency filter: 0.5 Hz; high-frequency filter: 70 Hz; sensitivity: 70 microvolt/cm; and sampling frequency: 256 Hz. Partially referring to the Salzburg consensus standard definition for nonconvulsive status epilepticus (Kaplan, 2007), we defined NCS as follows: epileptic discharge frequency >2.5 Hz; ②epileptic discharge frequency ≤2.5 Hz, or rhythmic delta/theta activity (>0.5 Hz) with mild clinical episodes or typical spatiotemporal evolution trends.
3.3. Comparison between NCS and non-NCS patients There were no significant differences in the underlying etiologies (hypertension, diabetes, hyperlipidemia, hyperhomocysteinemia), aneurysm diameter, or surgical methods (endovascular intervention or surgery) between the two groups. Univariate analysis showed that there were significant differences in gender, age, Hunt-Hess score (HHS), modified Fisher scale (mFS), Glasgow coma score (GCS), cerebral hemorrhage, hydrocephalus, lateral ventricle drainage, decompression craniectomy, fever, intracranial infection, Stroke-ICU length of stay, and Glasgow outcome score (GOS) at 3 months after discharge between the two groups (P < 0.05) (Table 1).
2.6. Laboratory assay All SAH patients received CSF decompressive drainage every 2 days after surgery; meanwhile, CSF specimens were tested for biochemistry, 2
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Fig. 1. Research flow chart.
3.4. NCS etiologies
4.1. NCS and termination
Because of the gender collection deviation (only 1 NCS patient was female), possible risk factors for NCS, such as age, GCS, HHS, mFS, intracerebral hemorrhage, hydrocephalus, lateral ventricular drainage, decompression craniectomy, fever, and intracranial infection, were included in the multivariate logistic regression equation. Logistic regression analysis results were as follows: SAH patients with older age [P = 0.003, OR = 1.193, 95 % CI (1.062–1.341)], intracranial infections [P = 0.000, OR = 171.939, 95 % CI (18.136–1630.064)] and higher increased mFS [P = 0.003, OR = 8.884, 95 % CI (2.125–37.148)] were more likely to develop NCS (Table 2).
Our study confirmed a 4.8 % occurrence rate of NCS in hostitalized SAH patients, which was greater than that reported in previous studies (2.8 %− 3.5 %). (Little et al., 2007; Dennis et al., 2002). This may be related to patient inclusion criteria, cEEG monitoring duration, etc. There are no reports on the NCS termination rate after SAH. Our exploratory research found that NCS control in SAH patients was not ideal, and relapse was common. This phenomenon is consistent with our previous research on encephalitic patients (Tian et al., 2013). Thus, doctors in the Stroke-ICU should be alerted that the termination of NCS induced by severe SAH may be intractable. This EEG NCS presentation may be a direct result of severe cortical dysfunction caused by brain damage rather than simple epileptic discharges.
3.5. NCS and CSF postinfectious inflammation Univariate analysis showed that the levels of protein, white blood cell (WBC) total count (neutrophilic leukocytosis), glucose (Glu), IL-6 and PCT in CSF were significantly different between the NCS and nonNCS patients. However, when we included all these variables in the logistic regression equation, only a higher CSF IL-6 level was an inde pendent risk factor for NCS occurrence [P = 0.000, OR = 1.015, 95 % CI (1.010–1.020)], with a threshold of 164.9 pg/mL (sensitivity = 0.84; specificity = 0.96) (Fig. 3).
4.2. NCS risk factors The factors associated with NCS in SAH patients included gender, age, Hunt-Hess score, mFS, GCS, cerebral hemorrhage, hydrocephalus, lateral ventricular drainage, decompression craniectomy, fever, intra cranial infection, Stroke-ICU length of stay and GOS at 3 months. After correction for gender, we found that patients with increased age and higher mFS with a complication of intracranial infection were more likely to develop NCS. This is consistent with previous studies on risk factors related to the prognosis of SAH (Lawton and Vates, 2017). Why did NCS occur in these patients? The reasons may be as follows: the older they were, the greater the decline in brain function in these pa tients who were already vulnerable to ischemia and hypoxia attacks (Leppik, 2018); ② increased mFS in SAH patients suggested severe brain damage (Pegoli et al., 2015); and ③ intracranial infection indicated a severe intracranial inflammatory response (Zelano et al., 2014). The synergistic effects of the above factors could damage the stability of the cerebral cortex neural network, reduce the threshold for seizure attacks in the brain, destroy the integrity of descending conduction pathways, and finally cause NCS.
3.6. Neurological prognosis Compared with the non-NCS patients, the patients with NCS were more likely to have poor GOS scores (GOS: 1–3) at 3 months after discharge (88 %) (Fig. 4). 4. Discussion In this study, the occurrence rate of NCS in severe SAH patients was 4.8 %, and the termination rate of NCS by intravenous diazepam in jection was only 8 %; with increases in patient age, NCS was more likely to occur with intracranial infection and higher mFS scores; increased IL6 levels in the CSF (≥164.9 pg/mL) was an independent risk factor for NCS; a severe SAH patient with NCS was more likely to have an unfa vorable neurological outcome (GOS 1–3: 88 %).
4.3. NCS and CSF inflammatory response After correction for CSF PCT, Glu, protein, and WBC total counts, our study confirmed that an increase in CSF IL-6 (≥164.9 pg/mL) was an independent risk factor for NCS in the SAH patients. This is a very 3
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Fig. 2. A~C: a 56-year-old SAH coma patient with nonconvulsive seizures. This patient showed EEG slow wave background (A) before continuous epileptic dis charges appeared (B), after diazepam intravenously injection, epileptic discharges disappeared and slow background reappeared (C). EEG epileptic discharges in this severe coma SAH patient became nontypical, but still showed apparent evolution tendency (slow wave backgroud abruptly became fast activities in most of the montages).
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Table 1 Patient baseline characteristics. Characteristics
NCS N = 25
non-NCS n = 118
Pvalue
Male, n (%) Age, median (IQR) Hypertension, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Hyperhomocysteinemia, n (%) Hunt-Hess score, n (%)
24 (96) 60 (58–66) 15 (60.0) 6 (24.0) 22 (88.0) 16 (64.0) 3, 5 (20.0) 4, 20 (80.0) 5, 0 (0) 2, 0 (0) 3, 14 (56.0) 4, 11 (44.0) 25 (100.0) 9 (8–11) I (16) (64.0) S (9) (36.0)
0.000 0.000 0.271 0.222 1.000 0.065 0.000
25 (100) 13 (52.0) 3 (12.0) 25 (100) 14 (56.0) 3 (12.0) 29 (21–35)
46 (39) 51 (45–58) 54 (45.8) 16 (13.6) 101 (85.6) 96 (81.4) 3, 99 (83.9) 4, 16 (13.6) 5, 3 (2.5) 2, 88 (74.6) 3, 20 (16.9) 4, 10 (8.5) 80 (67.8) 10 (9–11) I (91) (77.1) S (26) (22.0) I + S (1) (0.8) 79 (66.9) 17 (14.4) 7 (5.9) 62 (52.5) 13 (11.1) 7 (5.9) 7 (5–15)
3 (12.0)
95 (80.5)
0.000
24 (96.0) 21 (84.0) 20 (80) 7 (28) 260 (245–280)
85 (72.0) 5 (4.2) 75 (63.6) 18 (15.3) 250 (240–271)
0.018 0.000 0.161 0.149 0.239
467 (311–509)
101 (78–122)
0.000
299.5 (240.4–400.8) 0.393 (0.323–0.429) 1.08 (0.90–1.20) 1.80 (1.60–2.25)
23.4 (6.2–34.0)
0.000
0.294 (0.090–0.361) 0.50 (0.44–0.60) 2.90 (2.68–3.10)
0.000
mFS, n (%) GCS≤12, n (%) AD (mm), median (IQR) Intervention / Surgery (I/S), n (%) LVD, n (%) DC, n (%) DCI, n (%) Hydrocephalus, n (%) CH, n (%) DVT, n (%) Stroke ICU LOS (day), median (IQR) GOS 4~5 at 3 month after discharge, n (%) Fever, n (%) Intracranial infection, n (%) Pneumonia, n (%) Urinary infection, n (%) CSF pressure (mmHg), median (IQR) CSF WBC (×106/L), median (IQR) CSF IL-6 (pg/mL), median (IQR) CSF PCT (ug/L), median (IQR) CSF protein (g/L), median (IQR) CSF Glu (mmol/L), median (IQR)
Fig. 3. The ROC curve for IL-6.
0.000 0.000 0.814 0.312 0.000 0.000 0.380 0.000 0.000 0.380 0.000
Fig. 4. Compared with non-NCS, patients with NCS were more likely to have poor score (GOS:1~3) at 3 months after discharge (88 %).
0.000
2015; Avdic et al., 2019). Why did NCS occur in severe SAH patients with increased CSF IL-6? SAH causes severe brain damage, prompting the release of inflammatory mediators, including IL-6 (Chaudhry et al., 2017). ② By a variety of signal transduction pathways in the brain, these proinflammatory mediators reduce the intensity of inhibitory post synaptic potentials, and therefore, excitatory postsynaptic potentials dominate and lead to abnormal discharges in the cerebral cortex (Claassen et al., 2014; Rana and Musto, 2018; Van et al., 2018). Our study further confirmed the correlation between NCS and inflammatory responses from the perspective of infection and the CSF inflammatory response.
0.000
Abbreviations: IQR interquartile range; NCS nonconvulsive seizures; mFS modified Fisher score; GCS Glasgow coma score; ; Iintervention; ; Ssurgery; LVD lateral ventricular drainage; DC decompressive craniectomy; DCI delayed ce rebral ischemia; CH cerebral hemorrhage; DVT deep venous thrombosis; LOS length of stay; AD aneurysm diameter; GOS Glasgow outcome score; CSF cere brospinal fluid; WBC white blood cell; Glu glucose; PCT procalcitonin; IL-6 interleukin-6. Table 2 Logistic regression analysis for clinical etiologies in NCS patients. Characteristics
Odd ratio
95 % CI
Age Intracranial infection Modified Fisher score
1.193 171.939 8.884
1.062–1.341 18.136–1630.064 2.125–37.148
4.4. NCS and neurological outcome Our study found that these patients with NCS were more likely to have intracranial infection (84 %), worse mFS (44 %), older age (me dian: 60), and higher levels of CSF IL-6 (≥164.9 pg/mL). All these fac tors together led to poor neurological prognosis.
interesting phenomenon. IL-6 is a pro-inflammatory cytokine secreted by mast cells, osteoblasts, vascular smooth muscle cells and other cells. The expression of IL-6 increases rapidly when body tissues are damaged or infected, and it is involved in the regulation of the inflammatory response (Tanaka et al., 2014). Several clinical studies have found evi dence of increased IL-6 expression in blood or cerebrospinal fluid in patients with refractory epilepsy (Uludag et al., 2015, 2013; Jun et al., ´mez et al., 2018; Alapirtti et al., 2018). In addition, 2018; Mercado-Go increased IL-6 expression has been shown to be associated with epilepsy in animal studies (Zhang et al., 2019; Drion et al., 2018; Gouveia et al.,
4.5. Limitation of the study The study included 536 SAH patients, but only 25 NCS patients (4.7 %) were detected by the cEEG method, so the NCS sample size was low; the time-consuming collection period (greater than 5 years), strict cEEG monitoring standards (consciousness disturbance for at least 48 h postsurgery) and only 2 h cEEG monitoring every day (short duration) were all influential factors. Additionally, this study was not a clinical interventional study, and we were unable to examine the potential 5
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benefit from NCS complete termination. Therefore, we expect multi center and larger sample research studies to support these results.
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5. Conclusions Severe SAH patients with NCS were associated with poor neurolog ical prognosis and suffered from noneffective epileptic discharge con trol. With increasing age and mFS, these patients were more likely to develop NCS. As an intracranial infection marker, a high level of CSF IL6 was an independent risk factor for NCS. Regarding brain protection against severe brain injury after SAH, we should focus on the increas ingly important role of the inflammatory response. Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have declared that they had no competing interests. Acknowledgments I wish to thank my mentor, professor Yingying Su, for her guidance on the inspiration and direction for the study. References Alapirtti, T., Lehtim¨ aki, K., Nieminen, R., M¨ akinen, R., Raitanen, J., Moilanen, E., M¨ akinen, J., Peltola, J., 2018. The production of IL-6 in acute epileptic seizure: a video-EEG study. J. Neuroimmunol. 316, 50–55. Avdic, U., Ahl, M., Chugh, D., Ali, I., Chary, K., Sierra, A., Ekdahl, C.T., 2018. Nonconvulsive status epilepticus in rats leads to brain pathology. Epilepsia 59 (5), 945–958. ¨ Avdic, U., Ahl, M., Oberg, M., Ekdahl, C.T., 2019. Immune profile in blood following non-convulsive epileptic seizures in rats. Front. Neurol. 10, 701. Brenner, R.P., 2002. Is it status? Epilepsia 43 (Suppl 3), 103–113. Brophy, G.M., Bell, R., Claassen, J., Alldredge, B., Bleck, T.P., Glauser, T., Laroche, S.M., Riviello Jr., J.J., Shutter, L., Sperling, M.R., Treiman, D.M., Vespa, P.M., 2017. Neurocritical care society status epilepticus guideline writing committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit. Care 17 (1), 3–23. Chateauneuf, A.L., Moyer, J.D., Jacq, G., Cavelot, S., Bedos, J.P., Legriel, S., 2017. Superrefractory status epilepticus: epidemiology, early predictors, and outcomes. Intensive Care Med. 43 (10), 1532–1534. Chaudhry, S.R., Stoffel-Wagner, B., Kinfe, T.M., Güresir, E., Vatter, H., Dietrich, D., Lamprecht, A., Muhammad, S., 2017. Elevated systemic IL-6 levels in patients with aneurysmal subarachnoid hemorrhage is an unspecific marker for Post-SAH complications. Int. J. Mol. Sci. 18 (12) pii: E2580. Claassen, J., Albers, D., Schmidt, J.M., De Marchis, G.M., Pugin, D., Falo, C.M., Mayer, S. A., Cremers, S., Agarwal, S., Elkind, M.S., Connolly, E.S., Dukic, V., Hripcsak, G., Badjatia, N., 2014. Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann. Neurol. 75 (5), 771–781. Connolly Jr., E.S., Rabinstein, A.A., Carhuapoma, J.R., Derdeyn, C.P., Dion, J., Higashida, R.T., Hoh, B.L., Kirkness, C.J., Naidech, A.M., Ogilvy, C.S., Patel, A.B., Thompson, B.G., Vespa, P., American Heart Association Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, 2012. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 43 (6), 1711–1737. Dennis, L.J., Claassen, J., Hirsch, L.J., Emerson, R.G., Connolly, E.S., Mayer, S.A., 2002. Nonconvulsive status epilepticus after subarachnoid hemorrhage. Neurosurgery 51 (5), 1136–1143.
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