Continuous EEG Monitoring in Spontaneous Intracerebral Hemorrhage

Continuous EEG Monitoring in Spontaneous Intracerebral Hemorrhage Ayman M Selim 1, Ghada R Mousa 1, Eman Awad 2, Wael Reda 3, Sherif Abdelfattah 4 Departments of Neurology, Zagazig University 1 ; Neurology, Ain Shams University 2 ; Anesthesia, Ain Shams University 3 ; Radiology, Cairo University 4 ABSTRACT Aim: to study the frequency of clinical and electrical seizure activity among patients with acute intracerebral hemorrhage (ICH). Methods: sixty seven patients with acute ICH who was admitted to King Abdul-Aziz Hospital and Oncology Center and to Saudi German Hospital, Jeddah, Saudi Arabia during one year duration were included. Diagnosis of ICH was based on computed tomography (CT) scan; patients were either admitted to ICU or to the ward; full history and clinical data were obtained; follow-up CT brain was done to all patients 48 hours and by the end of the first week of admission; site, size and distance from the surface of ICH as well as midline shift were measured; continuous electroencephalographic recording (ceeg) was done within the day of admission and lasted for 2-3 days thereafter; outcome was measured using Glasgow Outcome Scale (GOS). Results: hypertension was the most common risk factor for ICH (in 55.2%), followed by anticoagulant usage (7.5%); seizures (either clinical or electrographic) occurred in 17 patients (25.4%), 76.5% of them were electrographic seizures; ICH proximity to the surface, its volume, midline shift and increase in the size of ICH in follow up CT were risk factors for seizure occurrence; those with seizure disorders showed worse GOS measure Conclusion: seizures occur in high percentage of patients with ICH and most of them is electrographic in nature, there occurrence depends on ICH volume or its expansion and midline shift,and they adversely affect the prognosis of the patients. (Egypt J. Neurol. Psychiat. Neurosurg., 2009, 46(1): 41-49) INTRODUCTION Sub clinical seizure activity has gained attention from an increased understanding of the potential harmful effect of clinical seizure. 1 The utility of continuous electroencephalographic monitoring (ceeg) for detection of sub clinical seizure activity in the intensive care unit (ICU) has been investigated for various conditions such as subarachnoid hemorrhage (SAH), head trauma and status epilepticus 2,3,4. The magnitude of this problem among patients with intracerebral hemorrhage (ICH) is poorly understood. The aim of this study was to detect the risk factors, frequency, characteristics and prognostic effects of seizure activities (both clinical and electrographic) among patients with acute ICH using ceeg monitoring. PATIENTS AND METHODS Most of the adult patients ( 18 years) with non-traumatic spontaneous ICH admitted to King Abdel-Aziz Hospital and Oncology Center and at Saudi German Hospital, Jeddah, Saudi Arabia over one year period were included in this study. The diagnosis of ICH was established by admission computed tomography (CT) brain. Patients with traumatic or aneurysmal hemorrhage as well as one patient who required immediate surgical evacuation of hematoma were excluded. All patients were subjected to the following: I) Clinical measures: - Full history taking (either from the patient or the family) including past medical history (e.g. Correspondence to Ayman Selim, e-mail: aymanseleem@hotmail.com. Contact number: 00966556614612 41

Egypt J. Neurol. Psychiat. Neurosurg. hypertension, diabetes, heart diseases, smoking, epilepsy etc.) and history of drug intake (e.g. anticoagulants) or abuse (e.g. alcohol, cocaine). - Patients were either admitted to the medical ward or to ICU. - Routine laboratory investigations were done including: CBC, coagulation profile, ESR, CRP, liver function, kidney function and electrolytes, serum glucose level, lipid profile, and routine serology test for viruses. Urine toxicology was done for suspected patients. - We followed the published guidelines for treatment of ICH. 5 - Prophylactic antiepileptic medications were not given routinely; only those who develop clinical fits were treated using phenytoin loading (20 mg/kg) and later on maintenance dose (3-4 mg/kg/day). - We used the Glasgow outcome scale GOS (1 for death, 2 for comatose or vegetative, 3 for severely disabled, 4 for moderate disability, and 5 for good recovery) to measure the patient's outcome one month after the date of admission. - Etiological causes of ICH were categorized into (hypertension, vascular malformation, anticoagulation abnormalities, amyloid angiopathy, other causes and unknown etiology). 6 II) Radiological studies: - CT scan of the brain was done on admission, 48-72 hours later on and after 1 week. 7 - Hemorrhage volume was determined by multiplying the longitudinal by horizontal by vertical diameters (number of 5 mm slices with hemorrhage divided by two). 7 - Midline shift was assessed by measuring the maximum displacement of the septum pellucidum across midline, using a reference line connecting anterior and posterior insertion of falx cerebri at the level of foramen of Monroe. 8 - The distance of the hematoma to the cortical surface was measured. The presence of associated intraventricular hemorrhage was documented. 6 - Cerebral hemorrhage was classified as either deep, lobar or multiple. 42 2009 Vol. 46 (1) - Jan - Cutoff points for dichotomization of ICH volume were ( 60 ml, increase of admission CT by 30%) and midline shift ( 1 mm or increase from admission CT of 2 mm). 9 III) ceeg monitoring: - ceeg recording was done using Nicolet (21 channels) and Xltek (16 channels) computerized video EEG machines, with the electrodes placed according to the international 10-20 system. - The ceeg monitoring was started within the first day of admission and for duration 48-72 hours. - We recorded convulsion (focal or generalized), electrographic seizures, periodic epileptiform discharges (PED), stage II sleep transients (kcomplexes and spindles), or slowness of background activity. 10 - Electrographic seizures was defined as rhythmic discharges or a spike-and-wave pattern with definite evolution in frequency, location, or morphologic features lasting at least 10 seconds; evolution in amplitude alone did not qualify. 11 - We categorized the time of ceeg until the first seizure as follows: present before or on starting; within the first 24 hours; within the first 2 days and after 2 days of monitoring. IV) Statistical analysis Data were checked, entered and analyzed using SPSS 11.0, Chicago, IL. Data were expressed as mean±sd or number and percentage for Quantitative or Qualitative variables respectively. Univariate analysis was used to find significant association, x 2 for categorical variables, t-test, Mann Whitney. We used for continuous variables significant variables p<0.05 were then included in multivariate logistic regression models (backward stepwise) to find the predictors for seizures occurrence. RESULTS The mean age of the patients was 51±10.8, males formed 60% of them (Table 1). History of hypertension was found among 65.7% of patients, valvular heart diseases in 10.4%, and old stroke

(either hemorrhagic or ischemic) in 8%, 23.9% were smokers and 2 patients were alcohol abusers. The possible cause of ICH is shown in the same table, hypertension was accused to be the causative factor in 37 patients (55.2%), anticoagulants in 7.5%, coagulopathy in 2.9%, suspected amyloid angiopathy in 4.5%, while 26.9% had no definite cause. Level of consciousness on the first 24 hours is also shown in the same table, most of the patients (46%) was drowsy or sleepy, and 30% was confused or stuperous state. In table (2), we reported the ceeg findings among our patients, 25.4% of the patients had seizure disorder, electrographic seizure formed 76.5% of them, and abnormal background activity was found in 20.9%. Most of the seizures (clinical or electrographic) started during the first 48 hours of monitoring (85.7%). CT findings in this study (Table 3) showed lobar hemorrhage in 38.8% of the patients and deep hemorrhage in 55.2%. The mean volume of ICH was 34±16 ml, 18% of them the amount was 60 ml, and the mean distance for midline shift was 3±5 mm. In follow up CT brain, midline shift increased by 2 mm in 16.4% of patients, and ICH increased significantly in 10% of them. Tables (4) and (5) compare results of patients with seizures (either clinical or electrographic), with those without. In table (4), CT findings were compared among both groups using univariate and multivariate analysis methods. Lobar hemorrhage was found in 58.8% of patients with seizures and in 36% of those without, but the result was insignificant after the multivariate analysis. The mean volume of ICH was nearly equal between both but those with volume 60 ml was more common among those with seizure disorders (p 0.05), ICH in those with seizures showed more proximity to cortical surface with statistically significant difference. The GOS (2-3) was found among 10 patients with seizures (58.8%) when compared to those without 23 (46%) with statistically significant result (p= 0.045) and the reverse was found in GOS 4-5 degree. A1 A2 B1 B2 Fig. (1): Case 1 (A1&A2): 42 y female, presented 1 week post partum with Rt. Focal sensory fits, CT showed, 12ml hemorrhage over left high fronto-parietal region. Case 2 (B1& B2): 44 y male, HPN, presented with Lt. 43

Egypt J. Neurol. Psychiat. Neurosurg. 2009 Vol. 46 (1) - Jan Sided weakness, initial CT showed 38 ml Rt. Putamen and capsular ICH, with 3.5 mm midline shift. Follow up CT 1 week showed resolving hematoma with increase of the midline shift to 4.8 mm. A B C D 44

Fig. (2): A, B, C & D continuous clip of developing electrographic seizure for case 1 without accompanying clinical seizure. Table 1. Patients characteristics and demographic data. Variables NO. (%) (N= 67) Age (mean ± SD) 51 ± 19.8 Gender (males) 40 (60%) Past Medical History* - Hypertension: 44 (65.7%) - Stroke: Ischemic: 4 (5.9%) Hemorrhagic: 2 (2.9%) - Valvular heart disease: 7 (10.4%) - Epilepsy 1 (1.5%) - Alcohol abuse: 2 (2.9%) - Smoking: 16 (23.9%) Possible etiological factor - Hypertension. 37 (55.2%) - Anticoagulants usage. 5 (7.5%) - Coagulopathies. 2 (2.9%) - Suspected amyloid angiopathy. 3 (4.5%) - Post-partum hemorrhage. 1 (1.5%) - Venous sinus thrombosis. 1 (1.5%) - Unknown causes. 18 (26.9%) Level of consciousness at the start of video EEG. - Full conscious 10 (14.9%) - Awake but sleepy 31 (46.2%) - Confused or stuperous 20 (29.9%) - Deep coma 6 (9%) * Some patients had more than one risk factor Table 2. Clinical and electrographic seizures and EEG changes among our patients. Variables NO. (%) Seizures and EEG changes* a- Clinical seizures before ceeg monitoring 2 (2.9%) b- Clinical seizures during ceeg monitoring 2 (2.9%) c- Non convulsive status epilepticus 2 (2.9%) d- Electrographic seizures 8 (11.9%) e- Focal EEG discharges 3 (4.5%) f- PED 2 (2.9%) g- Background abnormalities:** 14 (20.9%) Time of onset of seizures in relation to ceeg (including a to e) N= 14 - Before it or immediately on starting EEG monitoring 2 (14.3%) - Within 1 st 24 hours of starting EEG monitoring 9 (64.3%) - Within 1 st 48 hours of starting EEG monitoring 12 (85.7%) - More than 48 hours of starting EEG monitoring 14 (100%) 45

Egypt J. Neurol. Psychiat. Neurosurg. 2009 Vol. 46 (1) - Jan PED: periodic epileptiform discharges. * Two patients had more than one EEG findings. ** Including generalized slowing or absent sleep transients. Table 3. CT findings among our patients. Initial CT Follow-up CT CT findings Patients Lobar hemorrhage (N= 26) (38.8%) Deep hemorrhage (N= 37) (55.2%) Multiple (N= 4) (6%) Distance from the surface (mean ±SD) 9±14 Distance from the surface ( 1 mm) 51 (76.1%) Volume of ICH (mean ±SD) 34 ± 16 Volume of ICH 60 ml 12 (17.9%) Midline shift (mean ±SD ) 3±5 Midline shift ( 1 mm) 13 (19.4%) Associated Intra-ventricular hemorrhage 8 (7.5%) Midline shift (increase 2 ml) 11 (16.4%) Increase in follow-up CT by 30%. 7 (10.4%) Table 4. Comparison between radiographic findings and EEG changes. Initial CT Follow-up CT CT findings Patients with seizures or EEG discharges (N=17) Patients without seizures or EEG discharges (N=50) Univariate analysis p - value Multivariate analysis p - value Lobar hemorrhage (N=26) 10(58.8%) 16(36%) 0.049 NS Deep hemorrhage (N=37) 8 (47%) 29(58%) 0.43 - Multiple (N= 4) 1 (6%) 3 (6%) 0.57 - Proximity to surface (mean±sd) 4±10 14±16 0.011 < 0.01 Proximity to surface ( 1 mm) 4 (23.5%) 47 (94%) <0.001 < 0.01 Volume of ICH (mean±sd) 32± 15 35 ± 20 0.57 - Volume of ICH 60 ml 6 (35.3%) 6 (12%) 0.03 < 0.05 Midline shift (mean±sd ) 3±2 2 ± 4 0.18 - Midline shift ( 1 mm) 7 (41.2%) 6 (12.0%) 0.014 < 0.01 Associated Intraventricular hemorrhage 2 (11.7%) 6 (12%) 0.74 - Midline shift (increase 2 ml) 6 (35.3%) 5 (10.0%) 0.024 NS Increase in follow-up CT by 30%. 5 (29.4%) 2 (4.0%) 0.009 < 0.01 Table 5. Outcome measures using Glasgow outcome scale (GOS)*. Patients with seizures or EEG discharges (N=17 ) Patients without seizures or EEG discharges (N=50 ) P 46

GOS (2-3) 10 (58.8%) 23 (46%) 0.045 GOS (4-5) 7 (41.2%) 27 (54%) 0.046 *Adjusted for other factors that may affect outcome (e.g. level of conscious on admission, infratentorial ICH, intraventricular extension, age, and ICH volume). DISCUSSION In this study, we studied seizures and other EEG changes in patients 67 with acute ICH. Hypertension was the etiological cause in vast majority of the patients (55.2%), followed by anticoagulant usage (7.5%). Hypertension is the most common cause of spontaneous ICH in nearly all previous studies 12,13,14, anticoagulants usage was the second most common cause, this can be explained in part by the ignorance of our patients to frequent PT and INR testing and the use of other drugs that may interact with anticoagulants. Most of our patients were either full conscious or only drowsy (61.1%) and hence they were admitted to medical ward. This difference from other studies, [6,15] (where the vast majority of their patients were in coma state) can be explained by their cohort that included only ICU admitted cases. Seizures occurred in 17 of our patients (25.4%), 4 of them developed clinical seizures (either before or after ceeg monitoring) and the remaining 13 (19.4%) had electrographic seizures. This result is comparable to one previous study 15 on patients with ICH. The percentage of seizures in general and electrographic subtype specifically in this study is substantially higher than clinical seizures reported in previous studies that ranged between 2.8 to 18.7%. 12,13,14 This may be due to the use of ceeg monitoring in a routine fashion that increased liability for detection of nonconvulsive seizures. Similar rates of electrographic seizure activity have been reported by others 16,17 in critically ill neurologic populations and among head trauma patients. 18 Much higher figure than ours was reported in a recent study 6 (19% for clinical seizures, 13% for electrographic seizures and 5% for both). This retrospective study included only cases with ICH who underwent ceeg monitoring and admitted to ICU and therefore likely overestimates the real seizure frequency [6] Regarding status epilepticus (SE), no one of the patients had convulsive staus epilepticus, however, 2 patients (2.9%) had non convulsive SE which goes with the frequency of SE in previous studies 12,13,14 (1.1 to 2%). More than half of the seizures (64.3%) were detected within the first 24 hours, and 85.7% within the first 48 hours. This result is comparable to other studies in ICH patients [6] and in general ICU patient. [10] In the study of Classen et al. 6 56% had their seizures within the first hour of ceeg monitoring. This again can be explained by their inclusion criteria of only ICU patients with ICH (having more depressed level of consciousness and hence suspected to have more brain edema or massive hemorrhage). Focal and periodic discharges was found in 7.4% our patients and background abnormalities in 20.98%. These results is comparable to that of Vespa et al. [15] and much lower than the study of Classen et al. 6 (17% for focal and 73% abnormal stage II sleep transients), again due to their inclusion criteria. As in previously published studies 6,15, lobar hemorrhage was likely to produce seizures than deep hemorrhage with statistically significant result, although the result became insignificant after controlling other demographic and clinical predictors. We identified proximity to the cortical surface as a predictor of seizure occurrence. This result goes with the aforementioned one, because lobar hemorrhages are closer to the cortex than deep ones. ICH volume was a strong predictor for seizure occurrence only if it was more than 60 ml or if increased in follow up CT by more than 30%. These findings suggest that a more prolonged and active bleeding may serve as a trigger of seizures, or that seizures lead to additional bleeding. Hematoma growth due to active bleeding may result in multifocal areas of bleeding in the periphery of the existing clot. 19 After ICH, progressive brain edema is a well documented phenomenon 20, and occurs in 25 to 61% of patients. 21 Brain edema is most often manifested as midline shift. In the current study, midline shift of more than 1 mm only on admission CT was a predictor of seizure occurrence. On the other hand, data suggest that seizures may play a role in midline shift formation. 22 Seizure activity may lead to increases in extracellular glutamate and lipolysis 23 in 47

Egypt J. Neurol. Psychiat. Neurosurg. traumatic ICH, thus it can lead to cellular dysfunction that is manifested as worsening midline shift. 15 After adjusting other factors that may affect prognosis (e.g. level of conscious on admission, infratentorial ICH, intraventricular extension, age, and ICH volume), patients with seizure disorders showed significantly poor prognosis using GOS. This result is in line with previous studies 6,15 and one study among SAH patients. 2 The limitation of this study include: the relatively small sample size, and effect of medications, surgery and seizure subtypes were not studied. The findings in this study should be confirmed in a large cohort multicenter prospective study. Conclusion: The current study extends our knowledge base that patients with ICH are prone to seizures, and that those seizures may only be detected by ceeg monitoring in the majority of patients (the majority were electrographic seizures). The principal findings were: most seizures occurred in the first 48 hours of the insult, seizures occur in both lobar and deep hemorrhage; it is associated with worsening neurologic outcome, and progressive midline shift, ICH volume is a strong predictor for seizure occurrence. These results indicate that controlling seizures may be a target for improving clinical outcome. 48 REFERENCES 1. Fountain NB. Is it time for routine EEG monitoring after intracerebral hemorrhage? Neurology 2007, 69: 1312-3. 2. Claassen J, Hinch LJ, Frontera JA et al. prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage. Neurocrit Care 2006; 4: 103-112. 3. Vespa PM, Nuwer MR, Nenov. et al. Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous EEG monitoring. J Neurosurg 1999; 91: 750-60. 4. DeLorenzo RJ, Waterhouse EJ, Towne AR. et al. Persistant nonconvulsive status epilepticus after 2009 Vol. 46 (1) - Jan the control of convulsive status epilepticus. Epilepsia 1998; 39: 833-40. 5. Broderick JP, Adams HP, Barsan W et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the stroke. Council, American Heart association.stroke1999; 30:905-15 6. Classen J, Jette N, Chum F et al. Electrographic seizures and periodic discharges after intracerebral hemorrhage. Neurology 2007; 69: 1356-65. 7. Wiggins WS, Moody DM, Toole JF et al. Clinical and computerized tomographic study of hypertensive intracerebral hemorrhage. Arch Neurol 1978; 35: 832-43. 8. Zazulia AR, Diringer MN, Derdeyn CP et al. Progression of mass effect after intracerebral hemorrhage. Stroke 1999; 30: 1167-73. 9. Broderick JP, Brott TG, Duldner JE et al. Volume of intracerebral hemorrhage: a powerful and easyto-use predictor of 30-day mortality. Stroke 1993; 24: 987-93. 10. Classen J, Mayer SA, Kowalski RG et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004; 62: 1743-8. 11. Chong DJ, Hishch LJ. Which EEG patteren warrant treatment in critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterens. J Clin Neurophysiol 2005; 22: 79-91. 12. Faught E, Peters D, Bartolucci A et al. Seizures after primary intracerebral hemorrhage. Neurology 1989; 39:1089 93. 13. Arboix A, Garcia-Eroles L, Massons JB et al. Predictive factors of early seizures after acute cerebrovascular disease. Stroke 1997; 28: 1590 4. 14. Weisberg LA, Morteza S, Elliott D. Seizures caused by nontraumatic parenchymal brain hemorrhages. Neurology 1991;41: 1197 9. 15. Vespa PM, O'Phelan K, Shah M et al. Acute seizures after intracerebral hemorrhage, a factor in progressive midline shift and outcome. Neurology 2003; 60: 1441-8. 16. Jordan KG. Continuous EEG monitoring in the neuroscience intensive care unit and emergency department. J Clin Neurophysiol 1999; 16: 14 39. 17. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care

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