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1.  Post-Stroke Epilepsy in Young Adults: A Long-Term Follow-Up Study 
PLoS ONE  2013;8(2):e55498.
Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH).
Methods and Findings
We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18–50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03–1.11 and 1.08, 95% CI 1.02–1.14).
Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.
PMCID: PMC3563638  PMID: 23390537
2.  The prophylactic use of an antiepileptic drug in intracerebral hemorrhage 
Clinical neurology and neurosurgery  2011;113(10):895-897.
Patients with intracerebral hemorrhage (ICH) are at increased risk for both early seizures and later epilepsy. There is a common, but unproven, practice of prescribing a prophylactic antiepileptic drug (PAED) to prevent seizures, but the safety and efficacy of this practice is unclear, as is the optimal drug for this purpose. The objective of the study is to evaluate whether patients presenting with acute, spontaneous intracerebral hemorrhage (ICH) benefit from prescription of prophylactic antiepileptic drug (PAED).
All patients with a discharge diagnosis of acute, spontaneous ICH admitted to our institution in the calendar years 2004 and 2007 were included. We retrospectively reviewed the records for baseline characteristics, hospital course, PAED use, early seizures, length of stay, discharge disposition, and death.
157 patients met our criteria for review. 46 (29%) patients were placed on a PAED. 12 (7.6%) had early seizures. 11% of patients placed on a PAED had an early seizure versus 6.3% who not placed on a PAED. Death or hospice discharge was less common in patients prescribed a PAED, while length of stay was longer, however neither of these differences were significant after adjustment for multiple comparisons.
Our study confirms previous reports that patients with acute, spontaneous ICH are at an increased risk for early seizures. PAED use in our series was not significantly associated with the risk of early seizures, long-term epilepsy, disability, or death.
PMCID: PMC3215779  PMID: 21824722
Intracerebral hemorrhage; Antiepileptic drugs; Epilepsy
3.  A novel risk score to predict 1-year functional outcome after intracerebral hemorrhage and comparison with existing scores 
Critical Care  2013;17(6):R275.
Spontaneous intracerebral hemorrhage (ICH) is one of leading causes of mortality and morbidity worldwide. Several predictive models have been developed for ICH; however, none of them have been consistently used in routine clinical practice or clinical research. In the study, we aimed to develop and validate a risk score for predicting 1-year functional outcome after ICH (ICH Functional Outcome Score, ICH-FOS). Furthermore, we compared discrimination of the ICH-FOS and 8 existing ICH scores with regard to 30-day, 3-month, 6-month, and 1-year functional outcome and mortality after ICH.
The ICH-FOS was developed based on the China National Stroke Registry, in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Poor functional outcome was defined as modified Rankin Scale score (mRS) ≥3 at 1 year after ICH. Multivariable logistic regression was performed to determine independent predictors, and β-coefficients were used to generate scoring system of the ICH-FOS. The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration.
The overall 1-year poor functional outcome (mRS ≥ 3) was 46.7% and 44.9% in the derivation (n = 1,953) and validation (n = 1,302) cohorts, respectively. A 16-point ICH-FOS was developed from the set of independent predictors of 1-year poor functional outcome after ICH including age (P < 0.001), admission National Institutes of Health Stroke Scale score (P < 0.001), Glasgow Coma Scale score (P < 0.001), blood glucose (P = 0.002), ICH location (P < 0.001), hematoma volume (P < 0.001), and intraventricular extension (P < 0.001). The ICH-FOS showed good discrimination (AUROC) in the derivation (0.836, 95% CI: 0.819-0.854) and validation (0.830, 95% CI: 0.808-0.852) cohorts. The ICH-FOS was well calibrated (Hosmer-Lemeshow test) in the derivation (P = 0.42) and validation (P = 0.39) cohort. When compared to 8 prior ICH scores, the ICH-FOS showed significantly better discrimination with regard to 1-year functional outcome and mortality after ICH (all P < 0.0001). Meanwhile, the ICH-FOS also demonstrated either comparable or significantly better discrimination for poor functional outcome and mortality at 30-day, 3-month, and 6-month after ICH.
The ICH-FOS is a valid clinical grading scale for 1-year functional outcome after ICH. Further validation of the ICH-FOS in different populations is needed.
PMCID: PMC4056008  PMID: 24289116
4.  Pediatric Intracerebral Hemorrhage: Acute Symptomatic Seizures and Epilepsy 
JAMA neurology  2013;70(4):448-454.
To define the incidence of and explore risk factors for seizures and epilepsy in children with spontaneous intracerebral hemorrhage (ICH).
Prospective cohort study.
Three tertiary care pediatric hospitals.
Seventy-three pediatric subjects with spontaneous ICH including 20 perinatal (≥37 weeks gestation to 28 days) and 53 childhood subjects (>28 days to <18 years at presentation).
Main outcome measures
Acute symptomatic seizures (clinically evident and electrographic-only within 7 days), remote symptomatic seizures, and epilepsy.
Acute symptomatic seizures occurred in 35 subjects (48%). Acute symptomatic seizures as a presenting symptom of ICH occurred in 12 (60%) perinatal and 19 (36%) childhood subjects, P=.07. Acute symptomatic seizures after presentation occurred in 7 children. Electrographic-only seizures were present in 9/32 (28%) with continuous EEG monitoring. One-and two-year remote symptomatic seizure-free survival were 82% (95% CI 68%–90%) and 67% (95% CI 46%–82%), respectively. One- and two-year epilepsy-free survival were 96% (95% CI 83%–99%) and 87% (95% CI 65%–95%), respectively. Elevated intracranial pressure requiring acute intervention was a risk factor for acute seizures after presentation, remote symptomatic seizures, and epilepsy (P=.014, P=.025 and P=.0365, respectively log-rank test).
Presenting seizures are common in perinatal and childhood ICH. Continuous EEG may detect electrographic seizures in some subjects. Single remote symptomatic seizures occur in many, and development of epilepsy is estimated to occur in 13% at two-years. Elevated intracranial pressure requiring acute intervention is a risk factor for acute seizures after presentation, remote symptomatic seizures, and epilepsy.
PMCID: PMC3640376  PMID: 23392319
5.  The association between serum adhesion molecules and outcome in acute spontaneous intracerebral hemorrhage 
Critical Care  2011;15(6):R284.
Serum concentrations of adhesion molecules may be connected to the pathogenesis of secondary brain injury after spontaneous intracerebral hemorrhage (ICH). This study posits the hypothesis that levels of adhesion molecules substantially increase after ICH and are decreased thereafter, and that they can predict treatment outcomes.
Two hundred and thirty-nine blood samples were collected from 60 consecutive patients admitted within 24 hours after onset of spontaneous ICH and 60 blood samples were collected from 60 volunteers. Additional samples were obtained on Days 4, 7, 10, and 14 after onset of ICH regardless of clinical deterioration.
Upon discharge, the therapeutic outcomes of the 60 spontaneous ICH cases based on the modified Rankin Disability Scale (mMRS) showed that 17 had no disability while 8.3% developed delayed cerebral infarction (DCI). Statistical analysis of adhesion molecules between patient groups with good outcome (mMRS = 0 or 1) and poor outcome (mMRS ≥2) revealed significant differences in diabetes mellitus (P=0.049), hyperlipidemia (P=0.012), mentality change (P=0.043), ICH volume and intraventricular hemorrhage on admission (P=0.036 and 0.006, respectively), Glasgow Coma Scale (GCS) on admission (P≤0.001), neuro-surgical intervention (P=0.003), and sE-selectin and soluble intercellular cell adhesion-molecule-1 (sICAM-1) levels on admission (P=0.036 and 0.019, respectively). Multiple logistic regression analysis of these significant variables showed that GCS on admission, hyperlipidemia, and sICAM-1 (P=0.039, 0.042, and 0.022, respectively) were independently associated with outcome of acute spontaneous ICH.
Increased sICAM-1 and sE-selectin levels may imply poor therapeutic outcomes for the treatment of spontaneous ICH during hospitalization. These early inflammatory responses may cause whole-brain injury immediately after spontaneous ICH and offer a potential therapeutic target for such patients. The importance of these findings is that they offer a potential therapeutic target for patients with spontaneous ICH.
PMCID: PMC3388671  PMID: 22117900
6.  Seizures and Epilepsy following Aneurysmal Subarachnoid Hemorrhage : Incidence and Risk Factors 
Although prophylactic antiepileptic drug (AED) use in patients with aneurysmal subarachnoid hemorrhage (SAH) is a common practice, lack of uniform definitions and guidelines for seizures and AEDs rendered this prescription more habitual instead of evidence-based manner. We herein evaluated the incidence and predictive factors of seizure and complications about AED use.
From July 1999 to June 2007, data of a total of 547 patients with aneurysmal SAH who underwent operative treatments were reviewed. For these, the incidence and risk factors of seizures and epilepsy were assessed, in addition to complications of AEDs.
Eighty-three patients (15.2%) had at least one seizure following SAH. Forty-three patients (7.9%) had onset seizures, 34 (6.2%) had perioperative seizures, and 17 (3.1%) had late epilepsy. Younger age (< 40 years), poor clinical grade, thick hemorrhage, acute hydrocephalus, and rebleeding were related to the occurrence of onset seizures. Cortical infarction and thick hemorrhage were independent risk factors for the occurrence of late epilepsy. Onset seizures were not predictive of late epilepsy. Moreover, adverse drug effects were identified in 128 patients (23.4%) with AEDs.
Perioperative seizures are not significant predictors for late epilepsy. Instead, initial amount of SAH and surgery-induced cortical damage should be seriously considered as risk factors for late epilepsy. Because AEDs can not prevent early postoperative seizures (< 1 week) and potentially cause unexpected side effects, long-term use should be readjusted in high-risk patients.
PMCID: PMC2744032  PMID: 19763209
Aneurysm; Antiepileptic drug; Complication; Epilepsy; Risk factors; Seizure
7.  Prognostic Value of ICH Score and ICH-GS Score in Chinese Intracerebral Hemorrhage Patients: Analysis From the China National Stroke Registry (CNSR) 
PLoS ONE  2013;8(10):e77421.
No strongevidenceofefficacycurrently exists for different intracerebral hemorrhage (ICH) scoring system in predicting the prognosis of ICH in the Chinese population. This study aimed to test the accuracyof the ICH score and the ICH grading scale (ICH-GS) score in predicting the favorable prognosis in a large cohort of ICH patients in China.
This study was a multicenter, prospective cohort study. Patients diagnosed with ICH between September 2007 and August 2008 from the nationwide China National Stroke Registry (CNSR) databasewere screened andenrolled in this study. Demographics of the patients, treatments, mortalityas well as the clinic and radiologic findings of ICH were collected.AnICH score and anICH-GS score were evaluated for all the patients atadmission. Follow-ups were conducted by phone at 3, 6 and 12 months after ICH onset. The modified Rankin scale (mRS) score was used to evaluate favorable functional outcome and was obtained at hospital dischargeand duringthe 3-, 6- and 12-month follow-up visits.
There were 410 (12.6%) in-hospitalmortalityout of a total of 3,255 ICH patients. Thevalues of the Area Under Curve (AUC)at discharge, 3-, 6- and 12-month follow-up for ICH score were 0.72, 0.76, 0.76 and 0.75, respectively; whilethe numbers for the ICH-GS score were 0.71, 0.77, 0.78 and 0.78, respectively. At 6-month and 12-month follow-up, the ICH-GS score presented a significant better value in predicting favorable prognosis than did the ICH score (P=0.0003 and <0.0001, respectively).
Both the ICH and ICH-GS scores were effective inaccurately predicting the favorable functional outcome of ICH in the Chinese population. For mid-term and long-term prediction, the ICH-GS score was superiorover the ICH score.
PMCID: PMC3797805  PMID: 24146993
8.  Prospective validation of the ICH Score for 12-month functional outcome 
Neurology  2009;73(14):1088-1094.
The ICH Score is a commonly used clinical grading scale for outcome after acute intracerebral hemorrhage (ICH) and has been validated for 30-day mortality, but not long-term functional outcome. The goals of this study were to assess whether the ICH Score accurately stratifies patients with regard to 12-month functional outcome and to further delineate the pace of recovery of patients during the first year post-ICH.
We performed a prospective observational cohort study of all patients with acute ICH admitted to the emergency departments of San Francisco General Hospital and UCSF Medical Center from June 1, 2001, through May 31, 2004. Components of the ICH Score (admission Glasgow Coma Scale score, initial hematoma volume, presence of intraventricular hemorrhage, infratentorial ICH origin, and age) were recorded along with other clinical characteristics. Patients were then assessed with the modified Rankin Scale (mRS) at hospital discharge, 30 days, and 3, 6, and 12 months post-ICH.
Of 243 patients, 95 (39%) died during initial acute hospitalization. The ICH Score accurately stratified patients with regard to 12-month functional outcome for various dichotomous cutpoints along the mRS (p < 0.05). Many patients continued to improve across the first year, with a small number of patients becoming disabled or dying due to late events unrelated to the initial ICH.
The ICH Score is a valid clinical grading scale for long-term functional outcome after acute intracerebral hemorrhage (ICH). Many ICH patients improve after hospital discharge and this improvement may continue even after 6 months post-ICH.
= Committee on Human Research;
= emergency department;
= Glasgow Coma Scale;
= intracerebral hemorrhage;
= intraventricular hemorrhage;
= modified Rankin Scale;
= San Francisco General Hospital.
PMCID: PMC2764394  PMID: 19726752
9.  Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH 
Neurology  2009;72(16):1397-1402.
To examine whether antiplatelet medication use at onset of intracerebral hemorrhage (ICH) is associated with hemorrhage growth and outcome after spontaneous ICH using a large, prospectively collected database from a recent clinical trial.
The Cerebral Hemorrhage and NXY-059 Treatment trial was a randomized, placebo-controlled trial of NXY-059 after spontaneous ICH. We analyzed patients in the placebo arm, and correlated antiplatelet medication use at the time of ICH with initial ICH volumes, ICH growth in the first 72 hours, and modified Rankin Score at 90 days. Patients on oral anticoagulation were excluded.
There were 282 patients included in this analysis, including 70 (24.8%) who were taking antiplatelet medications at ICH onset. Use of antiplatelet medications at ICH onset had no association with the volume of ICH at presentation, growth of ICH at 72 hours, initial edema volume, or edema growth. In multivariable analysis, there was no association of use of antiplatelet medications with any hemorrhage expansion (relative risk [RR] 0.85 [upper limit of confidence interval (UCI) 1.03], p = 0.16), hemorrhage expansion greater than 33% (RR 0.77 [UCI 1.18], p = 0.32), or clinical outcome at 90 days (odds ratio 0.67, 95% confidence interval 0.39–1.14, p = 0.14).
Use of antiplatelet medications at intracerebral hemorrhage (ICH) onset is not associated with increased hemorrhage volumes, hemorrhage expansion, or clinical outcome at 90 days. These findings suggest that attempts to reverse antiplatelet medications after ICH may not be warranted.
= Cerebral Hemorrhage and NXY-059 Treatment;
= confidence interval;
= intracerebral hemorrhage;
= interquartile range;
= modified Rankin Scale;
= relative risk;
= upper limit of confidence interval.
PMCID: PMC2677505  PMID: 19129506
10.  Intraventricular hemorrhage 
Neurology  2008;70(11):848-852.
Spontaneous intracerebral hemorrhage (ICH) is frequently associated with intraventricular hemorrhage (IVH), which is an independent predictor of poor outcome. The purpose of this study was to examine the relationship between ICH volume and anatomic location to IVH, and to determine if ICH decompression into the ventricle is truly beneficial.
We retrospectively analyzed the CT scans and charts of all patients with ICH admitted to our stroke center over a 3-year period. Outcome data were collected using our prospective stroke registry.
We identified 406 patients with ICH. A total of 45% had IVH. Thalamic and caudate locations had the highest IVH frequency (69% and 100%). ICH volume and ICH location were predictors of IVH (p < 0.001). Within each location, decompression ranges (specific volume ranges where ventricular rupture tends to occur) were established. Patients with IVH were twice as likely to have a poor outcome (discharge modified Rankin scale of 4 to 6) (OR 2.25, p = 0.001) when compared to patients without IVH. Caudate location was associated with a good outcome despite 100% incidence of IVH. Spontaneous ventricular decompression was not associated with better outcome, regardless of parenchymal volume reduction (p = 0.72).
Intraventricular hemorrhage (IVH) occurs in nearly half of patients with spontaneous intracerebral hemorrhage (ICH) and is related to ICH volume and location. IVH is likely to occur within the “decompression ranges” that take into account both ICH location and volume. Further, spontaneous ventricular decompression does not translate to better clinical outcome. This information may prove useful for future ICH trials, and to the clinician communicating with patients and families.
PMCID: PMC2745649  PMID: 18332342
11.  High S100B levels in cerebrospinal fluid and peripheral blood of patients with acute basal ganglial hemorrhage are associated with poor outcome 
S100B is involved in brain injury. This study aimed to determine plasma and cerebral spinal fluid (CSF) levels of S100B in patients with spontaneous intracerebral hemorrhage (ICH), and to correlate S100B levels with Glasgow Coma Scale (GCS) scores, ICH volumes, presence of intraventricular hemorrhage (IVH), and survival rate, and to correlate CSF S100B levels with plasma S100B levels as well as CSF interleukin-1beta (IL-1β) levels.
Ten patients with suspicion of subarachnoid hemorrhage and 38 patients with spontaneous basal ganglia hemorrhage were included in the study. Their plasma and CSF samples were collected. The concentrations of IL-1β in CSF and S100B in plasma and CSF were analyzed by enzyme-linked immunosorbent assay.
Plasma or CSF S100B levels in the ICH group were significantly higher than those in the control group (178.7±74.2 versus 63.2±23.0 pg/ml; P<0.001 or 158.1±70.9 versus 1.8±0.7 ng/ml; P<0.001). S100B levels were highly associated with GCS scores, ICH volumes, presence of IVH, and survival rate (all P<0.05). CSF S100B levels were highly associated with plasma S100B levels as well as CSF IL-1β levels (both P<0.01) in patients with ICH. A receiver operating characteristic curve identified CSF and plasma S100B cutoff levels that predicted 1-week mortality of patients with a high sensitivity and specificity. The areas under curves (AUCs) of GCS scores and ICH volumes were larger than those of CSF and plasma S100B levels, but the differences were not statistically significant (P>0.05).
High levels of S100B are present in the cerebrospinal fluid and peripheral blood of patients with ICH and may contribute to the inflammatory processes of ICH. The levels of CSF and plasma S100B after spontaneous onset of ICH seem to correlate with clinical outcome in these patients. Increases in peripheral S100B properly reflect brain injury, and plasma S100B level may serve as a useful clinical marker for evaluating the prognosis of ICH.
PMCID: PMC4129764  PMID: 25214936
S100B; Interleukin-1 beta; Intracerebral hemorrhage; Intraventricular hemorrhage; Brain injury; Inflammation; Pathogenesis
12.  Epileptic seizures in intracerebral haemorrhage. 
Among 1402 patients with intracerebral haemorrhage (ICH), seizures occurred in 64 (4.6%) and epilepsy in 35 (2.5%). Seizure was the first manifestation of ICH in 19 patients (30%). Status epilepticus occurred in 11 patients (17%) and it was the initial presentation of ICH in six (9%). The majority had simple partial seizures that were predominantly focal and motor. There were 38 patients with early seizure and 26 patients with late seizure. Ninety per cent of seizures occurred within one year after ICH. Eleven patients (29%) with early seizure developed epilepsy, whereas 24 patients (93%) with late seizure developed recurrent seizures. The incidence of seizure was 32% for lobar haematoma, 2% respectively for putaminal, thalamic and pontine haemorrhages and 1% for cerebellar haemorrhage. Twenty-six (62%) out of 42 patients with lobar haematomas developed epilepsy. Thirteen patients (34%) with early seizure died within three months after the onset of seizures whereas three patients (12%) with late seizure died within the same period. The majority of patients who died had deep-seated haematomas.
PMCID: PMC1031636  PMID: 2512371
13.  Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage 
PLoS ONE  2013;8(11):e81664.
Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.
Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed.
In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.
While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.
PMCID: PMC3842307  PMID: 24312335
14.  Predictors of Late Neurological Deterioration After Spontaneous Intracerebral Hemorrhage 
Neurocritical care  2013;19(3):299-305.
Although intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease, little is known about factors leading to neurological deterioration occurring beyond 48 h after hematoma formation. The purpose of this study was to characterize the incidence, consequences, and associative factors of late neurological deterioration (LND) in patients with spontaneous ICH.
Using the Duke University Hospital Neuroscience Intensive Care Unit database from July 2007 to June 2012, a cohort of 149 consecutive patients with spontaneous supratentorial ICH met criteria for analysis. LND was defined as a decrease of two or more points in Glasgow Coma Scale score or death during the period from 48 h to 1 week after ICH symptom onset. Unfavorable outcome was defined as a modified Rankin Scale score of >2 at discharge.
Forty-three subjects (28.9 %) developed LND. Logistic regression models revealed hematoma volume (OR = 1.017, 95 % CI 1.003–1.032, p = 0.019), intraventricular hemorrhage (OR = 2.519, 95 % CI 1.142–5.554, p = 0.022) and serum glucose on admission (OR = 2.614, 95 % CI 1.146–5.965, p = 0.022) as independent predictors of LND. After adjusting for ICH score, LND was independently associated with unfavorable outcome (OR = 4.000, 95 % CI 1.280–12.500, p = 0.017). In 65 subjects with follow-up computed tomography images, an increase in midline shift, as a surrogate for cerebral edema, was independently associated with LND (OR = 3.822, 95 % CI 1.157–12.622, p = 0.028).
LND is a common phenomenon in patients with ICH; further, LND appears to affect outcome. Independent predictors of LND include hematoma volume, intraventricular hemorrhage, and blood glucose on admission. Progression of perihematomal edema may be one mechanism for LND.
PMCID: PMC4100944  PMID: 23979796
Intracerebral hemorrhage; Neurological deterioration; Predictors; Outcome; Brain edema
15.  Natural History and Prognostic Value of Corticospinal Tract Wallerian Degeneration in Intracerebral Hemorrhage 
The purpose of this study was to define the incidence, imaging characteristics, natural history, and prognostic implication of corticospinal tract Wallerian degeneration (CST‐WD) in spontaneous intracerebral hemorrhage (ICH) using serial MR imaging.
Methods and Results
Consecutive ICH patients with supratentorial ICH prospectively underwent serial MRIs at 2, 7, 14, and 21 days. MRIs were analyzed by independent raters for the presence and topographical distribution of CST‐WD on diffusion‐weighted imaging (DWI). Baseline demographics, hematoma characteristics, ICH score, and admission National Institute of Health Stroke Score (NIHSS) were systematically recorded. Functional outcome at 3 months was assessed by the modified Rankin Scale (mRS) and the motor‐NIHSS. Twenty‐seven patients underwent 93 MRIs; 88 of these were serially obtained in the first month. In 13 patients (48%), all with deep ICH, CST‐WD changes were observed after a median of 7 days (interquartile range, 7 to 8) as reduced diffusion on DWI and progressed rostrocaudally along the CST. CST‐WD changes evolved into T2‐hyperintense areas after a median of 11 days (interquartile range, 6 to 14) and became atrophic on MRIs obtained after 3 months. In univariate analyses, the presence of CST‐WD was associated with poor functional outcome (ie, mRS 4 to 6; P=0.046) and worse motor‐NIHSS (5 versus 1, P=0.001) at 3 months.
Wallerian degeneration along the CST is common in spontaneous supratentorial ICH, particularly in deep ICH. It can be detected 1 week after ICH on DWI and progresses rostrocaudally along the CST over time. The presence of CST‐WD is associated with poor motor and functional recovery after ICH.
PMCID: PMC3828779  PMID: 23913508
diffusion‐weighted imaging; intracerebral hemorrhage; magnetic resonance imaging; natural history; prognosis; wallerian degeneration
16.  The use of prophylactic anticonvulsants in patients with brain tumours—a systematic review 
Current Oncology  2006;13(6):222-229.
Should patients with newly diagnosed brain tumours receive prophylactic anticonvulsants to reduce seizure risk?
What is the best practice for patients with brain tumours who are taking anticonvulsant medications but who have never had a seizure?
Patients with primary or metastatic brain tumours who have never had a seizure still have a 20% risk of experiencing a seizure over the course of their disease. Because considerable practice variation exists in regard to the management of patients with brain tumours who have never had a seizure, and because conflicting evidence has been reported, the Neuro-oncology Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-based Care felt that a systematic review of the evidence was warranted.
Outcomes of interest were incidence of seizures and adverse effects of prophylactic anticonvulsant therapy.
The medline and Cochrane Library databases were systematically searched for relevant evidence. The review included fully published reports or abstracts of randomized controlled trials (rcts), systematic reviews, meta-analyses, and practice guidelines.
The present systematic review was reviewed and approved by the Neuro-oncology dsg, which comprises medical and radiation oncologists, surgeons, neurologists, a nurse, and a patient representative.
Quality of Evidence
The literature search located one evidence-based practice guideline, one systematic review, and five rcts that addressed prophylactic anticonvulsants for patients with brain tumours. Evidence for the best management of seizure-naïve patients who are already taking anticonvulsants was limited to one retrospective study and exploratory analyses within several rcts.
Benefits and Harms
Pooled results of the five rcts suggest that the incidence of seizures in patients who receive prophylactic anticonvulsants is not significantly different from that in patients who do not receive anticonvulsants (relative risk: 1.04; 95% confidence interval: 0.70 to 1.54; p = 0.84). This analysis accords with results from a published meta-analysis.
Evidence is insufficient to determine whether patients who are currently taking anticonvulsants but who have never had a seizure should taper the anticonvulsants. Patients who received anticonvulsants reported adverse effects, including rash, nausea, and hypotension, but whether these effects are a result of the anticonvulsants or of other treatments could not be determined.
Based on the available evidence, the routine use of postoperative anticonvulsants is not recommended in seizure-naïve patients with newly diagnosed primary or secondary brain tumours, especially in light of a significant risk of serious adverse effects and problematic drug interactions. Because data are insufficient to recommend whether anticonvulsants should be tapered in patients who are already taking anticonvulsants but who have never had a seizure, treatment must be individualized.
PMCID: PMC3394608  PMID: 22792022
Brain tumours; seizures; anticonvulsants; systematic review
17.  Prognostic Value of Serum S100 Protein by Elecsys S100 Immunoassay in Patients with Spontaneous Subarachnoid and Intracerebral Hemorrhages 
The serum S100 protein has been known to reflect the severity of neuronal damage. The purpose of this study was to assess the prognostic value of the serum S100 protein by Elecsys S100 immunoassay in patients with subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) and to establish reference value for this new method.
Serum S100 protein value was measured at admission, day 3 and 7 after bleeding in 42 consecutive patients (SAH : 20, ICH : 22) and 74 healthy controls, prospectively. Admission Glasgow coma scale (GCS) score, Hunt & Hess grade and Fisher grade for SAH, presence of intraventricular hemorrhage, ICH volume, and outcome at discharge were evaluated. Degrees of serum S100 elevation and their effect on outcomes were compared between two groups.
Median S100 levels in SAH and ICH groups were elevated at admission (0.092 versus 0.283 µg/L) and at day 3 (0.110 versus 0.099 µg/L) compared to healthy controls (0.05 µg/L; p<0001). At day 7, however, these levels were normalized in both groups. Time course of S100 level in SAH patient was relatively steady at least during the first 3 days, whereas in ICH patient it showed abrupt S100 surge on admission and then decreased rapidly during the next 7 days, suggesting severe brain damage at the time of bleeding. In ICH patient, S100 level on admission correlated well with GCS score (r=-0.859; p=0.0001) and ICH volume (r=0.663; p=0.001). A baseline S100 level more than 0.199 µg/L predicted poor outcome with 92% sensitivity and 90% specificity. Logistic regression analyses showed Ln (S100) on admission as the only independent predictor of poor outcome (odd ratio 36.1; 95% CI, 1.98 to 656.3).
Brain damage in ICH patient seems to develop immediately after bleeding, whereas in SAH patients it seems to be sustained for few days. Degree of brain damage is more severe in ICH compared to SAH group based on the S100 level. S100 level is considered an independent predictor of poor outcome in patient with spontaneous ICH, but not in SAH. Further study with large population is required to confirm this result.
PMCID: PMC2612568  PMID: 19119467
S100 protein; Prognosis; Subarachnoid hemorrhage; Elecsys S100 immunoassay; Intracerebral hemorrhage
18.  Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage 
BMC Neurology  2010;10:34.
Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown.
In 40 consecutive patients who were admitted to the hospital within 72 hours after a spontaneous ICH, the plasma copeptin level was measured with a sandwich immunoassay upon admission. The prognostic value of copeptin to predict 30 day mortality and functional outcome after 90 days was assessed. A favorable outcome was defined as a Barthel score above 85 and a score below 3 on the Modified Rankin Scale.
Copeptin correlated positively with hematoma volume (r = 0.32, p < 0.05) and negatively with the Glasgow Coma Scale (GCS) on admission (r = -0.35, p < 0.05). Copeptin levels were higher in patients who died within 30 days than in 30-day survivors (179.0 pmol/l (IQR 33.7- 566.0) vs. 12.9 pmol/l (IQR 5.2 - 42.8), p = 0.003). Copeptin levels were also higher in patients with an unfavorable functional outcome at 90 days compared to patients with a favorable outcome (32.4 pmol/l (IQR 9.5-97.8) vs. 11.9 pmol/l (IQR 3.2-19.8), p = 0.04). For the prediction of death, receiver-operating-characteristics analysis revealed an area under the curve (AUC) for copeptin of 0.88 (95%CI 0.75-1.00). The predictive value of the copeptin concentration was thus similar to that of GCS (AUC 0.82 (95%CI 0.59-1.00) p = 0.53), of the ICH Score (AUC 0.89, (95%CI 0.76-1.00), p = 0.94) and the ICH Grading Scale (AUC 0.86 (95%CI 0.69-1.00), p = 0.81).
Copeptin is a new prognostic marker in patients with an ICH. If this finding can be confirmed in larger studies, copeptin might be an additional valuable tool for risk stratification and decision-making in the acute phase of ICH.
Trial Registration
(Clinical Trial Registration: ISCTRN00390962)
PMCID: PMC2889932  PMID: 20504314
19.  Analysis of Risk Factors for First Seizure after Stroke in Chinese Patients 
BioMed Research International  2013;2013:702871.
The aim of this study is to assess related risk factors and predict early- and late-onset seizure after first-ever stroke. A total of 2474 consecutive patients with initial stroke in China from 1997 to 2007 were retrospectively investigated, in which, 24 clinical and radiological indexes were used for evaluation. Odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression. A total of 232 (11.1%) of patients developed seizures during a mean follow-up period of 18 months, with 123 experiencing early-onset and 109 late-onset seizure. The independent risk factors for early-onset seizure were large lesion (OR = 9.36), subarachnoid hemorrhage (OR = 5.28), initial hyponatremia (OR = 2.10), and cortical involvement (OR = 1.33). The independent risk factors for late-onset seizure were cortical involvement (OR = 11.84) and large lesion (OR = 1.87). These results demonstrated that the risk factors for early seizure after stroke are large lesion, subarachnoid hemorrhage, and cortical involvement. Surprisingly, hyponatremia also predicts seizure in stroke patients. Cortical involvement is a major risk factor for late-onset seizure after stroke.
PMCID: PMC3835814  PMID: 24298553
20.  Intracranial hemorrhage in full-term newborns: a hospital-based cohort study 
Neuroradiology  2010;52(6):567-576.
In recent years, intracranial hemorrhage (ICH) with parenchymal involvement has been diagnosed more often in full-term neonates due to improved neuroimaging techniques. The aim of this study is to describe clinical and neuroimaging data in the neonatal period and relate imaging findings to outcome in a hospital-based population admitted to a level 3 neonatal intensive care unit (NICU).
From our neuroimaging database, we retrospectively retrieved records and images of 53 term infants (1991–2008) in whom an imaging diagnosis of ICH with parenchymal involvement was made. Clinical data, including mode of delivery, clinical manifestations, neurological symptoms, extent and site of hemorrhage, neurosurgical intervention, and neurodevelopmental outcomes, were recorded.
Seventeen of the 53 term infants had infratentorial ICH, 20 had supratentorial ICH, and 16 had a combination of the two. Seizures were the most common presenting symptom (71.7%), another ten infants (18.9%) presented with apneic seizures, and five infants had no clinical signs but were admitted to our NICU because of perinatal asphyxia (n = 2), respiratory distress (n = 2), and development of posthemorrhagic ventricular dilatation (n = 1). Continuous amplitude-integrated electroencephalography recordings were performed in all infants. Clinical or subclinical seizures were seen in 48/53 (90.6%) infants; all received anti-epileptic drugs. Thirteen of all 53 (24.5%) infants died. The lowest mortality rate was seen in infants with supratentorial ICH (10%). Three infants with a midline shift required craniotomy, six infants needed a subcutaneous reservoir due to outflow obstruction, and three subsequently required a ventriculoperitoneal shunt. The group with poor outcome (death or developmental quotient (DQ) <85) had a significantly lower 5-min Apgar score (p = .006). Follow-up data were available for 37/40 survivors aged at least 15 months. Patients were assessed with the Griffiths Mental Developmental Scales, and the mean DQ of all survivors was 97 (SD = 12). Six infants (17%) had a DQ below 85 [two of them had cerebral palsy (CP)]. Three infants developed CP (8.6%); one had cerebellar ataxia, and two had hemiplegia.
ICH with parenchymal involvement carries a risk of adverse neurological sequelae with a mortality of 24.5% and development of CP in 8.6%. The high mortality rate could partly be explained by associated perinatal asphyxia. Infants with supratentorial ICH had a lower, although not significant, mortality rate compared with infants with infratentorial ICH and infants with a combination of supratentorial ICH and infratentorial ICH. In spite of often large intraparenchymal lesions, 30 of the 34 survivors without CP (88.2%) had normal neurodevelopmental outcome at 15 months.
PMCID: PMC2872016  PMID: 20393697
Intracranial hemorrhage; Intraparenchymal hemorrhage; Subdural hemorrhage; Full-term newborns
21.  Seizure Activity Occurs in the Collagenase but not the Blood Infusion Model of Striatal Hemorrhagic Stroke in Rats 
Seizures are a frequent complication of brain injury, including intracerebral hemorrhage (ICH), where seizures occur in about a third of patients. Rodents are used to study pathophysiology and neuroprotective therapies after ICH, but there have been no studies assessing the occurrence of seizures in these models. Thus, we compared seizure incidence and characteristics after infusing collagenase (0.14 U), which degrades blood vessels, and autologous blood (100 μL) into the striatum of rats. Saline was infused in others as a negative control, whereas iron, a by-product of degrading erythrocytes, served as a positive control. Ipsilateral and contralateral electroencephalographic (EEG) activity was continuously monitored with telemetry probes for a week after the stroke. There were no electrographic abnormalities during baseline recordings. As expected, saline did not elicit any epileptiform activity whereas iron caused seizure activity. Seizures occurred in 66 % of the collagenase group between 10 and 36 h, their duration ranged from 5 to 90 s, and these events were mostly observed bilaterally. No such activity occurred after blood infusion despite comparable lesion sizes of 32.5 and 40.9 mm3 in the collagenase and blood models, respectively (p = 0.222). Therefore, seizures are a common acute occurrence in the collagenase but not whole blood models of striatal ICH (p = 0.028, for incidence). These findings have potential implications for ICH studies such as for understanding model differences, helping select which model to use, and determining how seizures may affect or be affected by treatments applied after stroke.
PMCID: PMC4297611  PMID: 25053257
Intracerebral hemorrhage; Stroke; Collagenase; Autologous blood; Seizures; EEG
22.  The Pediatric Intracerebral Hemorrhage Score: A Simple Grading Scale for Intracerebral Hemorrhage in Children 
Background and Purpose
The ICH Score is the most commonly used clinical grading scale for outcome prediction after adult intracerebral hemorrhage (ICH). We created a similar scale in children to inform clinical care and assist in clinical research.
Children, full-term newborns to 18 years, with spontaneous ICH were prospectively enrolled from 2007-2012 at three centers. The pediatric ICH score was created by identifying factors associated with poor outcome. The score's ability to detect moderate disability or worse and severe disability or death was examined with sensitivity, specificity, and area under the receiver operating characteristic (ROC) curves.
The pediatric ICH score components include ICH volume >2-3.99% of total brain volume (TBV)=1 point, ICH volume ≥4% TBV=2 points; acute hydrocephalus=1 point; herniation=1 point; and infratentorial location=1 point. The score ranges from 0-5. At 3-month follow-up of 60 children, 10 were severely disabled or dead, 30 had moderate disability, and 20 had good recovery. A pediatric ICH score of ≥1 predicted moderate disability or worse with a sensitivity of 75% [95% confidence interval (CI): 59-87%] and a specificity of 70% (95% CI: 46-88%). A pediatric ICH score of ≥2 predicted severe disability or death with a sensitivity and specificity of 90% (95% CI: 55-99%) and 68% (95% CI: 53-80%). The area under the ROC curve for classifying outcome as severe disability or death was 0.88 (95% CI: 0.78-0.97).
The pediatric ICH score is a simple clinical grading scale that may ultimately be used for risk stratification, clinical care, and research.
PMCID: PMC3910321  PMID: 24281231
intracerebral hemorrhage; outcome; pediatric stroke; hemorrhage
23.  Is Emergency Department Disposition Associated with Intracerebral Hemorrhage Mortality? 
Early deterioration is common in intracerebral hemorrhage (ICH). Treatment at tertiary care centers has been associated with lower ICH mortality. Guidelines recommend aggressive care for 24 hours irrespective of the initial outlook. We examined the frequency of and factors associated with transfer to tertiary centers in ICH patients who initially presented at non-tertiary emergency departments (ED). We also compared observed to expected mortality in transferred and non-transferred patients using published short-term mortality predictors for ICH.
Adult patients who resided in a 5-county region and presented to non-tertiary EDs with nontraumatic ICH in 2005 were identified. ICH Score and ICH Grading Scale (ICH-GS) were determined. Of 16 local hospitals, 2 were designated tertiary care centers. Logistic regression was used to assess factors associated with transfer.
Of 205 ICH patients who presented to non-tertiary EDs, 80 (39.0%) were transferred to a tertiary center. In multivariate regression, better baseline function (modified Rankin scale 0-2 vs. 3-5) (OR=0.42, 95%CI 0.21-0.85, p=0.016) and black race (OR=2.28, 95%CI 1.01-5.12, p=0.046) were associated with transfer. A trend toward higher 30-day mortality was observed in non-transferred patients (32.5% vs. 45.6%, p=0.06). The ICH-GS overestimated mortality for all patients, while the ICH Score adequately predicted mortality.
We found no significant difference in mortality between transferred and non-transferred patients, but the trend toward higher mortality in non-transferred patients suggests that further evaluation of ED disposition decisions for ICH patients is warranted. Expected ICH mortality may be overestimated by published tools.
PMCID: PMC3005610  PMID: 20825807
emergency medicine; intracerebral hemorrhage; stroke; tertiary care center
24.  Factors Associated with Early Deterioration after Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(5):e96743.
Background and Purpose
Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with a poor prognosis overall. We conducted a systematic review and meta-analysis to identify and describe factors associated with early neurologic deterioration (END) after ICH.
We sought to identify any factor which could be prognostic in the absence of an intervention. The Cochrane Library, EMBASE, the Global Health Library, and PubMed were searched for primary studies from the years 1966 to 2012 with no restrictions on language or study design. Studies of patients who received a surgical intervention or specific experimental therapies were excluded. END was defined as death, or worsening on a reliable outcome scale within seven days after onset.
7,172 abstracts were reviewed, 1,579 full-text papers were obtained and screened. 14 studies were identified; including 2088 patients. Indices of ICH severity such as ICH volume (univariate combined OR per ml:1.37, 95%CI: 1.12–1.68), presence of intraventricular hemorrhage (2.95, 95%CI: 1.57–5.55), glucose concentration (per mmol/l: 2.14, 95%CI: 1.03–4.47), fibrinogen concentration (per g/l: 1.83, 95%CI: 1.03–3.25), and d-dimer concentration at hospital admission (per mg/l: 4.19, 95%CI: 1.88–9.34) were significantly associated with END after random-effects analyses. Whereas commonly described risk factors for ICH progression such as blood pressure, history of hypertension, and ICH growth were not.
This study summarizes the evidence to date on early ICH prognosis and highlights that the amount and distribution of the initial bleed at hospital admission may be the most important factors to consider when predicting early clinical outcomes.
PMCID: PMC4014549  PMID: 24809990
25.  Do-not-resuscitate orders and predictive models after intracerebral hemorrhage(e–Pub ahead of print) 
Neurology  2010;75(7):626-633.
To quantify the accuracy of commonly used intracerebral hemorrhage (ICH) predictive models in ICH patients with and without early do-not-resuscitate orders (DNR).
Spontaneous ICH cases (n = 487) from the Brain Attack Surveillance in Corpus Christi study (2000–2003) and the University of California, San Francisco (June 2001–May 2004) were included. Three models (the ICH Score, the Cincinnati model, and the ICH grading scale [ICH-GS]) were compared to observed 30-day mortality with a χ2 goodness-of-fit test first overall and then stratified by early DNR orders.
Median age was 71 years, 49% were female, median Glasgow Coma Scale score was 12, median ICH volume was 13 cm3, and 35% had early DNR orders. Overall observed 30-day mortality was 42.7% (95% confidence interval [CI] 38.3–47.1), with the average model-predicted 30-day mortality for the ICH Score, Cincinnati model, and ICH-GS at 39.9% (p = 0.005), 40.4% (p = 0.007), and 53.9% (p < 0.001). However, for patients with early DNR orders, the observed 30-day mortality was 83.5% (95% CI 78.0–89.1), with the models predicting mortality of 64.8% (p < 0.001), 57.2% (p < 0.001), and 77.8% (p = 0.02). For patients without early DNR orders, the observed 30-day mortality was 20.8% (95% CI 16.5–25.7), with the models predicting mortality of 26.6% (p = 0.05), 31.4% (p < 0.001), and 41.1% (p < 0.001).
ICH prognostic model performance is substantially impacted when stratifying by early DNR status, possibly giving a false sense of model accuracy when DNR status is not considered. Clinicians should be cautious when applying these predictive models to individual patients.
= Brain Attack Surveillance in Corpus Christi;
= confidence interval;
= do not resuscitate;
= Glasgow Coma Scale;
= intracerebral hemorrhage;
= intracerebral hemorrhage grading scale;
= receiver operating characteristic;
= San Francisco General Hospital;
= University of California San Francisco.
PMCID: PMC2931769  PMID: 20610832

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