Magnesium sulfate and risk of hypoxic-ischemic encephalopathy in a high-risk cohort.

BACKGROUND: Hypoxic-ischemic encephalopathy contributes to morbidity and mortality among neonates ≥36 weeks of gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic-ischemic encephalopathy, and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with preeclampsia with severe features. OBJECTIVE: (1) Determine trends in the incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate, and hypoxic-ischemic encephalopathy; (2) evaluate the association between hypertensive disorders of pregnancy and hypoxic-ischemic encephalopathy; and (3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic-ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate. STUDY DESIGN: We analyzed a prospective cohort of live births ≥36 weeks of gestation between 2012 and 2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic-ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic-ischemic encephalopathy. RESULTS: Among 44,314 unique infants, the diagnosis of hypoxic-ischemic encephalopathy, maternal hypertensive disorders of pregnancy, and the use of magnesium sulfate increased over time. Compared with patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a high-risk population. They were more likely to be publicly insured, born between 36 and 38 weeks of gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, experience preterm labor and fetal distress, and undergo operative delivery (all P<.002). Hypertensive disorders of pregnancy were associated with hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.13-1.40]; P<.001) and specifically moderate/severe hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.11-1.42]; P<.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.71 [95% confidence interval, 0.52-0.97]; P=.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.63 [95% confidence interval, 0.42-0.94]; P=.03). CONCLUSION: Hypertensive disorders of pregnancy are associated with hypoxic-ischemic encephalopathy and, specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with a significant reduction in the odds of hypoxic-ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to neonatal intensive care unit at ≥36 weeks of gestation. The findings of this observational study cannot prove causality and are intended to generate hypotheses for future clinical trials on magnesium sulfate in term infants.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

Low-velocity penetrating brain injury: a review of the literature and illustrative case.

INTRODUCTION: Low-velocity penetrating brain injury (LVPBI) is a class of brain injury where a foreign object violates the skull and damages the brain. Such injuries are rare and consequently understudied. CASE: As such, we report an illustrative case of a 29-year-old female with a dense, plastic spike penetrating her right orbit and into her midbrain. After assessment with a CT scan and angiography, the object was removed with careful attention to possible vascular injury. The patient had an uncomplicated post-operative course and received antibiotic and antiepileptic prophylaxis. She was discharged on post-operative day 5, experiencing only mild left-sided weakness. DISCUSSION: Common concerns regarding LVPBI include infection, post-traumatic epilepsy, and vascular injury. A review of published LVPBI cases over the past 20 years demonstrated that most cases (55.2%) are due to accidents. Of patients undergoing surgery, 43.4% underwent a craniotomy, and 22.8% underwent a craniectomy. Despite the grave nature of LVPBI, only 13.5% of the patients died. Additionally, 6.5% of patients developed an infection over their clinical course. CONCLUSION: In all, more reported cases further paint a picture of the current state of management and outcomes regarding LVPBI, paving the way for more cohesive guidelines to ensure the best possible patient outcomes.

Pharmacokinetics of Levetiracetam Seizure Prophylaxis in Severe Traumatic Brain Injury.

BACKGROUND: Drug pharmacokinetics (PK) are altered in neurocritically ill patients, and optimal levetiracetam dosing for seizure prophylaxis is unknown. OBJECTIVE: This study evaluates levetiracetam PK in critically ill patients with severe traumatic brain injury (sTBI) receiving intravenous levetiracetam 1000 mg every 8 (LEV8) to 12 (LEV12) hours for seizure prophylaxis. METHODS: This prospective, open-label study was conducted at a level 1 trauma, academic, quaternary care center. Patients with sTBI receiving seizure prophylaxis with LEV8 or LEV12 were eligible for enrollment. Five sequential, steady-state, postdose serum levetiracetam concentrations were obtained. Non-compartmental analysis (NCA) and compartmental approaches were employed for estimating pharmacokinetic parameters and projecting steady-state trough concentrations. Pharmacokinetic parameters were compared between LEV8 and LEV12 patients. Monte Carlo simulations (MCS) were performed to determine probability of target trough attainment (PTA) of 6 to 20 mg/L. A secondary analysis evaluated PTA for weight-tiered levetiracetam dosing. RESULTS: Ten male patients (5 LEV8; 5 LEV12) were included. The NCA-based systemic clearance and elimination half-life were 5.3 ± 1.2 L/h and 4.8 ± 0.64 hours. A one-compartment model provided a higher steady-state trough concentration for the LEV8 group compared with the LEV12 group (13.7 ± 4.3 mg/L vs 6.3 ± 1.7 mg/L; P = 0.008). Monte Carlo simulations predicted regimens of 500 mg every 6 hours, 1000 mg every 8 hours, and 2000 mg every 12 hours achieved therapeutic target attainment. Weight-tiered dosing regimens achieved therapeutic target attainment using a 75 kg breakpoint. CONCLUSION AND RELEVANCE: Neurocritically ill patients exhibit rapid levetiracetam clearance resulting in a short elimination half-life. Findings of this study suggest regimens of levetiracetam 500 mg every 6 hours, 1000 mg every 8 hours, or 2000 mg every 12 hours may be required for optimal therapeutic target attainment. Patient weight of 75 kg may serve as a breakpoint for weight-guided dosing to optimize levetiracetam therapeutic target attainment for seizure prophylaxis.

Levetiracetam dosing for seizure prophylaxis in neurocritical care patients.

BACKGROUND/OBJECTIVE: Levetiracetam is used for seizure prophylaxis in patients presenting with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI). We aim to characterize the optimal levetiracetam dosage for seizure prophylaxis. METHODS: This retrospective cohort study included adult patients at an academic tertiary hospital presenting with SAH or TBI who received levetiracetam at a total daily dose (TDD) equivalent to or greater than 1000 mg. The primary outcome was combined seizure incidence, including clinical and subclinical seizures. RESULTS: We identified 139 patients (49.6% male, mean age 53 years) for inclusion. For patients receiving a 1000-mg TDD, the administration was 500 mg twice daily. For patients receiving >1000-mg TDD, 77/78 patients received 1000 mg twice daily and one patient received 750 mg twice daily. Patients receiving 1000-mg TDD had a higher seizure incidence than those receiving >1000-mg TDD (p = 0.01), despite no difference in examined confounders, including history of alcoholism (p = 0.49), benzodiazepine use (p = 0.28), or propofol use (p = 0.17). No difference in adverse effects was observed (anemia, p = 0.44; leukopenia, p = 0.60; thrombocytopenia, p = 0.86). CONCLUSIONS: Patients may experience a reduced incidence of clinical and electroencephalographic seizures with levetiracetam dosing >1000-mg TDD.

A Retrospective Case Series on Valproic Acid for Early Post-Traumatic Seizure Prophylaxis After Traumatic Brain Injury in Patients With Concomitant Agitation.

Purpose: Early post-traumatic seizures occur within 7 days following a traumatic brain injury and may lead to additional brain damage and poor outcomes. Levetiracetam or phenytoin is often used for seizure prophylaxis in this patient population, but valproic acid may be an appropriate therapeutic alternative in patients with concomitant agitation. Evidence for the use of valproic acid for both early post-traumatic seizure prophylaxis and agitation is limited. The purpose of this study is to examine the safety and efficacy of valproic acid for both early post-traumatic seizure prophylaxis and agitation. Methods: This single-center, retrospective case series includes 18 patients who received valproic acid for both early post-traumatic seizure prophylaxis and agitation. Efficacy for early post-traumatic seizure prophylaxis is assessed by the incidence of seizures within 7 days of injury. Efficacy for agitation is assessed by changes in Riker Sedation-Agitation Scale scores during valproic acid therapy. The safety of valproic acid is defined by the incidence of selected adverse events. Results: Among 18 patients with traumatic brain injuries receiving valproic acid for both early post-traumatic seizures and agitation, one patient experienced a seizure during the period of prophylaxis and thrombocytopenia was the most common adverse event. Conclusion: In this small cohort of patients, valproic acid appears be a potential option to prevent early post-traumatic seizures in patients with traumatic brain injuries and concomitant agitation with minimal adverse effects. Randomized, controlled studies are needed to further investigate the role of valproic acid for this indication, including standards for dosing regimens, serum drug monitoring, and the relationship between valproic acid treatment and mortality.

Perioperative levetiracetam for seizure prophylaxis in seizure-naive brain tumor patients with focus on neurocognitive functioning.

INTRODUCTION: In seizure-naive brain tumor patients, the efficacy of perioperative prophylactic antiepileptic drug treatment remains controversial. In case of administration, the common preferred drug is levetiracetam (LEV) because of its favorable pharmacological profile. Research to date has not sufficiently determined how LEV affects cognition in the short term, as is the case in the perioperative period. The objective of this prospective study was to examine the neurocognitive functioning of seizure-naive brain tumor patients after receiving LEV perioperatively. METHODS: Fortythree patients with supratentorial brain tumor scheduled for surgery received LEV three days before until six days after surgery as seizure prophylaxis. Cognitive functioning (NeuroCogFX), LEV plasma-levels, hematotoxicity, side-effects, as well as health-related quality of life (HRQoL, Qolie31), were recorded preoperatively before (Baseline) and after onset of LEV (Pre-Op), 4-6 days postoperatively (Post-Op) and 21 days postoperatively (Follow-Up). RESULTS: No significant changes in cognitive functioning and HRQoL were seen after onset of preoperative LEV. There was a significant improvement of NeuroCogFX total-score at Follow-Up (p = 0.004) compared to Baseline. The overall-score Qolie31 showed simultaneous improvement patterns as cognitive functioning (p < 0.001). The most frequent side effect related to study drug was somnolence (in 28.6% of patients). CONCLUSIONS: A significant improvement of cognitive functioning, as well as an improvement in HRQoL, were detected postoperatively. This is presumably due to the debulking effect of the surgery. Nevertheless, LEV has no detrimental effect on cognitive functioning in the perioperative phase in seizure-naive brain tumor patients. TRIAL REGISTRATION: This study was registered prospectively (Date: 25/11/2015; EudraCT: 2015-003,916-19).

Incidence of neurobehavioral side effects associated with levetiracetam compared to phenytoin in traumatic brain injury patients.

Background: Phenytoin is recommended for seizure prophylaxis in traumatic brain injury (TBI). Levetiracetam has been proposed as an alternative agent. The purpose of this study was to determine whether there is a difference in the incidence of neurobehavioral side effects in patients with TBI receiving levetiracetam compared to those receiving phenytoin for seizure prophylaxis.Methods: This was a retrospective cohort study conducted at a level 1 trauma center from June 2008 to April 2014. Patients with TBI aged 16 years and older who received levetiracetam or phenytoin for seizure prophylaxis were evaluated and incidence of neurobehavioral side effects were compared for the two groups.Results: Of the 200 patients who met inclusion criteria, 95 (47.5%) received phenytoin and 105 (52.5%) received levetiracetam. Incidence of neurobehavioral side effects was not statistically different between groups (76 [80%] vs. 75 [71.4%], p = .189). The two groups were well matched.Conclusion: In patients with TBI, receipt of levetiracetam for seizure prophylaxis did not appear to be associated with increased neurobehavioral side effects compared to receipt of phenytoin.

Patterns of seizure prophylaxis after oncologic neurosurgery.

BACKGROUND: Evidence supporting routine postoperative antiepileptic drug (AED) prophylaxis following oncologic neurosurgery is limited, and actual practice patterns are largely unknown beyond survey data. OBJECTIVE: To describe patterns and predictors of postoperative AED prophylaxis following intracranial tumor surgery. METHODS: The MarketScan Database was used to analyze pharmacy claims data and clinical characteristics in a national sample over a 5-year period. RESULTS: Among 5895 patients in the cohort, levetiracetam was the most widely used AED for prophylaxis (78.5%) followed by phenytoin (20.5%). Prophylaxis was common but highly variable for patients who underwent open resection of supratentorial intraparenchymal tumors (62.5%, reference) or meningiomas (61.9%). In multivariate analysis, biopsies were less likely to receive prophylaxis (44.8%, OR 0.47, 95% CI 0.33-0.67), and there was near consensus against prophylaxis for infratentorial (9.7%, OR 0.07, CI 0.05-0.09) and transsphenoidal procedures (0.4%, OR 0.003, CI 0.001-0.010). Primary malignancies (52.1%, reference) and secondary metastases (42.2%) were more likely to receive prophylaxis than benign tumors (23.0%, OR 0.63, CI 0.48-0.83), as were patients discharged with home services and patients in the Northeast. There was a large spike in duration of AED use at approximately 30 days. CONCLUSIONS: Use of seizure prophylaxis following intracranial biopsies and supratentorial resections is highly variable, consistent with a lack of guidelines or consensus. Current practice patterns do not support a clear standard of care and may be driven in part by geographic variation, availability of post-discharge services, and electronic prescribing defaults rather than evidence. Given uncertainty regarding effectiveness, indications, and appropriate duration of AED prophylaxis, well-powered trials are needed.

Seizure Prophylaxis in Unruptured Aneurysm Repair: A Randomized Controlled Trial.

BACKGROUND: Prophylactic antiepileptic drugs (pAEDs) are often prescribed for seizure prophylaxis in patients undergoing surgical treatment of unruptured intracranial aneurysms (UIAs). We aimed to evaluate the benefit of pAEDs in patients undergoing surgical repair of UIAs. METHODS: We randomly assigned eligible patients undergoing surgical repair of UIAs to receive levetiracetam for seven days post-operatively or standard care alone. The primary outcome was the evaluation of seizures in the perioperative period (within 4 weeks). We also evaluated seizure occurrence throughout follow-up and assessed functional outcomes using the modified Rankin scale score (mRS). RESULTS: 35 patients were randomized to the "no-levetiracetam" group and 41 patients were randomized to receive levetiracetam. The two study groups had similar overall baseline characteristics and the surgical complication rate was similar for both groups (p = 0.8). One patient in the "no-levetiracetam" group had a seizure in the perioperative period versus 2 patients in the group randomized to receive levetiracetam (2.9% vs 4.9%, respectively, p = 1.00). No patients in the "no-levetiracetam" group had any additional late seizures (mean follow-up of 20.4 months), but three patients in the levetiracetam group had late seizures during follow-up (mean follow-up of 19.1 months) (0% vs 7.3%, p = 0.2). mRS score of 0-2 at 90 days and at the latest follow-up were similar between the two groups (p = 1.00). CONCLUSIONS: Perioperative seizure prophylaxis with levetiracetam does not reduce the rate of seizures as compared to controls in patients undergoing surgical repair of UIAs.

Association of Antiepileptic Medications with Outcomes after Allogeneic Hematopoietic Cell Transplantation with Busulfan/Cyclophosphamide Conditioning.

High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative antiepileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, including 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT between 2004 and 2014. We found no differences suggesting decreased overall survival or relapse-free survival or increased risks of relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or regimen-related toxicity associated with the use of alternative AEMs compared with phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin.

Use of Antiepileptic Drugs in Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Controversy exists in antiepileptic drug (AED) prophylaxis prescribing in patients with aneurysmal subarachnoid hemorrhage (SAH). We undertook the Use of Antiepileptic Drugs in Aneurysmal Subarachnoid Hemorrhage (ALIBI) study to identify factors associated with prescribing practices. METHODS: A retrospective chart review of all consecutive patients requiring Level 1 care with aneurysmal SAH admitted between 2012 and 2014 to the intensive care unit at Toronto Western Hospital, Ontario, Canada, was conducted. Data were collected on clinical and imaging characteristics. Primary and secondary outcomes were AED prophylaxis and clinical seizure activity during hospitalization. Data were compared using chi-square or Mann-Whitney U-tests. Those variables found to be significant, or trending toward significance, on univariate analysis were fitted to multivariate regression. RESULTS: Sixty-eight patients were included. Mean age was 62 ± 12.2, and 42.6% of patients were male. Of these, 21 patients (30.9%) received AED prophylactically, while 18 (26.5%) had reported seizures at some point during hospitalization. Female gender and presence of midline shift (MLS) were significantly associated or approached significance with AED prophylaxis in univariate analysis (p = 0.036 and p = 0.062, respectively). In multivariate analysis, only MLS was an independent predictor (odds ratio 5.09, p = 0.04). CONCLUSION: The presence of MLS was an independent predictor of seizure activity in patients with aneurysmal SAH. AED prophylaxis prescribing patterns seemed arbitrary and was not informed by identifiable clinical factors or true risk factors for seizure. A current lack of evidence guiding AED prescribing practice highlights the need for larger studies in this patient population.

Utiliser des médicaments antiépileptiques dans des cas d'hémorragie sous-arachnoïdienne anévrismale. Introduction: Dans les cas de patients victimes d'hémorragie sous-arachnoïdienne anévrismale, il faut savoir qu'un traitement prophylactique au moyen de médicaments antiépileptiques demeure controversé. Dans cette étude, nous avons donc entrepris d'identifier les facteurs associés aux pratiques de prescription de ces médicaments lorsque survient ce type d'hémorragie. Méthodes: Pour ce faire, nous avons passé en revue les dossiers de tous les patients vus consécutivement et ayant nécessité, après avoir été admis entre 2012 et 2014 à l'unité des soins intensifs du Toronto Western Hospital (Ontario, Canada), des soins de niveau 1 à la suite d'une hémorragie sous-arachnoïdienne anévrismale. Nous avons collecté nos données en nous basant sur des aspects cliniques et sur d'autres aspects liés à des examens d'IRM. Notre principal résultat mesuré a été l'efficacité d'un traitement prophylactique au moyen de médicaments antiépileptiques; dans un deuxième temps, nous avons aussi cherché à mesurer l'activité convulsive clinique en cours d'hospitalisation. Nous avons ensuite comparé nos données en utilisant les tests du X2 ou de U Mann-Whitney. Les variables apparues significatives ou tendant à être significatives dans le cadre d'une analyse univariée ont été ajustées pour une régression multivariée. Résultats: 68 patients ont été inclus dans cette étude. Leur âge moyen était de 62 ± 12,2; 42,6% d'entre eux étaient des hommes. De ce nombre, 21 patients (30,9%) ont alors suivi un traitement prophylactique au moyen de médicaments antiépileptiques tandis que 18 (26,5%) ont fait état de crises convulsives à un moment ou un autre de leur séjour à l'hôpital. Dans le cadre d'une analyse univariée, le fait d'être une femme et la présence d'une déviation de la ligne médiane (midline shift) ont été par ailleurs nettement associés ou en grande partie associés à un traitement prophylactique au moyen de médicaments antiépileptiques (respectivement p = 0,036 et p = 0,062). Dans le cadre d'une analyse multivariée, seule la déviation de la ligne médiane s'est avérée un facteur prédicteur indépendant (rapport des cotes de 5,09; P = 0,04). Conclusion: La présence de déviation de la ligne médiane constitue un facteur prédictif indépendant d'activité convulsive chez des patients victimes d'hémorragie sous-arachnoïdienne anévrismale. De plus, les tendances en matière de prescription de médicaments antiépileptiques apparaissent arbitraires et ne reposent pas sur des facteurs cliniques identifiables ou sur de véritables facteurs de risque liés aux convulsions. Le manque actuel de preuves pouvant orienter les pratiques de prescription de ces médicaments met en lumière la nécessité d'effectuer de plus amples études au sein de cette population de patients.

Pharmacological management of post-traumatic seizures in adults: current practice patterns in the UK and the Republic of Ireland.

BACKGROUND: Patient selection for seizure prophylaxis after traumatic brain injury (TBI) and duration of anti-epileptic drug treatment for patients with early post-traumatic seizures (PTS), remain plagued with uncertainty. In early 2017, a collaborative group of neurosurgeons, neurologists, neurointensive care and rehabilitation medicine physicians was formed in the UK with the aim of assessing variability in current practice and gauging the degree of uncertainty to inform the design of future studies. Here we present the results of a survey of clinicians managing patients with TBI in the UK and Ireland. MATERIALS AND METHODS: An online survey was developed and piloted. Following approval by the Academic Committee of the Society of British Neurological Surgeons, it was distributed via appropriate electronic mailing lists. RESULTS: One hundred and seventeen respondents answered the questionnaire, predominantly neurosurgeons (76%) from 30 (of 32) trauma-receiving hospitals in the UK and Ireland. Fifty-three percent of respondents do not routinely use seizure prophylaxis, but 38% prescribe prophylaxis for one week. Sixty percent feel there is uncertainty regarding the use of seizure prophylaxis, and 71% would participate in further research to address this question. Sixty-two percent of respondents use levetiracetam for treatment of seizures during the acute phase, and 42% continued for a total of 3 months. Overall, 90% were uncertain about the duration of treatment for seizures, and 78% would participate in further research to address this question. CONCLUSION: The survey results demonstrate the variation in practice and uncertainty in both described aspects of management of patients who have suffered a TBI. The majority of respondents would want to participate in future research to help try and address this critical issue, and this shows the importance and relevance of these two clinical questions.

The safety and efficacy of levetiracetam versus phenytoin for seizure prophylaxis after traumatic brain injury: A systematic review and meta-analysis.

BACKGROUND: The standard for early traumatic brain injury (TBI) seizure prophylaxis is phenytoin (PHT). Levetiracetam (LEV) has been proposed as an alternative to PHT. The aim of this study was to evaluate the safety and efficacy of LEV on TBI seizure when compared with PHT. METHODS: A search was carried out based on the databases from Pubmed, Embase and the Cochrane database up to May 2015. The relative risk (RR) and the relevant 95% confidence intervals (CI) were determined. RESULTS: Eight observational studies and one randomized controlled trial involving 2035 cases were included. The results indicated that no significant differences in terms of overall seizure (RR = 0.90; 95% CI = 0.51-1.53; p = 0.68), early seizure (RR = 1.06; 95% CI = 0.37-3.07; p = 0.92) and late seizure (RR = 1.10; 95% CI = 0.43-2.79; p = 0.85) occurrence. However, LEV was associated with a lower adverse drug reaction rate (RR = 0.43; 95% CI = 0.23-0.81; p = 0.01). Moreover, there were no significant differences in terms of mortality, length of ICU or hospital stay between groups. CONCLUSIONS: The meta-analysis suggests that LEV appears to have a similar efficacy to PHT on TBI. A better safety profile of LEV is supported by this analysis.

Early toxic epidermal necrolysis syndrome post-intra-cranial tumor resection.

INTRODUCTION: SJS and TEN are two rare self-limited but serious cutaneous drug reactions with significant morbidity and mortality. There are many drugs associated with the condition. We report a case of early TEN syndrome post Carbamazepine use, review the current literature and discuss the management challenges. CASE REPORT: A 51-year-old female was admitted to hospital for investigation and management of complex partial seizures secondary to a meningioma. She was commenced on 100mg BD of Carbamazepine for seizure control and discharged home. Surgical resection of the meningioma was performed electively 2 weeks later. A localized erythematous macular rash mainly in the left shoulder was noted on postoperative day 3. Two days later, the patient had sloughing of the mucosa of the lips in addition to progression of the rash. Early Toxic Epidermal Necrolysis (TEN) syndrome was diagnosed by the Burns and Dermatology teams and the culprit drug was discontinued. Skin biopsy confirmed the diagnosis. The patient was commenced on intravenous immunoglobulins with excellent improvement in skin integrity and resolution of excoriations noted on discharge. DISCUSSION: Stevens - Johnson syndrome (SJS) and TEN are two rare self-limited but serious cutaneous drug reactions with significant morbidity and mortality. The current treatment of TENS/SJS is divided into early management and symptom control. The immediate cessation of the culprit drug is quintessential. There is vast documented evidence of carbamazepine- induced SJS/TEN in patients of Asian ethnicity due to the presence of the HLA allele B*1502. HLA-B*1502 screening should be performed when using aromatic anticonvulsants such as carbamazepine in high-risk patients.

Levetiracetam-induced neutropenia following traumatic brain injury.

BACKGROUND: Levetiracetam is being increasingly utilized for post-traumatic brain injury seizure prophylaxis, in part because of its more favourable adverse effect profile compared to other anti-epileptics. This report highlights an unusual, clinically significant adverse drug reaction attributed to levetiracetam use in a patient with blunt traumatic brain injury. METHODS: This study describes a case of isolated neutropenia associated with levetiracetam in a 52-year-old man with traumatic brain injury. RESULTS: The patient developed neutropenia on day 3 of therapy with levetiracetam, with an absolute neutrophil count nadir of 200. There were no other medications that may have been implicated in the development of this haematological toxicity. Neutropenia rapidly resolved upon cessation of levetiracetam therapy. CONCLUSIONS: Clinicians should be aware of potentially serious adverse reactions associated with levetiracetam in patients with neurological injury.

Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after traumatic brain injury.

BACKGROUND: Much debate exists on the optimal medication for posttraumatic seizure prophylaxis after traumatic brain injury (TBI). There is some evidence that levetiracetam (LEV) could be neuroprotective and provide long-term benefits in this patient population. OBJECTIVE: The primary objective was to compare the Glasgow Outcome Scale-Extended (GOS-E) 6 months or more after severe TBI. Secondary end points were presence of early seizures (0 to 7 days post-TBI) or late seizures (8 days post-TBI to phone interview), use of anticonvulsant medication when interviewed, medication-related hospital complications, and a summary of phenytoin (PHT) and LEV dosing regimens. METHODS: This was an IRB-approved, single-center, prospective cohort analysis. Patients were identified by cross-referencing a list of patients receiving LEV or PHT, with a list of patients with ICD-9 code consistent with TBI. After study inclusion, patients were contacted by telephone, and the GOS-E was administered. Data for secondary end points were gathered by retrospective chart review. RESULTS: In all, 19 patients were included in the final analysis. There was no difference in the GOS-E score assessed ≥6 months after injury (5.07±1.69 vs 5.60±2.07, P=0.58). There was no difference in the secondary end points of early seizures (P=0.53) or late seizures (P=0.53). However, the PHT group experienced a higher rate of hospital days with recorded fever (0.20±0.22 vs 0±0; P=0.014). CONCLUSIONS: Long-term functional outcome in patients who experienced a TBI was not affected by treatment with PHT or LEV; however, patients treated with PHT had a higher incidence of fever during hospitalization.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

OBJECTIVE: The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. METHOD: A systematic review of English-language MEDLINE articles was undertaken. CONCLUSIONS: Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

Outcomes Associated With Levetiracetam Use After Spontaneous Intracerebral Hemorrhage.

Background and Purpose: The purpose of this study was to assess the incidence of seizures in patients with spontaneous intracerebral hemorrhage (ICH) who received prophylactic levetiracetam. Methods: This was a retrospective cohort study evaluating the use of levetiracetam in patients without a history of seizures who experienced a spontaneous intracerebral hemorrhage. Patients were excluded if they were younger than 18 years of age, had a documented history of a seizure disorder, or had an antiseizure drug documented on their home medication list. Patients were based on their exposure to levetiracetam. The primary outcome was incidence of seizure during hospital admission. Secondary outcomes included occurrence of adverse events, intensive care unit (ICU) length of stay (LOS), and hospital LOS. Results: Of the 229 patients included in the final analysis, 21 were in the levetiracetam group (LEV) and 208 were in the no levetiracetam group (no LEV). No statistical difference in seizure incidence was observed when comparing the LEV and no LEV groups (1 [4.8%] LEV vs 3 [1.4%] no LEV; P = .32). There was also no statistical difference in the median ICU LOS (2 days [1 day, 5 days] LEV vs 2 days [1 day, 3 days] no LEV; P = .27), median hospital LOS (6 days [2 days, 8 days] LEV vs 6 days [3 days, 9 days] no LEV; P = .27), or adverse events. Conclusions: This study does not support the use of levetiracetam prophylaxis in patients who have experienced an ICH.

Effectiveness of Levetiracetam versus phenytoin in preventing seizure in traumatic brain injury patients: A systematic review and meta-analysis.

OBJECTIVE: Traumatic brain injury (TBI) and the subsequent Post-traumatic seizure (PTS) is a growing public health concern. Generally, anti-seizure drugs (ASDs) are recommended for PTS prophylaxis and treatment. This meta-analysis aimed to review the current state of knowledge and the evidence for the efficacy and safety of Levetiracetam (LEV) on the incidence of seizure in TBI patients compared to Phenytoin (PHT). METHODS: A search was carried out based on PubMed, MEDLINE, Europe PMC database, and Cochrane Library up to November 2023. A total of 16 studies (3 randomized clinical trials, 10 retrospective cohort studies, and 3 prospective cohort studies) including 5821 TBI patients included in our meta-analysis. We included studies comparing LEV and PHT after brain injury in both adults and children. Risk of bias assessment was done for randomized controlled trials (RCTs) with a risk-of-bias tool (RoB-2) and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies. Two RCTs in our meta-analysis had a high risk of bias, therefore we applied sensitivity analysis to evaluate the robustness of our results. RESULTS: The most commonly reported dosage for LEV was 500 mg twice daily and for PHT it was 5 mg/kg. There was no significant difference between LEV and PHT groups in reducing the early seizure incidence (OR = 0.85; 95% CI = [0.60, 1.21]; p = 0.375, fixed-effect, I2 = 21.75%). The result of sensitivity analysis for late seizure showed no significant difference between LEV and PHT in reducing the late seizure occurrence after TBI (OR = 0.87; 95% CI = [0.21, 3.67]; p = 0.853, fixed-effect, I2 = 0%). The mortality in TBI patients treated with LEV was not statistically significant compared to the PHT group (OR = 1.11; 95% CI = [0.92, 1.34], p = 0.266). The length of stay in the hospital was not significantly different between the LEV and PHT groups (MD = -1.33; 95% CI = [-4.55, 1.90]; p = 0.421). However, in comparison to PHT, LEV shortened the length of ICU stay (MD = -2.25; 95% CI = [-3.58, -0.91]; p =0.001). In terms of adverse effects, more patients in the PHT group have experienced adverse events compared to LEV but the difference was not significant (OR = 0.69; 95% CI = [0.44, 1.08]; p = 0. 11). CONCLUSION: The results of our meta-analysis showed LEV and PHT have similar effects on the occurrence of early and late seizures in TBI patients. Therefore, none of the drugs is superior to the other in reducing PTS. However, treating TBI patients with LEV did not shorten the length of hospital stay in comparison to PHT but reduced the length of ICU stay significantly. The analysis showed that patients in the LEV experienced fewer side effects than in the PHT group, while it was not sufficiently clear whether all reported side effects were related to the drug alone or other factors. The mortality was similar between the LEV and PHT groups. Finally, we recommend more high-quality randomized controlled trials to confirm the current findings before making any recommendations in practice.