Prophylactic Anticonvulsant Therapy Research Articles

Levetiracetam or Phenytoin as Prophylaxis for Status Epilepticus: Secondary Analysis of the "Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial" (ADAPT) Dataset, 2014-2017.

To compare levetiracetam and phenytoin as prophylaxis for the short-term development of status epilepticus (SE) during care of pediatric patients with acute severe traumatic brain injury (TBI). Nonprespecified secondary analysis using propensity score matching. We used the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT NCT04077411) dataset (2014-2017). Patients less than 18 years old with Glasgow Coma Scale Score less than or equal to 8 who received levetiracetam or phenytoin as a prophylactic anticonvulsant therapy. None. Of the 516 total patients who qualified for the case-control study, 372 (72.1%) patients received levetiracetam, and 144 (27.9%) received phenytoin. After propensity score matching, the pair-matched analysis with 133 in each group failed to identify an association between levetiracetam versus phenytoin use and occurrent of SE (3.8% vs. 0.8%, p = 0.22), or mortality (i.e., in-hospital, 30-d and 60-d). However, on closer inspection of the statistical testing, we cannot exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with the following: up to a mean difference of 7.3% greater prevalence of SE; up to a mean difference of 13.9%, 12.1%, and 13.9% greater mortality during the hospital stay, and 30-, and 60-days after hospital arrival, respectively. Last, analysis of 6 months Glasgow Outcome Scale Extended score in those without premorbid comorbidities, there was an association between favorable outcomes and use of phenytoin rather than levetiracetam prophylaxis. In ADAPT, the decision to use prophylactic levetiracetam versus phenytoin failed to show an association with occurrence of subsequent SE, or mortality. However, we are unable to exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with greater prevalence of SE and mortality. We are unable to make any recommendation about one prophylactic anticonvulsant medication over the other, but recommend that further larger, contemporary studies in severe pediatric TBI are carried out.

Efficacy of phenytoin for 7 days versus 21 days as prophylactic anticonvulsant in traumatic brain injury patients - A comparative study.

Post traumatic seizures (PTS) are very common after traumatic brain injury and occur more common in severe form of injury. Prophylactic treatment with phenytoin has been found to be effective however till now no uniform internationally agreed guideline is available for the duration of anticonvulsant prophylaxis for traumatic brain injury patients. 100 patients of either sex between age group of 18-65 years who have suffered intracranial injury identified by CT scan, admitted in Trauma ICU were enrolled in this prospective randomized single blinded clinical study. Group 1 (n = 50) received 7 days prophylactic anticonvulsant therapy with phenytoin and Group 2 (n = 50) received for 21 days. The primary end point was the occurrence of seizures, which were classified as early (occurring from time of drug loading to day 7) or late (occurring on day 8 or later after loading of drug). Patients were also assessed for the possible adverse side effects of phenytoin. Out of 100 patients, 90 completed the study successfully as 5 patients from each group expired during the duration of the study. On comparing the frequency of seizure from 1st to 7th day after loading dose of phenytoin between two groups, out of 45 patient, 2 (4.4%) developed seizure in group 1 and 3 (6.7%) developed seizure in group 2 and found to be statistically insignificant (P = 0.645). On comparing the frequency of seizure from 1st to 21st day after loading dose of phenytoin between two groups, out of 45 patient, 4 (8.9%) developed seizure in groups 1 and 3 (11.1%) developed seizure in group 2 and found to be statistically insignificant (P = 0.725). A 21-day prophylactic anticonvulsant therapy with phenytoin was not more effective than a 7-day prophylactic therapy with phenytoin to reduce the frequency of seizure in a TBI patient in trauma ICU and was also associated with more adverse side effects that were insignificant.

Prophylactic anticonvulsant therapy in high-grade glioma: A systematic review and meta-analysis of longitudinal studies

It is common practice to prescribe prophylactic antiepileptic drugs (AED) to high-grade glioma (HGG) patients without a history of seizures, yet with limited evidence supporting its use. Ideally, the effectiveness of prophylactic anticonvulsants must outweigh the occurrence of adverse effects and interactions related to AED. The authors conducted a systematic review and metanalysis of longitudinal studies regarding the effectiveness of prophylactic AED in seizure-naïve HGG patients. PubMed/MEDLINE, Cochrane Central Register of Controlled trials, Embase and clinicaltrials.gov databases were systematically searched. Of the initial 1773 studies identified, 15 were finally selected for data extraction and analysis. Heterogeneity among studies, pooled hazard ratios, publication bias and sensitivity analyses were performed separately for a 15-study group (HGG patients within larger series of brain tumors) and a 6-study group (exclusively HGG patients). AED prophylaxis did not significantly reduce the incidence of postoperative seizures compared with controls, both in the 15-study group (Mantel-Haenszel random-effects pooled OR 1.08, 95% CI 0.82–1.43, 2123 patients) and in the 6-study group (pooled OR 1.22, 95% CI 0.77–1.92, 540 patients). However, some issues (paucity of prospective trials, overall moderate-risk of bias, and few studies addressing HGG patients exclusively) preclude firm conclusions against routine prophylactic AED prescription. Reported adverse effects attributable to AED were acceptable in the majority of studies. Within the limitations of this review, the results of this metanalysis do not support the routine administration of prophylactic AED to HGG patients without a history of seizures. Generalmente se administran fármacos antiepilépticos (FAE) a pacientes con gliomas de alto grado (GAG) sin historia previa de crisis, a pesar de una escasa evidencia a favor. Idealmente la efectividad de la profilaxis anticomicial debe compensar la aparición de efectos adversos debidos a la medicación. Realizamos una revisión sistemática y un metaanálisis de estudios longitudinales respecto a la utilidad de los FAE en pacientes con GAG sin historia de crisis previa. Se revisaron las bases de datos PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase y clinicaltrials.gov. De los 1.773 trabajos inicialmente identificados, 15 fueron seleccionados para la extracción de datos y análisis. Se realizaron análisis de heterogeneidad, sesgo de publicación, cálculo de OR combinadas y análisis de sensibilidad, por separado, en 2 grupos: grupo de 15 estudios (pacientes con GAG incluidos en series de tumores cerebrales) y grupo de 6 estudios (exclusivamente pacientes con GAG). La profilaxis con FAE no redujo de forma significativa la incidencia de crisis postoperatorias respecto a los controles, tanto en el grupo-15 (OR combinada de Mantel-Haenszel, efectos aleatorios de 1,08, IC 95%: 0,82-1,43, sobre 2.123 pacientes), como en el grupo-6 (OR combinada de 1,22, IC 95% 0,77-1,92, sobre 540 pacientes). Sin embargo, la escasez de ensayos aleatorizados y de estudios con GAG exclusivamente, junto a un sesgo global moderado, impiden establecer una recomendación sólida contra la profilaxis anticomicial. Los efectos adversos atribuidos a los FAE fueron aceptables en la mayoría de los estudios. Dentro de las limitaciones de esta revisión, los resultados del metaanálisis no apoyan el uso rutinario de profilaxis antiepiléptica en pacientes con GAG sin historia previa de crisis.

Preventing epilepsy after traumatic brain injury: A propensity score analysis

Background:Due to the potential consequences of post-traumatic epilepsy (PTE) exacerbating secondary injury following traumatic brain injury (TBI), the use of antiepileptic drugs (AEDs) is an accepted option for seizure prophylaxis. However, there is only a paucity of data that can be found regarding outcomes surrounding the use of AEDs. The purpose of this retrospective study is to evaluate whether the prophylactic administration of AEDs significantly decreased the incidence of PTE, when considering the severity of TBI.Methods:All trauma patients who had been newly diagnosed with TBI from January 1, 2010 to December 31, 2017 were retrospectively analyzed. Statistical comparisons were made using the chi-square test, Mann-Whitney U test, and Cox regression modeling. After excluding any exposed subjects with no appropriate match, patients who had received AED prophylaxis were matched by propensity score with those who did not receive AEDs. All of the TBI populations were followed up until June 30, 2018.Results:We identified 1316 patients who met the inclusion and exclusion criteria in our matched cohort through their propensity scores, where 138 patients had been receiving prophylactic AEDs and 138 patients had not. Baseline characteristics were similar in gender, age, Glasgow Coma Scale (GCS) scores, and risk factors of PTE including skull fracture, chronic alcoholism, subdural hematoma, epidural hematoma, and intracerebral hematoma. After adjusting for those risk factors, the relative incidence of seizure was not statistically significant in either of the groups (p = 0.566).Conclusion:In our cohort analysis, AED prophylaxis was ineffective in preventing seizures, as the rate of seizures was similar whether patients had been receiving the drugs or not. We therefore concluded that the benefits of routine prophylactic anticonvulsant therapy in patients with TBI need to be re-evaluated.

Prophylactic anticonvulsant therapy in high-grade glioma: A systematic review and meta-analysis of longitudinal studies.

It is common practice to prescribe prophylactic antiepileptic drugs (AED) to high-grade glioma (HGG) patients without a history of seizures, yet with limited evidence supporting its use. Ideally, the effectiveness of prophylactic anticonvulsants must outweigh the occurrence of adverse effects and interactions related to AED. The authors conducted a systematic review and metanalysis of longitudinal studies regarding the effectiveness of prophylactic AED in seizure-naïve HGG patients. PubMed/MEDLINE, Cochrane Central Register of Controlled trials, Embase and clinicaltrials.gov databases were systematically searched. Of the initial 1773 studies identified, 15 were finally selected for data extraction and analysis. Heterogeneity among studies, pooled hazard ratios, publication bias and sensitivity analyses were performed separately for a 15-study group (HGG patients within larger series of brain tumors) and a 6-study group (exclusively HGG patients). AED prophylaxis did not significantly reduce the incidence of postoperative seizures compared with controls, both in the 15-study group (Mantel-Haenszel random-effects pooled OR 1.08, 95% CI 0.82-1.43, 2123 patients) and in the 6-study group (pooled OR 1.22, 95% CI 0.77-1.92, 540 patients). However, some issues (paucity of prospective trials, overall moderate-risk of bias, and few studies addressing HGG patients exclusively) preclude firm conclusions against routine prophylactic AED prescription. Reported adverse effects attributable to AED were acceptable in the majority of studies. Within the limitations of this review, the results of this metanalysis do not support the routine administration of prophylactic AED to HGG patients without a history of seizures.

Imaging biomarkers of posttraumatic epileptogenesis.

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long-term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large-scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.

Development of an assay for cellular efflux of pharmaceutically active agents and its relevance to understanding drug interactions.

Drug interactions may dictate the failure or success of a treatment. Patients undergoing hematopoietic stem cell transplantation (HSCT) are exposed to various types of drugs, and understanding how these drugs interact is of the utmost importance. The pharmacokinetics of busulfan, melphalan, and cyclophosphamide, drugs commonly used for HSCT, are known to be affected by a variety of other drugs with differing molecular structures. We hypothesized that these structurally unrelated drugs affect the transport of DNA-alkylating agents. To test this hypothesis, we developed a flow cytometry assay that used 5-carboxyfluorescein diacetate acetoxymethyl ester, which is cleaved by nonspecific intracellular esterases to 5-carboxyfluorescein (5-CF), a fluorescent ligand for the drug transporter MRP1. A decreased 5-CF efflux in the presence of a test compound suggests competitive inhibition. We demonstrated that chlorambucil, 4-hydroperoxycyclophosphamide, ketoconazole, ethacrynic acid, everolimus, and sirolimus strongly inhibited 5-CF efflux in lymphoma and leukemia cell lines. The efflux of these drugs partially depends on the glutathione (GSH) level, and their cytotoxicity is synergistic with inhibited GSH synthesis. This is consistent with the hypothesis that their GSH-conjugated products are ligands of a common cellular drug transporter. Our results may explain clinical observations on the effects of various drugs on the pharmacokinetics and pharmacodynamics of alkylating agents, and the assay may be used to deduce interaction mechanisms of drugs transported by a common system.

Levetiracetam Prophylaxis for Post-traumatic Brain Injury Seizures is Ineffective: A Propensity Score Analysis.

Early seizures after severe traumatic brain injury (TBI) have a reported incidence of up to 15%. Prophylaxis for early seizures using 1 week of phenytoin is considered standard of care for seizure prevention. However, many centers have substituted the anticonvulsant levetiracetam without good data on the efficacy of this approach. Our hypothesis was that the treatment with levetiracetam is not effective in preventing early post-traumatic seizures. All trauma patients sustaining a TBI from January 2007 to December 2009 at an urban level-one trauma center were retrospectively analyzed. Seizures were identified from a prospectively gathered morbidity database and anticonvulsant use from the pharmacy database. Statistical comparisons were made by Chi square, t tests, and logistic regression modeling. Patients who received levetiracetam prophylaxis were matched 1:1 using propensity score matching with those who did not receive the drug. 5551 trauma patients suffered a TBI during the study period, with an overall seizure rate of 0.7% (39/5551). Of the total population, 1795 were diagnosed with severe TBI (Head AIS score 3-5). Seizures were 25 times more likely in the severe TBI group than in the non-severe group [2.0% (36/1795) vs. 0.08% (3/3756); OR 25.6; 95% CI 7.8-83.2; p<0.0001]. Of the patients who had seizures after severe TBI, 25% (9/36) received pharmacologic prophylaxis with levetiracetam, phenytoin, or fosphenytoin. In a matched cohort by propensity scores, no difference was seen in seizure rates between the levetiracetam group and no-prophylaxis group (1.9 vs. 3.4%, p=0.50). In this propensity score-matched cohort analysis, levetiracetam prophylaxis was ineffective in preventing seizures as the rate of seizures was similar whether patients did or did not receive the drug. The incidence of post-traumatic seizures in severe TBI patients was only 2.0% in this study; therefore we question the benefit of routine prophylactic anticonvulsant therapy in patients with TBI.

Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia.

Seizures are common following perinatal asphyxia and may exacerbate secondary neuronal injury. Barbiturate therapy has been used for infants with perinatal asphyxia in order to prevent seizures. However, barbiturate therapy may adversely affect neurodevelopment leading to concern regarding aggressive use in neonates. To determine the effect of administering prophylactic barbiturate therapy on death or neurodevelopmental disability in term and late preterm infants following perinatal asphyxia. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 11), MEDLINE via PubMed (1966 to 30 November 2015), EMBASE (1980 to 30 November 2015), and CINAHL (1982 to 30 November 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCT) and quasi-RCTs. We included all RCTs or quasi-RCTs of prophylactic barbiturate therapy in term and late preterm infants without clinical or electroencephalographic evidence of seizures compared to controls following perinatal asphyxia. Three review authors independently selected, assessed the quality of, and extracted data from the included studies. We assessed methodologic quality and validity of studies without consideration of the results. The review authors independently extracted data and performed meta-analyses using risk ratios (RR) and risk differences (RD) for dichotomous data and mean difference for continuous data with 95% confidence intervals (CI). For significant results, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH). In this updated review, we identified nine RCTs of any barbiturate therapy in term and late preterm infants aged less than three days old with perinatal asphyxia without evidence of seizures. Eight of these studies compared prophylactic barbiturate therapy to conventional treatment (enrolling 439 infants) and one study compared barbiturate therapy to treatment with phenytoin (enrolling 17 infants). Prophylactic barbiturate therapy versus conventional treatment: one small trial reported a decreased risk of death or severe neurodevelopmental disability for barbiturate therapy (phenobarbital) versus conventional treatment (RR 0.33, 95% CI 0.14 to 0.78; RD -0.55, 95% CI -0.84 to -0.25; NNTB 2, 95% CI 1 to 4; 1 study, 31 infants) (very low quality evidence).Eight trials comparing prophylactic barbiturate therapy with conventional treatment following perinatal asphyxia demonstrated no significant impact on the risk of death (typical RR 0.88, 95% CI 0.55 to 1.42; typical RD -0.02, 95% CI -0.08 to 0.05; 8 trials, 429 infants) (low quality evidence) and the one small trial noted above reported a significant decrease in the risk of severe neurodevelopmental disability (RR 0.24, 95% CI 0.06 to 0.92; RD -0.43, 95% CI -0.73 to -0.13; NNTB 2, 95% CI 1 to 8; 1 study, 31 infants) (very low quality evidence).A meta-analysis of the six trials reporting on seizures in the neonatal period demonstrated a statistically significant reduction in seizures in the prophylactic barbiturate group versus conventional treatment (typical RR 0.62, 95% CI 0.48 to 0.81; typical RD -0.18, 95% CI -0.27 to -0.09; NNTB 5, 95% CI 4 to 11; 6 studies, 319 infants) (low quality evidence). There were similar results in subgroup analyses based on type of barbiturate and Sarnat score. Prophylactic barbiturate therapy versus other prophylactic anticonvulsant therapy: one study reported on prophylactic barbiturate versus prophylactic phenytoin. There was no significant difference in seizure activity in the neonatal period between the two study groups (RR 0.89, 95% CI 0.07 to 12.00; 1 trial, 17 infants). We found only low or very low quality evidence addressing the use of prophylactic barbiturates in infants with perinatal asphyxia. Although the administration of prophylactic barbiturate therapy to infants following perinatal asphyxia did reduce the risk of seizures, there was no reduction seen in mortality and there were few data addressing long-term outcomes. The administration of prophylactic barbiturate therapy for late preterm and term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice. If used at all, barbiturates should be reserved for the treatment of seizures. The results of the current review support the use of prophylactic barbiturate therapy as a promising area of research. Future studies should be of sufficient size and duration to detect clinically important reductions in mortality and severe neurodevelopmental disability and should be conducted in the context of the current standard of care, including the use of therapeutic hypothermia.

Protocol for Seizure Prophylaxis following Intracerebral Hemorrhage Study (SPICH): A Randomized, Double-Blind, Placebo-Controlled Trial of Short-Term Sodium Valproate Prophylaxis in Patients with Acute Spontaneous Supratentorial Intracerebral Hemorrhage

Seizures after intracerebral hemorrhage are a common complication and may adversely affect neurological outcome. However, studies are inadequate on the utility of prophylactic anticonvulsant therapy in patients with hemorrhagic stroke, and the results remains controversial. This study aims to determine if short-duration sodium valproate prevents seizure onset or improves the survival and neurological outcome in adults after acute spontaneous supratentorial intracerebral hemorrhage. In this randomized, double blinded, placebo-controlled trial, 258 patients meeting the inclusion criteria will be enrolled in the Department of Neurosurgery, West China Hospital. In addition to standard care, patients will be randomly assigned to receive seven-day prophylaxis of sodium valproate 500 mg daily (alternatively 400 mg daily by intravenous infusion in 250 ml 0·9% normal saline) or matching placebo. Patients will be followed up at seven-days, 3, 6, and 12 months. The primary outcomes are early (≤7 days) and late onset seizures (>7 days). Secondary outcomes include midline shift, enlargement of hematoma, death (all cause), adverse effects, and functional outcome assessed by Glasgow Outcome Scale and modified Rankin Scale. Given the lack of evidence for seizure prophylaxis in patients with acute supratentorial intracerebral hemorrhage, randomized controlled trials are desperately needed. The results from our study are believed to directly influence future prophylactic anticonvulsant therapy of intracerebral hemorrhage.

Availability of intravenous lipid emulsion therapy on endosulfan-induced cardiovascular collapse

Acute Endosulfan poisoning is associated with a high mortality rate in humans, and can exceed 30% [Moon JM, Chun BJ. Acute endosulfan poisoning: a retrospective study. Hum Exp Toxicol 2009;28:309-16]. Prophylactic anticonvulsant therapy for symptomatic patients and aggressive treatment for seizures may limit morbidity, but, no effective antidote is available [Moses V, Peter JV. Acute intentional toxicity: endosulfan and other organochlorines. Clin Toxicol (Phila) 2010;48:539-44]. However, endosulfan poisoning is often completely reversible with the appropriate management [Karatas AD, Aygun D, Baydin A. Characteristics of endosulfan poisoning: a study of 23 cases. Singapore Med J 2006;47:1030-2]. Intravenous lipid emulsion (ILE) may be a useful in treatment of lipophilic medication overdoses as an adjunct to antidotal therapy [Rothschild L, Berns S, Oswald S, et al. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med 2010;18:51]. We believe that this is its first reported use in endosulfan toxicity.

A Case of Toxic Epidermal Necrolysis with Diverse Etiologies: Successful Treatment with Intravenous Immunoglobulin and Pulse Prednisolone and Effects on sTRAIL and sCD200 Levels

Here, we report the first case of patient with intracranial tumors (ICT) who developed a cutaneous adverse drug reaction during lansoprazole and prophylactic anticonvulsant treatment. SCORTEN is a scoring system used to predict mortality in TEN patients. If SCORTEN index is 5 or more, mortality rate is more than 90%. SCORTEN of our patient was calculated as 5. Our patient is a 64 year-old white female, who had glioma and had been on post-op prophylactic anticonvulsant therapy. On the 3rd day post operation, lansoprazole was added to the therapy. After the first lansoprazole dose, erythematous dusky red macules occurred on extremities and trunk and on the following day confluent purpuric lesions tended to run together in 95% of the whole body including scalp, oral and genital mucosa. Nikolsky's Sign was positive on the skin. Physical examination; body temperature was 38.4 degrees C with a heart rate of 146 beats/minute and 80/50 mm Hg arterial blood pressure, Glascow Coma Scale was E1 M1e, pupillary light reflex was 2/2 +/+ and she was confused. Her biopsy resulted as toxic epidermal necrolysis. Moreover, sTRAIL and sCD200 levels of serum and blister fluid were investigated as an apoptotic marker and a negative marker for inflammation. sTRAIL and sCD200 were evaluated both in the sera and blister fluid. sTRAIL level was lower than for healthy individuals with high levels in blister fluid; and sCD200 level was depressed by up to 10% of the normal values of healthy individuals but with high levels in the blister fluid during the active phase of the disease. After our successful treatment with human albumin, prednisolone pulse therapy, and IVIG at a dose of 400 mg/kg, she was discharged from the hospital on the 23rd day and followed up after 2 months. The increase in sTRAIL (up to two-fold) and sCD200 (up to six-fold) levels may provide useful information in understanding disease pathogenesis and monitoring treatment efficacy.

Recurrent Seizures in Tramadol Intoxication: Implications for Therapy Based on 100 Patients

Tramadol is an atypical opioid analgesic used in the treatment of mild to moderate pain. Despite being a GABA(A) agonist, seizures are a prominent complication with its therapeutic use, abuse or overdose. For patients who have had a tramadol-induced seizure, the likelihood of recurrent seizures and the need for emergent anticonvulsant prophylaxis is unknown. However, treatment of patients with anticonvulsants prophylactically may cause adverse effects and increased morbidity in tramadol poisoning. We studied the outcome and frequency of recurrent seizures in tramadol-intoxicated patients in an attempt to determine the need for prophylactic anticonvulsant therapy. This was a retrospective cohort study of tramadol-intoxicated patients who had at least one seizure. Patients' age, sex, cause(s) of intoxication, route of poisoning, dose or number of capsules or tablets taken, vital signs, other signs or symptoms, numbers of seizures, length of stay, co-ingestions and past medical history were ascertained. Exactly 100 patients met the inclusion criteria. Eighty-two per cent were men, and 50% were between 21 and 30 years old. By our standard clinical protocol, none were treated with seizure prophylaxis after their first seizure. Only 7% had recurrent seizures and all patients recovered without sequelae. Because of the low risk of multiple seizures in tramadol poisoning and the lack of morbidity in patients who do seize, it appears to be unnecessary to administer prophylactic anticonvulsant therapy in patients with tramadol poisoning, even if they have an initial seizure.

Incidence and management of late postsurgical seizures in clinical practice.

Seizures are a frequent complication in patients who undergo neurosurgery, and can complicate the post-operative course and deteriorate patients' quality of life. Evidence on the prophylactic anticonvulsant therapy after craniotomy is still lacking. We undertook an observational longitudinal study following neurosurgical supratentorial interventions, to evaluate seizures onset or persistence, and differences in effectiveness between conventional and newer AEDs. A total of 100 consecutive subjects were enrolled. Each patient underwent a neurosurgical treatment by craniotomy. Pre-operative seizures occurred in 33% patients, early seizures in 13%. Late seizures occurred in 46 patients. At baseline (1 month after surgery) and during follow up the main therapeutic regimen was monotherapy. At last follow up adjustment of antiepileptic regimen or AED dosage had rendered 27 subjects seizure free. People taking newer AEDs at baseline maintain the same antiepileptic regimen more often than patients taking conventional AEDs; late seizures tended to have a higher incidence in the latter group. Adverse events from baseline AEDs were reported by 17% of patients. In this study population late postsurgical seizures had a remarkable occurrence. Newer AEDs were continued more often than conventional AEDs, with a better tolerability but no significant differences in late seizures incidence.

Steady‐State Pharmacokinetics of Intravenous Levetiracetam in Neurocritical Care Patients

To characterize the steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients requiring seizure prophylaxis after a neurologic injury and to determine which dosing regimens achieve serum concentrations within the recommended therapeutic range of 6-20 μg/ml. DESIGN. Prospective, open-label, steady-state pharmacokinetic study. Neurocritical care unit in a tertiary care medical center. PATIENTS. Twelve adults (five men, seven women) admitted to the neurocritical care unit who required prophylactic anticonvulsant therapy after subarachnoid hemorrhage, subdural hematoma, or traumatic brain injury. Patients received an intravenous infusion of levetiracetam 500 mg over 15 minutes every 12 hours. Serial blood samples were collected from all patients after a minimum of four doses of therapy. Serum levetiracetam concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection, and pharmacokinetic data were analyzed by compartmental and noncompartmental methods. Monte Carlo simulations were performed for multiple levetiracetam dosing regimens to determine the probability of achieving a target trough concentration of 6 μg/ml or greater, 20 μg/ml or greater, and 6-20 μg/ml. The mean ± SD levetiracetam maximum serum concentration was 28.0 ± 8.0 μg/ml, minimum serum concentration 3.1 ± 1.8 μg/ml, half-life 5.2 ± 1.2 hours, systemic clearance 5.6 ± 1.8 L/hour, and volume of distribution at steady state 36.8 ± 6.3 L. Increasing the doses of levetiracetam increased the probability of achieving a target trough concentration of 6 μg/ml or greater but also increased the probability of achieving trough concentrations greater than 20 μg/ml. Levetiracetam doses of 1000 mg every 8 hours and 1500-2000 mg every 12 hours provided the highest probability of achieving a target trough concentration between 6 and 20 μg/ml. Compared with previously published results in healthy volunteers and adults in status epilepticus, levetiracetam systemic clearance was faster and the terminal elimination half-life was shorter in neurocritical care patients. Higher doses or more frequent dosing may be needed to achieve target trough concentrations of 6-20 μg/ml.

Development and Validation of a Test Dose Strategy for Once-Daily i.v. Busulfan: Importance of Fixed Infusion Rate Dosing

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

The role of prophylactic anticonvulsants in moderate to severe head injury

BackgroundPost-traumatic seizures cause secondary brain injury, contributing to morbidity and mortality after traumatic brain injury. Seizure activity may be undetectable if the patient is paralysed and ventilated.AimsThe effect of prophylactic anticonvulsant therapy on the prevention of seizures after moderate to severe traumatic brain injury was studied.MethodsA structured systematic literature review was performed.ResultsThere may be a place for prophylactic anticonvulsants in the prophylaxis of early post-traumatic seizures.ConclusionFurther randomised controlled trials are needed to firmly establish the benefits of prophylactic anticonvulsants.

Post-traumatic seizure disorder following acquired brain injury

Objective: The present study aimed to evaluate the effectiveness of prophylactic anticonvulsant pharmacological strategies for the prevention of seizure disorders following acquired brain injury (ABI) to provide guidance for clinical practice based on the best available evidence.Methods and main outcomes: A systematic review of the literature from 1980–2005 was conducted focusing on treatment interventions available for post-traumatic seizures following ABI. The evidence for the efficacy of a given intervention was ranked as strong (supported by at least two randomized controlled trials (RCTs), moderate (supported by a single RCT), or limited (supported by other types of studies in the absence of RCTs).Results: Based on a previous meta-analysis and the findings of this review, there is strong evidence that prophylactic anticonvulsant therapy decreases the occurrence of early seizures but only within the first week post-injury. Moreover, the evidence indicates that prophylactic anticonvulsant therapy does not decrease the incidence of seizure onset more than one week post-injury. In children, there is moderate evidence that prophylactic phenytoin does not reduce the incidence of early or late seizures. The efficacy of anticonvulsants after the development of seizures has not been specifically studied in ABI.Conclusions: Prophylactic anti-convulsants are effective in reducing seizures in the first week post-injury in adults. However, they do not reduce the occurrence of seizures after the first week.

The use of prophylactic anticonvulsants in patients with brain tumours-a systematic review.

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. 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.

Risk factors for developing epilepsy after craniotomy in children

We performed a retrospective analysis of children undergoing supratentorial craniotomy, attempting to identify possible risk factors for postoperative epilepsy and the need for prophylactic anticonvulsant therapy. We analysed 107 consecutive patients (55% males) who had supratentorial craniotomy for a variety of diagnoses (tumours, trauma, infection, vascular malformations and others) during 1995-1999. Mean age at operation was 89 months (range: 1-180 months). Patients who presented with epilepsy were excluded. Postoperative epilepsy was considered present if patients required systematic pharmacological treatment, at a minimum follow-up of 6 months. Linear regression was used to analyse the effect of sex, anticonvulsant prophylaxis, duration of operation, closure of dura, postoperative infection, the diagnosis, anatomical region of brain affected, operation type (craniotomy/craniectomy) and the need for brain resection. Prophylactic anticonvulsants were given to 52% of the patients; 97% had craniotomy; in five patients, the dura was left open; in 33%, some kind of brain tissue resection had been performed; two patients (1.8%) developed postoperative infection; one patient died. Only 13 patients (12%) developed postoperative epilepsy. The only two factors with statistical significance were female sex (p=0.045) and the absence of dural closure (p=0.001). All other factors were not significant (p>0.258). Postoperative epilepsy after supratentorial craniotomy is uncommon in children, incidence being 12%. The administration of prophylactic anticonvulsants does not appear to influence the risk of epilepsy. Surprisingly, females have statistically higher risk. Lack of dural closure has higher risk of epilepsy, but this may reflect the type of pathology.