A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria.

BACKGROUND: Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital. METHODS: Children 24-83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken. RESULTS: Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 µg/mL) and all were above 6 µg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects. CONCLUSION: Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital. TRIAL REGISTRATION: NCT01660672 . NCT01982812 .

Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis.

OBJECTIVE: The antifibrinolytic agent tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding, but its effectiveness in patients with traumatic brain injury (TBI) is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hemorrhage (ICH) secondary to TBI, does TXA compared to placebo improve patients' outcomes? METHODS: MEDLINE, EMBASE, CINAHL, and other databases were searched for randomized controlled trial (RCT) or quasi-RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurologic function, hematoma expansion, and adverse effects. We used "Grading quality of evidence and strength of recommendations" to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate. RESULTS: Of 1030 references identified through the search, 2 high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk of 0.64 (95% confidence interval [CI], 0.41-1.02); on unfavorable functional status, a relative risk of 0.77 (95% CI, 0.59-1.02); and on ICH progression, a relative risk of 0.76 (95% CI, 0.58-0.98). No serious adverse effects (such as thromboembolic events) associated with TXA group were reported in the included trials. CONCLUSION: Pooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Further evidence is required to support its routine use in patients with TBI.

Folate deficiency in rat pups during weaning causes learning and memory deficits.

Folate is essential for fetal development, and its deficiency during gestation causes behavioural deficits in the offspring. The present study investigated its influence during weaning on brain function in the pups of rats that were put on a folate-deficient (FD) diet on postnatal day (PND) 1. Systemic folate deficiency in pups on the FD diet (n 15) was evident from the dramatically lower hepatic folate concentrations (median 23·7, range 8·1-48·4 ng/mg protein) and higher homocysteine concentrations (median 27·7, range 14·7-45·5 pmol/mg protein), respectively, compared with those of pups on the normal diet (ND; n 9) (median 114·5, range 64·5-158·5 ng/mg protein and median 15·5, range 11·6-18·9 pmol/mg protein) on PND 23. Brain folate concentrations although low were similar in pups on the FD diet (median 10·5, range 5·5-24·5 ng/mg protein) and ND (median 11·1, range 7·1-24·2 ng/mg protein). There was a high accumulation of homocysteine in the brain of FD pups, mostly in the hippocampus (median 58·1, range 40·8-99·7 pmol/mg protein) and cerebellum (median 69·1, range 50·8-126·6 pmol/mg protein), indicating metabolic folate deficiency despite normal brain folate concentrations. Developmental deficits or autistic traits were more frequent in the FD group than in the ND group and repetitive self-grooming occurred, on average, three times (range 1-8) v. once (range 0-3) during 5 min, respectively. Long-term memory or spatial learning and set-shifting deficits affected 12 to 62% of rats in the FD group compared with none in the ND group. Post-weaning folic acid supplementation did not correct these deficits. These observations indicate that folate deficiency during weaning affects postnatal development even when gestational folate supply is normal.

Diagnostic accuracy of microEEG: a miniature, wireless EEG device.

Measuring the diagnostic accuracy (DA) of an EEG device is unconventional and complicated by imperfect interrater reliability. We sought to compare the DA of a miniature, wireless, battery-powered EEG device ("microEEG") to a reference EEG machine in emergency department (ED) patients with altered mental status (AMS). Two hundred twenty-five ED patients with AMS underwent 3 EEGs. Two EEGs, EEG1 (Nicolet Monitor, "reference") and EEG2 (microEEG) were recorded simultaneously with EEG cup electrodes using a signal splitter. The remaining study, EEG3, was recorded with microEEG using an electrode cap immediately before or after EEG1/EEG2. The official EEG1 interpretation was considered the gold standard (EEG1-GS). EEG1, 2, and 3 were de-identified and blindly interpreted by two independent readers. A generalized mixed linear model was used to estimate the sensitivity and specificity of these interpretations relative to EEG1-GS and to compute a diagnostic odds ratio (DOR). Seventy-nine percent of EEG1-GS were abnormal. Neither the DOR nor the κf representing interrater reliabilities differed significantly between EEG1, EEG2, and EEG3. The mean setup time was 27 min for EEG1/EEG2 and 12 min for EEG3. The mean electrode impedance of EEG3 recordings was 12.6 kΩ (SD: 31.9 kΩ). The diagnostic accuracy of microEEG was comparable to that of the reference system and was not reduced when the EEG electrodes had high and unbalanced impedances. A common practice with many scientific instruments, measurement of EEG device DA provides an independent and quantitative assessment of device performance.

Effect of microEEG on clinical management and outcomes of emergency department patients with altered mental status: a randomized controlled trial.

OBJECTIVES: Altered mental status (AMS) is a common presentation in the emergency department (ED). A previous study revealed 78% electroencephalogram (EEG) abnormalities, including nonconvulsive seizure (NCS; 5%), in ED patients with AMS. The objective of this study was to assess the impact of EEG on clinical management and outcomes of ED patients with AMS. METHODS: This was a randomized controlled trial at two urban teaching hospitals. Adult patients (≥18 years old) with AMS were included. Excluded patients had immediately correctable AMS (e.g., hypoglycemia) or were admitted before enrollment. Patients were randomized to routine care (control) or routine care plus EEG (intervention). Research assistants used a scalp electrode set with a miniature, wireless EEG device (microEEG) to record standard 30-minute EEGs at presentation, and results were reported to the ED attending physician by an off-site epileptologist within 30 minutes. Primary outcomes included changes in ED management (differential diagnosis, diagnostic work-up, and treatment plan from enrollment to disposition) as determined by surveying the treating physicians. Secondary outcomes were length of ED and hospital stay, intensive care unit (ICU) requirement, and in-hospital mortality. RESULTS: A total of 149 patients were enrolled (76 control and 73 intervention). Patients in the two groups were comparable at baseline. EEG in the intervention group revealed abnormal findings in 93% (95% confidence interval [CI] = 85% to 97%), including NCS in 5% (95% CI = 2% to 13%). Using microEEG was associated with change in diagnostic work-up in 49% (95% CI = 38% to 60%) of cases and therapeutic plan in 42% (95% CI = 31% to 53%) of cases immediately after the release of EEG results. Changes in probabilities of differential diagnoses and the secondary outcomes were not statistically significant between the groups. CONCLUSIONS: An EEG can be obtained in the ED with minimal resources and can affect clinical management of AMS patients.

EEG interpretation reliability and interpreter confidence: a large single-center study.

The intrarater and interrater reliability (I&IR) of EEG interpretation has significant implications for the value of EEG as a diagnostic tool. We measured both the intrarater reliability and the interrater reliability of EEG interpretation based on the interpretation of complete EEGs into standard diagnostic categories and rater confidence in their interpretations and investigated sources of variance in EEG interpretations. During two distinct time intervals, six board-certified clinical neurophysiologists classified 300 EEGs into one or more of seven diagnostic categories and assigned a subjective confidence to their interpretations. Each EEG was read by three readers. Each reader interpreted 150 unique studies, and 50 studies were re-interpreted to generate intrarater data. A generalizability study assessed the contribution of subjects, readers, and the interaction between subjects and readers to interpretation variance. Five of the six readers had a median confidence of ≥99%, and the upper quartile of confidence values was 100% for all six readers. Intrarater Cohen's kappa (κc) ranged from 0.33 to 0.73 with an aggregated value of 0.59. Cohen's kappa ranged from 0.29 to 0.62 for the 15 reader pairs, with an aggregated Fleiss kappa of 0.44 for interrater agreement. Cohen's kappa was not significantly different across rater pairs (chi-square=17.3, df=14, p=0.24). Variance due to subjects (i.e., EEGs) was 65.3%, due to readers was 3.9%, and due to the interaction between readers and subjects was 30.8%. Experienced epileptologists have very high confidence in their EEG interpretations and low to moderate I&IR, a common paradox in clinical medicine. A necessary, but insufficient, condition to improve EEG interpretation accuracy is to increase intrarater and interrater reliability. This goal could be accomplished, for instance, with an automated online application integrated into a continuing medical education module that measures and reports EEG I&IR to individual users.

Prevalence of non-convulsive seizure and other electroencephalographic abnormalities in ED patients with altered mental status.

UNLABELLED: Four to ten percent of patients evaluated in emergency departments (ED) present with altered mental status (AMS). The prevalence of non-convulsive seizure (NCS) and other electroencephalographic (EEG) abnormalities in this population is unknown. OBJECTIVES: To identify the prevalence of NCS and other EEG abnormalities in ED patients with AMS. METHODS: A prospective observational study at 2 urban ED. Inclusion: patients ≥13 years old with AMS. Exclusion: An easily correctable cause of AMS (e.g. hypoglycemia). A 30-minute standard 21-electrode EEG was performed on each subject upon presentation. OUTCOME: prevalence of EEG abnormalities interpreted by a board-certified epileptologist. EEGs were later reviewed by 2 blinded epileptologists. Inter-rater agreement (IRA) of the blinded EEG interpretations is summarized with κ. A multiple logistic regression model was constructed to identify variables that could predict the outcome. RESULTS: Two hundred fifty-nine patients were enrolled (median age: 60, 54% female). Overall, 202/259 of EEGs were interpreted as abnormal (78%, 95% confidence interval [CI], 73-83%). The most common abnormality was background slowing (58%, 95% CI, 52-68%) indicating underlying encephalopathy. NCS (including non-convulsive status epilepticus [NCSE]) was detected in 5% (95% CI, 3-8%) of patients. The regression analysis predicting EEG abnormality showed a highly significant effect of age (P < .001, adjusted odds ratio 1.66 [95% CI, 1.36-2.02] per 10-year age increment). IRA for EEG interpretations was modest (κ: 0.45, 95% CI, 0.36-0.54). CONCLUSIONS: The prevalence of EEG abnormalities in ED patients with undifferentiated AMS is significant. ED physicians should consider EEG in the evaluation of patients with AMS and a high suspicion of NCS/NCSE.

Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury.

Traumatic brain injury (TBI) differs in severity from severe to mild. This study examined whether a combination of the drugs minocycline (MINO) plus N-acetylcysteine (NAC) produces behavioral and histological improvements in a mild version of the controlled cortical impact model of TBI (mCCI). Following mCCI, rats acquired an active place avoidance task by learning the location of a stationary shock zone on a rotating arena. Rats acquired this task with a training protocol using a 10-minute intertrial interval. Mildly injured rats had an apparent deficit in long-term memory since they did not acquire the task when the intertrial interval was increased to 24 h. Mildly injured rats also had an apparent deficit in set shifting since, after successfully learning one shock zone location they did not learn the location of a second shock zone. MINO plus NAC synergistically limited these behavioral deficits in long-term memory and set shifting. mCCI also produced neuroinflammation at the impact site and at distal white matter tracts including the corpus callosum. At the impact site, MINO plus NAC attenuated CD68-expressing phagocytic microglia without altering neutrophil infiltration or astrocyte activation. The drugs had no effect on astrocyte activation in the corpus callosum or hippocampus. In the corpus callosum, MINO plus NAC decreased CD68 expression yet increased overall microglial activation as measured by Iba-1. MINO plus NAC acted synergistically to increase Iba-1 expression since MINO alone suppressed expression and NAC alone had no effect. Despite the known anti-inflammatory actions of the individual drugs, MINO plus NAC appeared to modulate, rather than suppress neuroinflammation. This modulation of neuroinflammation may underlie the synergistic improvement in memory and set-shifting by the drug combination after mCCI.

Reversible behavioral deficits in rats during a cycle of demyelination-remyelination of the fimbria.

Traumatic brain injury (TBI) selectively damages white matter. White matter damage does not produce deficits in many behavioral tests used to analyze experimental TBI. Rats were impaired on an active place avoidance task following inactivation of one hippocampal injection of tetrodotoxin. The need for both hippocampi suggests that acquisition of the active place avoidance task may require interhippocampal communication. The controlled cortical impact model of TBI demyelinates midline white matter and impairs rats on the active place avoidance task. One white matter region that is demyelinated is the fimbria that contains hippocampal commissural fibers. We therefore tested whether demyelination of the fimbria produces deficits in active place avoidance. Lysophosphatidylcholine (LPC) was injected stereotaxically to produce a cycle of demyelination-remyelination of the fimbria. At 4 days, myelin loss was observed in the fimbria of LPC-, but not saline-injected rats. Fourteen days after injection, myelin content increased in LPC-, but not saline-injected rats. Three days after injection, both saline- and LPC-injected rats had similar performance on an open field and passive place avoidance task in which the rat avoided a stationary shock zone on a stationary arena. The following day, on the active place avoidance task, LPC-injected rats had a significantly higher number of shock zone entrances suggesting learning was impaired. At 14 days after injection, saline- and LPC-injected rats had similar performance on open field and passive place avoidance. On active place avoidance, however, saline- and LPC-injected rats had a similar number of total entrances suggesting that the impairment seen at 4 days was no longer present at 14 days. These data suggest that active place avoidance is highly sensitive to white matter injury.

Electroencephalographic findings in consecutive emergency department patients with altered mental status: a preliminary report.

Electroencephalography (EEG) can help narrow the differential diagnosis of altered mental status (AMS) and is necessary to diagnose nonconvulsive seizure (NCS). The objective of this prospective observational study is to identify the prevalence of EEG abnormalities in emergency department patients with AMS. Patients of at least 13 years of age with AMS were enrolled, whereas those with an easily identifiable cause (e.g. hypoglycemia) underlying their AMS were excluded. Easily identifiable cause of AMS (e.g. hypoglycemia). A 30-min EEG with the standard 19 electrodes was performed on each patient. Descriptive statistics (%, 95% confidence interval) are used to report EEG findings of the first 50 enrolled patients. Thirty-five EEGs (70%, 57-81%) were abnormal. The most common abnormality was slowing of background activities (46%, 33-60%), reflecting an underlying encephalopathy. NCS was diagnosed in three (6%, 1-17%), including one patient in nonconvulsive status epilepticus. Nine patients (18%, 10-31%) had interictal epileptiform abnormalities, indicating an increased risk of spontaneous seizure. Patients presenting to the emergency department with AMS have a high prevalence of EEG abnormalities, including NCS.

Nonconvulsive seizures in patients presenting with altered mental status: an evidence-based review.

Definitive diagnosis of nonconvulsive seizures (NCS) can be made only by electroencephalography, and delay in diagnosis can increase morbidity, resource utilization, and length of hospitalization. We performed an evidence-based literature review to estimate the prevalence of NCS in patients with altered mental status (AMS) of unknown cause. PUBMED, EMBASE, the Cochrane Library, and other resources were searched for studies that included AMS and seizure as topics. The resulting 276 articles were screened for predetermined inclusion and exclusion criteria, leaving 5 studies enrolling 478 patients for review. The prevalence of NCS in patients with AMS ranged from 8 to 30% (overall prevalence of 21.5%, 95% CI: 18-25%), suggesting that the prevalence of NCS is sufficiently high to consider routine use of urgent electroencephalography in such patients. However, methodological weaknesses limit the generalizability of the results. A large, prospective study enrolling and screening for NCS in all patients who present with acute AMS is needed.

The new wave: time to bring EEG to the emergency department.

Emergency electroencephalography (EEG) is indicated in the diagnosis and management of non-convulsive status epilepticus (NCSE) underlying an alteration in the level of consciousness. NCSE is a frequent, treatable, and under-diagnosed entity that can result in neurological injury. This justifies the need for EEG availability in the emergency department (ED). There is now emerging evidence for the potential benefits of EEG monitoring in various acute conditions commonly encountered in the ED, including convulsive status after treatment, breakthrough seizures in chronic epilepsy patients who are otherwise controlled, acute head trauma, and pseudo seizures. However, attempts to allow for routine EEG monitoring in the ED face numerous obstacles. The main hurdles to an optimized use of EEG in the ED are lack of space, the high cost of EEG machines, difficulty of finding time, as well as the expertise needed to apply electrodes, use the machines, and interpret the recordings. We reviewed the necessity for EEGs in the ED, and to meet the need, we envision a product that is comprised of an inexpensive single-use kit used to wirelessly collect and send EEG data to a local and/or remote neurologist and obtain an interpretation for managing an ED patient.

Minocycline synergizes with N-acetylcysteine and improves cognition and memory following traumatic brain injury in rats.

BACKGROUND: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. METHODOLOGY/PRINCIPAL FINDINGS: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co-administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when the drugs were dosed one hour after injury. CONCLUSIONS/SIGNIFICANCE: These observations suggest a potentially valuable role for MINO plus NAC to treat TBI.

A hierarchy of neurobehavioral tasks discriminates between mild and moderate brain injury in rats.

Behavioral analysis commonly assesses cognitive deficits in rodents following traumatic brain injury (TBI). We examined rats that received sham, mild or moderate injury in the controlled cortical impact model of TBI. The rats were tested in a novel hierarchy of four behavioral tasks with increasing cognitive demand. All three groups had similar performance on the first two phases of training: open field exploration and passive place avoidance using a stationary shock zone on a non-rotating arena. The similar performance on the first two tasks suggested comparable sensory, motor skills and contextual memory in all three groups. In phase three, rats were tested on active place avoidance, their ability to avoid a stationary shock zone on the rotating arena. Control and mildly-injured rats learned this task within four ten-minute trials while moderately-injured animals were impaired. Moderately-injured animals were also impaired if tested 3 weeks after injury. One day after phase three, sham- and mildly-injured animals were tested on a phase four conflict active avoidance task with the shock zone shifted 180 degrees from its phase three location and mildly-injured animals were impaired. The speed in which the animals complete the four phases of testing as well as the ability to discriminate between differing injury severity suggests that this set of neurobehavioral tasks will be useful to understand cognitive deficits underlying TBI as well as a useful screening method for therapeutic drugs.