Prophylactic treatment with CN-105 improves functional outcomes in a murine model of closed head injury.

The treatment of traumatic brain injury (TBI) in military populations is hindered by underreporting and underdiagnosis. Clinical symptoms and outcomes may be mitigated with an effective pre-injury prophylaxis. This study evaluates whether CN-105, a 5-amino acid apolipoprotein E (ApoE) mimetic peptide previously shown to modify the post-traumatic neuroinflammatory response, would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model. CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) and administered to C57-BL/6 mice intravenously (IV) and/or by intraperitoneal (IP) injection at various time points prior to injury while vehicle treated animals received IV and/or IP normal saline. Animals were randomized following injury and behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy), and hippocampal microglial activation was assessed using F4/80 immunohistochemical staining in treated and untreated mice 7 days post-TBI. Separate, in vivo assessments of the pharmacokinetics was performed in healthy CD-1. IV CN-105 administered prior to head injury improved vestibulomotor function compared to vehicle control-treated animals. CN-105 co-administered by IP and IV dosing 6 h prior to injury also improved vestibulomotor function up to 28 days following injury. Microglia counted in CN-105 treated specimens were significantly fewer (P = 0.03) than in vehicle specimens. CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury and could be adapted as a pre-injury prophylaxis for soldiers at high risk for TBI.

Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.

OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS: Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION: LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy.

We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ≥4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as #NCT00412984.

ApoE mimetic improves pathology and memory in a model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by Aß plaques. Current treatments are purely symptomatic despite decades of intensive research interest. Notably, patients with the APOE4 allele are at increased risk for developing AD. One hypothesis regarding the mechanism by which the APOE4 allele might increase AD risk is loss of adaptive function, raising the possibility that the exogenous administration of apoE mimetics would have therapeutic effects. In this study, we utilized a previously characterized murine model of AD containing human APP, PS1 and APOE4TR, the APP/PS1/APOETR mouse. We treated male APP/PS1/APOETR mice with the apoE mimetic CN-105 or vehicle for 40d, beginning either at 14-18 or 25-28 weeks of age. After termination of treatment we tested animals in both Morris water maze and contextual fear conditioning, and examined soluble Aß by biochemistery and Aß deposition in cortex by unbiased stereology. We found that transient treatment with CN-105 for 40d beginning at 14-18 weeks reduced Aß pathology and rescued memory deficits in male APP/PS1/APOETR mice. Notably, delaying treatment onset to 25-28 weeks did not produce as robust an effect. These results suggest CN-105 treatment in a mouse model of AD results in a reduction in AD pathology and improved behavioral outcomes when administered early in the course of disease. As CN-105 has an excellent safety profile and is already in clinical trials, these findings raise the possibility that CN-105 represents a novel and translatable therapeutic strategy for AD.

Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH.

Objective: Subarachnoid haemorrhage (SAH) accounts for 3% of all strokes, and is associated with significant morbidity and mortality. There is growing evidence implicating apolipoprotein E (apoE) in mediating adaptive anti-inflammatory and neuroprotective responses following ischaemic and traumatic brain injury. In the current study, we test the efficacy of a small apoE mimetic peptide, CN-105 in a murine model of SAH. Methods: Mice subjected to SAH received repeated intravenous injections of CN-105 every 12 hours for 3 days, with the first dose given 2 hours after injury. Daily functional outcomes were assessed by rotarod and neurological severity score. Haemorrhage grade and cerebral vascular diameters were measured at 5 days post-SAH. Cerebral microgliosis, neuronal degeneration and survival were analysed at 5 and 35 days post-SAH, respectively. Results: CN-105 reduces histological evidence of inflammation, reduces vasospasm and neuronal injury and is associated with improved long-term behavioural outcomes in a murine model of SAH. Conclusions: Given its favourable pharmacokinetic profile, central nervous system penetration and demonstration of clinical safety, CN-105 represents an attractive therapeutic candidate for treatment of brain injury associated with SAH.

Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial.

Background Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model.

At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by Rotarod and Morris Water Maze and a reduction in positive Fluoro-Jade B stained injured neurons and microglial activation. Administration of CN-105 was also associated with reduction in mRNA expression of a subset of inflammatory and immune-related genes.

Spontaneous retinal activity is tonic and does not drive tectal activity during activity-dependent refinement in regeneration.

During development, waves of activity periodically spread across retina to produce correlated activity that is thought to drive activity-dependent ordering in optic fibers. We asked whether similar waves of activity are produced in the retina of adult goldfish during activity-dependent refinement by regenerating optic fibers. Dual-electrode recordings of spontaneous activity were made at different distances across retina but revealed no evidence of retinal waves in normal retina or during regeneration. Retinal activity was tonic and lacked the episodic bursting associated with waves. Cross-correlation analysis showed that the correlated activity that was normally restricted to near neighbors (typically seen across 100-200 microm and absent at >500 microm) was not altered during regeneration. The only change associated with regeneration was a twofold reduction in ganglion cell firing rates. Because spontaneous retinal activity is known to be sufficient to generate refinement during regeneration in goldfish, we examined its effect on tectal activity. In normal fish, acutely eliminating retinal activity with TTX rapidly reduced tectal unit activity by >90%. Surprisingly, during refinement at 4-6 weeks, eliminating retinal activity had no detectable effect on tectal activity. Similar results were obtained in recordings from torus longitudinalis. After refinement at 3 months, tectal activity was again highly dependent on ongoing retinal activity. We conclude that spontaneous retinal activity drives tectal cells in normal fish and after regeneration but not during activity-dependent refinement. The implications of these results for the role of presynaptic activity in refinement are considered.

Diagnostic Accuracy of Electrographic Seizure Detection by Neurophysiologists and Non-Neurophysiologists in the Adult ICU Using a Panel of Quantitative EEG Trends.

PURPOSE: To evaluate the sensitivity and specificity of a panel of quantitative EEG (qEEG) trends for seizure detection in adult intensive care unit (ICU) patients when reviewed by neurophysiologists and non-neurophysiologists. METHODS: One hour qEEG panels (n = 180) were collected retrospectively from 45 ICU patients and were distributed to 5 neurophysiologists, 7 EEG technologists, and 5 Neuroscience ICU nurses for evaluation of seizures. Each panel consisted of the following qEEG tools, displayed separately for left and right hemisphere electrodes: rhythmicity spectrogram (rhythmic run detection and display; Persyst Inc), color density spectral array, EEG asymmetry index, and amplitude integrated EEG. The reviewers did not have access to the raw EEG data. RESULTS: For the reviewer's ability to detect the presence of seizures on qEEG panels when compared with the gold standard of independent raw EEG review, the sensitivities and specificities are as follows: neurophysiologists 0.87 and 0.61, EEG technologists 0.80 and 0.80, and Neuroscience ICU nurses 0.87 and 0.61, respectively. There was no statistical difference among the three groups regarding sensitivity. CONCLUSIONS: Quantitative EEG display panels are a promising tool to aid detection of seizures by non-neurophysiologists as well as by neurophysiologists. However, even when used as a panel, qEEG trends do not appear to be adequate as the sole method for reviewing continuous EEG data.

Endovascular treatment of venous sinus thrombosis: a case report and review of the literature.

Dural venous sinus thrombosis (DVST) is a pathological phenomenon resulting from vascular occlusion of the cerebral venous sinuses. The mainstay of therapy for DVST is anticoagulation but more aggressive interventional therapies must be considered when medical therapy fails. A case is presented of a patient who was diagnosed with DVST, medically treated immediately but continued to deteriorate. Invasive endovascular therapies ultimately obliterated the thrombi in her sinuses. A brief review of the literature is reported.

Factor XIII deficiency mistaken for battered child syndrome: case of "correct" test ordering negated by a commonly accepted qualitative test with limited negative predictive value.

We report herein a case of Factor XIII deficiency that remained undiagnosed until 2 years of age. Part of the delay in diagnosis was a consequence of testing that was performed on a blood sample obtained after plasma transfusion therapy for a life-threatening bleeding episode. Due to insufficient family follow-up after discharge from the hospital, the diagnosis was delayed 1 year until the child was rehospitalized and a pre-transfusion plasma sample was tested. The commonly accepted approach of using only a qualitative test for the diagnosis of factor XIII deficiency is challenged by this case report.