Melissa Motta

Delayed inhibition of Nogo-A does not alter injury-induced axonal sprouting but enhances recovery of cognitive function following experimental traumatic brain injury in rats

Traumatic brain injury causes long-term neurological motor and cognitive deficits, often with limited recovery. The inability of CNS axons to regenerate following traumatic brain injury may be due, in part, to inhibitory molecules associated with myelin. One of these myelin-associated proteins, Nogo-A, inhibits neurite outgrowth in vitro, and inhibition of Nogo-A in vivo enhances axonal outgrowth and sprouting and improves outcome following experimental CNS insults. However, the involvement of Nogo-A in the neurobehavioral deficits observed in experimental traumatic brain injury remains unknown and was evaluated in the present study using the 11C7 monoclonal antibody against Nogo-A. Anesthetized, male Sprague-Dawley rats were subjected to either lateral fluid percussion brain injury of moderate severity (2.5-2.6 atm) or sham injury. Beginning 24 h post-injury, monoclonal antibody 11C7 (n=17 injured, n=6 shams included) or control Ab (IgG) (n=16 injured, n=5 shams included) was infused at a rate of 5 microl/h over 14 days into the ipsilateral ventricle using osmotic minipumps connected to an implanted cannula. Rats were assessed up to 4 weeks post-injury using tests for neurological motor function (composite neuroscore, and sensorimotor test of adhesive paper removal) and, at 4 weeks, cognition was assessed using the Morris water maze. Hippocampal CA3 pyramidal neuron damage and corticospinal tract sprouting, using an anterograde tracer (biotinylated dextran amine), were also evaluated. Brain injury significantly increased sprouting from the uninjured corticospinal tract but treatment with monoclonal antibody 11C7 did not further increase the extent of sprouting nor did it alter the extent of CA3 cell damage. Animals treated with 11C7 showed no improvement in neurologic motor deficits but did show significantly improved cognitive function at 4 weeks post-injury when compared with brain-injured, IgG-treated animals. To our knowledge, the present findings are the first to suggest that (1) traumatic brain injury induces axonal sprouting in the corticospinal tract and this sprouting may be independent of myelin-associated inhibitory factors and (2) that post-traumatic inhibition of Nogo-A may promote cognitive recovery unrelated to sprouting in the corticospinal tract or neuroprotective effects on hippocampal cell loss following experimental traumatic brain injury.

Differential effects of the anticonvulsant topiramate on neurobehavioral and histological outcomes following traumatic brain injury in rats

The efficacy of topiramate, a novel therapeutic agent approved for the treatment of seizure disorders, was evaluated in a model of traumatic brain injury (TBI). Adult male rats were anesthetized (sodium pentobarbital, 60 mg/kg, i.p.), subjected to lateral fluid percussion brain injury (n = 60) or sham injury (n = 47) and randomized to receive either topiramate or vehicle at 30 min (30 mg/kg, i.p.), and 8, 20 and 32 h postinjury (30 mg/kg, p.o.). In Study A, memory was evaluated using a Morris water maze at 48 h postinjury, after which brain tissue was evaluated for regional cerebral edema. In Study B, animals were evaluated for motor function at 48 h and 1, 2, 3, and 4 weeks postinjury using a composite neuroscore and the rotating pole test and for learning ability at 4 weeks. Brains were analyzed for hemispheric tissue loss and hippocampal CA3 cell loss. Topiramate had no effect on posttraumatic cerebral edema or histologic damage when compared to vehicle. At 48 h, topiramate treatment improved memory function in sham but not brain-injured animals, while at one month postinjury it impaired learning performance in brain-injured but not sham animals. Topiramate significantly improved composite neuroscores at 4 weeks postinjury and rotating pole performance at 1 and 4 weeks postinjury, suggesting a potentially beneficial effect on motor function following TBI.

Predictors of outcome in acute encephalitis

Objective: To investigate predictors of outcome in patients with all-cause encephalitis receiving care in the intensive care unit. Methods: A retrospective analysis of encephalitis cases at The Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center was performed. Using multivariate logistic regression analysis, we examined mortality and predictors of good outcome (defined as modified Rankin Scale scores of 1–3) and poor outcome (scores 4 and 5) in those surviving to hospital discharge. Results: In our cohort of 103 patients, the median age was 52 years (interquartile range 26), 52 patients (50.49%) were male, 28 patients (27.18%) had viral encephalitis, 19 (18.45%) developed status epilepticus (SE), 15 (14.56%) had cerebral edema, and 19 (18.45%) died. In our multivariate logistic regression analysis, death was associated with cerebral edema (odds ratio [OR] 18.06, 95% confidence interval [CI] 3.14–103.92), SE (OR 8.16, 95% CI 1.55–43.10), and thrombocytopenia (OR 6.28, 95% CI 1.41–28.03). Endotracheal intubation requirement with ventilator support was highly correlated with death (95%). In addition, in those patients who survived, viral, nonviral, and unknown causes of encephalitis were less likely to have a poor outcome at hospital discharge compared with an autoimmune etiology (viral encephalitis: OR 0.09, 95% CI 0.01–0.57; nonviral encephalitis: OR 0.02, 95% CI 0.01–0.31; unknown etiology: OR 0.18, 95% CI 0.04–0.91). Conclusions: Our study suggests that predictors of death in patients with encephalitis comprise potentially reversible conditions including cerebral edema, SE, and thrombocytopenia. Further prospective studies are needed to determine whether aggressive management of these complications in patients with encephalitis improves outcome.

Acute, transient hemorrhagic hypotension does not aggravate structural damage or neurologic motor deficits but delays the long-term cognitive recovery following mild to moderate traumatic brain injury.

Objectives:Posttraumatic hypotension is believed to increase morbidity and mortality in traumatically brain-injured patients. Using a clinically relevant model of combined traumatic brain injury with superimposed hemorrhagic hypotension in rats, the present study evaluated whether a reduction in mean arterial blood pressure aggravates regional brain edema formation, regional cell death, and neurologic motor/cognitive deficits associated with traumatic brain injury. Design:Experimental prospective, randomized study in rodents. Setting:Experimental laboratory at a university hospital. Subjects:One hundred nineteen male Sprague-Dawley rats weighing 350–385 g. Interventions:Experimental traumatic brain injury of mild to moderate severity was induced using the lateral fluid percussion brain injury model in anesthetized rats (n = 89). Following traumatic brain injury, in surviving animals one group of animals was subjected to pressure-controlled hemorrhagic hypotension, maintaining the mean arterial blood pressure at 50–60 mm Hg for 30 mins (n = 47). The animals were subsequently either resuscitated with lactated Ringers solution (three times shed blood volume, n = 18) or left uncompensated (n = 29). Other groups of animals included those with isolated traumatic brain injury (n = 34), those with isolated hemorrhagic hypotension (n = 8), and sham-injured control animals receiving anesthesia and surgery alone (n = 22). Measurements and Main Results:The withdrawal of 6–7 mL of arterial blood significantly reduced mean arterial blood pressure by 50% without decreasing arterial oxygen saturation or Pao2. Brain injury induced significant cerebral edema (p < .001) in vulnerable brain regions and cortical tissue loss (p < .01) compared with sham-injured animals. Neither regional brain edema formation at 24 hrs postinjury nor the extent of cortical tissue loss assessed at 7 days postinjury was significantly aggravated by superimposed hemorrhagic hypotension. Brain injury-induced neurologic deficits persisted up to 20 wks after injury and were also not aggravated by the hemorrhagic hypotension. Cognitive dysfunction persisted for up to 16 wks postinjury. The superimposition of hemorrhagic hypotension significantly delayed the time course of cognitive recovery. Conclusions:A single, acute hypotensive event lasting 30 mins did not aggravate the short- and long-term structural and motor deficits but delayed the speed of recovery of cognitive function associated with experimental traumatic brain injury.

Diffusion–Perfusion Mismatch: An Opportunity for Improvement in Cortical Function

Objective: There has been controversy over whether diffusion–perfusion mismatch provides a biomarker for the ischemic penumbra. In the context of clinical stroke trials, regions of the diffusion–perfusion mismatch that do not progress to infarct in the absence of reperfusion are considered to represent “benign oligemia.” However, at least in some cases (particularly large vessel stenosis), some of this hypoperfused tissue may remain dysfunctional for a prolonged period without progressing to infarct and may recover function if eventually reperfused. We hypothesized that patients with persistent diffusion–perfusion mismatch using a hypoperfusion threshold of 4–5.9 s delay on time-to-peak (TTP) maps at least sometimes have persistent cognitive deficits relative to those who show some reperfusion of this hypoperfused tissue. Methods: We tested this hypothesis in 38 patients with acute ischemic stroke who had simple cognitive tests (naming or line cancelation) and MRI with diffusion and perfusion imaging within 24 h of onset and again within 10 days, most of whom had large vessel stenosis or occlusion. Results: A persistent perfusion deficit of 4–5.9 s delay in TTP on follow up MRI was associated with a persistent cognitive deficit at that time point (p < 0.001). When we evaluated only patients who did not have infarct growth (n = 14), persistent hypoperfusion (persistent mismatch) was associated with a lack of cognitive improvement compared with those who had reperfused. The initial volume of hypoperfusion did not correlate with the later infarct volume (progression to infarct), but change in volume of hypoperfusion correlated with change in cognitive performance (p = 0.0001). Moreover, multivariable regression showed that the change in volume of hypoperfused tissue of 4–5.9 s delay (p = 0.002), and change in volume of ischemic tissue on diffusion weighted imaging (p = 0.02) were independently associated with change in cognitive function. Conclusion: Our results provide additional evidence that non-infarcted tissue with a TTP delay of 4–5.9 s may be associated with persistent deficits, even if it does not always result in imminent progression to infarct. This tissue may represent the occasional opportunity to intervene to improve function even days after onset of symptoms.

A Retrospective Analysis of Prolonged Empiric Antibiotic Therapy for Pneumonia Among Adult Neurocritical Care Patients

Background and Purpose: Current literature reports that half of critically ill patients are continued on broad-spectrum antibiotics beyond 72 hours despite no confirmed infection. The purpose of this retrospective study was to identify the incidence of and risk factors for prolonged empiric antimicrobial therapy (PEAT) in adult neurocritical care (NCC) patients treated for pneumonia, hypothesizing that NCC patients will have a higher incidence of PEAT. Methods: This is a retrospective chart review of adult NCC patients treated for pneumonia. Antibiotic therapy was classified as restrictive, definitive, or PEAT based on culture results and timing of discontinuation or de-escalation. Results: A total of 95 patients (median age: 57 years; 28.4% female; admission diagnosis: 73.7% cerebrovascular, 10.5% neuromuscular, and 15.8% seizure-related) were included in this study. Overall, 59% of antibiotic regimens were considered PEAT, with vancomycin and piperacillin/tazobactam being most commonly prescribed. Median duration of therapy was 6.8 days, with shorter duration in patients with negative culture results compared to those with positive culture results (6.1 days [interquartile range, IQR 4.0-8.3] vs 7.2 days [IQR 5.8-10.3], P < .05). On multivariable analysis, elevated baseline white blood cell count, meeting Centers for Disease Control criteria for pneumonia, and negative bacterial culture were significantly associated with PEAT. Conclusion: The incidence of prolonged empiric antibiotic use was high in the NCC population. Patients are at particular risk for PEAT if they have negative cultures. All but one patient did not meet criteria for central fever, highlighting the challenges in identifying fever etiology in the NCC population.

Anticipatory grief and impaired problem solving among surrogate decision makers of critically ill patients: A cross-sectional study

OBJECTIVES Anticipatory grief, the experience of grief before the death of a mourned individual, is common among people with seriously ill loved ones and associated with impaired social problem solving. We sought to evaluate anticipatory grief in the Intensive Care Unit setting. RESEARCH METHODOLOGY/DESIGN Cross-sectional study of surrogate decision-makers of patients admitted to an intensive care unit, incorporating survey methodology. SETTING Intensive care units at a tertiary care centre. MAIN OUTCOME MEASURES Surrogates completed a 78-question, self-administered questionnaire consisting of demographic and clinical data, as well as three validated instruments: Anticipatory Grief Scale (AGS), Hospital Anxiety and Depression Scale (HADS), and Social Problem Solving Inventory Revised Short Form (SPSI-R:S). MAIN RESULTS Surveys were completed by 50 surrogate decision-makers, among whom anticipatory grief was elevated and associated with anxiety and depression. Anticipatory grief was also significantly associated with worsened overall problem solving (Spearmans Rho -0.32, p value 0.02). Surrogates with loved ones who were older or admitted to a trauma unit experienced anticipatory grief at lower levels. Prior admission and Charlson Comorbidity Index scores were not associated with anticipatory grief. CONCLUSION Levels of anticipatory grief in the intensive care unit are high and associated with concurrent anxiety and depression. Association of anticipatory grief with worsened social problem solving may worsen decision making ability in surrogates.