Holly E. Hinson

Clinical evidence of inflammation driving secondary brain injury: A systematic review

BACKGROUND Despite advances in both prevention and treatment, traumatic brain injury (TBI) remains one of the most burdensome diseases; 2% of the US population currently lives with disabilities resulting from TBI. Recent advances in the understanding of inflammation and its impact on the pathophysiology of trauma have increased the interest in inflammation as a possible mediator in TBI outcome. OBJECTIVES The goal of this systematic review is to address the question: “What is the evidence in humans that inflammation is linked to secondary brain injury?” As the experimental evidence has been well described elsewhere, this review will focus on the clinical evidence for inflammation as a mechanism of secondary brain injury. DATA SOURCES Medline database (1996-Week 1 June 2014), Pubmed and Google Scholar databases were queried for relevant studies. STUDY ELIGIBILITY CRITERIA Studies were eligible if participants were adults and/or children who sustained moderate or severe TBI in the acute phase of injury, published in English. Studies published in the last decade (since 2004) were preferentially included. Trials could be observational or interventional in nature. APPRAISAL AND SYNTHESIS METHODS To address the quality of the studies retrieved, we applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria to assess the limitations of the included studies. RESULTS Trauma initiates local central nervous system as well as systemic immune activation. Numerous observational studies describe elevation of pro-inflammatory cytokines that are associated with important clinical variables including neurologic outcome and mortality. A small number of clinical trials have included immunomodulating strategies, but no intervention to date has proven effective in improving outcomes after TBI. LIMITATIONS Inclusion of studies not initially retrieved by the search terms may have biased our results. Additionally, some reports may have been inadvertently excluded due to use of non-search term key words. Conclusions and Implications of Key Findings Clinical evidence of inflammation causing secondary brain injury in humans is gaining momentum. While inflammation is certainly present, it is not clear from the literature at what juncture inflammation becomes maladaptive, promoting secondary injury rather than facilitating repairand identifying patients with maladaptive inflammation (neuro-inflammation, systemic, or both) after TBI remains elusive. Direct agonism/antagonism represents an exciting target for future study. LEVEL OF EVIDENCE Systematic review, level III.

Manifestations of the hyperadrenergic state after acute brain injury.

Purpose of reviewHyperadrenergic activity leading to autonomic dysfunction after acute brain injury is an underrecognized, yet important source of complications following a variety of neurologic injuries. Autonomic dysfunction may prolong ICU stay and increase healthcare costs driven by extensive diagnostic workups and/or ensuing complications. In this review article, we intend to illustrate commonalities between various hyperadrenergic states in acquired brain injury. Specifically, this review will focus on autonomic dysfunction in two common conditions in the neurocritical care unit, traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH). Recent findingsElevated levels of catecholamines have been well documented in SAH and to a lesser extent in paroxysmal sympathetic hyperactivity, hinting at the underlying increased sympathetic tone in both disease states. The resultant hyperadrenergic state may manifest with vital sign alterations, or end-organ dysfunction such as heart failure. Neuroimaging and limited clinical data have elucidated some information regarding underlying mechanisms, but the gaps in understanding have thus far limited prospective clinical trials. A multitude of therapeutic options to reduce adrenergic tone have been employed with varying degrees of success. SummaryThe pathophysiology of autonomic dysfunction is incompletely understood and treatment options are few. However, recognizing hyperadrenergic commonality in disparate neurologic disease may facilitate novel inquiries into lesion localization and therapeutics. It is possible that adrenergic blockade may diminish or abrogate end-organ dysfunction in TBI and SAH.

Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction. METHODS For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18-80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82-300 cm(3) on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182. FINDINGS Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0-4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32-2·32; p=0·77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00). INTERPRETATION Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide. FUNDING Remedy Pharmaceuticals.

Management of intraventricular hemorrhage.

Brain hemorrhage is the most fatal form of stroke and has the highest morbidity of any stroke subtype. Intraventricular extension of hemorrhage (IVH) is a particularly poor prognostic sign, with expected mortality between 50% and 80%. IVH is a significant and independent contributor to morbidity and mortality, yet therapy directed at ameliorating intraventricular clot has been limited. Conventional therapy centers on managing hypertension and intracranial pressure while correcting coagulopathy and avoiding complications such as rebleeding and hydrocephalus. Surgical therapy alone has not changed the natural history of the disease significantly. However, fibrinolysis in combination with extraventricular drainage shows promise as a technique to reduce intraventricular clot volume and to manage the concomitant complications of IVH.

Hypertonic Saline and Mannitol Therapy in Critical Care Neurology

Osmotic agents play a vital role in the reduction of elevated intracranial pressure and treatment of cerebral edema in Neurologic critical care. Both mannitol and hypertonic saline reduce cerebral edema in many clinical syndromes, yet there is controversy over agent selection, timing, and dosing regimens. Despite the lack of randomized, controlled trials, our knowledge base on the appropriate clinical use of osmotic agents continues to expand. This review will summarize the evidence for the use of mannitol and hypertonic saline in a variety of disease states causing cerebral edema, as well as outlining monitoring and safety considerations.

Autonomic dysfunction syndromes after acute brain injury

The central autonomic nervous system (CAN) is a multifaceted, richly connected neural network incorporating the hypothalamus, its descending tracts through the brainstem, the insular cortex and down into the spinal cord. All levels of the CAN are susceptible to injury following traumatic brain injury (TBI), whether from focal or diffuse injury. Focal injuries would be expected to produce localized damage to CAN control centers, whereas the effects of diffuse injuries are presumed to be more diverse and/or widely distributed. As the combination of focal and diffuse injury following TBI can vary widely from one individual to the next, the impact of focal injuries is best understood with reference to the focal ischemic stroke literature. Subarachnoid hemorrhage (SAH), a common complication following TBI, also has predictable effects on autonomic control that can be understood with reference to spontaneous SAH literature. Finally, paroxysmal sympathetic hyperactivity (PSH), a syndrome incorporating episodes of heightened sympathetic drive and motor overactivity following minor stimulation, is discussed as an example of what happens when central inhibitory control of spinal cord autonomics is impaired.

Anti-NMDA receptor encephalitis with paroxysmal sympathetic hyperactivity: an under-recognized association?

A 31-year-old woman had a generalized tonic–clonic seizure and then developed progressively worsening neuropsychiatric symptoms, including mania, hallucinations, echolalia, and suicidal ideation. She was previously healthy; she did not have any known medical or psychiatric disease. She was not on any medications prior to presentation. She was initially admitted to a psychiatric unit but was transferred to a medical ward after one week of psychiatric treatment, as her symptoms worsened despite anti-psychotic medications. Neurologic examination was notable for catatonia that progressed to coma. She was intubated and mechanically ventilated due to apnea. Brain magnetic resonance imaging (MRI) was normal. Electroencepahlography (EEG) revealed right hemispheric rhythmic slowing with episodic suppression, suggesting non-convulsive status epilepticus. The patient was then transferred to our hospital for further evaluation. Lumbar puncture was notable for lymphocytic pleocytosis (white blood cell count =115), negative viral polymerase chain reactions (PCR). AntiNMDA receptor antibodies were detected in the serum and cerebrospinal fluid (CSF). An oophorectomy was performed and this revealed a benign adenoma. Patient was treated with high-dose cortiosteroids, plasma exchange, and finally rituximab. Over six weeks the patient’s condition slowly improved and she was discharged to home awake, conversant and ambulating with assistance. One week after symptom onset, the patient experienced intermittent episodes of sinus tachycardia, hypertension, tachypnea, diaphoresis and extensor posturing. During a typical episode, which could last for 20–120 min and occurred as often as three times per day, her heart rates were 100–125 beats/minute, blood pressures 160–180/ 80–100 mmHg, and respiratory rates 20–25 breaths/minute (Fig. 1). For comparison, the patient’s basal vital signs are heart rates 80–90 beats/minute, blood pressures 100–120/ 60–80 mmHg, and respiratory rates 16–20 breaths/minute. During these episodes, there was no electrographic correlate on EEG. The episodes were both spontaneous and stimulus responsive (for example, during endotracheal suctioning). The episodes, consistent with PSH, were initially treated with dexmedetomidine, which was titrated to a maximum dose of 1.0 mcg/kg/hr for 7 days. The episodes were recognized as PSH and initially treated about six days into the patient’s hospital course. She was already had already received a full course of corticosteroids and was receiving plasma exchange at this time. Gabapentin and H. E. Hinson (&) C. Takahashi G. Altowaijri D. Bourdette Department of Neurology and Neurocritical Care, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, CR-127, Portland, OR 97239, USA e-mail: hinson@ohsu.edu

Neuroanatomical basis of paroxysmal sympathetic hyperactivity: a diffusion tensor imaging analysis

Abstract Primary objective: Paroxysmal sympathetic hyperactivity (PSH) is observed in a sub-set of patients with moderate-to-severe traumatic brain injury (TBI). The neuroanatomical basis of PSH is poorly understood. It is hypothesized that PSH is linked to changes in connectivity within the central autonomic network. Research design: Retrospective analysis in a sub-set of patients from a multi-centre, prospective cohort study Methods and procedures: Adult patients who were <3 weeks after severe TBI were enrolled and screened for PSH using a standard definition. Patients underwent multimodal MRI, which included quantitative diffusion tensor imaging. Main outcomes and results: Principal component analysis (PCA) was used to resolve the set of tracts into components. Ability to predict PSH was evaluated via area under the receiver operating characteristic (AUROC) and tree-based classification analyses. Among 102 enrolled patients, 16 met criteria for PSH. The first principle component was significantly associated (p = 0.024, AUROC = 0.867) with PSH status even after controlling for age and admission GCS. In a classification tree analysis, age, GCS and decreased FA in the splenium of the corpus callosum and in the right posterior limb of the internal capsule discriminated PSH vs no PSH with an AUROC of 0.933. Conclusions: Disconnection involving the posterior corpus callosum and of the posterior limb of the internal capsule may play a role in the pathogenesis or expression of PSH.

Paroxysmal sympathetic hyperactivity in hemispheric intraparenchymal hemorrhage.

Paroxysmal sympathetic hyperactivity (PSH) is a hyperadrenergic syndrome that may follow acute brain injury characterized by episodic, hyperadrenergic alterations in vital signs. Identifying commonality in lesion localization in patients with PSH is challenging, but intraparenchymal hemorrhage (IPH) represents a focal injury that might provide insight. We describe a series of patients with IPH that developed PSH, and review the literature.

Antithrombotic therapy and outcomes of cervical arterial dissection in the trauma patient: a case series

BackgroundThe use of antithrombotic therapy (anticoagulants and/or antiplatelets) in the setting of traumatic cervical arterial dissection (CAD) for the prevention of stroke remains controversial. This issue is further complicated by the frequent co-existence of intracranial hemorrhage (ICH) and other intracranial injuries, and also the wide variability in treatment due to a lack of evidence-based guidance. To address these controversies, a registry in a major Level I trauma center was created. The purpose of this investigation was to compare the safety of antithrombotic therapy in post-traumatic CAD. Analysis from the first year is presented.MethodsAll cervical dissections from the year 2005 were identified in patients at least 18 years of age by diagnosis code from radiology and trauma databases. Presence of arterial injury and grade, and other intracranial disease or injury such as stroke was diagnosed by a trauma radiologist and adjudicated by a neuroradiologist.ResultsFifty-five patients with cervical artery dissection were identified. Fourteen patients presented with a total of 20 acute, post-traumatic intracranial hemorrhages (ICH). Seven of the 14 patients with ICH were treated with antithrombotic therapy, and none extended their intracranial hemorrhages. Of the 41 patients without pre-existing ICH, 28 were treated with antithrombotic therapy and only one developed an interval hematoma. Among all 55 cases, two patients developed an acute ischemic stroke in the territory of the dissected artery after admission; both patients were in the untreated group.ConclusionIn so far as antithrombotic therapy may offer benefit in preventing early ischemic stroke following cervical artery dissection, these data suggest withholding antiplatelet or other antithrombotics following trauma may not be warranted, even in the setting of intracranial hemorrhage. From a safety perspective, this registry-based case series indicates antithrombotic management of arterial injury did not contribute to development or progression of ICH, even in patients with pre-existing ICH. This data suggest that instituting early antithrombotic therapy presents a low risk of ICH or hemorrhage extension among traumatic cervical dissection patients.