Eric M. Bershad

Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature

Warfarin-related intracranial hemorrhage carries a high mortality and poor neurological outcome. Rapid reversal of coagulopathy is a cornerstone of medical therapy to halt bleeding progression; however the optimal approach remains undefined. Prothrombin complex concentrates have promising features that may rapidly reverse coagulopathy, but remain relatively unstudied. We aim to review the literature regarding the use of prothrombin complex concentrates in patients with warfarin-related intracranial hemorrhage. A comprehensive review of the literature was conducted using PUBMED and Google Scholar databases to identify the use of PCC in patients with warfarin-related intracranial hemorrhage. The characteristics abstracted included the type of PCC, dosing, study design, type of intracranial hemorrhage, changes in the INR, and adverse effects. Prothrombin complex concentrates are heterogenous in regards to factor concentration. PCC consistently reversed the INR in patients with intracranial hemorrhage. There is some evidence that PCC may reverse the INR more rapidly compared to fresh frozen plasma. Serious adverse effects were uncommon and included mainly thromboembolism. PCC has features which make it a promising therapy for patients with warfarin-related intracranial hemorrhage, and deserves more rigorous study in prospective-randomized controlled trials.

Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia.

The ability of gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DTPA) enhanced MRI to localize and quantitate blood–brain barrier (BBB) opening was evaluated against quantitative autoradiographic (QAR) imaging of 14C‐α‐aminoisobutyric acid (AIB) distribution. The blood‐to‐brain transfer constant (Ki) for Gd‐DTPA was determined by MRI in rats after 3 h of focal cerebral ischemia plus 2.5 h of reperfusion (n = 9), and that of AIB was determined by QAR shortly thereafter. Tissue regions of interest (ROIs) for Gd‐DTPA leakage were identified by ISODATA segmentation of pre‐ and post‐Gd‐DTPA Look–Locker (L‐L) T1 maps. Patlak plots were constructed using time course of blood and tissue T1 changes induced by Gd for estimating Ki. Among the nine rats, 14 sizable regions of AIB uptake were found; 13 were also identified by ISODATA segmentation. Although the 13 MRI‐ROIs spatially approximated those of AIB uptake, the segmentation sometimes missed small areas of lesser AIB uptake that did not extend through more than 60% of the 2.0‐mm‐thick slice. Mean Kis of AIB were highly correlated with those of Gd‐DTPA across the 13 regions; the group means (±SD) were similar for the two tracers (7.1 ± 3.3 × 10−3 and 6.8 ± 3.5 × 10−3 ml.g−1 · min−1, respectively). In most instances, Gd‐DTPA MRI accurately localized areas of BBB opening. Magn Reson Med, 2005.

The SILK flow diverter in the treatment of intracranial aneurysms

The SILK flow diverter (SFD; Balt Extrusion, Montmorency, France) is a flow diverting stent used in the endovascular treatment of intracranial aneurysms. It works on the principle of redirecting flow away from the aneurysm sac, leading to occlusion over time. We present a systematic review on the clinical outcomes and complications of the SFD. A literature search for English language articles were conducted on PubMed, Medline and EMBASE for articles on the treatment of intracranial aneurysms with the SILK flow diverter. The inclusion criteria were n>10, use of SFD only, data on complications and aneurysm occlusion rate (AOR). Eight studies with 285 patients and 317 intracranial aneurysms were included. The mean age was 52.7 years and nearly 80% were women. In terms of angiographic distribution, 86.8% of aneurysms were located in the anterior circulation and 13.2% in the posterior circulation. As for the aneurysm size, 37.9% were classed as small, 44.4% as large and 17.7% as giant. Ischemic complications and parent artery occlusion each occurred in 10% of patients. Aneurysm rupture rate was 3.5%, while the cumulative mortality was 4.9%. The main outcome measure, 12 month AOR, was 81.8% with complete occlusion in 216 out of 264 aneurysms. Use of flow diverters for the treatment of intracranial aneurysm with complex morphologies has gained in popularity over the last few years. Our review suggests that SFD achieves comparable AOR to its contemporary, the Pipeline Embolization Device (ev3 Endovascular, Plymouth, MN, USA) but has a higher rate of higher rate of ischemic complications, aneurysm rupture and mortality.

Coagulopathy and inhospital deaths in patients with acute subdural hematoma: Clinical article

OBJECT Acute subdural hematoma (SDH) is one of the most lethal forms of intracranial injury; several risk factors predictive of a worse outcome have been identified. Emerging research suggests that patients with coagulopathy and intracerebral hemorrhage have a worse outcome than patients without coagulopathy but with intracerebral hemorrhage. The authors sought to determine if such a relationship exists for patients with acute SDH. METHODS The authors conducted a retrospective analysis of consecutive patients admitted to a neurosciences intensive care unit with acute SDH over a 4-year period (January 1997-December 2001). Demographic data, laboratory values, admission source, prior functional status, medical comorbidities, treatments received, and discharge disposition were recorded, as were scores on the Acute Physiology, Age, and Chronic Health Evaluation III (APACHE III). Coagulopathy was defined as an internal normalized ratio>1.2 or a prothrombin time>or=12.7 seconds. Univariate and multivariate analyses were performed on 244 patients to determine factors associated with worse short-term outcomes. RESULTS The authors identified 248 patients with acute SDH admitted to the neurointensive care unit during the study period, of which 244 had complete data. Most were male (61%), and the mean age of the study population was 71.3+/-15 years (range 20-95 years). Fifty-three patients (22%) had coagulopathy. The median APACHE III score was 43 (range 11-119). Twenty-nine patients (12%) died in the hospital. Independent predictors of inhospital death included APACHE III score (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.4-13.4, p=0.011) and coagulopathy (OR 2.7, 95% CI 1.1-7.1, p=0.037). Surgical evacuation of acute SDH was associated with reduced inhospital deaths (OR 0.2, 95% CI 0.1-0.6, p=0.003). CONCLUSIONS Coagulopathy is independently associated with inhospital death in patients with acute SDH. Time to treatment to correct coagulopathy using fresh frozen plasma and/or vitamin K was prolonged.

Therapeutic Hypothermia in Stroke and Traumatic Brain Injury

Therapeutic hypothermia (TH) is considered to improve survival with favorable neurological outcome in the case of global cerebral ischemia after cardiac arrest and perinatal asphyxia. The efficacy of hypothermia in acute ischemic stroke (AIS) and traumatic brain injury (TBI), however, is not well studied. Induction of TH typically requires a multimodal approach, including the use of both pharmacological agents and physical techniques. To date, clinical outcomes for patients with either AIS or TBI who received TH have yielded conflicting results; thus, no adequate therapeutic consensus has been reached. Nevertheless, it seems that by determining optimal TH parameters and also appropriate applications, cooling therapy still has the potential to become a valuable neuroprotective intervention. Among the various methods for hypothermia induction, intravascular cooling (IVC) may have the most promise in the awake patient in terms of clinical outcomes. Currently, the IVC method has the capability of more rapid target temperature attainment and more precise control of temperature. However, this technique requires expertise in endovascular surgery that can preclude its application in the field and/or in most emergency settings. It is very likely that combining neuroprotective strategies will yield better outcomes than utilizing a single approach.

Myasthenia gravis crisis.

Myasthenia gravis (MG) is an autoimmune disorder resulting from the production of antibodies against acetylcholine receptors leading to the destruction of the postsynaptic membrane at the neuromuscular junction. In the US there are about 18,000 people with MG. Myasthenia gravis crisis (MGC) is defined as any MG exacerbation necessitating mechanical ventilation. Most patients presenting with MGC have an identifiable risk factor. The diagnosis of MGC should be suspected in all patients with respiratory failure, particularly those with unclear etiology. Acute management of MGC requires supportive general and ventilatory therapy and institution of measures to improve the neuromuscular blockade. The latter includes plasma exchange or IV immunoglobulin, and removal of the offending trigger. The outcome of patients with MGC has improved significantly and the current mortality rate is about 4 to 8%.

Neurogenic Stunned Myocardium Following Acute Subarachnoid Hemorrhage Pathophysiology and Practical Considerations

Neurogenic stunned myocardium (NSM) is a triad of transient left ventricular dysfunction, electrocardiogram changes, and elevation in cardiac enzymes, often mimicking a myocardial infarction. It has been described following acute brain injury. The purported mechanism is catecholamine excess resulting in cardiac dysfunction. From the clinical standpoint, the most frequently encountered electrocardiographic changes are QTc prolongation and ST-T changes, with modest elevations in troponin levels. Basal and mid-ventricular segments of the left ventricle are most commonly involved. NSM poses therapeutic challenges when it occurs secondary to aneurysmal subarachnoid hemorrhage, particularly in the setting of coexisting vasospasm. Overall, NSM carries good prognosis if recognized early, with appropriate management of hemodynamic and cardiopulmonary parameters.

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Pathologic changes in brain tissue during and after stroke may lead to injury of the blood–brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T1 and T2, and magnetization transfer (MT) related parameters (T1sat, Kfor and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n = 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd‐diethylenetriaminepentaacetic acid (Gd‐DTPA) by MRI and 14C‐α‐aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia‐injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T1sat in the caudate‐putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/contralateral T1sat ratio > 1.6 demarcates leakage of small molecules such as Gd‐DTPA and AIB across the BBB. As to clinical relevance, the quantitation of MT parameters in acute stroke may enable the early detection of areas of BBB opening and potential HT. Magn Reson Med, 2005.

Thrombolysis for Acute Ischemic Stroke in Patients With Cancer: A Population Study

Background and Purpose— The safety of thrombolysis for acute stroke in patients with cancer is not well established. Our aim is to study the outcomes after thrombolysis in patients with stroke with cancer. Methods— Patients with acute ischemic stroke who received thrombolysis were identified from the 2009 and 2010 Nationwide Inpatient Sample. Patients with cancer-associated strokes and noncancer strokes were compared based on demographics, comorbidities, and outcomes. Results— Of the 32 576 strokes treated with thrombolysis, cancer-associated strokes had significantly higher comorbidity indices overall, but fewer vascular risk factors than noncancer strokes. There was no difference in the rates of home discharge and in-hospital mortality, after adjusting for confounders. Subgroup analysis showed that compared with liquid cancers, patients with solid tumors had worse home discharge (odds ratio, 0.178; 95% confidence interval, 0.109–0.290; P<0.001) and higher in-hospital mortality (odds ratio, 3.018; 95% confidence interval, 1.37–6.646; P=0.006) after thrombolysis. Metastatic cancers had poorest outcomes, but intracerebral hemorrhage rates were similar. Conclusions— Thrombolytic therapy for acute stroke in patients with cancer is not associated with increased risk of intracerebral hemorrhage or in-hospital mortality. However, careful consideration of the cancer subtype may help delineate the subset of patients with poor response to thrombolysis. Prospective confirmation is warranted.

Marked olfactory impairment in idiopathic intracranial hypertension

Objective Many long-duration astronauts develop signs of elevated intracranial pressure and have neuro-ophthalmological findings similar to idiopathic intracranial hypertension (IIH) patients. Some also present with nasal congestion and subjective olfactory impairment. We prospectively evaluated olfactory function in IIH patients and the effect of 6° head-down tilt, which simulates the headward fluid shifting in microgravity, as spaceflight analogues. Design Olfaction was tested for all subjects in upright and 6° head-down tilt positions using two different measures: University of Pennsylvania Smell Identification Test and Olfactory Threshold Sniffin’ Sticks with phenylethyl alcohol. Results IIH patients (n=19) had significant impairment on both olfactory measures compared with matched controls (n=19). The olfactory threshold dilution levels were 9.07 (95% CI 1.85 to 5.81) and 3.83 (95% CI 7.04 to 11.10), p=0.001, and smell identification scores were 35.61 (95% CI 34.03 to 37.18) and 32.47 (95% CI 30.85 to 34.09), p=0.008, for control and IIH subjects, respectively. The threshold detection was mildly impaired in head-down tilt compared with upright position in the combined subjects (6.05 (95% CI 4.58 to 7.51) vs 6.85 (95% CI 5.43 to 8.27), p=0.004). Conclusions We demonstrated that IIH patients have marked impairment in olfactory threshold levels, out of proportion to smell identification impairment. There was also impairment in olfactory threshold in head-down tilt compared with upright positioning, but not for smell identification. The underlying mechanisms for olfactory threshold dysfunction in IIH patients need further exploration.