Karen G. Hirsch

Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21 CIP1/WAF1 induction rather than AKT inhibition

Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 μM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of ΔΨm), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB±LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21CIP1/WAF1; moreover, enforced expression of p21CIP1/WAF1 significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21CIP1/WAF1 induction.

Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia.

Objective:Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during postresuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy. Design:Prospective, balanced animal study. Setting:Basic physiology laboratory at an academic institution. Subjects:Eighty-four neonatal swine. Interventions:Piglets underwent hypoxic-asphyxic cardiac arrest or sham surgery and recovered for 2 hrs with normothermia followed by 4 hrs of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hrs postresuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared. Measurements and Main Results:Laser-Doppler flux was lower in postarrest animals compared to sham-operated controls during the 2-hr normothermic period after resuscitation. During the subsequent 4-hr recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and postarrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, postarrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to postarrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension. Conclusions:In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from noninvasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.

Clinical and Radiographic Natural History of Cervical Artery Dissections

BACKGROUND Cervical artery dissection (CADsx) is a common cause of stroke in young patients, but long-term clinical and radiographic follow-up from a large population is lacking. METHODS Epidemiologic data, treatment, recurrence, and other features were extracted from the records of all patients seen at our stroke center with confirmed CAD during a 15-year period. A subset of cases was examined to provide detailed information about vessel status. RESULTS In all, 177 patients (mean age 44.0 +/- 11.1 years) were identified, with the male patients being older than the female patients. Almost 60% of dissections were spontaneous, whereas the remainder involved some degree of head and/or neck trauma. More than 70% of patients were treated with anticoagulation. During follow-up (mean 18.2 months; 0-220 months) there were 15 cases (8.5%) of recurrent ischemic events, and two cases (1.1%) of a recurrent dissection. About half of recurrent stroke/transient ischemic attack events occurred within 2 weeks of presentation. There was no clear association between the choice of antithrombotic agent and recurrent ischemic events. Detailed analysis of imaging findings was performed in 51 cases. Some degree of recanalization was seen in 58.8% of patients overall, and was more frequent in women. The average time to total or near-total recanalization was 4.7 +/- 2.5 months. Patients with complete occlusions at presentation tended not to recanalize. CONCLUSIONS This large series from a single institution highlights many of the features of CAD. A relatively benign course with low recurrence rate is supported, independent of the type and duration of antithrombotic therapy.

Prognostic Value of A Qualitative Brain MRI Scoring System After Cardiac Arrest

To develop a qualitative brain magnetic resonance imaging (MRI) scoring system for comatose cardiac arrest patients that can be used in clinical practice.

Functional Neurologic Outcomes Change Over the First 6 Months After Cardiac Arrest.

Objectives:To determine the longitudinal changes in functional outcome and compare ordinal outcome scale assessments in comatose cardiac arrest survivors. Design:Prospective observational study of comatose cardiac arrest survivors. Subjects who survived to 1 month were included. Setting:Academic medical center ICU. Patients:Ninety-eight consecutive patients who remained comatose after resuscitation from cardiac arrest; 45 patients survived to 1 month. Interventions:None. Measurements and Main Results:Patients’ functional neurologic outcomes were assessed by phone call or in-person clinic visit at 1, 3, 6, and 12 months postcardiac arrest using the modified Rankin Scale, Glasgow Outcome Scale, and Barthel Index. A “good” outcome was defined as modified Rankin Scale 0–3, Barthel Index 70–100, and Glasgow Outcome Scale 4–5. Changes in dichotomized outcomes and shifts on each outcome scale were analyzed. The mean age of survivors was 51 ± 19 years and 18 (40%) were women. Five (19%) out of 26 patients with data available at all timepoints improved to good modified Rankin Scale outcome and none worsened to poor outcome between postarrest months 1 and 6 (p = 0.06). Thirteen patients (50%) improved on the modified Rankin Scale by 1–3 points and four (15%) worsened by 1–2 points between months 1 and 6 (overall improvement by 0.5 points; 95% CI, 0–1; p = 0.04). From postarrest months 6 to 12, there was no change in the number of patients with good versus poor outcomes. The modified Rankin Scale and Barthel Index were more sensitive to detecting changes in outcome than the Glasgow Outcome Scale. Conclusions:In initially comatose cardiac arrest survivors, improvements in functional status occur over the first 6 months after the event. There was no significant change in outcome between postarrest months 6 and 12. The modified Rankin Scale is a sensitive outcome scale in this population.

Prognostic Value of Quantitative Diffusion-Weighted MRI in Patients with Traumatic Brain Injury

Data about the predictive value of quantitative diffusion‐weighted MRI in traumatic brain injury (TBI) patients is lacking. This study aimed to determine if specific apparent diffusion coefficient (ADC) thresholds could be determined that correlate with outcome in moderate‐severe TBI.

An Update on Neurocritical Care for the Patient With Kidney Disease

Patients with kidney disease have increased rates of neurologic illness such as intracerebral hemorrhage and ischemic stroke. The acute care of patients with critical neurologic illness and concomitant kidney disease requires unique management considerations including attention to hyponatremia, renal replacement modalities in the setting of high intracranial pressure, reversal of coagulopathy, and seizure management to achieve good neurologic outcomes.

Management of brain injury after cardiac arrest

Cardiac arrest survivors are commonly admitted to an intensive care unit. Neurologic complications of cardiac arrest lead to significant morbidity in survivors. Advances in resuscitative efforts have led to an increase in the number of people who survive cardiac arrest, with a resultant increase in survivors suffering from postanoxic encephalopathy. The focus of resuscitation has shifted to emphasize interventions that restore adequate systemic circulation and those that will ameliorate brain injury after cardiac arrest resuscitation. Recent data about therapeutic hypothermia and other interventions have led to a shift in the role of the neurologist caring for these patients to promote more aggressive management of neurologic complications, including coma, encephalopathy, seizures and myoclonus, elevated intracranial pressure, and metabolic derangements. This chapter will review the neurologic complications of cardiac arrest and focus on the role of the neurologist in the management of such complications.

Practical Pearl: Use of MRI to Differentiate Pseudo-subarachnoid Hemorrhage from True Subarachnoid Hemorrhage

Introduction We present a case of pseudo-subarachnoid hemorrhage (pSAH) in a patient with renal insufficiency and undiagnosed meningitis who received multiple injections of iodinated contrast material. We highlight and review causes of pSAH as well as techniques to differentiate pSAH from true subarachnoid hemorrhage (SAH). Non-contrast-enhanced computed tomography (CT) is widely accepted as the radiographic standard for the diagnosis of acute SAH, as it boosts a sensitivity and specificity as high as 100% in the first 6 h after headache onset [1, 2]. While false-negative CT is often the clinical concern, false-positive CT findings for SAH also occur and are called pSAH [3]. An inappropriate diagnosis of SAH can lead to aggressive and invasive neurosurgical management, as acute SAH must be treated as ruptured intracranial aneurysm until vascular lesions are definitively excluded [4]. Magnetic resonance imaging (MRI) can be useful in the imaging of suspected SAH. Fluid-attenuated inversion recovery (FLAIR) and gradient echo (GRE) are two sequences which provide complementary information. FLAIR is a sequence in which simple fluid, such as cerebrospinal fluid (CSF), has its signal suppressed. Anything that alters the composition of the CSF, including blood, pus, hypercellularity, and elevated protein, can cause high signal in the basal cisterns, sulci, and/or ventricles [5]. Gadolinium contrast leaking into the subarachnoid space from abnormal blood vessels or inflamed leptomeninges can also increase subarachnoid signal on FLAIR. FLAIR is therefore sensitive but not specific for the diagnosis of SAH. GRE is a sequence that is sensitive to disturbances in the homogeneity of the magnetic field (i.e., “magnetic susceptibility”). Blood contains paramagnetic substances that alter the homogeneity of the magnetic field, so the presence of blood products such as deoxyhemoglobin leads to low signal intensity on GRE [6]. For both FLAIR and GRE, however, the amount or concentration of blood is a relevant consideration, as very small amounts of blood in the CSF may not be detectable [7].

The neuron specific enolase (NSE) ratio offers benefits over absolute value thresholds in post-cardiac arrest coma prognosis

INTRODUCTION Serum neuron-specific enolase (NSE) levels have been shown to correlate with neurologic outcome in comatose survivors of cardiac arrest but use of absolute NSE thresholds is limited. This study describes and evaluates a novel approach to analyzing NSE, the NSE ratio, and evaluates the prognostic utility of NSE absolute value thresholds and trends over time. METHODS 100 consecutive adult comatose cardiac arrest survivors were prospectively enrolled. NSE levels were assessed at 24, 48, and 72 h post-arrest. Primary outcome was the Glasgow Outcome Score (GOS) at 6 months post-arrest; good outcome was defined as GOS 3-5. Absolute and relative NSE values (i.e. the NSE ratio), peak values, and the trend in NSE over 72 h were analyzed. RESULTS 98 patients were included. 42 (43%) had a good outcome. Five good outcome patients had peak NSE >33 µg/L (34.9-46.4 µg/L). NSE trends between 24 and 48 h differed between outcome groups (decrease by 3.0 µg/L (0.9-7.0 µg/L) vs. increase by 13.4 µg/L (-3.7 to 69.4 µg/L), good vs. poor, p = 0.004). The 48:24 h NSE ratio differed between the good and poor outcome groups (0.8 (0.6-0.9) vs. 1.4 (0.8-2.5), p = 0.001), and a 48:24 h ratio of ≥1.7 was 100% specific for poor outcome. CONCLUSIONS The NSE ratio is a unique method to quantify NSE changes over time. Values greater than 1.0 indicate increasing NSE and may be reflective of ongoing neuronal injury. The NSE ratio obviates the need for an absolute value cut-off.