Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial.

INTRODUCTION: Patients with unknown stroke onset are generally excluded from acute recanalisation treatments. We designed a pilot study to assess feasibility of a trial of perfusion computed tomography (PCT)-guided thrombolysis in patients with ischemic tissue at risk of infarction and unknown stroke onset. METHODS: Patients with a supratentorial stroke of unknown onset in the middle cerebral artery territory and significant volume of at-risk tissue on PCT were randomized to intravenous thrombolysis with alteplase (0.9 mg/kg) or placebo. Feasibility endpoints were randomization and blinded treatment of patients within 2 h after hospital arrival, and the correct application (estimation) of the perfusion imaging criteria. RESULTS: At baseline, there was a trend towards older age [69.5 (57-78) vs. 49 (44-78) years] in the thrombolysis group (n = 6) compared to placebo (n = 6). Regarding feasibility, hospital arrival to treatment delay was above the allowed 2 h in three patients (25%). There were two protocol violations (17%) regarding PCT, both underestimating the predicted infarct in patients randomized in the placebo group. No symptomatic hemorrhage or death occurred during the first 7 days. Three of the four (75%) and one of the five (20%) patients were recanalized in the thrombolysis and placebo group respectively. The volume of non-infarcted at-risk tissue was 84 (44-206) cm(3) in the treatment arm and 29 (8-105) cm(3) in the placebo arm. CONCLUSIONS: This pilot study shows that a randomized PCT-guided thrombolysis trial in patients with stroke of unknown onset may be feasible if issues such as treatment delays and reliable identification of tissue at risk of infarction tissue are resolved. Safety and efficiency of such an approach need to be established.

Impact of an intervention to control risk associated with patient transfer.

QUESTION UNDER STUDY: Hospitals transferring patients retain responsibility until admission to the new health care facility. We define safe transfer conditions, based on appropriate risk assessment, and evaluate the impact of this strategy as implemented at our institution. METHODS: An algorithm defining transfer categories according to destination, equipment monitoring, and medication was developed and tested prospectively over 6 months. Conformity with algorithm criteria was assessed for every transfer and transfer category. After introduction of a transfer coordination centre with transfer nurses, the algorithm was implemented and the same survey was carried out over 1 year. RESULTS: Over the whole study period, the number of transfers increased by 40%, chiefly by ambulance from the emergency department to other hospitals and private clinics. Transfers to rehabilitation centres and nursing homes were reassigned to conventional vehicles. The percentage of patients requiring equipment during transfer, such as an intravenous line, decreased from 34% to 15%, while oxygen or i.v. drug requirement remained stable. The percentage of transfers considered below theoretical safety decreased from 6% to 4%, while 20% of transfers were considered safer than necessary. A substantial number of planned transfers could be "downgraded" by mutual agreement to a lower degree of supervision, and the system was stable on a short-term basis. CONCLUSION: A coordinated transfer system based on an algorithm determining transfer categories, developed on the basis of simple but valid medical and nursing criteria, reduced unnecessary ambulance transfers and treatment during transfer, and increased adequate supervision.

Neurally adjusted ventilatory assist (NAVA) improves patient-ventilator interaction during non-invasive ventilation delivered by face mask.

PURPOSE: To determine if, compared to pressure support (PS), neurally adjusted ventilatory assist (NAVA) reduces patient-ventilator asynchrony in intensive care patients undergoing noninvasive ventilation with an oronasal face mask. METHODS: In this prospective interventional study we compared patient-ventilator synchrony between PS (with ventilator settings determined by the clinician) and NAVA (with the level set so as to obtain the same maximal airway pressure as in PS). Two 20-min recordings of airway pressure, flow and electrical activity of the diaphragm during PS and NAVA were acquired in a randomized order. Trigger delay (T(d)), the patient's neural inspiratory time (T(in)), ventilator pressurization duration (T(iv)), inspiratory time in excess (T(iex)), number of asynchrony events per minute and asynchrony index (AI) were determined. RESULTS: The study included 13 patients, six with COPD, and two with mixed pulmonary disease. T(d) was reduced with NAVA: median 35 ms (IQR 31-53 ms) versus 181 ms (122-208 ms); p = 0.0002. NAVA reduced both premature and delayed cyclings in the majority of patients, but not the median T(iex) value. The total number of asynchrony events tended to be reduced with NAVA: 1.0 events/min (0.5-3.1 events/min) versus 4.4 events/min (0.9-12.1 events/min); p = 0.08. AI was lower with NAVA: 4.9 % (2.5-10.5 %) versus 15.8 % (5.5-49.6 %); p = 0.03. During NAVA, there were no ineffective efforts, or late or premature cyclings. PaO(2) and PaCO(2) were not different between ventilatory modes. CONCLUSION: Compared to PS, NAVA improved patient ventilator synchrony during noninvasive ventilation by reducing T(d) and AI. Moreover, with NAVA, ineffective efforts, and late and premature cyclings were absent.

Early occurrence of lung adenocarcinoma and breast cancer after radiotherapy of a chest wall sarcoma in a patient with a de novo germline mutation in TP53.

We report a 26-year-old female patient who was diagnosed within 4 years with chest sarcoma, lung adenocarcinoma, and breast cancer. While her family history was unremarkable, DNA sequencing of TP53 revealed a germline de novo non-sense mutation in exon 6 p.Arg213X. One year later, she further developed a contralateral ductal carcinoma in situ, and 18 months later a jaw osteosarcoma. This case illustrates the therapeutic pitfalls in the care of a young cancer patient with TP53 de novo germline mutations and the complications related to her first-line therapy. Suggestion is made to use the less stringent Chompret criteria for germline TP53 mutation screening. Our observation underlines the possibly negative effect of radiotherapy in generating second tumors in patients with a TP53 mutation. We also present a review of six previously reported cases, comparing their cancer phenotypes with those generally produced by TP53 mutations.

Standardization of Stroke Perfusion CT for Reperfusion Therapy

With the advances in terms of perfusion imaging, the "time is brain" approach used for acute reperfusion therapy in ischemic stroke patients is slowly being replaced by a "penumbra is brain" or "imaging is brain" approach. But the concept of penumbra-guided reperfusion therapy has not been validated. The lack of standardization in penumbral imaging is one of the main contributing factors for this absence of validation. This article reviews the issues underlying the lack of standardization of perfusion-CT for penumbra imaging, and offers avenues to remedy this situation

Late outcome of spinal cord stimulation for unreconstructable and limb-threatening lower limb ischemia.

OBJECTIVES: To determine whether the initial benefits of spinal cord stimulation (SCS) treatment for critical limb ischemia (CLI) persist over years. DESIGN: Analysis of data prospectively collected for every CLI patient receiving permanent SCS. Follow-up range 12 to 98 months (mean 46+/-23, median 50 months). POPULATION: 87 patients (28% stage III, 72%stage IV) with unreconstructable CLI due (83%) or not (17%) to atherosclerosis and with an initial sitting/supine transcutaneous pO2 gradient >15 mmHg. METHODS: Assessment of actuarial patient survival (PS), limb salvage (LS) and amputation-free patient survival (AFPS). Analysis of the impact of 15 risk factors on long-term outcomes using the Fischer's exact test for categorical variables and the t test for continuous variables. RESULTS: Follow-up was complete for patient and limb survival. A single non-atherosclerotic patient died during follow-up. Among atherosclerotic patients PS decreased from 88% at 1y, to 76% at 3y, 64% at 5y and 57% at 7y. LS reached 84% at 1y, 78% at 2y, 75% at 3y and remained stable thereafter. Diabetes was found to affect LS (p<0.05) and heart disease to reduce PS (p<0.01). AFPS was reduced in heart patients (p<0.01), diabetics (p<0.05) and in patients with previous stroke (p<0.05). CONCLUSIONS: In CLI patients the beneficial effects of SCS persist far beyond the first year of treatment and major amputation becomes infrequent after the second year.

Perfusion ct based thrombolysis in acute ischaemic stroke

Background Despite use in clinical practice and trials of thrombolysis, a non-contrast CT is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how it compares with physiological imaging using CT perfusion.Methods 40 imaging datasets with non-contrast CT (NCCT) and perfusion CT (CTP) were retrospectively identified. 2 sets of observers (n¼6) and a neuroradiologist made a blind evaluation of the images. Inter-observer agreement was calculated for identifying ischaemic change on NCCT, and abnormalities on cerebral blood flow, time to peak and cerebral blood volume maps. A prospective cohort of 73 patients with anterior circulation cortical strokes were thrombolysed based on qualitative assessment of penumbral tissue on CTP within 3 h of stroke onset. Functional outcome was assessed at 3 months.Results Inter-rater agreement was moderate (k¼0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for deficit in cerebral blood volume (k¼0.67) and almost perfect for time to peak and cerebral blood flow (both k¼0.87). In the prospective arm, 58.9% of patients with cortical strokes were thrombolysed. There was no significant difference in attainment of complete recovery (p¼0.184) between the thrombolysed and nonthrombolysed group.Conclusions We demonstrate how perfusion CT aids clinical decision- making in acute stroke. Good functional outcomes from thrombolysis can be safely achieved using this physiologically informed approach.

Le syndrome hépatorénal chez le patient cirrhotique [Hepatorenal syndrome in patients with liver cirrhosis].

Hepatorenal syndrome is a particular form of functional renal failure which may develop in patients with liver cirrhosis. On a clinical standpoint, precise diagnostic criteria have been established to clearly define this entity, whereas recent advances in the understanding of the biology of vasoactive mediators and the physiology of microcirculation have allowed to better anticipate its pathophysiological mechanisms. During the course of cirrhosis, sinusoidal portal hypertension leads to splanchnic and systemic vasodilation, responsible for a reduction of effective arterial blood volume. As a result, a state of intense renal vasoconstriction develops, leading to renal failure in the absence of any organic renal disease. At this stage, liver transplantation is the only definitive therapy able to reverse renal dysfunction. In recent years, innovative therapies have shown promise to prolong survival in patients with hepatorenal syndrome, including the administration of analogs of vasopressin (mainly terlipressin), the insertion of transjugular intrahepatic portosystemic shunts and the use of novel techniques of dialysis. On a preventive viewpoint, several simple measures have been shown to reduce the risk of hepatorenal syndrome in cirrhotic patients, including the appropriate use of diuretics, the avoidance of nephrotoxic drugs, the prophylaxis of spontaneous bacterial peritonitis and optimal fluid management in patients undergoing large volume paracentesis.

Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.

BACKGROUND: Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. METHODS: We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. RESULTS: In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. CONCLUSIONS: This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus.

Efavirenz in an obese HIV-infected patient - a report and an in vitro-in vivo extrapolation model indicate risk of underdosing.

Here, we report suboptimal efavirenz exposure in an obese patient treated with the standard 600 mg dose. Tripling the dose allowed attainment of therapeutic efavirenz concentrations. We developed an in vitro-in vivo extrapolation model to quantify dose requirements in obese individuals. Obesity represents a risk factor for antiretroviral therapy underdosing.

The effect of thrombolysis on short-term improvement depends on initial stroke severity.

A large number of parameters have been identified as predictors of early outcome in patients with acute ischemic stroke. In the present work we analyzed a wide range of demographic, metabolic, physiological, clinical, laboratory and neuroimaging parameters in a large population of consecutive patients with acute ischemic stroke with the aim of identifying independent predictors of the early clinical course. We used prospectively collected data from the Acute Stroke Registry and Analysis of Lausanne. All consecutive patients with ischemic stroke admitted to our stroke unit and/or intensive care unit between 1 January 2003 and 12 December 2008 within 24 h after last-well time were analyzed. Univariate and multivariate analyses were performed to identify significant associations with the National Institute of Health Stroke Scale (NIHSS) score at admission and 24 h later. We also sought any interactions between the identified predictors. Of the 1,730 consecutive patients with acute ischemic stroke who were included in the analysis, 260 (15.0%) were thrombolyzed (mostly intravenously) within the recommended time window. In multivariate analysis, the NIHSS score at 24 h after admission was associated with the NIHSS score at admission (β = 1, p < 0.001), initial glucose level (β = 0.05, p < 0.002) and thrombolytic intervention (β = -2.91, p < 0.001). There was a significant interaction between thrombolysis and the NIHSS score at admission (p < 0.001), indicating that the short-term effect of thrombolysis decreases with increasing initial stroke severity. Thrombolytic treatment, lower initial glucose level and lower initial stroke severity predict a favorable early clinical course. The short-term effect of thrombolysis appears mainly in minor and moderate strokes, and decreases with increasing initial stroke severity.

Safety and feasibility of NeuroFlo use in eight- to 24-hour ischemic stroke patients.

BACKGROUND: Acute treatment of ischemic stroke patients presenting more than eight-hours after symptom onset remains limited and largely unproven. Partial aortic occlusion using the NeuroFlo catheter can augment cerebral perfusion in animals. We investigated the safety and feasibility of employing this novel catheter to treat ischemic stroke patients eight-hours to 24 h following symptom onset. METHODS: A multicenter, single-arm trial enrolled ischemic stroke patients at nine international academic medical centers. Eligibility included age 18-85 years old, National Institutes of Health stroke scale (NIHSS) score between four and 20, within eight-hours to 24 h after symptom onset, and perfusion-diffusion mismatch confirmed by magnetic resonance imaging. The primary outcome was all adverse events occurring from baseline to 30 days posttreatment. Secondary outcomes included stroke severity on neurological indices through 90 days. This study is registered with ClinicalTrials.gov, number NCT00436592. RESULTS: A total of 26 patients were enrolled. Of these, 25 received treatment (one excluded due to aortic morphology); five (20%) died. Favorable neurological outcome at 90 days (modified Rankin score 0-2 vs. 3-6) was associated with lower baseline NIHSS (P < 0·001) and with longer duration from symptom discovery to treatment. There were no symptomatic intracranial hemorrhages or parenchymal hematomas. Asymptomatic intracranial hemorrhage was visible on computed tomography in 32% and only on microbleed in another 20%. CONCLUSIONS: Partial aortic occlusion using the NeuroFlo catheter, a novel collateral therapeutic strategy, appears safe and feasible in stroke patients eight-hours to 24 h after symptom onset.

REDUCTION OF MIGRAINES AFTER TREATMENT OF HEREDITARYHEMORRHAGIC TELANGIECTASIA (HHT)

Background: Pulmonary arteriovenous malformations (PAVMs) due to hereditaryhemorrhagic telangiectases (HHT) is associated with paradoxical strokes, brainabcesses, and increased prevalence of migraines. We report a patient in whom wefound a relationship between PAMVs and a reduction in frequency of migrainewith aura after the treatment of the first pulmonary malformation.Patient and methods: A 67-year-old woman developed migraine with visual auraand major epistaxis during childhood. A PAVM is discovered and surgically removedin 1969. Migraines nearly disappeared during several years, after which theystarted to reappear progressively. A HHT syndrome is diagnosed based on recurrentepistaxis, the development of cutaneous telangiectases and a positive family history.She suffered a left subcortical stroke in 2008. Perfusion CT, chest radiography,thoracic CT-angiography, contrast echocardiography, contrast transcranial Dopplerand cerebral MRI were performed.Results: Perfusion CT showed previous asymptomatic strokes in cerebellum andbasal ganglia. 4 PAMVs were confirmed on the chest x-ray whose structural conformationis identified on thoracic CT. Contrast echocardiography and transcranialDoppler showed a massive right to left shunt. It is planned to embolize the 4PAVMs, and migraine frequency will now be prospectively assessed.Conclusion: This patient with a pulmonary arteriovenous malformation showeda reduced migraine frequency after resection of her lung lesion. This suggests acausal relationship between a right to left shunt and migraine, as discussed inpatients with patent foramen ovale.