PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND AND PURPOSE: Subfebrile body temperature and fever in the first days after stroke are strongly associated with unfavorable outcome. A subgroup analysis of a previous trial suggested that early treatment with paracetamol may improve functional outcome in patients with acute stroke and a body temperature of ≥36.5°C. In the present trial, we aimed to confirm this finding. METHODS: PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2) was a multicenter, randomized, double-blind, placebo-controlled clinical trial. We aimed to include 1500 patients with acute ischemic stroke or intracerebral hemorrhage within 12 hours of symptom onset. Patients were treated with paracetamol in a daily dose of 6 g or matching placebo for 3 consecutive days. The primary outcome was functional outcome at 3 months, assessed with the modified Rankin Scale and analyzed with multivariable ordinal logistic regression. Because of slow recruitment and lack of funding, the study was stopped prematurely. RESULTS: Between December 2011 and October 2015, we included 256 patients, of whom 136 (53%) were allocated to paracetamol. In this small sample, paracetamol had no effect on functional outcome (adjusted common odds ratio, 1.15; 95% confidence interval, 0.74-1.79). There was no difference in the number of serious adverse events (paracetamol n=35 [26%] versus placebo n=28 [24%]). CONCLUSIONS: Treatment with high-dose paracetamol seemed to be safe. The effect of high-dose paracetamol on functional outcome remains uncertain. Therefore, a large trial of early treatment with high-dose paracetamol is still needed. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR2365.

Phase-based vascular input function: Improved quantitative DCE-MRI of atherosclerotic plaques.

PURPOSE: Quantitative pharmacokinetic modeling of dynamic contrast-enhanced (DCE)-MRI can be used to assess atherosclerotic plaque microvasculature, which is an important marker of plaque vulnerability. Purpose of the present study was (1) to compare magnitude- versus phase-based vascular input functions (m-VIF vs ph-VIF) used in pharmacokinetic modeling and (2) to perform model calculations and flow phantom experiments to gain more insight into the differences between m-VIF and ph-VIF. METHODS: Population averaged m-VIF and ph-VIFs were acquired from 11 patients with carotid plaques and used for pharmacokinetic analysis in another 17 patients. Simulations, using the Bloch equations and the MRI scan geometry, and flow phantom experiments were performed to determine the effect of local blood velocity on the magnitude and phase signal enhancement. RESULTS: Simulations and flow phantom experiments revealed that flow within the lumen can lead to severe underestimation of m-VIF, while this is not the case for the ph-VIF. In line, the peak concentration of the m-VIF is significantly lower than ph-VIF (p < 0.001), in vivo. Quantitative model parameters for m- and ph-VIF differed in absolute values but were moderate to strongly correlated with each other [K(trans) Spearman's ρ > 0.93 (p < 0.001) and vp Spearman's ρ > 0.58 (p < 0.05)]. CONCLUSIONS: m-VIF is strongly influenced by local blood velocity, which leads to underestimation of the contrast medium concentration. Therefore, it is advised to use ph-VIF for DCE-MRI analysis of carotid plaques for accurate quantification.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial.

BACKGROUND: In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS: In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS: Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION: Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Early seizures after intracerebral hemorrhage predict drug-resistant epilepsy.

Seizures are a common complication after an intracerebral hemorrhage (ICH) and the epilepsy might even be drug resistant. It is not known which factors determine the treatment response in post-ICH epilepsy. We included ICH patients retrospectively who survived at least the first 7 days, in the period from 2004 to 2009 and assessed seizure occurrence up to May 2013. We defined early seizures (ES) as seizures occurring within the first 7 days after the ICH, and late seizures (LS) as seizures occurring later than 7 days after the ICH. We defined drug-resistant epilepsy as a non-response to two adequately chosen and dosed drug regimens. In 857 patients surviving at least 7 days after ICH 69 (8.1 %), patients developed ES whereas LS occurred in 84 (9.8 %) subjects. Patients with ES had higher odds to develop LS, as compared to patients without ES [OR 3.4; 95 % confidence interval (CI) 2.1-5.6]. Drug-resistant post-ICH epilepsy occurred in 19 patients (22.6 %). The most important independent risk factor was the occurrence of ES (OR 3.0; 95 %-CI 1.1-8.4). ES are the main independent risk factor for the development of LS and for the development of drug-resistant epilepsy. Thus, ES might hallmark the start of chronic epilepsy after intracerebral hemorrhage and are not to be considered of no significance.

Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5 °C or above.

RATIONALE: In the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 37.0 °C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1.43; 95% confidence interval: 1.02-1.97). This relation was also found in the patients with a body temperature of 36.5 °C or higher (odds ratio 1.31; 95% confidence interval 1.01-1.68). These findings need confirmation. AIM: The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36.5 °C or above on functional outcome. DESIGN: The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 0.05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36.5 °C or above will be included within 12 h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. STUDY OUTCOMES: The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. DISCUSSION: If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.

[A woman with finger drop]. / Een vrouw met hangende vingers.

A 38-year-old woman presented with difficulty in stretching the fingers of her left hand. Physical examination revealed finger drop without a dropping hand. These findings along with results of the EMG were consistent with supinator syndrome.

[A woman without speech]. / Een vrouw zonder spraak.

A 56-year-old woman with a history of alcohol abuse was found at home amidst empty wine bottles with somnolence and severe dysarthria. MRI of the brain revealed selective demyelination of the corpus callosum, consistent with Marchiafava-Bignami disease.

[Does paracetamol improve recovery after stroke?]. / Verbetert paracetamol het herstel na een beroerte?

An increase in body temperature in the first days following stroke is related to poor functional outcome. High-dose paracetamol (acetaminophen) reduces the body temperature by 0.3°C and can prevent fever. Paracetamol treatment is simple, cheap and has few side effects. In the first "Paracetamol (Acetaminophen) in Stroke" (PAIS) study, there was a beneficial effect of high-dose paracetamol on functional outcome in patients with stroke and a body temperature of 37.0°C or above. Because this result was found in a subgroup analysis, a new study is needed to confirm this finding. Recently the randomised PAIS 2 study was initiated. This study aims to assess the effect of high-dose paracetamol on functional outcome in patients with acute stoke and a body temperature of 37.0°C or above.

The diagnostic value of provocative clinical tests in ulnar neuropathy at the elbow is marginal.

BACKGROUND: Provocative clinical tests are often performed in the diagnosis of ulnar neuropathy at the elbow (UNE) although the evidence for the usefulness of these tests is limited. The aim of this study was to determine the diagnostic value of provocative clinical tests in the diagnosis of UNE in a relevant spectrum of patients and controls. METHODS: A prospective cohort study was performed in consecutive patients clinically suspected of having UNE. All patients underwent a neurological examination and four commonly used provocative clinical tests (Tinel's test, flexion compression test, palpating for local ulnar nerve tenderness and nerve thickening). Subsequently, in all patients a reference standard test comprising electrophysiological studies and neurosonography was independently assessed. RESULTS: 192 eligible patients completed the study protocol. UNE was diagnosed in 137 and an alternative diagnosis was made in 55 patients. The sensitivity, specificity, and positive and negative predictive values were as follows: Tinel's test 62%, 53%, 77% and 30%; flexion compression test 61%, 40%, 72% and 29%; palpating for nerve thickening 28%, 87%, 84% and 33%; and palpating for nerve tenderness 32%, 80%, 80% and 32%. Logistic regression and receiver operating characteristic curves showed that the added value of one or more provocative tests over routine clinical examination is minimal. CONCLUSION: The diagnostic value of provocative clinical tests in UNE is poor.

[Success of carotid endarterectomy dependent on type of atherosclerotic plaque and gender, among others]. / Succes van carotisendarteriëctomie afhankelijk van onder meer het type atherosclerotische plaque en het geslacht.

Carotid endarterectomy (CEA) reduces the risk of stroke in both symptomatic and asymptomatic patients with a high-grade stenosis of the internal carotid artery. Surgery, however, is less beneficial for women than for men. Besides gender, other factors, like degree ofstenosis and plaque morphology, influence the risk of stroke and the beneficial effect of CEA. A recent study shows that women, asymptomatic women in particular, have more stable atherosclerotic carotid plaques than men. Increasing knowledge regarding local plaque characteristics should be carried through to clinical practice. Further studies, especially prospective studies, are needed to identify subgroups of patients that will benefit most from CEA. Low surgical morbidity and mortality remain a prerequisite to perform CEA in symptomatic carotid stenosis and even more so in asymptomatic carotid stenosis.

[From gene to disease; the PABN1 gene and oculopharyngeal muscular dystrophy]. / Van gen naar ziekte; het PABN1-gen en oculofaryngeale spierdystrofie.

Oculopharyngeal muscular dystrophy is a rare disease, presenting with bilateral ptosis and dysphagia, followed by slow progressive muscle weakness. The pathological hallmark of the disease is the presence of intranuclear inclusions in muscle cells. Inheritance is autosomal dominant in almost all cases. The mutation responsible is a short guanine-cytosine-guanine (GCG) expansion in the 'poly adenylate binding nuclear I protein' (PABN1) gene. This expansion is stable in subsequent generations and is translated into a polyalanine tract. The aberrant protein is found within the intranuclear inclusions and interferes with normal mRNA function.

[Balance disorder and subacute hydrocephalus due to haemorrhage in a cerebral cavernous malformation]. / Evenwichtsstoornis en subacute hydrocefalus door bloeding in een cerebrale caverneuze malformatie.

A 58-year-old man presented with a balance disorder, followed by progressive memory disturbance, urinary incontinence and vomiting. MRI of the brain revealed multiple cavernous malformations, with recent haemorrhage from one of them, in the brainstem, causing a hydrocephalus. After treatment for the hydrocephalus, the symptoms resolved quickly. Cerebral cavernomas may cause epileptic seizures, haemorrhaging and progressive neurological deficits. Diagnosis is on the basis of the typical MRI pattern of a hyperintense core, surrounded by a hypointense rim of old blood. Treatment consists of surgery if the lesion is easily accessible and can be completely removed. Other options are gamma-knife surgery, stereotactic radiotherapy and conservative treatment.