Optimal patient protocols in regional acute stroke care.

In acute stroke care two proven reperfusion treatments exist: (1) a blood thinner and (2) an interventional procedure. The interventional procedure can only be given in a stroke centre with specialized facilities. Rapid initiation of either is key to improving the functional outcome (often emphasized by the common phrase in acute stroke care "time=brain"). Delays between the moment the ambulance is called and the initiation of one or both reperfusion treatment(s) should therefore be as short as possible. The speed of the process strongly depends on five factors: patient location, regional patient allocation by emergency medical services (EMS), travel times of EMS, treatment locations, and in-hospital delays. Regional patient allocation by EMS and treatment locations are sub-optimally configured in daily practice. Our aim is to construct a mathematical model for the joint decision of treatment locations and allocation of acute stroke patients in a region, such that the time until treatment is minimized. We describe acute stroke care as a multi-flow two-level hierarchical facility location problem and the model is formulated as a mixed integer linear program. The objective of the model is the minimization of the total time until treatment in a region and it incorporates volume-dependent in-hospital delays. The resulting model is used to gain insight in the performance of practically oriented patient allocation protocols, used by EMS. We observe that the protocol of directly driving to the nearest stroke centre with special facilities (i.e., the mothership protocol) performs closest to optimal, with an average total time delay that is 3.9% above optimal. Driving to the nearest regional stroke centre (i.e., the drip-and-ship protocol) is on average 8.6% worse than optimal. However, drip-and-ship performs better than the mothership protocol in rural areas and when a small fraction of the population (at most 30%) requires the second procedure, assuming sufficient patient volumes per stroke centre. In the experiments, the time until treatment using the optimal model is reduced by at most 18.9 minutes per treated patient. In economical terms, assuming 150 interventional procedures per year, the value of medical intervention in acute stroke can be improved upon up to € 1,800,000 per year.

Help seeking behavior and onset-to-alarm time in patients with acute stroke: sub-study of the preventive antibiotics in stroke study.

BACKGROUND: Patients with acute stroke often do not seek immediate medical help, which is assumed to be driven by lack of knowledge of stroke symptoms. We explored the process of help seeking behavior in patients with acute stroke, evaluating knowledge about stroke symptoms, socio-demographic and clinical characteristics, and onset-to-alarm time (OAT). METHODS: In a sub-study of the Preventive Antibiotics in Stroke Study (PASS), 161 acute stroke patients were prospectively included in 3 Dutch hospitals. A semi-structured questionnaire was used to assess knowledge, recognition and interpretation of stroke symptoms. With in-depth interviews, response actions and reasons were explored. OAT was recorded and associations with socio-demographic, clinical parameters were assessed. RESULTS: Knowledge about stroke symptoms does not always result in correct recognition of own stroke symptoms, neither into correct interpretation of the situation and subsequent action. In our study population of 161 patients with acute stroke, median OAT was 30 min (interquartile range [IQR] 10-150 min). Recognition of one-sided weakness and/or sensory loss (p = 0.046) and adequate interpretation of the stroke situation (p = 0.003), stroke at daytime (p = 0.002), severe stroke (p = 0.003), calling the emergency telephone number (p = 0.004), and transport by ambulance (p = 0.040) were associated with shorter OAT. CONCLUSION: Help seeking behavior after acute stroke is a complex process. A shorter OAT after stroke is associated with correct recognition of one-sided weakness and/or sensory loss, adequate interpretation of the stroke situation by the patient and stroke characteristics and logistics of stroke care, but not by knowledge of stroke symptoms.

The ThRombolysis in UnconTrolled Hypertension (TRUTH) protocol: an observational study on treatment strategy of elevated blood pressure in stroke patients eligible for IVT.

BACKGROUND: Intravenous thrombolysis (IVT) with (recombinant) tissue plasminogen activator is an effective treatment in acute ischemic stroke. However, IVT is contraindicated when blood pressure is above 185/110 mmHg, because of an increased risk on symptomatic intracranial hemorrhage. In current Dutch clinical practice, two distinct strategies are used in this situation. The active strategy comprises lowering blood pressure with antihypertensive agents below these thresholds to allow start of IVT. In the conservative strategy, IVT is administered only when blood pressure drops spontaneously below protocolled thresholds. A retrospective analysis in two recent stroke trials showed a non-significant signal towards better functional outcome in the active group; robust evidence for either strategy, however, is lacking. We hypothesize that (I) the active strategy leads to a better functional outcome three months after acute ischemic stroke. Secondary hypotheses are that this effect occurs despite (II) increasing the number of symptomatic intracranial hemorrhages, and could be attributable to (III) a higher rate of IVT treatments and (IV) a shorter door-to-needle time. METHODS AND DESIGN: The TRUTH is a prospective, observational, cluster-based, parallel group follow-up study; in which participating centers continue their current local treatment guidelines. Outcomes of patients admitted to centers with an active will be compared to those admitted to centers with a conservative strategy. The primary outcome is functional outcome on the modified Rankin Scale at three months. Secondary outcomes are symptomatic intracranial hemorrhage, IVT treatment and door-to-needle time. We based our sample size estimate on an ordinal analysis of the mRS with the "proportional odds" model. With the aforementioned signal observed in a recent retrospective study in these patients as an estimate of the effect size and with alpha 0 · 05, this analysis would have an 80 % power with a total number of 600 patients. Corrections for expected imbalance in group size and clustering effects resulted in a sample size of 1235 patients. DISCUSSION: The TRUTH is the first large prospective study specifically studying IVT-candidates with elevated blood pressure, and has the potential to change clinical practice and optimize acute stroke care in these patients.

Stroke mimicking conversion disorder: two young women who put our feet back on the ground.

We describe two young female patients with symptoms and signs initially of conversion disorder. It became apparent, however, that both patients had a posterior circulation stroke. These cases remind us of just how broad the clinical presentation of neurological diseases is and illustrate how careful we must be in our own attributions, actions and diagnoses particularly when assessing patients with bizarre behaviour and with apparent inconsistencies on neurological examination.

Beta-cell dysfunction and insulin resistance after subarachnoid haemorrhage.

BACKGROUND: Hyperglycaemia is a common finding and an independent risk factor for increased morbidity and mortality in aneurysmal subarachnoid haemorrhage (SAH). Although in these patients hyperglycaemia is commonly ascribed to insulin resistance, there is little understanding of underlying mechanisms. AIMS: To prospectively study temporal disturbances of glucose metabolism after aneurysmal SAH in patients without known abnormalities of glucose metabolism and to explore possible correlations with markers of stress. METHODS: In consecutive aneurysmal SAH patients not subjected to insulin therapy, in-hospital and follow-up oral glucose tolerance tests (OGTTs) and assessments of insulin resistance, pancreatic ß-cell function, free fatty acids (FFA) and cortisol were performed and compared with reference values. RESULTS: We included 13 patients. In the first 2 weeks of admission, median fasting glucose and FFA levels were elevated while insulin levels were not. OGTTs were indicative of glucose intolerance in all patients at days 3 and 7, while on follow-up 1 patient had glucose intolerance and all patients had normal fasting glucose levels. Pancreatic ß-cell function was impaired throughout the first week and insulin resistance from day 4 to 10. Levels of cortisol correlated with higher fasting glucose and increased FFA. FFA in turn correlated with pancreatic ß-cell dysfunction. CONCLUSIONS: Aneurysmal SAH patients have transient abnormalities of glucose metabolism. During the first week, it appears to result predominantly from transient pancreatic ß-cell dysfunction, in combination with insulin resistance.

Sex differences in intracranial and extracranial atherosclerosis in patients with acute ischemic stroke.

BACKGROUND AND AIM: To investigate sex differences with respect to presence and location of atherosclerosis in acute ischemic stroke patients. METHODS: Participants with acute ischemic stroke were included from the Dutch acute stroke trial, a large prospective multicenter cohort study performed between May 2009 and August 2013. All patients received computed tomography/computed tomography-angiography within 9 h of stroke onset. We assessed presence of atherosclerosis in the intra- and extracranial internal carotid and vertebrobasilar arteries. In addition, we determined the burden of intracranial atherosclerosis by quantifying internal carotid and vertebrobasilar artery calcifications, resulting in calcium volumes. Prevalence ratios between women and men were calculated with Poisson regression analysis and adjusted prevalence ratio for potential confounders (age, hypertension, hyperlipidemia, diabetes, smoking, and alcohol use). RESULTS: We included 1397 patients with a mean age of 67 years, of whom 600 (43%) were women. Presence of atherosclerosis in intracranial vessel segments was found as frequently in women as in men (71% versus 72%, adjusted prevalence ratio 0.95; 95% CI 0.89-1.01). In addition, intracranial calcification volume did not differ between women and men in both intracranial internal carotid (large burden 35% versus 33%, adjusted prevalence ratio 0.93; 95% CI 0.73-1.19) and vertebrobasilar arteries (large burden 26% versus 40%, adjusted prevalence ratio 0.69; 95% CI 0.41-1.12). Extracranial atherosclerosis was less common in women than in men (74% versus 81%, adjusted prevalence ratio 0.86; 95% CI 0.81-0.92). CONCLUSIONS: In patients with acute ischemic stroke the prevalence of intracranial atherosclerosis does not differ between women and men, while extracranial atherosclerosis is less often present in women compared with men.

Evolutionary algorithms and decision trees for predicting poor outcome after endovascular treatment for acute ischemic stroke.

Despite the large overall beneficial effects of endovascular treatment in patients with acute ischemic stroke, severe disability or death still occurs in almost one-third of patients. These patients, who might not benefit from treatment, have been previously identified with traditional logistic regression models, which may oversimplify relations between characteristics and outcome, or machine learning techniques, which may be difficult to interpret. We developed and evaluated a novel evolutionary algorithm for fuzzy decision trees to accurately identify patients with poor outcome after endovascular treatment, which was defined as having a modified Rankin Scale score (mRS) higher or equal to 5. The created decision trees have the benefit of being comprehensible, easily interpretable models, making its predictions easy to explain to patients and practitioners. Insights in the reason for the predicted outcome can encourage acceptance and adaptation in practice and help manage expectations after treatment. We compared our proposed method to CART, the benchmark decision tree algorithm, on classification accuracy and interpretability. The fuzzy decision tree significantly outperformed CART: using 5-fold cross-validation with on average 1090 patients in the training set and 273 patients in the test set, the fuzzy decision tree misclassified on average 77 (standard deviation of 7) patients compared to 83 (±7) using CART. The mean number of nodes (decision and leaf nodes) in the fuzzy decision tree was 11 (±2) compared to 26 (±1) for CART decision trees. With an average accuracy of 72% and much fewer nodes than CART, the developed evolutionary algorithm for fuzzy decision trees might be used to gain insights into the predictive value of patient characteristics and can contribute to the development of more accurate medical outcome prediction methods with improved clarity for practitioners and patients.

Subjecting acute ischemic stroke patients to continuous tube feeding and an intensive computerized protocol establishes tight glycemic control.

INTRODUCTION: Tight glycemic control (TGC) after ischemic stroke may improve clinical outcome but previous studies failed to establish TGC, principally because of postprandial glucose surges. The aim of the present study was to investigate if safe, effective and feasible TGC can be achieved with continuous tube feeding and a computerized treatment protocol. METHODS: We subjected ten acute ischemic stroke patients with admission hyperglycemia (glucose >7.0 mmol/l (126.0 mg/dl)) to continuous tube feeding and a computerized intensive protocol with insulin adjustments every 1-2 h. Two groups of regularly fed patients from a previous study with a similar design served as controls. These groups comprised hyperglycemic patients treated according to an intermediate protocol with insulin adjustments at standard intervals (N = 13), and normoglycemic controls treated according to standard care (N = 15). The primary outcome was the percentage of time within target (4.4-6.1 mmol/l (79.2-109.8 mg/dl)). Secondary outcome was the number of patients with hypoglycemic episodes (glucose <3.0 mmol/l (54.0 mg/dl)). RESULTS: Median time within target was 55% in the continuously fed intensive group compared to 19% in the regularly fed intermediate group, and 58% in normoglycemic controls. Hypoglycemic episodes occurred in 20% of patients in the continuously fed group-lowest glucose level 2.4 mmol/l (43.2 mg/dl). In contrast, in the regularly fed group, this was 31%-lowest glucose level 1.6 mmol/l (28.8 mg/dl). CONCLUSIONS: TGC after acute ischemic stroke is feasible with continuous tube feeding and a computerized intensive treatment protocol. Although glycemic control is associated with hypoglycemia, no severe hypoglycemia occurred in the continuous tube feeding group.

Efficacy and safety of two 5 day insulin dosing regimens to achieve strict glycaemic control in patients with acute ischaemic stroke.

BACKGROUND: In patients with acute ischaemic stroke and hyperglycaemia, prolonged strict glycaemic control may improve clinical outcome. The question is how to achieve this prolonged strict glycaemic control. In this study, the efficacy and safety of two regimens with different basal to meal related insulin ratio are described. METHODS: 33 patients with ischaemic stroke and hyperglycaemia at admission were randomised in an open design to receive: (1) conventional glucose lowering therapy, (2) strict glucose control with predominantly basal insulin using intravenous insulin or (3) strict glucose control with predominantly meal related insulin using subcutaneous insulin in the first 5 days after stroke. The target range of glucose control for the last two groups was 4.4-6.1 mmol/l. 16 consecutive patients without hyperglycaemia at admission were included to serve as normoglycaemic controls. RESULTS: The median area under the curve (AUC) in the meal related insulin group was 386 mmol/l x 58 h (range 286-662) for days 2-5, and did not differ from the hyperglycaemic control group (median AUC 444 mmol/l x 58 h; range 388-620). There was also no difference in median AUC of the basal insulin group (453 mmol/l x 58 h, range 347-629) and the hyperglycaemic control group on days 2-5. In the first 12 hours, glucose profiles were lower in the groups treated with strict glucose control; median AUC was 90 mmol/l x 12 h (range 77-189) for the hyperglycaemic control group versus 81 mmol/l x 12 h (range 60-118) for the meal related insulin group (p = 0.03) and 74 mmol/l x 12 h (range 52-97) for the basal insulin group (p = 0.008). CONCLUSION: In intermittently fed ischaemic stroke patients, strict glycaemic control between day 2 and day 5 with two different basal bolus regimens did not result in lower glucose profiles due to postprandial hyperglycaemia. Continuous enteral feeding may therefore be needed to achieve prolonged strict glycaemic control in acute stroke patients.

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

INTRODUCTION: The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS. METHODS: Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written. RESULTS: Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre. CONCLUSION: This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

High mean fasting glucose levels independently predict poor outcome and delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage.

BACKGROUND: Hyperglycaemia has been related to poor outcome and delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH). OBJECTIVE: This study aimed to assess whether in patients with aSAH, levels of mean fasting glucose within the first week predict poor outcome and DCI better than single admission glucose levels alone. METHODS: Data on non-diabetic patients admitted within 48 h after aSAH with at least two fasting glucose assessments in the first week were retrieved from a prospective database (n = 265). The association of admission glucose or mean fasting glucose, dichotomised at the median levels, with outcome was assessed using logistic regression, and for DCI using Cox regression. To explore whether the association between glucose levels and outcome was mediated by DCI, we adjusted for DCI. RESULTS: The crude and multivariable adjusted odds ratios and 95% confidence intervals for poor outcome were 1.9 (1.1 to 3.2) and 1.6 (0.9 to 2.7) for high admission glucose and 3.5 (2.0 to 6.1) and 2.5 (1.4 to 4.6) for high mean fasting glucose. The crude and adjusted hazard ratios for DCI were 1.7 (1.1 to 2.5) and 1.4 (0.9 to 2.1) for high admission glucose and 2.0 (1.3 to 3.0) and 1.7 (1.1 to 2.7) for high mean fasting glucose. After adjusting for DCI, the odds ratios on poor outcome for high mean fasting glucose decreased only marginally. CONCLUSIONS: Compared with high admission glucose, high mean fasting glucose, representing impaired glucose metabolism, is a better and independent predictor of poor outcome and DCI. DCI is not the key determinant in the relationship between high fasting glucose and poor outcome.

Hyperglycemia and cognitive outcome after ischemic stroke.

BACKGROUND: Post-stroke hyperglycemia (HG) is associated with poor physical recovery, in particular in patients with cortical stroke. We tested whether HG is also associated with cognitive impairment after ischemic stroke. METHODS: We recruited patients from a prospective consecutive cohort with a first-ever supratentorial infarct. Neuropsychological examination included abstract reasoning, verbal memory, visual memory, visual perception and construction, language, and executive functioning. We related HG (glucose >7.0 mmol/L) to cognition and functional outcome (modified Barthel Index) at baseline and after 6-10 months, and to neurological deficit (National Institutes of Health Stroke Scale) and infarct size at baseline. In additional analyses cortical and subcortical infarcts were considered separately. RESULTS: Of 113 patients, 43 had HG (38%) and 55 had cortical infarcts (49%). Follow-up was obtained from 76 patients (68%). In the acute phase, in patients with cortical infarcts HG was associated with impaired executive function (B=-0.65; 95% confidence limits (CL): -1.3-0.00; p<0.05), larger lesion size (p<0.01), and more severe neurological deficits (p<0.01). These associations were not observed in patients with subcortical infarcts and the association between HG and cognitive functioning at follow-up was not significant in either group. CONCLUSIONS: In first-ever ischemic stroke, HG was not associated with impaired cognition after 6-10 months. In the acute phase of stroke HG was associated with impaired executive function, but only in patients with cortical infarcts.

[Congenital pain-insensitivity syndrome; a rare indication of the benefit of pain]. / Congenitaal pijnongevoeligheidssyndroom; een zeldzame aanwijzing voor het nut van pijn.

A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.

[Cerebral infarction due to polycythaemia as the initial manifestation of renal cell carcinoma]. / Herseninfarct door polycytemie als eerste uiting van een niercelcarcinoom.

A 65-year-old man with known diabetes mellitus and hypertension (cardiovascular risk factors) presented to the Emergency Clinic with a transient language disorder and motor- and cognitive-function disorders that had been present for the past half a year. Brain imaging revealed multiple white-matter lesions and a recent infarction. Routine blood tests revealed polycythaemia. Further tests revealed an elevated erythropoietin level and bilateral renal tumours. The cognitive functions improved after repeated phlebotomies and surgical resection of the renal-cell carcinomas. Before surgery, transcranial ultrasound had shown very low cerebral flow velocities, which became normal after correction of the haematocrit. This case emphasises the importance of routine blood tests in patients with suspected cerebral infarction. To our knowledge, this is the first case of cerebral infarction as the first manifestation ofa renal-cell carcinoma.

[A patient with Melkersson-Rosenthal syndrome]. / Een patiënt met het syndroom van Melkersson-Rosenthal.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a relatively rare syndrome characterised by the clinical triad of persisting or recurrent facial oedema, recurrent peripheral facial palsy, and a fissured tongue. CASE DESCRIPTION: A 30-year-old male patient presented with a left peripheral facial palsy spreading to the right side of the face. The left-sided facial paralysis recurred twice after initial recovery. The patient had also suffered from oedema of the lip and face, which sometimes occurred simultaneously with the paralysis, and he had always had a fissured tongue. Extensive biochemical tests, tests for infection and imaging tests revealed no abnormalities, and MRS was diagnosed. No treatment was required as the symptoms always disappeared spontaneously. CONCLUSION: Patients with MRS can present to the general practitioner, dermatologist, or ENT-specialist as well as to the neurologist. As this is a relatively unknown syndrome, the diagnosis is often made late, and it is often over-diagnosed and over-treated. There is no proven effective treatment, but systemic corticosteroids can be considered.

True status of smear-positive pulmonary tuberculosis defaulters in Malawi.

The article reports the results of a study to determine the true outcome of 8 months of treatment received by smear-positive pulmonary tuberculosis (PTB) patients who had been registered as defaulters in the Queen Elizabeth Central Hospital (QECH) and Mlambe Mission Hospital (MMH), Blantyre, Malawi. The treatment outcomes were documented from the tuberculosis registers of all patients registered between 1 October 1994 and 30 September 1995. The true treatment outcome for patients who had been registered as defaulters was determined by making personal inquiries at the treatment units and the residences of patients or relatives and, in a few cases, by writing to the appropriate postal address. Interviews were carried out with patients who had defaulted and were still alive and with matched, fully compliant PTB patients who had successfully completed the treatment to determine the factors associated with defaulter status. Of the 1099 patients, 126 (11.5%) had been registered as defaulters, and the true treatment outcome was determined for 101 (80%) of the latter; only 22 were true defaulters, 31 had completed the treatment, 31 had died during the treatment period, and 17 had left the area. A total of 8 of the 22 true defaulters were still alive and were compared with the compliant patients. Two significant characteristics were associated with the defaulters; they were unmarried; and they did not know the correct duration of antituberculosis treatment. Many of the smear-positive tuberculosis patients who had been registered as defaulters in the Blantyre district were found to have different treatment outcomes, without defaulting. The quality of reporting in the health facilities must therefore be improved in order to exclude individuals who are not true defaulters.

PIP: This study investigates the status of patients with smear-positive pulmonary tuberculosis (PTB), and determines the true 8-month treatment outcome of patients who had been registered as defaulters in Queen Elizabeth Central Hospital (QECH) and Mlambe Mission Hospital (MMH), Blantyre, Malawi. All patients registered between October 1, 1994, and September 30, 1995, were studied, with name, age, sex, home address, and treatment unit as the determining factors. Interviews were carried out with patients who had defaulted and were still alive and with matched, fully compliant PTB patients to determine the factors associated with defaulter status. Results showed that of the 1099 patients, 126 (11.5%) had been registered as defaulters, and the true treatment outcome was determined for 101 (80%) of the latter; only 22 were true defaulters, 31 had completed the treatment, 31 had died during the treatment period, and 17 had left the area. A total of 8 of the 22 true defaulters were still alive. Unmarried status and ignorance of the duration of antituberculosis treatment were the significant characteristics of defaulting behavior. Many of the smear-positive tuberculosis patients had been registered as defaulters in the Blantyre District were found to have different treatment outcomes that did not involve defaulting. Thus, the quality of reporting in the health facilities must be improved in order to exclude individuals who are not true defaulters. The public should be given more information about tuberculosis via intensive health education--especially regarding the total duration of treatment and the need to complete the full course.