Uwe Malzahn

PHANTOM-S: the prehospital acute neurological therapy and optimization of medical care in stroke patients – study

Rationale Time from symptom onset to treatment is closely associated with the effectiveness of intravenous thrombolysis in acute ischemic stroke patients. Hospitals are encouraged to take every effort to shorten delay of treatment. Despite combined efforts to streamline procedures in hospitals to provide treatment as soon as possible, most patients receive tissue plasminogen activator with considerable delay and very few of them within 90 mins. Germany has an internationally acknowledged prehospital emergency care system with specially trained doctors on ambulances. We developed an ambulance equipped with a Computed Tomography (CT) scanner, point-of-care laboratory, teleradiological support, and an emergency-trained neurologist on board. In the Pre-Hospital Acute Neurological Therapy and Optimization of Medical care in Stroke Patients study, we aim at a reduction of the current alarm-to-needle time by prehospital use of tissue plasminogen activator in an ambulance. Aims We hypothesized that compared with regular care, we will reduce alarm-to-needle time by a minimum of 20 mins by implementation of the stroke emergency mobile unit. Design Prospective study comparing randomly allocated periods with and without stroke emergency mobile unit availability. Study Outcomes Primary end point of the study is alarm-to-needle time. Secondary outcomes include thrombolysis treatment rates, modified Rankin scale after three-months, and alarm-to-imaging or alarm-to-laboratory time; safety aspects to be evaluated are mortality and rates of (symptomatic) intracerebral hemorrhage.

Development and Validation of a Dispatcher Identification Algorithm for Stroke Emergencies

Background and Purpose— Recent innovations such as CT installation in ambulances may lead to earlier start of stroke-specific treatments. However, such technically complex mobile facilities require effective methods of correctly identifying patients before deployment. We aimed to develop and validate a new dispatcher identification algorithm for stroke emergencies. Methods— Dispatcher identification algorithm for stroke emergencies was informed by systematic qualitative analysis of the content of emergency calls to ambulance dispatchers for patients with stroke or transient ischemic attack (N=117) and other neurological (N=39) and nonneurological (N=51) diseases (Part A). After training of dispatchers, sensitivity and predictive values were determined prospectively in patients admitted to Charité hospitals by using the discharge diagnosis as reference standard (Part B). Results— Part A: Dysphasic/dysarthric symptoms (33%), unilateral symptoms (22%) and explicitly stated suspicion of stroke (47%) were typically identified in patients with stroke but infrequently in nonstroke cases (all <10%). Convulsive symptoms (41%) were frequent in other neurological diseases but not strokes (3%). Pain (26%) and breathlessness (31%) were often expressed in nonneurological emergencies (6% and 7% in strokes). Part B: Between October 15 and December 16, 2010, 5774 patients were admitted by ambulance with 246 coded with final stroke diagnoses. Sensitivity of dispatcher identification algorithm for stroke emergencies for detecting stroke was 53.3% and positive predictive value was 47.8% for stroke and 59.1% for stroke and transient ischemic attack. Of all 275 patients with stroke dispatcher codes, 215 (78.5%) were confirmed with neurological diagnosis. Conclusions— Using dispatcher identification algorithm for stroke emergencies, more than half of all patients with stroke admitted by ambulance were correctly identified by dispatchers. Most false-positive stroke codes had other neurological diagnoses.

Vitamin D receptor haplotypes protect against development of colorectal cancer

ObjectiveWe investigated the association of vitamin D receptor polymorphisms and colorectal cancer incidence in a Caucasian population.MethodsFrequencies of the vitamin D receptor gene polymorphisms 23005G>A (CDX-2), 27823C>T (FokI), 60890G>A (BsmI), 61050G>A (Tru9I), 61888G>T (ApaI), and 61968T>C (TaqI) were determined in a series of 256 colorectal cancer patients and 256 patients without malignant disease (case-control study) using polymerase chain reaction and restriction fragment length polymorphism genotyping assays (PCR-RFLP). Haplotype analysis based on the six genetic loci was applied to the received genotypes.ResultsPairwise linkage disequilibrium between BsmI, ApaI, TaqI, and Tru9I was confirmed (P < 0.001). Allele frequencies did not differ between the groups. There was no association between any single variant and colorectal cancer. However, haplotypes BsmI(G)#TaqI(C) and BsmI(A)#TaqI(T) were inversely associated with colorectal cancer incidence (P < 0.001), the odds being 15.0 times smaller [odds ratio (OR) 0.067; 95% confidence interval (CI), 0.016–0.284] and 5.3 times smaller (OR 0.188; 95% CI 0.077–0.461), respectively, compared with noncarriers.ConclusionOur findings suggest that vitamin D receptor haplotypes BsmI(G)#TaqI(C) and BsmI(A)#TaqI(T) have a protective effect against colorectal cancer in Caucasians.

Thalamic sensory strokes with and without pain: differences in lesion patterns in the ventral posterior thalamus

Objective Vascular lesions of the posterolateral thalamus typically result in a somatosensory syndrome in which some patients develop central neuropathic post-stroke pain (CPSP). Damage to the spinothalamic tract terminus is assumed to be a prerequisite for thalamic CPSP. At the nuclear level, it remains a matter of debate whether the ventral posterolateral nucleus (VPL) or the posterior portion of the ventral medial nucleus (VMpo) constitutes the decisive lesion site. The hypothesis of the study was that lesion location in thalamic CPSP patients differs from that in thalamic stroke patients without pain, and the aim was to identify whether this difference comprises the VPL and/or the VMpo. Design 30 patients with chronic thalamic stroke and a persistent contralateral somatosensory syndrome were examined. CPSP patients (n=18) were compared with non-pain control patients. By coregistration of a digitised thalamic atlas with T1 weighted MR images, lesion clusters were allocated to the thalamic nuclei. Results VPL was affected in both groups, but CPSP lesion clusters comprised the more posterior, inferior and lateral parts of the VPL compared with controls. Additional partial involvement of the VMpo was seen in only three pain patients. In three other pain patients, lesions involved neither the VPL nor the VMpo, but mainly affected the anterior pulvinar. Conclusion This study specifies the role of the VPL in thalamic CPSP and shows that the posterolateratal and inferior parts in particular are critically lesioned in pain patients. In this thalamic subregion, afferents of the spinothalamic tract are known to terminate. In contrast, the data do not support a pivotal impact of the VMpo on thalamic CPSP.

Fluid-Attenuated Inversion Recovery Images and Stroke Outcome After Thrombolysis

Background and Purpose— We investigated if hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in arteries and parenchyma are associated with poor outcome 3 months after thrombolysis. Methods— Consecutive acute stroke patients with known time of symptom onset who had an MRI before and 1 day after thrombolysis were included in this study. Blinded to follow-up imaging and outcome, 2 raters independently judged the presence or absence of arterial and parenchymal FLAIR hyperintensities. Functional outcome (modified Rankin Scale) was assessed after 3 months. Results— Out of 90 patients, 22 had parenchymal FLAIR hyperintensities and 42 had hyperintense vessels. The combination of FLAIR hyperintensities in arteries and parenchyma occurred in 15 patients. Stepwise forward regression analysis revealed an adjusted odds ratio of 14.5 for a worse outcome (modified Rankin Scale score >2) in patients with FLAIR hyperintensities in arteries and parenchyma (95% confidence interval, 1.3–158.5; P=0.03). Conclusions— FLAIR hyperintensities in arteries and parenchyma are an easy-to-use MRI feature in acute ischemic stroke associated with poor outcome 3 months after thrombolysis.

Decision-making in the diagnosis and treatment of stroke-associated pneumonia

Background Stroke-associated pneumonia (SAP) is associated with impaired outcome in acute stroke patients. Current European and American guidelines for acute stroke care are lacking standardised recommendations for the management of SAP. We investigated current diagnostic and treatment practice for SAP in German stroke units (SU). Methods We developed a standardised questionnaire including characteristics of SU, questions related to antibiotic treatment approaches of SAP and five case vignettes describing relevant clinical scenarios based on Centers for Disease Control and Prevention (CDC) criteria for ‘clinically defined pneumonia’. All certified German SU were invited to take part in the survey. Results The survey took place from April to August 2010. Of all 162 German SU contacted, 83 (51%) responded. Classification and regression trees analysis suggested that SAP was diagnosed on the basis of clinical criteria such as fever and stroke severity. Chest x-ray showed only limited influence on the diagnosis of SAP. C-reactive protein was frequently requested as additional diagnostic information (38–76%). Group 3 cephalosporines and (acyl-) aminopenicillins/β-lactamase inhibitors are the most frequently used antibiotics (46–60%) in empiric mono (58%) and combination (42%) therapy. A minority of SU (5%) use prophylactic antibiotic treatment. Standardised procedures are available in 61% of SU. Conclusion Clinical criteria were the main determinants for SAP diagnosis. In contrast, chest x-ray—the central diagnostic item in CDC criteria—was of minor importance. Our survey demonstrates heterogeneous diagnostic and therapeutic strategies in German SU. Future studies need to establish and to evaluate standardised criteria for SAP care.

White Matter Lesion Severity in Mild Acute Ischemic Stroke Patients and Functional Outcome After 1 Year

Background and Purpose— To determine if severity of visually assessed white matter disease is associated with disability after ischemic stroke. Methods— In this Berlin “Cream & Sugar” substudy, all first ischemic stroke patients who received magnetic resonance imaging and completed follow-up between January 2009 and December 2010, were enrolled. Severity of white matter disease was assessed on fluid-attenuated inversion recovery or T2-weighted sequences using the Wahlund and Fazekas visual scales. Functional outcome was assessed after 1 year using the modified Rankin Scale (follow-up [FU] modified Rankin Scale [mRS]). Results— Of 101 patients (37% female; median age, 67 years; interquartile range, 54–75; National Institutes of Health Stroke Scale score, 1; interquartile range, 0–2), median FU mRS was 1 (interquartile range, 0–2). Binary logistical regression adjusted for age (at 5-year intervals), acute National Institutes of Health Stroke Scale scores, fasting glucose, insulin, glycosylated hemoglobin, creatinine, C-reactive protein quartiles, waist circumference, and systolic blood pressure revealed that Fazekas scores of 2 and 3 independently associated with FU mRS (Fazekas score 2: adjusted odds ratio, 8.4; 95% confidence interval, 2.35–30.09; P=0.001; Fazekas score 3: adjusted odds ratio, 4.2; 95% confidence interval, 1.04–16.96; P=0.044). Wahlund scores >10 were significantly associated with FU mRS when fasting glucose levels were removed from the regression analysis (adjusted odds ratio, 12.17; 95% confidence interval, 1.91–77.54; P=0.008). Conclusion— Severe white matter disease defined by standard criteria in acute ischemic stroke patients is associated with disability at 1 year and can be assessed quickly using visual rating scales. Clinical Trial Registration Information— URLs: http://www.clinicaltrials.gov and https://eudract.ema.europa.eu. Unique identifiers: NCT 01378468 and 2009-010356-97.

Breastfeeding is associated with lower risk for multiple sclerosis.

Background: Multiple sclerosis (MS) is an autoimmune disease with known genetic and environmental susceptibility factors. Breastfeeding has been shown to be protective in other autoimmune diseases. Objective: This case-control study analyzed the association of breastfeeding in infancy on the risk of developing MS. Methods: A case-control study was performed in Berlin of 245 MS patients and 296 population-based controls, who completed a standardized questionnaire on their history and duration of breastfeeding in infancy and demographic characteristics. Univariable and multivariable logistic regression analysis was performed to investigate the association between breastfeeding and MS. The multivariate model was adjusted for age, gender, number of older siblings, number of inhabitants in place of domicile between ages 0 and 6 (categorized in each case), and daycare attendance between ages 0 and 3. Results: In multivariable analysis, breastfeeding showed an independent association with MS (adjusted OR 0.58; p = 0.028). However, with no breastfeeding as reference, the protective effect only emerges after four months of breastfeeding (multivariable analysis for ≤ four months adjusted OR 0.87; p = 0.614 and for > four months OR 0.51; p = 0.016). Conclusion: The results of this case-control study support the hypothesis that breastfeeding is associated with a lower risk of MS. These results are in line with findings of previous studies on other autoimmune diseases, in which breastfeeding was shown to have protective effects.

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study

BackgroundMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS.MethodsA case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.ResultsMean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.ConclusionsThe hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.

Reliable Perfusion Maps in Stroke MRI Using Arterial Input Functions Derived From Distal Middle Cerebral Artery Branches

Background and Purpose— Perfusion imaging is widely used in stroke, but there are uncertainties with regard to the choice of arterial input function (AIF). Two important aspects of AIFs are signal-to-noise ratio and bolus-related signal drop, ideally close to 63%. We hypothesized that distal branches of the middle cerebral artery (MCA) provide higher quality of AIF compared with proximal branches. Methods— Over a period of 3 months, consecutive patients with suspected stroke were examined in a 3-T MRI scanner within 24 hours of symptom onset. AIFs were selected manually in M1, M2, and M3 branches of the MCA contralateral to the suspected ischemia. Signal-to-noise ratio and bolus-related signal drop were analyzed. Perfusion maps were created for every patient and mean values at the insular level as well as relative ranges were compared. Results— Mean age of 132 included patients (53 females) was 67.3 years (SD, 14.9) and median National Institutes of Health Stroke Scale was 3 (interquartile range [IQR] 0 to 6). For further analyses, 4 patients were excluded due to discontinuation of scanning or insufficient bolus arrival (signal drop <15%). Median signal-to-noise ratio was highest in M3 branches (36.41; IQR, 29.29 to 43.58). Median signal-to-noise ratio in M2 branches was intermediate (27.54; IQR, 20.78 to 34.00) and median signal-to-noise ratio in M1 was low (12.40; IQR, 9.11 to 17.15). Using AIFs derived from M1 and M2 branches of the MCA median signal drop was 77% (IQR, 72% to 82%) and 78% (IQR, 73% to 83%), respectively. Signal drop was significantly reduced when AIF was selected in M3 branches with a median of 72% (IQR, 63% to 77%; P<0.01). Highest variability of 3456 perfusion maps was found in those derived from M1. Conclusion— The level of AIF selection in the MCA has a major impact on reliability and even quantitative parameters of perfusion maps. For better comparison of perfusion maps, the AIF should be defined by selection of distal branches of the MCA contralateral to the suspected ischemia. In future trials involving perfusion imaging, the MCA segment used for the AIF should be specified.