Grethe Andersen

Lamotrigine for central poststroke pain A randomized controlled trial

Objective: Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain. Methods: Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia. Results: Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study. Conclusions: Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

BACKGROUND The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. METHODS In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet‐only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24‐month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. RESULTS We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow‐up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet‐only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet‐only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet‐only group (P=0.22). Serious device‐related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure. CONCLUSIONS Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894.)

Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: Findings with the soluble adhesion molecules E‐selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1

OBJECTIVE To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease. METHODS We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting. RESULTS Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate. CONCLUSION NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

Dimensions of Post-Stroke Fatigue: A Two-Year Follow-Up Study

Background: The aim of this study was to examine the course of poststroke fatigue in a cohort of first-time stroke patients compared to the general population, and to identify clinically relevant features of post-stroke fatigue. Methods: We performed a follow-up study of 165 patients with first-time stroke admitted to acute stroke units at the Aarhus University Hospital, Denmark. A reference group of 1,069 persons was sampled from the general population. Fatigue was assessed using the Multidimensional Fatigue Inventory (MFI-20) covering five scales of fatigue (General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue). Results: Compared to the general population, stroke patients reported higher levels of Physical Fatigue. Minor or no differences were found for the other fatigue scales. Pathological fatigue, defined as a score ≧12 on the General Fatigue scale, was reported by 59% (95% CI: 51–66%), 44% (95% CI: 36–51%), 38% (95% CI: 31–46%), and 40% (95% CI: 32–48%) of stroke patients 10 days, 3 months, 1 year, and 2 years following hospitalization for stroke, respectively. Post-stroke fatigue levels decreased after three months and remained stable throughout the remainder of follow-up. Poor functional outcome was consistently associated with increased levels of fatigue. Conclusions: Post-stroke fatigue is a common condition primarily characterized by increased levels of Physical Fatigue. The pathological mechanisms underlying post-stroke fatigue and its clinical implications require further study.

Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales.

Background and Purpose— We designed and validated a simple prehospital stroke scale to identify emergent large vessel occlusion (ELVO) in patients with acute ischemic stroke and compared the scale to other published scales for prediction of ELVO. Methods— A national historical test cohort of 3127 patients with information on intracranial vessel status (angiography) before reperfusion therapy was identified. National Institutes of Health Stroke Scale (NIHSS) items with the highest predictive value of occlusion of a large intracranial artery were identified, and the most optimal combination meeting predefined criteria to ensure usefulness in the prehospital phase was determined. The predictive performance of Prehospital Acute Stroke Severity (PASS) scale was compared with other published scales for ELVO. Results— The PASS scale was composed of 3 NIHSS scores: level of consciousness (month/age), gaze palsy/deviation, and arm weakness. In derivation of PASS 2/3 of the test cohort was used and showed accuracy (area under the curve) of 0.76 for detecting large arterial occlusion. Optimal cut point ≥2 abnormal scores showed: sensitivity=0.66 (95% CI, 0.62–0.69), specificity=0.83 (0.81–0.85), and area under the curve=0.74 (0.72–0.76). Validation on 1/3 of the test cohort showed similar performance. Patients with a large artery occlusion on angiography with PASS ≥2 had a median NIHSS score of 17 (interquartile range=6) as opposed to PASS <2 with a median NIHSS score of 6 (interquartile range=5). The PASS scale showed equal performance although more simple when compared with other scales predicting ELVO. Conclusions— The PASS scale is simple and has promising accuracy for prediction of ELVO in the field.

Quantitative Measurement of the Levels of Melanocortin Receptor Subtype 1, 2, 3 and 5 and Pro-Opio-Melanocortin Peptide Gene Expression in Subsets of Human Peripheral Blood Leucocytes

Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro‐opio‐melanocortin (POMC) protein mRNA were measured by the real‐time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co‐ordinating role for MCR subtypes and their naturally occurring ligands in the co‐operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR‐mediated tolerance induction in Th cells.

Post Stroke Use of Selective Serotonin Reuptake Inhibitors and Clinical Outcome Among Patients With Ischemic Stroke: A Nationwide Propensity Score–matched Follow-up Study

Background and Purpose— Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed after stroke. We aimed to investigate whether potential antiplatelet or vasospastic effects have important clinical implications. Methods— Using data from Danish medical registries, we did a nationwide follow-up study among ischemic stroke patients between 2003 and 2009. We identified 5833 SSRI users, and propensity score matched these patients with nonusers in a 1:1 ratio, followed by Cox regression analysis to compute hazard ratios (HRs) of acute myocardial infarction, recurrent stroke, major bleeding, and death. Results— Median follow-up time (from 30 days after discharge to death/end of follow-up) was 1159 days. In total, 2.9% had myocardial infarction, 8.1% recurrent ischemic stroke, 20.2% major bleeding, 1.4% intracranial bleeding, and 34.4% died during follow-up. SSRI users had a lower risk of the combined outcome of myocardial infarction or recurrent ischemic stroke (adjusted HR, 0.77; confidence interval [CI], 0.62–0.96). However, the SSRI users also experienced a higher risk of overall major bleeding (adjusted HR, 1.33; CI, 1.14–1.55) and a nonsignificantly higher risk of intracranial bleedings (adjusted HR, 1.14; CI, 0.62–2.12). Mortality increased in SSRI users (adjusted HR, 1.13; CI, 1.00–1.28) and death caused by bleeding increased (adjusted HR, 1.89; CI, 0.97–3.66) as compared with death by other causes (adjusted HR, 1.11; CI; 0.98–1.26). Conclusions— SSRI use after ischemic stroke was associated with a lower risk of new cardiovascular events and also with an increased bleeding risk. There was an increased mortality among SSRI users, which may be related to the increased bleeding risk.

Sex-Related Differences in Quality of Care and Short-Term Mortality Among Patients With Acute Stroke in Denmark: A Nationwide Follow-Up Study

Background and Purpose— Sex may predict level of care and successive outcome among patients with stroke. We examined fulfillment of quality of care criteria according to sex and possible impact of any sex-related differences on short-term mortality in a population-based nationwide follow-up study in Denmark. Methods— We identified 29 549 patients admitted with stroke between January 2003 and October 2005 in the Danish National Indicator Project. Data on 30- and 90-day mortality were obtained from The Civil Registration System. We compared proportions of patients receiving adequate care between sexes, as measured by admission to a specialized stroke unit, administration of antiplatelet or anticoagulant therapy, examination with CT/MRI scan, and assessment by a physiotherapist, an occupational therapist, and of nutritional risk. Further, we computed 30- and 90-day mortality rate ratios (MRR), adjusted for patient characteristics, fulfillment of quality of care criteria, and department. Results— The proportion of patients who received adequate care was either slightly lower or similar among women when compared to men. The relative risks (RR) of receiving specific components of care ranged from 0.84 (95% confidence interval [CI]:0.74 to 0.96) to 1.01 (95% CI:0.96 to 1.06) when comparing sexes. The adjusted mortality rate ratios were lower among women and adjustment for fulfillment of quality of care criteria had only marginal impact. Conclusions— There appear not to be any substantial sex-related differences in acute hospital care among patients with stroke in Denmark. The lower female short-term mortality is therefore most likely explained by other factors.

Intellectual Impairment in the First Year following Stroke, Compared to an Age-Matched Population Sample

General intellectual impairment during the first year following stroke in 188 unselected, previously not demented patients aged 60–80 years was assessed with a comprehensive screening test, the Mattis Dementia Rating Scale, and compared to an age-matched population sample. Significant impairment occurred in 32, 26 and 26% of the stroke patients at 1, 6 and 12 months, which correlated to subjective complaints and a dependent life after discharge. Most patients scored stable or improved (84%), while 16% deteriorated significantly. Intellectual impairment correlated to CT lesion size and central atrophy, age and pre-stroke lower functional and social activity, as well as to stroke-induced handicap including aphasia, neglect, and increased mood symptoms. Thus, stroke-induced brain damage influences general intellectual function but may not be the sole reason for intellectual impairment.

Acute Ischemic Stroke and Long-Term Outcome After Thrombolysis Nationwide Propensity Score–Matched Follow-Up Study

Background and Purpose— Data on long-term outcome after intravenous tissue-type plasminogen activator (tPA) in ischemic stroke are limited. We examined the risk of long-term mortality, recurrent ischemic stroke, and major bleeding, including intracranial and gastrointestinal bleeding, in intravenous tPA-treated patients when compared with intravenous tPA eligible but nontreated patients with ischemic stroke. Methods— We conducted a register-based nationwide propensity score–matched follow-up study among patients with ischemic stroke in Denmark (2004–2011). Cox regression analysis was used to compute adjusted hazard ratios for all outcomes. Results— Among 4292 ischemic strokes (2146 intravenous tPA-treated and 2146 propensity score–matched nonintravenous tPA-treated patients), with a follow-up for a median of 1.4 years, treatment with intravenous tPA was associated with a lower risk of long-term mortality (adjusted hazard ratio, 0.66; 95% confidence interval, 0.49–0.88). The long-term risk of recurrent ischemic stroke (adjusted hazard ratio, 1.05; 95% confidence interval, 0.68–1.64) and major bleeding (adjusted hazard ratio, 0.59; 95% confidence interval, 0.24–1.47) did not differ significantly between the intravenous tPA-treated and nontreated patients. Conclusions— Treatment with intravenous tPA in patients with ischemic stroke was associated with improved long-term survival.