Adverse Events and All-Cause Mortality in Danish Patients with Cerebral Venous Thrombosis: A Nationwide Cohort Study.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare manifestation of stroke and venous thromboembolism (VTE), compared with deep vein thrombosis (DVT) and pulmonary embolism (PE). We examined whether CVT was associated with adverse cardiovascular events. METHODS: A Danish cohort study with adult patients diagnosed with CVT (N = 1,015) between 1997 and 2017. We matched 10 patients with VTE (DVT and PE) to each patient with CVT for age, sex, and diagnosis year. We also matched 10 individuals from the general population to each patient with CVT. We computed cumulative incidence and estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs) at 5 years for major bleeding, intracranial bleeding, ischemic stroke, and cardiovascular events. Death was examined separately. RESULTS: Major bleeding risks were 1.2% for CVT and 0.7% for VTE at 6 months; these risks increased to 2.7% and 2.6%, respectively, at 5 years. Although rare, intracranial bleeding risks were markedly higher for CVT (2.9%) than for VTE (0.4%) at 5 years (HR = 8.9, 95% CI: 5.3-15.1). Incidences of ischemic stroke were 5.9% for CVT and 0.3% for VTE, at 6 months; and 10.0% and 1.4%, respectively, at 5 years (HR = 9.5, 95% CI: 7.1-12.7). In contrast, incidence of cardiac events was lower for CVT that VTE (1.7% vs. 3.6% at 5 years). Mortality risk was higher after CVT compared with VTE, at 6 months (6.6% vs. 3.8%), but the risks differed little at 5 years (14.3% vs. 14.1%). CONCLUSION: Intracranial bleeding, ischemic stroke, and mortality risks were higher for patients with CVT than matched patients with VTE and the general population, particularly within 6 months after diagnosis.

Incidence and prognostic factors for recurrence of intracerebral hemorrhage in patients with and without atrial fibrillation: A cohort study.

BACKGROUND: Intracerebral hemorrhage is a devastating vascular event. Clinical factors prognostic of recurrence facilitating individualized post-bleeding patient management are sparsely described. We aimed to describe incidence of recurrence of intracerebral hemorrhage and explore the prognostic value of 25 clinical characteristics in patients with and without atrial fibrillation. METHODS: Cohort study of patients with incident intracerebral hemorrhage diagnosed from 2003 to 2016 identified using nationwide Danish administrative registries. Results reported as cumulative incidence of intracerebral recurrence accounting for competing risk of death. Univariate and multivariate prognostic factors for recurrence estimated using Cox regression (hazard ratios [HRs], 95% confidence intervals [CI]). RESULTS: We identified 9255 patients with incident intracerebral hemorrhage (median age 73 years, 46.6% females, 16% with atrial fibrillation). Five-year risks of recurrence of intracerebral hemorrhage were approximately 10% in the study population, although slightly higher for patients without atrial fibrillation. Prognostic factors for recurrence were broadly similar for patients with and without atrial fibrillation. Age in categories <60 years (reference), age 60-70 years (HR 1.29, 95% CI 1.02-1.64), age 70-80 years (HR 1.59, 95% CI 1.26-2.00), age >80 years (HR 1.19, 95% CI 0.91-1.55), nursing home residency (HR 1.48, 95% CI 1.02-2.13), and Scandinavian Stroke Scale score ('mild' versus 'moderate' (HR 1.40, 95% CI 1.13-1.72) and 'severe' (HR 1.96, 95% CI 1.61-2.39)) were the strongest prognostic factors. CONCLUSION: Risk of recurrence of intracerebral hemorrhage after five years was approximately 10%. Clinical characteristics associated with recurrence were few and broadly similar for patients with and without atrial fibrillation, with age and measure of incident bleeding severity, as reflected by Scandinavian Stroke Scale score, being the most important.

Risk Stratification for Ischemic Cerebrovascular Events and Mortality among Intracerebral Hemorrhage Patients with and without Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: Intracerebral hemorrhage is a devastating clinical event, and secondary prevention is pivotal to avoid further cerebral complications, but no clear guidance exist for selecting high-risk patients. The CHA2DS2-VASc score is a widespread tool to assess the risk of stroke among patients with atrial fibrillation (AF). OBJECTIVES: We investigated the ability of the CHA2DS2-VASc score for estimating cerebrovascular ischemic events in patients with recent intracerebral hemorrhage with or without comorbid AF. METHODS: Patients with a diagnosis of intracerebral hemorrhage between 2003 and 2018 were considered for inclusion. Four registries were linked to obtain individual-level information, and included patients were followed for the occurrence of cerebrovascular ischemic events and all-cause mortality. We report absolute risks at 5 years stratified by baseline CHA2DS2-VASc score and AF prevalence. RESULTS: The study included 12,245 patients (46.4% females) of whom 19% had prevalent AF. Patients without AF were younger (mean age: 70 vs. 78 years) and had a lower CHA2DS2-VASc score (2.5 vs. 3.6). The overall 5-year risk of cerebrovascular ischemic events was 5.2% (95% CI 4.7-5.6) for patients without AF and 7.3% (95% CI 6.0-8.5) for AF patients; all-cause mortality was higher than 30 and 50% in patients without or with AF, respectively. The predictive performance of the CHA2DS2-VASc score was poor with c-statistics around 0.56 regardless of AF status. Among patients without AF, a score ≥6 was associated with a 7.0% risk of cerebrovascular ischemic events. In patients with AF, the associated risk was lowest for patients with a CHA2DS2-VASc score of 1 (4.1%) and highest among those with a score of 5 (11.9%). CONCLUSION: In this nationwide cohort of intracerebral hemorrhage patients with or without AF, the risk of cerebrovascular ischemic events and mortality was substantial. The CHA2DS2-VASc score may be used for the estimation of stroke risk in patients sustaining an intracerebral hemorrhage, although its discriminative performance was poor.

White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction.

BACKGROUND: Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA2DS2VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. METHODS: In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA2DS2VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. RESULTS: White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA2DS2VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA2DS2VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73). CONCLUSIONS: An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA2DS2VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence.

Multiple Silent Lacunes Are Associated with Recurrent Ischemic Stroke.

BACKGROUND: Silent lacunes are a common finding on brain imaging in ischemic stroke patients, but the prognostic significance of these lesions is uncertain. We aimed at investigating the association of silent lacunes and the risk of ischemic stroke recurrence, death, and cardiovascular events in a cohort of patients with incident ischemic stroke and no atrial fibrillation (AF). METHODS: We included 786 patients (mean age 59.5 (SD 14.0); 42.9% females) in a registry-based, observational cohort study on patients with first-ever ischemic stroke. On brain MRI we assessed the number of silent lacunes as none, single, or multiple and we calculated stratified incidence rates of the outcomes. Cox proportional hazard ratios (HRs) adjusted for age, gender, congestive heart failure, hypertension, diabetes, and vascular disease were calculated with no silent lacunes as reference. In additional analyses, we further adjusted for white matter hyperintensities. Patients were followed up until death or recurrence of ischemic stroke. RESULTS: In 81 (10.3%) patients, a single silent lacune was present, and in 87 (11.1%) patients, multiple silent lacunes were present. Patients with at least one silent lacune were older (mean age 66.1 vs. 57.7, p < 0.001) and were more often hypertensive (60.1 vs. 43.4%, p < 0.001) compared to patients with no silent lacunes. During a median follow-up time of 2.9 (interquartile range 3.1) years, we observed 53 recurrent ischemic strokes, 76 deaths, and 96 cardiovascular events. Incidence rates per 100 person-years of ischemic stroke recurrence were 1.6, 2.5, and 5.0 for none, single, and multiple silent lacunes respectively. Corresponding incidence rates were 2.6, 2.4, and 4.4 for death, and 3.4, 4.0, and 6.6 for cardiovascular events respectively. Adjusted HRs of ischemic stroke recurrence were 1.53 (0.67-3.49) and 2.52 (1.25-5.09) for a single and multiple silent lacunes, respectively. Further adjustment for white matter hyperintensities maintained positive association although not significant. Corresponding adjusted HRs were 0.56 (0.25-1.25) and 0.65 (0.33-1.25) for death and 1.16 (0.61-2.22) and 1.51 (0.86-2.66) for cardiovascular events. CONCLUSIONS: In this large cohort of patients with incident ischemic stroke and no AF, an increasing number of silent lacunes was associated with increasing incidence rates of ischemic stroke recurrence. In the adjusted Cox proportional hazard analyses, the presence of multiple silent lacunes was significantly associated with an increased risk of ischemic stroke recurrence. The risk of death or cardiovascular events was not significantly influenced by the presence of silent lacunes.

Recurrent Stroke: The Value of the CHA2DS2VASc Score and the Essen Stroke Risk Score in a Nationwide Stroke Cohort.

BACKGROUND AND PURPOSE: The CHA2DS2VASc score and the Essen Stroke Risk Score are respectively used for risk stratification in patients with atrial fibrillation and in patients with cerebrovascular incidents. We aimed to test the ability of the 2 scores to predict stroke recurrence, death, and cardiovascular events (stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism) in a nationwide Danish cohort study, among patients with incident ischemic stroke and no atrial fibrillation. METHODS: We conducted a registry-based study in patients with incident ischemic stroke and no atrial fibrillation. Patients were stratified according to the CHA2DS2VASc score and the Essen Stroke Risk Score and were followed up until stroke recurrence or death. We estimated stratified incidence rates and hazard ratios and calculated the cumulative risks. RESULTS: 42 182 patients with incident ischemic stroke with median age 70.1 years were included. The overall 1-year incidence rates of recurrent stroke, death, and cardiovascular events were 3.6%, 10.5%, and 6.7%, respectively. The incidence rates, the hazard ratios, and the cumulative risk of all outcomes increased with increasing risk scores. C-statistics for both risk scores were around 0.55 for 1-year stroke recurrence and cardiovascular events and correspondingly for death around 0.67 for both scores. CONCLUSIONS: In this cohort of non-atrial fibrillation patients with incident ischemic stroke, increasing CHA2DS2VASc score and Essen Stroke Risk Score was associated with increasing risk of recurrent stroke, death, and cardiovascular events. Their discriminatory performance was modest and further refinements are required for clinical application.

Central neuronal mechanisms of gastric electrical stimulation in diabetic gastroparesis.

OBJECTIVE: The mechanisms underlying symptom improvement in gastric electrical stimulation (GES) are not fully understood. Modulation of the central nervous system excitability may be involved. The objective of the study was to investigate the central effects of GES, including the possible modulation of the visceral sensory nervous system. MATERIAL AND METHODS: A gastric electrical stimulator was implanted in seven diabetic patients with medically refractory gastroparesis. A double-blinded protocol was used to investigate the patients at baseline and one month after recovery with the stimulator turned on and off (1-month periods). The following assessments were carried out: mechanical, thermal and electrical stimulations with sensory recordings in the esophagus and duodenum, and standardized, self-administered, daily symptom questionnaires. RESULTS: No difference was found between baseline and the on- and off periods in overall gut pain thresholds across all stimulus modalities in the esophagus (p=0.63), duodenum (p=0.19) or esophagus and duodenum combined (p=0.76). No difference in the sensory response to mechanical stimulation was found in the esophagus before (all p>0.31) and after (all p>0.43) smooth muscle relaxation with butylscopolamine. Similar findings were observed in the duodenum. No differences were found in thermal sensitivity (esophagus (p=0.67) and duodenum (p=0.17)), sensory response to electrical stimulation (esophagus (p=0.57) and duodenum (p=0.52)) or induced somatic referred pain areas (esophagus (p=0.75) and duodenum (p=0.51)). No difference was seen in the induced somatic referred pain areas or self-reported symptoms. CONCLUSIONS: No evidence was found for GES-induced modulation of the visceral sensory system and central excitability. However, GES has been proven to modulate the central nervous system in animal studies, necessitating further human experiments in order unambiguously to establish the possible central effects of GES.

Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1.

AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy. METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed. RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 +/- 0.6 vs 3.3 +/- 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 +/- 0.6 vs 0.5 +/- 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P < 0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14). CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.

Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis.

OBJECTIVES: Comprehensive experimental methods are of major relevance assessing pain mechanisms in patients with chronic pain. Chronic pancreatitis is thought to involve the sensory response in other visceral organs and somatic tissue. We, therefore, aimed at exploring the pain mechanisms in chronic pancreatitis (CP) using a multimodal and multitissue stimulation approach. METHODS: Ten patients (mean age, 50 years) with CP and 13 healthy controls (mean age, 35 years) participated. None of the patients took analgesics regularly. All were exposed to multimodal (mechanical, thermal, and electrical) experimental pain in the skin, muscles, and esophagus. RESULTS: The patients were hyposensitive to mechanical stimulations of the skin (P = 0.001), but there were no differences in the pain to thermal and electrical stimulations. In the muscle and esophagus, no differences in pain thresholds were found. The difference between single and repeated stimulations reflecting the degree of central sensitization was 17% in controls and 36% in patients (P = 0.001). The referred pain area to electrical stimulation was 30.1 cm2 in the patients and 7.7 cm2 for the controls (P = 0.02). CONCLUSIONS: The findings suggest that the balance among central hyperexcitability, neuroplastic changes, and descending pain-modulating pathways may explain the pain response to experimental multimodal stimulations in CP. This will likely also reflect the clinical pain mechanisms and may have important impact in selection of treatment, where drugs with potential effects on these mechanisms should be used.

Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study.

OBJECTIVE: Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis. MATERIAL AND METHODS: Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration. RESULTS: In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F=12.4, p<0.001, muscle: F=11.0, p<0.001) and thermally (skin: F=8.5, p<0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F=9.5, p<0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F=8.6, p<0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied. CONCLUSIONS: Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.

Ultrasound-determined geometric and biomechanical properties of the human duodenum.

Methods based on cross-sectional ultrasound imaging may be valuable for assessment of biomechanical parameters in the duodenum in health and disease. In 12 healthy volunteers a specially designed duodenal bag containing a high-frequency ultrasound probe was inflated until the perception of moderate pain. The ultrasound images and bag pressures were recorded before and after administration of butylscopolamine. The duodenum approached a circular shape as the load was increased (P = 0.01). The tension-strain relations were exponential and the curve fitting constant alpha (stiffness) was 1.72+/-0.81 before and 1.13+/-0.22 after administration of butylscopolamine (P=0.5). In three subjects construction of stress-strain diagrams was possible. The wall thickness decreased after administration of butylscopolamine (P < 0.001). The wall thickness was nonhomogeneously distributed along the duodenal circumference, being thickest at high curvatures. In the future this may be useful for assessing the geometry, stiffness, remodeling, and mechanosensory properties in the duodenum and small intestine in health and disease.

A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model.

Visceral pain can be difficult to treat with classical mu-opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles. In animal experiments, oxycodone has shown different effects compared to morphine, and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine in the treatment of visceral pain. In the current study, we randomised 24 healthy subjects to treatment with either morphine (30 mg), oxycodone (15 mg) or placebo in a crossover study. The experimental pain model involved multi-modal (mechanical, thermal and electrical) pain tests in the skin, muscles and viscera. The pain tests were carried out at baseline and 30, 60 and 90 min after oral administration of the drugs. The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues (all P values <0.001). Both opioids attenuated the sensory response mainly to painful stimulations. Morphine and oxycodone were equipotent in pain modulation of the skin and muscles, but oxycodone had superior analgesic effect to both morphine and placebo on the mechanical (P<0.001) and thermal (P<0.001) stimulations of the oesophagus. In conclusion, the multi-modal and tissue-differentiated pain model could link findings from animal experiments to clinical findings. A different pharmacological profile of oxycodone compared to that of morphine was shown, and thus oxycodone may be a useful alternative to morphine in the treatment of visceral pain syndromes.

Multi-modal and tissue-differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics.

Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (>0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.

An experimental study of viscero-visceral hyperalgesia using an ultrasound-based multimodal sensory testing approach.

Widespread visceral hypersensitivity and the overlap of symptom complexes observed in functional gastrointestinal disorders may be related to central sensitization and neuroplastic changes. A multimodal and multi-segmental model was developed to evaluate viscero-visceral hyperalgesia induced by experimental esophageal sensitization in healthy volunteers. Twelve healthy subjects were studied using a double-blinded, placebo-controlled design. The sensitivity to mechanical and heat stimulations was assessed in the proximal esophagus, duodenum and rectum before and after perfusion of the distal esophagus with acid or saline. A special-designed probe was used allowing cross-sectional ultrasound imaging during mechanical and heat stimulation of the esophagus and duodenum. Another probe was used for mechanical stimulation of the rectum. The referred somatic pain areas to gut pain stimulations were also assessed. Following acid perfusion 11 of 12 volunteers showed increased sensitivity to one or more stimulation modalities. An overall increased sensitivity to mechanical stretch in the three gut segments was seen (P=0.0001). Posthoc analysis showed that this was mainly due to increased sensitivity in the rectum (P<0.001). No changes were seen to thermal stimulations (all P-values>0.4). The somatic referred pain area to duodenal stimulations increased (P=0.04), while it was unaffected to esophageal and rectal stimulations (P>0.3). The present method demonstrated a new approach to assess multimodal sensitivity to experimental sensitization of the esophagus and related viscero-visceral hyperalgesia. Central mechanisms can explain the remote hyperalgesia to mechanical visceral stimulation and the increase in referred pain areas. The present method may be used to explore pathophysiology and pharmacological interventions in patients with visceral hypersensitivity.