Assessment of Pain Modulatory and Somatosensory Profiles in Chronic Tension-Type Headache Patients.

OBJECTIVE: The aim of this study was to thoroughly phenotype a group of chronic tension-type headache (CTTH) patients. METHODS: Fifteen CTTH patients diagnosed according to the International Classification of Headache Disorders-3 and 15 healthy controls were included in this study. Furthermore, 70 healthy controls were included to establish normative values. Quantitative sensory testing (QST), including temporal summation of pain (TSP), conditioned pain modulation (CPM), and psychological and sleep variables, was assessed in a single session. TSP and CPM were then combined to build pain modulation profiles (PMP) for each individual. RESULTS: No difference was found between groups for PMP, TSP, and CPM. However, 10 CTTH patients showed a pronociceptive PMP, with 8 related to a deficient CPM and 2 to both a deficient CPM and increased TSP. Increased cold detection thresholds were the most common sensory disturbance found in CTTH patients. Significant differences were seen between groups for pain catastrophizing, depression, and sleep quality although not all patient's scores were above the clinically meaningful cutoffs. CONCLUSIONS: In summary, CTTH patients presented with different PMP. These PMP may be related to increased TSP, deficient CPM, alterations in thermal detection that may be related to autonomic dysregulation, or a combination of all three. Overall, this suggests that due to their heterogeneous pathophysiology, CTTH patients should be managed according to their underlying pathophysiology and not with a one-size-fits-all approach.

Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 3rd edition, 2020.

Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.

Marine n-3 Polyunsaturated Fatty Acids and the Risk of Ischemic Stroke.

Background and Purpose- We hypothesized that total marine n-3 polyunsaturated fatty acids (PUFA), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the diet and in adipose tissue (biomarkers of long-term intake and endogenous exposure) were inversely associated with the risk of ischemic stroke and its subtypes. Methods- The Diet, Cancer and Health cohort consisted of 57 053 participants aged 50 to 65 years at enrolment. All participants filled in a food frequency questionnaire and had an adipose tissue biopsy taken at baseline. Information on ischemic stroke during follow-up was obtained from The Danish National Patient Register, and all cases were validated. Cases and a random sample of 3203 subjects from the whole cohort had their fatty acid composition of adipose tissue determined by gas chromatography. Results- During 13.5 years of follow-up 1879 participants developed an ischemic stroke. Adipose tissue content of EPA was inversely associated with total ischemic stroke (hazard ratio [HR], 0.74; 95% CI, 0.62-0.88) when comparing the highest with the lowest quartile. Also, lower rates of large artery atherosclerosis were seen with higher intakes of total marine n-3 PUFA (HR, 0.69; 95% CI, 0.50-0.95), EPA (HR, 0.66; 95% CI, 0.48-0.91) and DHA (HR, 0.72; 95% CI, 0.53-0.99), and higher adipose tissue content of EPA (HR, 0.52; 95% CI, 0.36-0.76). Higher rates of cardioembolism were seen with higher intakes of total marine n-3 PUFA (HR, 2.50; 95% CI, 1.38-4.53) and DHA (HR, 2.12; 95% CI, 1.21-3.69) as well as with higher adipose tissue content of total marine n-3 PUFA (HR, 2.63; 95% CI, 1.33-5.19) and DHA (HR, 2.00; 95% CI, 1.04-3.84). The EPA content in adipose tissue was inversely associated with small-vessel occlusion (HR, 0.69; 95% CI, 0.55-0.88). Conclusions- EPA was associated with lower risks of most types of ischemic stroke, apart from cardioembolism, while inconsistent findings were observed for total marine n-3 PUFA and DHA.

Treatment of acute migraine by a partial rebreathing device: A randomized controlled pilot study.

Background Impaired brain oxygen delivery can trigger and exacerbate migraine attacks. Normoxic hypercapnia increases brain oxygen delivery markedly by vasodilation of the cerebral vasculature, and hypercapnia has been shown to abort migraine attacks. Stable normoxic hypercapnia can be induced by a compact partial rebreathing device. This pilot study aimed to provide initial data on the device's efficacy and safety. Methods Using a double-blinded, randomized, cross-over study design, adult migraine-with-aura patients self-administered the partial rebreathing device or a sham device for 20 minutes at the onset of aura symptoms. Results Eleven participants (mean age 35.5, three men) self-treated 41 migraine attacks (20 with the partial rebreathing device, 21 with sham). The partial rebreathing device increased mean End Tidal CO2 by 24%, while retaining mean oxygen saturation above 97%. The primary end point (headache intensity difference between first aura symptoms and two hours after treatment (0-3 scale) - active/sham difference) did not reach statistical significance (-0.55 (95% CI: -1.13-0.04), p = 0.096), whereas the difference in percentage of attacks with pain relief at two hours was significant ( p = 0.043), as was user satisfaction ( p = 0.022). A marked efficacy increase was seen from first to second time use of the partial rebreathing device. No adverse events occurred, and side effects were absent or mild. Conclusion Normoxic hypercapnia shows promise as an adjunctive/alternative migraine treatment, meriting further investigation in a larger population. Clinical study registered at ClinicalTrials.gov with identifier NCT03472417.

Substitution of Linoleic Acid for Other Macronutrients and the Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its subtypes with a higher intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or glycemic carbohydrates. METHODS: In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline, information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic stroke adjusting for appropriate confounders. RESULTS: During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard ratio, 0.98; 95% confidence interval, 0.83-1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval, 0.63-1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78-1.09), although not statistically significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions. CONCLUSIONS: This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty acid with linoleic acid may be associated with a lower risk of ischemic stroke.

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.

Predictive value of stroke discharge diagnoses in the Danish National Patient Register.

AIMS: To determine the positive predictive values for stroke discharge diagnoses, including subarachnoidal haemorrhage, intracerebral haemorrhage and cerebral infarction in the Danish National Patient Register. METHODS: Participants in the Danish cohort study Diet, Cancer and Health with a stroke discharge diagnosis in the National Patient Register between 1993 and 2009 were identified and their medical records were retrieved for validation of the diagnoses. RESULTS: A total of 3326 records of possible cases of stroke were reviewed. The overall positive predictive value for stroke was 69.3% (95% confidence interval (CI) 67.8-70.9%). The predictive values differed according to hospital characteristics, with the highest predictive value of 87.8% (95% CI 85.5-90.1%) found in departments of neurology and the lowest predictive value of 43.0% (95% CI 37.6-48.5%) found in outpatient clinics. CONCLUSIONS: The overall stroke diagnosis in the Danish National Patient Register had a limited predictive value. We therefore recommend the critical use of non-validated register data for research on stroke. The possibility of optimising the predictive values based on more advanced algorithms should be considered.

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.

A comparison of coping strategies in patients with fibromyalgia, chronic neuropathic pain, and pain-free controls.

Patients suffering from chronic pain may benefit from learning adaptive coping strategies. Consensus on efficient strategies for this group of patients is, however, lacking, and previous studies have shown inconsistent results. The present study has examined coping strategies in two distinctly different groups of chronic pain patients and a group of healthy controls. Thirty neuropathic pain (NP) patients, 28 fibromyalgia (FM) patients, and 26 pain-free healthy controls completed the Coping Strategy Questionnaire (CSQ-48/27) and rated their daily pain. The results showed that FM and NP patients did not cope differently with pain. The only difference between the groups was that FM patients felt more in control of their pain than NP patients. Both patient groups used more maladaptive/passive coping strategies, but surprisingly also more adaptive/active coping strategies than healthy controls. However, FM patients with high levels of passive strategies felt less in control than FM patients with low levels of passive strategies. This was not seen in NP patients. An important implication for clinical practice is therefore that passive coping strategies should be restructured into active ones, especially for FM patients. Otherwise, the same psychological treatment model can be applied to both groups since they use similar coping styles.

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.

Impact of variability in baseline pain on the placebo response in randomized, placebo-controlled, crossover trials in peripheral neuropathic pain.

ABSTRACT: Large placebo responses often negatively affect randomized controlled trials within the pain area. Understanding different possible factors that influence the placebo response is therefore important. In this retrospective analysis, we hypothesized that a large variability in baseline pain score would predict a greater placebo response and analyzed the impact of the coefficient of variation, SD, and difference between the highest and lowest numeric rating scale (NRS) score at baseline on the placebo response. A total of 160 observations on placebo response from 3 controlled clinical trials with a crossover design were included in this study. In general, the placebo response was low with a mean reduction in pain intensity of 0.5 points (range -5 to 7) measured on a 0 to 10 point NRS, and only 15% were placebo responders as defined by more than 30% reduction in NRS pain score from baseline to the end of the placebo treatment period. We found no significant impact of baseline pain coefficient of variation, SD, or the difference between lowest and highest baseline pain score on the placebo response. Placebo response in one trial did not predict placebo response in another trial. A large placebo response was not associated with a large treatment response. In conclusion, in this retrospective data analysis, there was no impact of baseline pain variability on the placebo response in controlled clinical trials with a crossover design in patients with peripheral neuropathic pain.

Relationships between changes in pain severity and other patient-reported outcomes: an analysis in patients with posttraumatic peripheral neuropathic pain.

BACKGROUND: The objective of this study is to use the pain numeric rating scale (NRS) to evaluate associations between change in pain severity and changes in sleep, function, and mood assessed via patient-reported outcomes (PROs) in patients with posttraumatic pain. METHODS: This is a secondary analysis of a clinical trial evaluating pregabalin in patients with posttraumatic peripheral neuropathic pain (N = 254). Regression models were used to determine associations between changes in pain (0-10 NRS) as the predictor and scores on the following PRO measures as the outcome: Pain Interference Index; Hospital Anxiety and Depression Scale anxiety and depression subscales; Medical Outcomes Study-Sleep Scale 9-item Sleep Problems Index and Sleep Disturbance subscale; and Daily Sleep Interference Scale (0-10 NRS). RESULTS: Change in pain severity showed clear, direct relationships with changes in function, anxiety, depression, and sleep PROs, all of which were statistically significant (P <.001). Results from subgroup analyses (≥30% or ≥50% pain responders, pregabalin or placebo treatment, age ≤ 51 years or > 51 years) tended to be consistent with results from the overall sample. CONCLUSIONS: Overall, a direct relationship exists between pain and various aspects of patient's well-being and functioning, which can provide a quantitative assessment of how improvements in pain may be expected to relate to other patient outcomes. (http://ClinicalTrials.gov Identifier number NCT00292188; EudraCT #2005-003048-78).

A randomized, controlled trial of a ß2-agonist in painful polyneuropathy.

ABSTRACT: Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a ß2-agonist action. The aim of this study was to test if the ß2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo-controlled and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5-15 mg), imipramine (30-150 mg), or placebo in a random order. Drug doses depended on age and metabolizer status. The change in total pain recorded from ratings in diaries (numeric rating scale [NRS] 0-10) was the primary outcome, and the change in rating of specific pain symptoms (NRS 0-10), patient global impression of change, and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. The median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared with placebo of 0.13 (95% confidence interval -0.12 to 0.38, P = 0.32). The median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared with placebo of -1.17 (95% confidence interval -1.42 to -0.92, P < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The ß2-agonist terbutaline has no effect in painful polyneuropathy. ß2-agonism seems not to be an important mechanism of action of tricyclic antidepressants in neuropathic pain.

Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort.

OBJECTIVE: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS. METHODS: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response. RESULTS: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking. INTERPRETATION: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.

Factors with impact on magnitude of the placebo response in randomized, controlled, cross-over trials in peripheral neuropathic pain.

The presence and magnitude of placebo responses is important for the outcome in clinical trials of analgesics. This explorative study aimed at identifying patients and trial-specific factors with impact on this response in randomized, controlled, cross-over trials in peripheral neuropathic pain. Data were derived from 7 trials and included observations on pinprick hyperalgesia, allodynia, and pain on repetitive stimulation. The studies were all performed by the same collaboration group in Denmark. Pain was rated daily using numeric 0 to 10 point rating scales (NRS) and placebo response was calculated as the difference in weekly average or median numeric rating scale from baseline to the last week of treatment. A clinically meaningful placebo response was defined as more than 30% reduction of pain on placebo. In 318 individual observations, the response was on average small (0.17 points, range -4.5 to 6). There was no significant impact on size of placebo response of trial-specific factors such as treatment sequence and chance of having placebo treatment in each period or of the patient-specific factors age, sensory signs, and pain symptoms. The findings were similar in patients having placebo in the first treatment period. There was no marked difference between patients with (n = 43) and without (n = 275) a clinically meaningful placebo response with respect to the patient-specific factors including frequency of sensory signs and symptoms. In conclusion, this study on cross-over trials in peripheral neuropathic pain found no robust impact of trial and patient-specific factors on the placebo response.

Abnormal neurovascular coupling as a cause of excess cerebral vasodilation in familial migraine.

AIMS: Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R mice) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these α2+/G301R mice also have increased cerebrovascular hyperaemic responses to these local metabolites leading to hyperperfusion in the affected part of the brain. METHODS AND RESULTS: Neurovascular coupling was compared in α2+/G301R and matching wild-type (WT) mice using Laser Speckle Contrast Imaging. In brain slices, parenchymal arteriole diameter and intracellular calcium changes in neuronal tissue, astrocytic endfeet, and smooth muscle cells in response to neuronal excitation were assessed. Wall tension and smooth muscle membrane potential were measured in isolated middle cerebral arteries. Quantitative polymerase chain reaction, western blot, and immunohistochemistry were used to assess the molecular background underlying the functional changes. Whisker stimulation induced larger increase in blood perfusion, i.e. hyperaemic response, of the somatosensory cortex of α2+/G301R than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from α2+/G301R than WT mice. These hyperaemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (Kir). Relaxation to elevated bath K+ was larger in arteries from α2+/G301R compared to WT mice. This difference was endothelium-dependent. Endothelial Kir2.1 channel expression was higher in arteries from α2+/G301R mice. No sex difference in functional responses and Kir2.1 expression was found. CONCLUSION: This study suggests that an abnormally high cerebrovascular hyperaemic response in α2+/G301R mice is a result of increased endothelial Kir2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack.

Autonomic skin responses in females with Fabry disease.

Fabry disease is a genetic lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system and with neuropathy as a prominent manifestation. Neurological symptoms include pain and autonomic dysfunction. This study examined peripheral autonomic nerve function in 19 female patients with Fabry disease and 19 sex and age-matched controls by measuring (1) sweat production following acetylcholine challenge; (2) the sympathetically mediated vasoconstrictor responses to inspiratory gasp, stress, and the cold pressor test; and (3) cutaneous blood flow following capsaicin. The vasoconstrictor response to inspiratory gasp was increased in Fabry patients compared to controls (p = 0.03), while the response to cold and mental stress did not change. Female patients with Fabry disease had a reduced sweat response to iontophoresis of acetylcholine (p = 0.04) and a smaller capsaicin-induced flare compared to controls. These findings suggest that female patients both have an impaired C-fiber function and local abnormalities in blood vessels and sweat glands.

Effect of lacosamide in peripheral neuropathic pain: study protocol for a randomized, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite decades of research, it remains difficult to treat neuropathic pain. Lacosamide is a sodium-channel blocker that is efficacious in animal models of neuropathic pain. In humans, its effect in neuropathic pain is inconclusive, based on inconsistent results and very large placebo responses. Previous trials have not used patient stratification or looked for predictors for response. METHODS: This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 2, proof-of-concept, phenotype-stratified study. The study will enroll 108 patients with peripheral neuropathic pain who will be randomized to a 12-week treatment with lacosamide or placebo up to 400 mg/day in a 2:1 ratio. The primary objective is to compare the change in the mean value of the patients' daily ratings of average pain intensity from baseline to the last week of treatment in patients with and without the irritable nociceptor phenotype in the per-protocol population. A supportive objective is to compare the effect of lacosamide with that of placebo in the two phenotypes. Secondary and tertiary outcomes include the Patient Global Impression of Change, pain relief, presence of 30% and 50% pain reduction, sleep disturbance, depression, and anxiety. DISCUSSION: We will examine the concept of individualized therapy based on phenotyping, and expect that this study will provide important information on the usefulness of lacosamide in the treatment of peripheral neuropathic pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03777956 . Registered on 18 December 2018.

Experimental forearm immobilization in humans induces cold and mechanical hyperalgesia.

BACKGROUND: Complex regional pain syndrome is a painful condition of unknown etiology. Clinical and experimental observations suggest that limb immobilization may induce symptoms and signs characteristic of complex regional pain syndrome. This study examined the effect of forearm immobilization on regional sensory and autonomic functions in healthy subjects. METHODS: Thermal and mechanical sensitivity, skin temperature, and vasoconstrictor responses were measured in 30 healthy subjects before and 0, 3, and 28 days after scaphoid cast immobilization. Fifteen subjects served as nonimmobilized controls. RESULTS: At cast removal, 27 subjects experienced pain at joint movement. Cast immobilization induced cold hyperalgesia in glabrous and hairy skin on the immobilized hand and induced significant skin temperature differences between the control and the immobilized hand at cast removal and after 3 days. Immobilization also reduced pain threshold at skin fold testing at all time points after cast removal. All measures except pain threshold at skin fold testing were normalized after 28 days. Immobilization did not affect thermal detection, heat pain, and pressure pain thresholds; resting skin perfusion; or vasoconstrictor responses induced by mental stress or deep inspirations. CONCLUSIONS: Four weeks of forearm immobilization caused transient changes in skin temperature, mechanosensitivity, and thermosensitivity, without alteration in the sympathetically mediated vascular tone.

Substitution of Fish for Red Meat or Poultry and Risk of Ischemic Stroke.

We investigated the risk of ischemic stroke and its subtypes when red meat or poultry was substituted with fish. A total of 57,053 participants aged 50⁻65 years at baseline were included in the Danish Diet, Cancer and Health study. All participants filled in a food-frequency questionnaire at recruitment. Potential ischemic stroke cases were identified by linkage to the Danish National Patient Register, and all cases were validated and subclassified. Substitutions were investigated as 150 g/week of fish for 150 g/week of red meat or of poultry using multivariable Cox proportional hazard regression models. During 13.5 years of follow-up, 1879 participants developed an ischemic stroke. Replacing red meat or poultry with fish was not associated with the rate of total ischemic stroke, but there was a statistically significant lower rate of large artery atherosclerosis when fish replaced processed (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.67; 0.90) and unprocessed (HR: 0.87; 95% CI: 0.75; 0.99) red meat. A statistically significant higher rate of cardioembolism was found when poultry was replaced by total fish (HR: 1.42; 95% CI: 1.04; 1.93). When fatty fish replaced unprocessed red meat, a statistically significant lower rate of small-vessel occlusion was found (HR: 0.88; 95% CI: 0.77; 0.99). In conclusion, replacing red meat with fish was not associated with risk of total ischemic stroke but was associated with a lower risk of subtypes of ischemic stroke.