Prospective cohort study of routine exercise and headache outcomes among adults with episodic migraine.

OBJECTIVE: To evaluate the association of routine exercise with headache frequency, intensity, and duration among adults with episodic migraine (EM). BACKGROUND: A comprehensive management plan for EM must aim at reducing disability and cost of care; to do so requires optimizing acute and preventive medications, and behavior changes. Prophylactic medication use is associated with adverse events and contraindications with comorbidities. Aerobic exercise is reported to decrease migraine frequency. However, no study has evaluated a potential synergistic relation between regular exercise and preventive medication use among patients with EM. DESIGN AND METHODS: This was a secondary analysis of data from a prospective cohort study of adults with EMs. In that study, adults with EM (using International Classification of Headache Disorders-3 criteria confirmed by study physicians) were recruited from three academic medical centers in Boston, MA. At baseline, participants provided information on exercise, clinical and demographic characteristics, and lifestyle behaviors. We prospectively collected daily information on headaches and health behavior over at least 6 weeks using electronic questionnaires from 94 participants. We assessed the association between baseline self-reported moderate-vigorous exercise at least three times per week, at baseline, and prospectively recorded headache frequency, intensity, and duration. We further assessed whether these associations differed by the prevalent use of prophylactic migraine medication. RESULTS: Data from 94 of 98 eligible participants were used in the analysis as 4 participants had missing data on routine exercise frequency or intensity at baseline. On average, patients who reported moderate-vigorous exercise at least three times per week at enrollment had 1.5 fewer headache days per month (-1.5 headache days/month; 95% confidence interval [CI] -3.1 to 0.1) compared to less exercise; this was not statistically significant (p = 0.066). The association between exercise and headache days per month varied by baseline use of migraine prophylaxis (p-value of interaction = 0.009). Among those who reported regular use of migraine prophylaxis, a report of moderate-vigorous exercise at least three times per week was associated with 5.1 fewer headache days (-5.1: 95% CI -8.2 to -2.0; p = 0.001) compared to those who reported lower levels of exercise. However, among those not using migraine prophylaxis, we observed only 0.4 fewer headache days per month (-0.4: 95% CI -2.2 to 1.3; p = 0.636) associated with moderate-vigorous exercise at least three times/week, a result that was not statistically significant. There was no association of self-reported moderate-vigorous exercise at least three times a week with headache intensity or duration. CONCLUSION: In patients with EM, those who reported moderate-vigorous exercise at least three times per week had fewer headache days per month, though not statistically significant. This association was significantly stronger in those who used prophylactic medication for migraines. Exercise appeared not to be associated with the severity or duration of headaches. Routine moderate-vigorous exercise may be an important adjunctive strategy for improving headache burden in patients eligible for migraine prophylaxis.

Prospective cohort study of daily alcoholic beverage intake as a potential trigger of headaches among adults with episodic migraine.

PURPOSE: To determine whether alcohol intake is associated with occurrence of headaches on the following day. METHODS: In this prospective cohort study, adults with episodic migraine completed electronic diaries every morning and evening for at least six weeks in March 2016-October 2017. Every day, participants reported alcohol intake, lifestyle factors, and details about each headache. We constructed within-person fixed-effect models adjusted for time-varying factors to calculate odds ratios for the association between 1,2,3,4, or 5+ servings of alcohol and headache the following day. We also calculated the adjusted risk of headache the following day for each level of intake. RESULTS: Among 98 participants who reported 825 headaches over 4,467 days, there was a statistically significant linear association (p-trend = 0.03) between alcohol and headache the following day. Compared to no alcohol, 1-2 servings were not associated with headaches, but 5+ servings were associated with a 2.08-fold (95% confidence interval [CI] 1.16-3.73) odds of headache. The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol compared with 33% (95%CI 22%-44%) on days following 5+ servings. CONCLUSION: 1-2 servings of alcoholic beverages were not associated with higher risk of headaches the following day, but 5+ servings were associated with higher risk. KEY MESSAGES 1-2 servings of alcoholic beverages were not associated with a higher risk of headaches on the following day, but higher levels of intake may be associated with higher risk. Five or more servings were associated with 2.08 times (95% confidence interval 1.16-3.73 the odds of headache on the following day. The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol consumption compared with 33% (95% CI 22%-44%) on days following 5+ servings.

Nightly sleep duration, fragmentation, and quality and daily risk of migraine.

OBJECTIVE: To test the hypotheses that insufficient duration, high fragmentation, and poor sleep quality are temporally associated with migraine onset on the day immediately following the sleep period (day 0) and the following day (day 1). METHODS: In this prospective cohort study of 98 adults with episodic migraine, participants completed twice-daily electronic diaries on sleep, headaches, and other health habits, and wore wrist actigraphs for 6 weeks. We estimated the incidence of migraine following nights with short sleep duration, high fragmentation, or low quality compared to nights with adequate sleep with conditional logistic regression models stratified by participant and adjusted for caffeine intake, alcohol intake, physical activity, stress, and day of week. RESULTS: Participants were a mean age of 35.1 ± 12.1 years. We collected 4,406 days of data, with 870 headaches reported. Sleep duration ≤6.5 hours and poor sleep quality were not associated with migraine on day 0 or day 1. Diary-reported low efficiency was associated with 39% higher odds of headache on day 1 (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.06-1.81). Actigraphic-assessed high fragmentation was associated with lower odds of migraine on day 0 (wake after sleep onset >53 minutes, OR 0.64, 95% CI 0.48-0.86; efficiency ≤88%, OR 0.74, 95% CI 0.56-0.99). CONCLUSION: Short sleep duration and low sleep quality were not temporally associated with migraine. Sleep fragmentation, defined by low sleep efficiency, was associated with higher odds of migraine on day 1. Further research is needed to understand the clinical and neurobiologic implications of sleep fragmentation and risk of migraine.

Weather, ambient air pollution, and risk of migraine headache onset among patients with migraine.

OBJECTIVE: Migraine is a common recurrent headache disorder affecting 14% American adults. Although weather and air pollution are often reported by patients with migraine as precipitating factors, previous studies have had mixed results. METHODS: We prospectively collected migraine headache onset data using electronic questionnaires from 98 adults with episodic migraine in the Greater Boston area (2016-2017). Each participant was followed for an average of 45 days for a total of 4406 days of observation. Temperature, relative humidity, and barometric pressure data were obtained from local weather station. Daily average fine particulate matter, daily maximum 1-hour sulfur dioxide, daily maximum 1-hour nitrogen dioxide, daily maximum 8-hour ozone, and daily maximum 8-hour carbon monoxide from local air pollution monitors. We conducted a repeated measures analysis using fixed effects logistic regression models. In the models we adjusted for day of week, a natural cubic spline term of day of the year with 4 degrees of freedom, and a participant identifier. We additionally adjusted for linear terms of temperature and relative humidity in the air pollution analyses. We also applied logistic regression models with generalized estimating equation (GEE) and autoregressive correlation structure in the sensitivity analysis. RESULTS: The mean age was 35 years and 88% were women. Mean temperature was 56.9 °F, relative humidity 67.3%, and fine particulate matter 7.3 µg/m3. Higher relative humidity was associated with higher odds of migraine headache, but the association was only observed in warm season (April-September). Higher levels of daily maximum 8-hour ozone and daily maximum 8-hour carbon monoxide appeared to be associated with higher odds of migraine headache onset in cold season (October-March). Although the associations for ozone and relative humidity were attenuated and no longer statistically significant in the overall GEE analysis, the differing associations by season remained. CONCLUSIONS: We found that higher relative humidity was associated with higher odds of migraine headache onset in warm season, and traffic-related gaseous pollutants may be associated with higher odds of migraine headache onset in cold season.

Prospective Cohort Study of Caffeinated Beverage Intake as a Potential Trigger of Headaches among Migraineurs.

PURPOSE: We aimed to evaluate the role of caffeinated beverage intake as a potential trigger of migraine headaches on that day or on the following day. METHODS: In this prospective cohort study, 101 adults with episodic migraine completed electronic diaries every morning and evening. Ninety-eight participants completed at least 6 weeks of diaries in March 2016-October 2017. Every day, participants reported caffeinated beverage intake, other lifestyle factors, and the timing and characteristics of each migraine headache. We compared a participant's incidence of migraines on days with caffeinated beverage intake to the incidence of migraines among the same individual on days with no intake, accounting for day of week. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals. RESULTS: Among 98 participants (86 women, 12 men) with mean age 35.1 years, 83% white, and 10% Hispanic or Latino, the average age when headaches started was 16.3 years. In total, the participants reported 825 migraines during 4467 days of observation. There was a statistically significant nonlinear association between the number of caffeinated beverages and the odds of migraine headache occurrence on that day (P-quadratic trend = .024), though estimates for each level of intake were not statistically significant. The associations varied according to habitual intake and oral contraceptive use. CONCLUSIONS: There was a nonlinear association between caffeinated beverage intake and the odds of migraine headache occurrence on that day. This suggests that high levels of caffeinated beverage intake may be a trigger of migraine headaches on that day.

The migraine eye: distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory.

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.

Color-selective photophobia in ictal vs interictal migraineurs and in healthy controls.

Aversion to light is common among migraineurs undergoing acute attacks. Using psychophysical assessments in patients with episodic migraine, we reported that white, blue, amber, and red lights exacerbate migraine headache in a significantly larger percentage of patients and to a greater extent compared with green light. This study aimed at determining whether these findings are phase-dependent-namely, manifested exclusively during migraine (ictally) but not in its absence (interictally), or condition-dependent-ie, expressed uniquely in migraineurs but not in healthy controls. To determine whether the color preference of migraine-type photophobia is phase- or condition-dependent, we compared the effects of each color of light in each intensity between migraineurs during and in-between attacks and healthy controls. During the ictal and interictal phases, the proportion of migraineurs reporting changes in headache severity when exposed to the different colors of light increased in accordance with elevated light intensities. During the ictal phase, white, blue, amber, and red lights exacerbated headaches in ∼80% of the patients; however, during the interictal phase, light initiated headache in only 16% to 19%. Notably, green light exacerbated headaches in 40% and triggered headaches in 3% of the patients studied during the ictal and interictal phases, respectively. With one exception (highest red light intensity), no control subject reported headache in response to the light stimuli. These findings suggest that color preference is unique to migraineurs-as it was not found in control subjects-and that it is independent of whether or not the patients are in their ictal or interictal phase.

Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine.

Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin-concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification.

Effects of Coenzyme Q10 on Skeletal Muscle Oxidative Metabolism in Statin Users Assessed Using 31P Magnetic Resonance Spectroscopy: a Randomized Controlled Study.

OBJECTIVES: Statins partially block the production of coenzyme Q10 (CoQ10), an essential component for mitochondrial function. Reduced skeletal muscle mitochondrial oxidative capacity has been proposed to be a cause of statin myalgia and can be measured using 31phosphorus magnetic resonance spectroscopy (31P-MRS). The purpose of this study is to assess the effect of CoQ10 oral supplementation on mitochondrial function in statin users using 31P-MRS. DESIGN/SETTING: In this randomized, double-blind, placebo-controlled pilot study, 21 adults aged 47-73 were randomized to statin+placebo (n=9) or statin+CoQ10 (n=12). Phosphocreatine (PCr) recovery kinetics of calf muscles were assessed at baseline (off statin and CoQ10) and 4 weeks after randomization to either statin+CoQ10 or statin+placebo. RESULTS: Baseline and post-treatment PCr recovery kinetics were assessed for 19 participants. After 4 weeks of statin+ CoQ10 or statin+placebo, the overall relative percentage change (100*(baseline-follow up)/baseline) in PCr recovery time was -15.1% compared with baseline among all participants, (p-value=0.258). Participants randomized to statin+placebo (n=9) had a relative percentage change in PCr recovery time of -18.9%, compared to -7.7% among participants (n=10) receiving statin+CoQ10 (p-value=0.448). CONCLUSIONS: In this pilot study, there was no significant change in mitochondrial function in patients receiving 4 weeks of statin+CoQ10 oral therapy when compared to patients on statin+placebo.

Migraine photophobia originating in cone-driven retinal pathways.

Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients' experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache.

OBJECTIVE: Chronic migraine (CM) is often associated with chronic tenderness of pericranial muscles. A distinct increase in muscle tenderness prior to onset of occipital headache that eventually progresses into a full-blown migraine attack is common. This experience raises the possibility that some CM attacks originate outside the cranium. The objective of this study was to determine whether there are extracranial pathophysiologies in these headaches. METHODS: We biopsied and measured the expression of gene transcripts (mRNA) encoding proteins that play roles in immune and inflammatory responses in affected (ie, where the head hurts) calvarial periosteum of (1) patients whose CMs are associated with muscle tenderness and (2) patients with no history of headache. RESULTS: Expression of proinflammatory genes (eg, CCL8, TLR2) in the calvarial periosteum significantly increased in CM patients attesting to muscle tenderness, whereas expression of genes that suppress inflammation and immune cell differentiation (eg, IL10RA, CSF1R) decreased. INTERPRETATION: Because the upregulated genes were linked to activation of white blood cells, production of cytokines, and inhibition of NF-κB, and the downregulated genes were linked to prevention of macrophage activation and cell lysis, we suggest that the molecular environment surrounding periosteal pain fibers is inflamed and in turn activates trigeminovascular nociceptors that reach the affected periosteum through suture branches of intracranial meningeal nociceptors and/or somatic branches of the occipital nerve. This study provides the first set of evidence for localized extracranial pathophysiology in CM. Ann Neurol 2016;79:1000-1013.

Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial.

OBJECTIVE: The aim of this work was to assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine. METHODS: We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice-daily plus vitamin D3 1,000 international units capsules twice-daily or matching placebo tablets and capsules. RESULTS: Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1 to 12: a change of -8.0 (interquartile range [IQR]: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: -1.0 to + 6.0) days in the placebo group, p < 0.001; and to intervention weeks 13 to 24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to + 5.0) days in the placebo group, p < 0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks postrandomization. In comparison, only 1 patient (3%) in the placebo group (p = 0.03) experienced such a reduction. Adverse events were similar in both active treatment and placebo groups. INTERPRETATION: The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins' ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs.

Association of statin use and risk for severe headache or migraine by serum vitamin D status: a cross-sectional population-based study.

OBJECTIVE: The objective of this article is to evaluate whether statin use and vitamin D status is associated with severe headache or migraine in a nationally representative sample. METHODS: We conducted a cross-sectional study of US individuals aged ≥40 years for whom information on statin use, serum 25-hydroxy vitamin D (25(OH)D), and self-reported severe headache or migraine had been collected. We calculated prevalence estimates of headache according to statin and 25(OH)D, and conducted adjusted logistic regression analyses stratified by the median 25(OH)D (≤57 and >57 nmol/l). RESULTS: Among 5938 participants, multivariable-adjusted logistic regression showed that statin use was significantly associated with a lower prevalence of severe headache or migraine (OR 0.67; 95% CI 0.46, 0.98, p = 0.04). We found a significant interaction between statin use and 25(OH)D with the prevalence of severe headache or migraine (p for interaction = 0.005). Among participants who had serum 25(OH)D > 57 nmol/l, statin use was associated with a multivariable-adjusted odds ratio of 0.48 (95% CI 0.32, 0.71, p = 0.001) for having severe headache or migraine. Among those with 25(OH)D ≤ 57 nmol/l, no significant association was observed between statin use and severe headache or migraine. CONCLUSION: Statin use in those with higher serum vitamin D levels is significantly associated with lower odds of having severe headache or migraine.

Vitamin D status modifies the association between statin use and musculoskeletal pain: a population based study.

BACKGROUND: Past studies examining the effect of vitamin D on statin myalgia have been variable; however, these studies were done in limited samples not representative of the general population. We aimed to evaluate whether vitamin D status modifies the association between statin use and musculoskeletal pain in a sample representative of the general population. METHODS: We conducted a cross-sectional study using the National Health and Nutrition Examination Survey 2001-2004. Musculoskeletal symptoms and statin use were self-reported. Vitamin D status was assessed using serum 25 hydroxyvitamin D (25[OH]D), categorized as <15 ng/mL or ≥15 ng/mL. To evaluate if vitamin D status modifies the association between statin use and prevalent musculoskeletal pain, we performed multivariable-adjusted logistic regression models stratified by 25(OH)D status. RESULTS: Among 5907 participants ≥40 years old, mean serum 25(OH)D was 23.6 ng/mL (95% CI, 22.9-24.3). In stratified multivariable-adjusted logistic regression models, individuals with 25(OH)D <15 ng/mL, using a statin had a significantly higher odds of musculoskeletal pain compared to those not using a statin (adjusted odds ratio [aOR], 1.90; 95% CI, 1.18-3.05). Among those with 25(OH)D ≥15 ng/mL, we found no significant association between statin use and musculoskeletal pain (aOR, 0.91; 95% CI, 0.71-1.16). CONCLUSION: Among adults ≥ 40 years old with 25(OH)D <15 ng/mL, statin users had nearly 2 times greater odds of reporting musculoskeletal pain compared to non-statin users. Our findings support the hypothesis that vitamin D deficiency modifies the risk of musculoskeletal symptoms experienced with statin use.

National use of prescription medications for insomnia: NHANES 1999-2010.

STUDY OBJECTIVES: To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey, 1999-2010. PARTICIPANTS: 32,328 noninstitutionalized community-dwelling U.S. adults. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: WE DEFINED MCUFI USE AS USE OF ANY OF THE FOLLOWING MEDICATIONS IN THE PRECEDING MONTH: benzodiazepine receptor agonists (eszopiclone, zaleplon, zolpidem, estazolam, flurazepam, quazepam, temazepam, triazolam), barbiturates (amobarbital, amobarbitalsecobarbital, chloral hydrate), doxepin, quetiapine, ramelteon, and trazodone. We estimated prevalence of MCUFI use and concurrent use of another sedating medication. We determined predictors of MCUFI use using multivariate logistic regression. Overall, 3% percent of adults used a MCUFI within the preceding month. Zolpidem and trazodone were used most commonly. Overall MCUFI use increased between 1999-2000 and 2009-2010 (P value for trend < 0.001). Concurrent use of other sedating medications was high, with 55% of MCUFI users taking at least one other sedating medication and 10% taking ≥ 3 other sedating medications. Concurrent use of MCUFIs with opioids (24.6%) and non-MCUFI benzodiazepines (19.5%) were most common. After adjustment, adults seeing a mental health provider (aOR 4.68, 95% C.I. 3.79, 5.77), using other sedating medications (aOR 4.18, 95% C.I. 3.36, 5.19), and age ≥ 80 years (aOR 2.55, 95% C.I. 1.63, 4.01) had highest likelihood of MCUFI use. CONCLUSION: In this nationally representative sample, reported use of prescription medications commonly used for insomnia (MCUFIs) within the preceding month was common, particularly among older adults and those seeing a mental health provider, with high use of sedative polypharmacy among MCUFI users.

Ezogabine (KCNQ2/3 channel opener) prevents delayed activation of meningeal nociceptors if given before but not after the occurrence of cortical spreading depression.

We proposed recently that induction of delayed activation of trigeminovascular neurons by cortical spreading depression (CSD) can explain the delayed onset of headache after the migraine aura ("aura"). This prompted us to search for ways to block the neuronal activation by CSD - a preclinical correlate of an attempt to find a drug that can block the initiation of headache when administered shortly after onset of aura (i.e., preemptively). Because migraine headache and epileptic seizures are comorbid chronic neurological disorders characterized by hyperexcitable brain networks, we began the search for such goal with an M-type potassium channel opener. We opted to use ezogabine, recently approved by the FDA as adjunctive treatment of partial onset seizures in adults, because it is a selective KCNQ2/3 channel opener. When CSD was induced before ezogabine injection (8.25 mg/kg, i.p.), 40% (6/15) of the units doubled their firing rate about 45 min later for about 95 min. Similarly, when CSD was induced before vehicle was injected (4% DMSO, 0.5% methylcellulose), 50% (3/6) of the units doubled their firing rate about 30 min later for about 120 min. When CSD was triggered 1h after ezogabine injection, it activated only 8% of the units. By itself, ezogabine injection resulted in a 30% attenuation of ongoing firing in all 10 control units. Thus, activation of KCNQ2/3 channels during the aura is unlikely to preempt the onset of headache but may reduce the incidence of migraine if given during prodromes that precede the headache by hours. Given the mechanistic similarities between migraine aura and epileptic seizures, it may be worthwhile to determine whether preemptive administration of ezogabine can prevent oncoming seizures in patients whose warning signs precede their seizures by more than an hour.

Coenzyme Q10 levels are low and associated with increased mortality in post-cardiac arrest patients.

AIM: Survival after cardiac arrest (CA) is limited by the profound neurologic insult from ischemia-reperfusion injury. Therapeutic options are limited. Previous data suggest a benefit of coenzyme Q(10) (CoQ(10)) in post-arrest patients. We hypothesized that plasma CoQ(10) levels would be low after CA and associated with poorer outcomes. METHODS: Prospective observational study of post-arrest patients presenting to a tertiary care center. CoQ(10) levels were drawn 24h after return of spontaneous circulation (ROSC) and compared to healthy controls. Levels of inflammatory cytokines and biomarkers were analyzed. Primary endpoints were survival to discharge and neurologic status at time of discharge. RESULTS: 23 CA subjects and 16 healthy controls were enrolled. CoQ(10) levels in CA patients (0.28 µmol L(-1), inter-quartile range (IQR): 0.22-0.39) were significantly lower than in controls (0.75 µmol L(-1), IQR: 0.61-1.08, p<0.0001). The mean CoQ(10) level in CA patients who died was significantly lower than in those who survived (0.27 vs 0.47 µmol L(-1), p = 0.007). There was a significant difference in median CoQ(10) level between patients with a good vs poor neurological outcome (0.49 µmol L(-1), IQR: 0.30-0.67 vs 0.27 µmol L(-1), IQR: 0.21-0.30, p = 0.02). CoQ(10) was a statistically significant predictor of poor neurologic outcome (adjusted p = 0.02) and in-hospital mortality (adjusted p = 0.026). CONCLUSION: CoQ(10) levels are low in human subjects with ROSC after cardiac arrest as compared to healthy controls. CoQ(10) levels were lower in those who died, as well as in those with a poor neurologic outcome.

Statin use and musculoskeletal pain among adults with and without arthritis.

BACKGROUND: Musculoskeletal symptoms are common adverse effects of statins, yet little is known about the prevalence of musculoskeletal pain and statin use in the general population. METHODS: We conducted a cross-sectional study of the National Health and Nutrition Examination Survey 1999-2004. We estimated the prevalence of self-reported musculoskeletal pain according to statin use and calculated prevalence ratio estimates of musculoskeletal pain obtained from adjusted multiple logistic regression modeling. RESULTS: Among 5170 participants without arthritis, the unadjusted prevalence of musculoskeletal pain was significantly higher for statin users reporting pain in any region (23% among statin users, 95% confidence interval [CI], 19-27, compared with 18% among those not using statins, 95% CI, 17-20; P=.02) and in the lower extremities (12% among statin users, 95% CI, 8-16, compared with 8% among those not using statins, 95% CI, 7-9; P=.02). Conversely, among 3058 participants with arthritis, statin use was not associated with higher musculoskeletal pain in any region. After controlling for confounders, among those without arthritis, statin use was associated with a significantly higher prevalence of musculoskeletal pain in any region, the lower back, and the lower extremities (adjusted prevalence ratios: 1.33 [CI, 1.06-1.67]; 1.47 [CI, 1.02-2.13]; 1.59 [CI, 1.12-2.22], respectively). Among participants with arthritis, no association was observed between musculoskeletal pain and statin use on adjusted analyses. CONCLUSION: In this population-based study, statin use was associated with a higher prevalence of musculoskeletal pain, particularly in the lower extremities, among individuals without arthritis. Evidence that statin use was associated with musculoskeletal pain among those with arthritis was lacking.

Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock.

INTRODUCTION: Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo. METHODS: We conducted a post hoc analysis of a prospective, randomized trial of simvastatin versus placebo in patients with septic shock (ClinicalTrials.gov ID: NCT00676897). Adult patients with suspected or confirmed infection and the need for vasopressor support were included in the initial trial. For the current analysis, blood specimens were analyzed for plasma CoQ10 and low-density lipoprotein (LDL) levels. The relationship between CoQ10 levels and inflammatory and vascular endothelial biomarkers was assessed using either the Pearson or Spearman correlation coefficient. RESULTS: We analyzed 28 samples from 14 patients. CoQ10 levels were low, with a median of 0.49 (interquartile range 0.26 to 0.62) compared to levels in healthy control patients (CoQ10 = 0.95 µmol/L ± 0.29; P < 0.0001). Statin therapy had no effect on plasma CoQ10 levels over time (P = 0.13). There was a statistically significant relationship between plasma CoQ10 levels and levels of vascular cell adhesion molecule (VCAM) (r2 = 0.2; P = 0.008), TNF-α (r2 = 0.28; P = 0.004), IL-8 (r2 = 0.21; P = 0.015), IL-10 (r2 = 0.18; P = 0.025), E-selectin (r2 = 0.17; P = -0.03), IL-1ra (r2 = 0.21; P = 0.014), IL-6 (r2 = 0.17; P = 0.029) and IL-2 (r2 = 0.23; P = 0.009). After adjusting for LDL levels, there was a statistically significant inverse relationship between plasma CoQ10 levels and levels of VCAM (r2 = 0.24; P = 0.01) (Figure 3) and IL-10 (r2 = 0.24; P = 0.02). CONCLUSIONS: CoQ10 levels are significantly lower in septic shock patients than in healthy controls. CoQ10 is negatively associated with vascular endothelial markers and inflammatory molecules, though this association diminishes after adjusting for LDL levels.