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1.  Genomic expression patterns in medication overuse headaches 
Background
Chronic daily headache (CDH) and chronic migraine (CM) are one of the most frequent problems encountered in neurology, are often difficult to treat, and frequently complicated by medication-overuse headache (MOH). Proper recognition of MOH may alter treatment outcome and prevent long term disability.
Objective
This study identifies the unique genomic expression pattern MOH that respond to cessation of the overused medication.
Methods
Baseline occurrence of MOH and typical pattern of response to medication cessation were measured from a large database. Whole blood samples from patients with CM with or without MOH were obtained and their genomic profile was assessed. Affymetrix human U133 plus2 arrays were used to examine the genomic expression patterns prior to treatment and 6–12 weeks later. Headache characterisation and response to treatment based on headache frequency and disability were compared.
Results
Of 1311 patients reporting daily or continuous headaches, 513 (39.1%) reported overusing analgesic medication. At follow-up, 44.5% had a 50% or greater reduction in headache frequency, while 41.6% had no change. Blood genomic expression patterns were obtained on 33 patients with 19 (57.6%) overusing analgesic medication with a unique genomic expression pattern in MOH that responded to cessation of analgesics. Gene ontology of these samples indicated a significant number were involved with brain and immunological tissues, including multiple signalling pathways and apoptosis.
Conclusions
Blood genomic patterns can accurately identify MOH patients that respond to medication cessation. These results suggest that MOH involves a unique molecular biology pathway that can be identified with a specific biomarker.
doi:10.1177/0333102410373155
PMCID: PMC4893192  PMID: 20974594
Migraine; paediatric headache; adolescent headaches; chronic migraine; chronic daily headache; gene expression; microarray; personalised medicine
2.  Cognitive Behavioral Therapy Plus Amitriptyline for Chronic Migraine in Children and Adolescents 
JAMA  2013;310(24):2622-2630.
IMPORTANCE
Early, safe, effective, and durable evidence-based interventions for children and adolescents with chronic migraine do not exist.
OBJECTIVE
To determine the benefits of cognitive behavioral therapy (CBT) when combined with amitriptyline vs headache education plus amitriptyline.
DESIGN, SETTING, AND PARTICIPANTS
A randomized clinical trial of 135 youth (79% female) aged 10 to 17 years diagnosed with chronic migraine (≥15 days with headache/month) and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to the CBT plus amitriptyline group (n = 64) or the headache education plus amitriptyline group (n = 71). The study was conducted in the Headache Center at Cincinnati Children’s Hospital between October 2006 and September 2012; 129 completed 20-week follow-up and 124 completed 12-month follow-up.
INTERVENTIONS
Ten CBT vs 10 headache education sessions involving equivalent time and therapist attention. Each group received 1 mg/kg/d of amitriptyline and a 20-week end point visit. In addition, follow-up visits were conducted at 3, 6, 9, and 12 months.
MAIN OUTCOMES AND MEASURES
The primary end point was days with headache and the secondary end point was PedMIDAS (disability score range: 0–240 points; 0–10 for little to none, 11–30 for mild, 31–50 for moderate, >50 for severe); both end points were determined at 20 weeks. Durability was examined over the 12-month follow-up period. Clinical significance was measured by a 50% or greater reduction in days with headache and a disability score in the mild to none range (<20 points).
RESULTS
At baseline, there were a mean (SD) of 21 (5) days with headache per 28 days and the mean (SD) PedMIDAS was 68 (32) points. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group vs 6.8 for the headache education plus amitriptyline group (difference, 4.7 [95% CI, 1.7–7.7] days; P = .002). The PedMIDAS decreased by 52.7 points for the CBT group vs 38.6 points for the headache education group (difference, 14.1 [95% CI, 3.3–24.9] points; P = .01). In the CBT group, 66% had a 50% or greater reduction in headache days vs 36% in the headache education group (odds ratio, 3.5 [95% CI, 1.7–7.2]; P < .001). At 12-month follow-up, 86% of the CBT group had a 50% or greater reduction in headache days vs 69% of the headache education group; 88% of the CBT group had a PedMIDAS of less than 20 points vs 76% of the headache education group. Measured treatment credibility and integrity was high for both groups.
CONCLUSIONS AND RELEVANCE
Among young persons with chronic migraine, the use of CBT plus amitriptyline resulted in greater reductions in days with headache and migraine-related disability compared with use of headache education plus amitriptyline. These findings support the efficacy of CBT in the treatment of chronic migraine in children and adolescents.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00389038
doi:10.1001/jama.2013.282533
PMCID: PMC4865682  PMID: 24368463
3.  Childhood and Adolescent Migraine Prevention (CHAMP) Study: A Double-blinded, Placebo-controlled, Comparative Effectiveness Study of Amitriptyline, Topiramate and Placebo in the Prevention of Childhood and Adolescent Migraine 
Headache  2013;53(5):799-816.
Background
Migraine is one of the most common health problems for children and adolescents. If not successfully treated, it can impact patients and families with significant disability due to loss of school, work and social function. When headaches become frequent, it is essential to try to prevent the headaches. For children and adolescents this is guided by extrapolation from adult studies, a limited number of small studies in children and adolescents and practitioner preference. The aim of the Childhood and Adolescent Migraine Prevention (CHAMP) study is to determine the most effective preventive agent to use in children and adolescents.
Methods
CHAMP is a double-blinded, placebo-controlled, multi-center, comparative-effectiveness study of amitriptyline and topiramate for the prevention of episodic and chronic migraine, designed to mirror real-world practice, sponsored by the US National Institute of Neurological Disorders and Stroke/National Institutes of Health (U01NS076788). The study will recruit 675 subjects between the ages of 8 and 17 years old, inclusive, who have migraine with or without aura or chronic migraine as defined by the International Classification of Headache Disorders, 2nd Edition, with at least 4 headaches in the 28 days prior to randomization. The subjects will be randomized in a 2:2:1 (amitriptyline: topiramate: placebo) ratio. Doses are weight based and will be slowly titrated over an 8 week period to a target dose of 1 mg/kg of amitriptyline and 2 mg/kg of topiramate. The primary outcome will be a 50% reduction in headache frequency between the 28 day baseline and the final 28 days of treatment (weeks 20–24).
Conclusions
The goal of the CHAMP study is to obtain level 1 evidence for the effectiveness of amitriptyline and topiramate in the prevention of migraine in children and adolescents. If this study proves to be positive, it will provide information to the practicing physician as how to best prevent migraine in children and adolescents and subsequently improve the disability and outcomes.
doi:10.1111/head.12105
PMCID: PMC3637406  PMID: 23594025
Childhood and Adolescent Migraine Prevention; Amitriptyline; Topiramate
4.  Quantitative neuromagnetic signatures of aberrant cortical excitability in pediatric chronic migraine 
Background
Reports have suggested that abnormal cortical excitability may be associated with acute migraines. The present study quantitatively assesses the degree of cortical excitability in chronic migraine as compared to acute migraine and healthy controls within the pediatric population.
Methods
We investigated 27 children suffering from chronic migraine, 27 children suffering from acute migraine, and 27 healthy controls using a magnetoencephalography (MEG) system, recording at a sampling rate of 6000 Hz. All groups were age-matched and gender-matched. Neuromagnetic brain activation was elicited by a finger-tapping motor task. The spatiotemporal and spectral signatures of MEG data within a 5–2884 Hz range were analyzed using Morlet wavelet transform and beamformer analyses.
Results
Compared with controls, the chronic migraine group showed (1) significantly prolonged latencies of movement-elicited magnetic fields (MEFs) between 5 and 100 Hz; (2) increased spectral power between 100 and 200 Hz, and between 2200 and 2800 Hz; and (3) a higher likelihood of neuromagnetic activation in the ipsilateral sensorimotor cortices, supplementary motor area, and occipital regions. Compared with acute migraine group, chronic migraine patients showed (1) significantly higher odds of having strong MEFs after 150 ms; and (2) significantly higher odds of having neuromagnetic activation from the deep brain areas.
Conclusions
Results demonstrated that chronic migraine subjects were not only different from the healthy controls, but also different from acute migraine subjects. The chronification of migraines may be associated with elevated cortical excitability, delayed and spread neural response, as well as aberrant activation from deep brain areas.
doi:10.1186/s10194-016-0641-x
PMCID: PMC4844586  PMID: 27113076
Migraine; Magnetoencephalography (MEG); Pediatric; High frequency oscillations; Deep brain sources; Wavelet transform
5.  Relationship between Daily Mood and Migraine in Children 
Headache  2013;53(10):1624-1634.
Background
Retrospective and cross-sectional studies have suggested a bidirectional relationship between migraine and mood disturbance.
Objective
The present prospective daily diary study examined the prevalence and temporal associations between migraine and daily mood, mood and next-day headache, and headache and next-day mood.
Methods
Sixty-nine children (50 females, 19 males) between the ages of 7–12 years and their parents attending neurology clinic appointments and having a diagnosis of migraine as defined by ICHD-II criteria completed measures on quality of life, headache disability, child emotions and child behaviors. Children and parents then recorded children’s headache occurrence, headache duration, headache severity, mood, daily hassles, and medication use on paper diaries once a day for two consecutive weeks. “Mood” was defined using the facial affective scale, which is a visual representation of negative and positive affect. Data were analyzed using multilevel models.
Results
Controlling for age, sex, quality of life, headache disability, and medication use, worse mood was associated with same-day occurrence, longer duration and more severe headache in both child and parent report. Today’s mood was not consistently associated with next-day headache and today’s headache was not associated with next-day mood in either child or parent report.
Conclusions
Results of this study lend support for a complex relationship between mood and headache in children with migraine. More research is needed to further elucidate the temporal nature of this relationship within a given day and over an extended period of time.
doi:10.1111/head.12215
PMCID: PMC4270347  PMID: 24102349
children; migraine; mood; daily hassles; daily diary
6.  Quality of Life and Emotional Functioning in Youth with Chronic Migraine and Juvenile Fibromyalgia 
The Clinical journal of pain  2013;29(12):10.1097/AJP.0b013e3182850544.
Chronic pain in children is associated with significant negative impact on social, emotional, and school functioning. Previous studies on the impact of pain on children's functioning have primarily used mixed samples of pain conditions or single pain conditions (e.g., headache, abdominal pain) with relatively small sample sizes. As a result, the similarities and differences in the impact of pain in sub-groups of children with chronic pain have not been closely examined.
Objectives
To compare pain characteristics, quality of life, and emotional functioning among youth with pediatric chronic migraine (CM) and juvenile fibromyalgia (JFM).
Methods
We combined data obtained during screening of patients for two relatively large intervention studies of youth (ages 10-18) with CM (N = 153) and JFM (N = 151). Measures of pain intensity, quality of life (Pediatric Quality of Life; PedsQL™, child and parent-proxy), depressive symptoms (Children's Depression Inventory; CDI), and anxiety symptoms (Adolescent Symptom Inventory-4 - Anxiety subscale) were completed by youth and their parent. A multivariate analysis of co-variance (MANCOVA) controlling for effects of age and gender was performed to examine differences in quality of life and emotional functioning between the CM and JFM groups.
Results
Youth with JFM had significantly higher anxiety and depressive symptoms, and lower quality of life in all domains. Among children with CM, overall functioning was higher but school functioning was a specific area of concern.
Discussion
Results indicate important differences in sub-groups of pediatric pain patients and point to the need for more intensive multidisciplinary intervention for JFM patients.
doi:10.1097/AJP.0b013e3182850544
PMCID: PMC3675174  PMID: 23446072
Pediatric pain; chronic migraine; pediatric headache; juvenile fibromyalgia; quality of life
7.  Altered Cortical Activation in Adolescents With Acute Migraine: A Magnetoencephalography Study 
To quantitatively assess cortical dysfunction in pediatric migraine, 31 adolescents with acute migraine and age- and gender-matched controls were studied using a magnetoencephalography (MEG) system at a sampling rate of 6,000 Hz. Neuromagnetic brain activation was elicited by a finger-tapping task. The spectral and spatial signatures of magnetoencephalography data in 5 to 2,884 Hz were analyzed using Morlet wavelet and beamformers. Compared with controls, 31 migraine subjects during their headache attack phases (ictal) showed significantly prolonged latencies of neuromagnetic activation in 5 to 30 Hz, increased spectral power in 100 to 200 Hz, and a higher likelihood of neuromagnetic activation in the supplementary motor area, the occipital and ipsilateral sensorimotor cortices, in 2,200 to 2,800 Hz. Of the 31 migraine subjects, 16 migraine subjects during their headache-free phases (interictal) showed that there were no significant differences between interictal and control MEG data except that interictal spectral power in 100 to 200 Hz was significantly decreased. The results demonstrated that migraine subjects had significantly aberrant ictal brain activation, which can normalize interictally. The spread of abnormal ictal brain activation in both low- and high-frequency ranges triggered by movements may play a key role in the cascade of migraine attacks.
Perspective
This is the first study focusing on the spectral and spatial signatures of cortical dysfunction in adolescents with migraine using MEG signals in a frequency range of 5 to 2,884 Hz. This analyzing aberrant brain activation may be important for developing new therapeutic interventions for migraine in the future.
doi:10.1016/j.jpain.2013.04.009
PMCID: PMC3844550  PMID: 23792072
Migraine; magnetoencephalography (MEG); pediatric; high-frequency oscillations; wavelet
8.  mRNA Blood Expression Patterns In New Onset Idiopathic Pediatric Epilepsy 
Epilepsia  2012;54(2):272-279.
Purpose
Determine if blood mRNA expression patterns in children with newly diagnosed untreated idiopathic epilepsy are different than those in healthy controls. Determine the differential expression patterns between epilepsy subjects with generalized onset or partial onset seizures compared to healthy controls.
Methods
Whole blood was obtained from otherwise healthy pediatric subjects with newly diagnosed untreated idiopathic epilepsy along with healthy pediatric controls. mRNA was isolated and hybridized to Affymetrix HGU 133 2.0+ microarrays. Analysis was performed using Genespring. Differentially expressed gene lists resulted from comparison of i) epilepsy and control groups and ii) seizure type subgroups with controls.. Tissue expression and gene ontology analysis was performed using DAVID.
Key findings
Thirty-seven epilepsy patients and 28 controls were included. Overall, 575 genes were differentially expressed in subjects with epilepsy compared to controls. The generalized seizure subgroup versus control (GvC) gene list and the partial seizure subgroup versus control (PvC) gene list were different (p < 0.05). Tissue expression analysis identified almost half of the genes in GvC and PvC as brain based. Functional group analysis identified several biologically relevant pathways. In GvC, these included mitochondria and lymphocyte activation. In PvC, apoptosis, inflammatory defense and cell motion pathways were identified.
Significance
A unique, biologically meaningful mRNA expression pattern is detectable in whole blood of pediatric subjects with new onset and untreated epilepsy. This analysis finds many similar pathways to those identified in brain studies examining lesional intractable epilepsy. Blood mRNA expression patterns show promise as a target for biomarker development in pediatric epilepsy.
doi:10.1111/epi.12016
PMCID: PMC3566372  PMID: 23167847
Gene expression; mRNA; pediatric epilepsy; genomics; epilepsy
9.  Headstrong intervention for pediatric migraine headache: a randomized clinical trial 
Background
The purpose of this study was to evaluate the efficacy of a self-guided CD-ROM program (“Headstrong”) containing cognitive-behavioral self-management strategies versus an educational CD-ROM program for treating headaches, headache-related disability, and quality of life.
Methods
Participants were 35 children ages 7–12 years with migraine recruited from one university medical center and two children’s hospital headache clinics. Participants were randomly assigned to complete the Headstrong or educational control CD-ROM program over a 4-week period. Data on headache frequency, duration, and severity, migraine-related disability, and quality of life (QOL) were obtained at baseline, post-intervention, and 3-months post-intervention.
Results
At post-intervention, Headstrong resulted in lower severity (on a 10-point scale) than the control group by child report (5.06 ± 1.50 SD vs. 6.25 ± 1.92 SD, p = 0.03, ES = 0.7). At 3-months post-intervention, parents reported less migraine-related disability (on the PedMIDAS) in the Headstrong group compared to the control group (1.36 ± 2.06 SD vs. 5.18 ± 6.40 SD; p = 0.04, ES = 0.8). There were no other group differences at post treatment or at 3-months post-intervention.
Conclusions
When compared to an educational control, Headstrong resulted in lower pain severity at post-treatment and less migraine-related disability at 3-months post-intervention, by child and parent report respectively. Headache frequency and quality of life did not change more for Headstrong versus control. Additional research is needed on the Headstrong Program to increase its efficacy and to test it with a larger sample recruited from multiple centers simultaneously.
doi:10.1186/1129-2377-15-12
PMCID: PMC3996073  PMID: 24580721
Headache; Children; Migraine; Behavioral treatments; E-health; CD-ROM; Child; Migraine headaches; Cognitive-behavioral treatment
10.  Neuromagnetic Abnormality of Motor Cortical Activation and Phases of Headache Attacks in Childhood Migraine 
PLoS ONE  2013;8(12):e83669.
The cerebral cortex serves a primary role in the pathogenesis of migraine. This aberrant brain activation in migraine can be noninvasively detected with magnetoencephalography (MEG). The objective of this study was to investigate the differences in motor cortical activation between attacks (ictal) and pain free intervals (interictal) in children and adolescents with migraine using both low- and high-frequency neuromagnetic signals. Thirty subjects with an acute migraine and 30 subjects with a history of migraine, while pain free, were compared to age- and gender-matched controls using MEG. Motor cortical activation was elicited by a standardized, validated finger-tapping task. Low-frequency brain activation (1∼50 Hz) was analyzed with waveform measurements and high-frequency oscillations (65–150 Hz) were analyzed with wavelet-based beamforming. MEG waveforms showed that the ictal latency of low-frequency brain activation was significantly delayed as compared with controls, while the interictal latency of brain activation was similar to that of controls. The ictal amplitude of low-frequency brain activation was significantly increased as compared with controls, while the interictal amplitude of brain activation was similar to that of controls. The ictal source power of high-frequency oscillations was significantly stronger than that of the controls, while the interictal source power of high-frequency oscillations was significantly weaker than that of controls. The results suggest that aberrant low-frequency brain activation in migraine during a headache attack returned to normal interictally. However, high-frequency oscillations changed from ictal hyper-activation to interictal hypo-activation. Noninvasive assessment of cortical abnormality in migraine with MEG opens a new window for developing novel therapeutic strategies for childhood migraine by maintaining a balanced cortical excitability.
doi:10.1371/journal.pone.0083669
PMCID: PMC3873943  PMID: 24386250
12.  Psychiatric comorbidity in pediatric chronic daily headache 
Objectives
The objectives of this study were to assess comorbid psychiatric diagnoses in youth with chronic daily headache (CDH) and to examine relationships between psychiatric status and CDH symptom severity, as well as headache-related disability.
Methods
Standardized psychiatric interviews (Kiddie Schedule for Affective Disorders and Schizophrenia, KSADS) were conducted with 169 youth ages 10–17 diagnosed with CDH. Participants provided prospective reports of headache frequency with a daily headache diary and completed measures of symptom severity, headache-related disability (PedMIDAS) and quality of life (PedsQL).
Results
Results showed that 29.6% of CDH patients met criteria for at least one current psychiatric diagnosis, and 34.9% met criteria for at least one lifetime psychiatric diagnosis. No significant relationship between psychiatric status and headache frequency, duration, or severity was found. However, children with at least one lifetime psychiatric diagnosis had greater functional disability and poorer quality of life than those without a psychiatric diagnosis.
Discussion
Contrary to research in adults with chronic headaches, most youth with CDH did not appear to be at an elevated risk for comorbid psychiatric diagnosis. However, patients with a comorbid psychiatric diagnosis were found to have higher levels of headache-related disability and poorer quality of life. Implications for treatment are discussed.
doi:10.1177/0333102412460776
PMCID: PMC3692295  PMID: 22990686
Chronic daily headache; pediatric; psychiatric comorbidity; emotional adjustment; headache-related disability; quality of life
13.  Aberrant Neuromagnetic Activation in the Motor Cortex in Children with Acute Migraine: A Magnetoencephalography Study 
PLoS ONE  2012;7(11):e50095.
Migraine attacks have been shown to interfere with normal function in the brain such as motor or sensory function. However, to date, there has been no clinical neurophysiology study focusing on the motor function in children with migraine during headache attacks. To investigate the motor function in children with migraine, twenty-six children with acute migraine, meeting International Classification of Headache Disorders criteria and age- and gender-matched healthy children were studied using a 275-channel magnetoencephalography system. A finger-tapping paradigm was designed to elicit neuromagnetic activation in the motor cortex. Children with migraine showed significantly prolonged latency of movement-evoked magnetic fields (MEF) during finger movement compared with the controls. The correlation coefficient of MEF latency and age in children with migraine was significantly different from that in healthy controls. The spectral power of high gamma (65–150 Hz) oscillations during finger movement in the primary motor cortex is also significantly higher in children with migraine than in controls. The alteration of responding latency and aberrant high gamma oscillations suggest that the developmental trajectory of motor function in children with migraine is impaired during migraine attacks and/or developmentally delayed. This finding indicates that childhood migraine may affect the development of brain function and result in long-term problems.
doi:10.1371/journal.pone.0050095
PMCID: PMC3502360  PMID: 23185541
14.  The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research 
Background
Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking.
Methods
In order to define subphenotypes of allergic disease accurately, we established an infrastructure to link and efficiently utilize clinical and epidemiologic data with biospecimens into a single biorepository called the Greater Cincinnati Pediatric Clinic Repository (GCPCR). Children with allergic disorders as well as healthy controls are followed longitudinally at hospital clinic, emergency department, and inpatient visits. Subjects' asthma, allergy, and skin symptoms; past medical, family, social, diet, and environmental histories; physical activity; medication adherence; perceived quality of life; and demographics are ascertained. DNA is collected from all participants, and other biospecimens such as blood, hair, and nasal epithelial cells are collected on a subset.
Results
To date, the GCPCR has 6,317 predominantly Caucasian and African American participants, and 93% have banked DNA. This large sample size supports adequately powered genetic, epidemiologic, environmental, and health disparities studies of childhood allergic diseases.
Conclusions
The GCPCR is a unique biorepository that is continuously evaluated and refined to achieve and maintain rigorous clinical phenotype and biological data. Development of similar disease-specific repositories using common data elements is necessary to enable studies across multiple populations of comprehensively phenotyped patients.
doi:10.1089/ped.2011.0116
PMCID: PMC3377950  PMID: 22768387

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