Effects of gender and age on paediatric headache.

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.

Friendships and social interactions of school-aged children with migraine.

We set out to evaluate the friendships and social behaviour of school-aged children with migraine. Concern exists regarding the impact of paediatric migraine on daily activities and quality of life. We hypothesized that children with migraine would have fewer friends and be identified as more socially sensitive and isolated than comparison peers. Sixty-nine children with migraine participated in a school-based study of social functioning. A comparison sample without migraine included classmates matched for gender, race and age. Children with migraine had fewer friends at school; however, this effect was limited to those in elementary school. Behavioural difficulties were not found. Middle-school students with migraine were identified by peers as displaying higher levels of leadership and popularity than comparison peers. Concern may be warranted about the social functioning of pre-adolescent children with migraine; however, older children with migraine may function as well as or better than their peers.

Assessing quality and normalization of microarrays: case studies using neurological genomic data.

BACKGROUND: Genomic analysis using microarray tools has the potential benefit of enhancing our understanding of neurological diseases. The analysis of these data is complex due to the large amount of data generated. Many tools have been developed to assist with this, but standard methods of analysis of these tools have not been established. OBJECTIVE: This study analyzed the sensitivity and specificity of different analytical methods for gene identification and presents a standardized approach. METHODS: Affymetrix HG-U133 plus 2.0 microarray datasets from two neurological diseases - chronic migraine and new-onset epilepsy - were used as source data and methods of analysis for normalization of data and identification of gene changes were compared. Housekeeping genes were used to identify non-specific changes and gender related genes were used to identify specific changes. RESULTS: Initial normalization of data revealed that 5-10% of the microarray were potential outliers due to technical errors. Two separate methods of analysis (dChip and Bioconductor) identified the same microarray chips as outliers. For specificity and sensitivity testing, performing a per-gene normalization was found to be inferior to standard preprocessing procedures using robust multichip average analysis. CONCLUSIONS: Technical variation in microarray preprocessing may account for chip-to-chip and batch-to-batch variations and outliers need to be removed prior to analysis. Specificity and sensitivity of the final results are best achieved following this identification and removal with standard genomic analysis techniques. Future tools may benefit from the use of standard tools of measurement.

Development of a patient-based grading scale for PedMIDAS.

The objective was to develop and validate a patient-based grading scale for PedMIDAS. PedMIDAS was administered to 329 children, who rated their overall disability based on the adult MIDAS grades. This patient-based rating and PedMIDAS scores were compared to develop the grading scale. Headache disability was rated little to none, 49.5%; mild, 26.7%; moderate, 15.8%; and severe, 7.9%, with PedMIDAS raw scores of 4.9 +/- 6.3, 17.8 +/- 14.9, 40.6 +/- 34.2, and 91.4 +/- 69.8. Convergence of these results yielded an empirically derived grading system: Grade I, 0-10; II, 11-30; III, 31-50 and IV, > 50. Higher grades corresponded to an increased need for prophylactic treatment. A patient-based grading scale further increases the utility of PedMIDAS in assessing migraine disability in children, so that it can be widely used in routine clinical evaluation and management.

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Quality of life in paediatric migraine: characterization of age-related effects using PedsQL 4.0.

The aim of this study was to measure quality of life (QOL) across a broad age range of paediatric migraine patients. Children and adolescents (n=686) with migraine completed the Pediatric Quality of Life Inventory, version 4.0 (PedsQL 4.0) and a standardized headache assessment at an initial clinic visit. The sample size for each PedsQL age group was: age 2-4=21, age 5-7=86, age 8-12=298, and age 13-18=281. Mean total score was 72.7 +/- 14.8, significantly less than healthy norms (P<0.01). Teens reported lower School Functioning than older and young children (P<0.05) and young children reported lower Social Functioning than older children and teens (P<0.001). A moderate relation was found between self and parent report. Age-related effects on QOL have implications for the evaluation and management of migraine in paediatric practice. The self and parent report forms of the PedsQL can be used in a practice setting.

Migraine headaches and sleep disturbances in children.

OBJECTIVE: The aim of the present study was to investigate the prevalence of sleep disturbances in children with migraine headaches and to describe individual differences in sleep behaviors based on headache features (eg, frequency, duration, intensity). BACKGROUND: A relationship between migraine headaches and sleep disturbances has been suggested in both children and adults, but there is a lack of research examining the relationship between specific headache features and the range of sleep behaviors in children. METHODS: One hundred eighteen children, aged 2 to 12 years (mean, 9.1; standard deviation, 2.3) were evaluated for headaches at two pediatric neurology departments. Parents completed the Children's Sleep Habits Questionnaire and a standardized questionnaire regarding headache characteristics. RESULTS: Parents reported a high rate of sleep disturbances in children, including sleeping too little (42%), bruxism (29%), child co-sleeping with parents (25%), and snoring (23%). Children with migraine headaches experienced more sleep disturbances compared to published healthy control norms. After controlling for child demographics, we found that the frequency and duration of migraine headaches predicted specific sleep disturbances, including sleep anxiety, parasomnias, and bedtime resistance. CONCLUSIONS: Children with migraine headaches have a high prevalence of sleep disturbances. The direction of the relationship between headaches and sleep is unknown. Regardless, interventions targeting sleep habits may improve headache symptoms, and effective treatment of headaches in children may positively impact sleep.

PedMIDAS: development of a questionnaire to assess disability of migraines in children.

BACKGROUND: For adults, disability produced by migraines has been assessed with a migraine-specific disability tool-MIDAS. The objective of this study was to develop and validate a similar tool that accurately depicts the disability of headaches in school-age children and adolescents. METHODS: A six-question tool (PedMIDAS) was developed and administered to patients attending a tertiary referral center for pediatric headaches. Internal consistency and test/retest reliability were assessed. Validity was assessed by correlating scores with headache frequency, severity, and duration. Changes in the total score in response to treatment were assessed in a portion of the patients. RESULTS: The PedMIDAS questionnaire was administered to 441 patients for a total of 724 trials. The mean score at the initial visit was 44.3 +/- 47.9, whereas the overall mean score was 25.1 +/- 36.5. A 2-week test/retest reliability assessment for 56 patients confirmed the stability of the instrument with a Pearson coefficient of 0.80. The correlation of the PedMIDAS score with frequency, severity, and duration had Pearson's coefficient values of 0.58, 0.27, and 0.23. The PedMIDAS score was reduced to 20.0 +/- 32.3 (p < 0.0001) at the first follow-up assessment with subsequent continued reduction. CONCLUSIONS: The PedMIDAS questionnaire provided a developmentally sensitive, reliable, and valid assessment of the disability of childhood and adolescent headaches. This questionnaire provides a tool to assess the impact of migraines in children and to monitor response to treatment. Further research should focus on additional validation of the PedMIDAS using a larger population and sampling from other populations (e.g., primary care and community samples).

Effectiveness of nasal sumatriptan in 5- to 12-year-old children.

OBJECTIVE: To assess the tolerability and effectiveness of nasal sumatriptan in the treatment of migraine in 5- to 12-year-old children. BACKGROUND: Although headaches are a common disorder and occur in up to 10.6% of children, many of the new migraine abortive agents have not been well evaluated in this population. It has recently been reported that nasal sumatriptan is effective in the treatment of migraine in adolescents. In younger children, it is yet to be characterized. In addition, many children have significant amounts of vomiting with their migraines, limiting their use of oral medications. DESIGN AND METHODS: Children with headache were evaluated by a child neurologist, child psychologist, and pediatric nurse practitioner. Clinical and International Headache Society diagnoses were established for each child. Patients with headaches that were either unresponsive to oral medications or had significant vomiting were treated with nasal sumatriptan. Initial administration and tolerability were performed in the Headache Center at Cincinnati's Children's Hospital Medical Center. Patients or their parents were contacted to assess the overall effectiveness of nasal sumatriptan after home administration. RESULTS: Ten patients aged between 5 and 12 years (mean, 9.9 years) received either a 5-mg (n = 2) or 20-mg (n = 8) dose of sumatriptan. All 10 patients had a clinical diagnosis of migraine; 7 met the International Headache Society criteria for migraine. The mean age of headache onset was 6.6 years. A total of 57 headaches were treated; 47 (82.5%) responded to sumatriptan. Of the patients who treated headaches, the mean number of headaches treated was 5.2, while the mean number of responsive headaches was 4.3. One patient had no response, 2 patients had a 50% response, and 6 patients had 100% response to the nasal sumatriptan. Three patients reported persistent "bad taste." CONCLUSIONS: This report demonstrates that nasal sumatriptan may be effective in aborting migraine in young children (aged 5 to 12 years). It also suggests that there may be subgroups for which it works well. This information suggests that double-blind, placebo-controlled studies are necessary to determine the overall effectiveness of nasal sumatriptan in this age group.

Tolerability and effectiveness of prochlorperazine for intractable migraine in children.

OBJECTIVE: To study the effectiveness of prochlorperazine in aborting severe, intractable migraines in children. STUDY DESIGN: Patients for this study were drawn from the population seen and evaluated in the Headache Center at Cincinnati Children's Hospital Medical Center. All patients were diagnosed with migraine headache by both clinical and International Headache Society criteria. The effectiveness of intravenous prochlorperazine in 20 consecutive patients referred to the emergency department for severe, prolonged migraines was retrospectively reviewed. RESULTS: Patients evaluated in this study presented with a mean headache severity of 8.4 on a 0- to 10-point scale and an average duration of 54 hours. At 1 hour, 90% of the patients reported feeling better with 50% becoming pain-free. A 50% or greater reduction in severity occurred in 75% of patients at 1 hour and in 95% at 3 hours. At 3 hours, 95% of the patients reported feeling better, and 60% were pain-free. Only 1 patient failed to respond to prochlorperazine. CONCLUSION: Prochlorperzaine was shown to be highly effective in aborting intractable migraines in children. It was well tolerated with no significant side effects. Additional large, double-blinded, randomized, placebo-controlled studies are needed to further investigate its effectiveness.

Characterization of chronic daily headaches in children in a multidisciplinary headache center.

BACKGROUND: Chronic daily headaches (CDH) occur in >4% of the adult population. The criteria for CDH, however, are controversial. In children, the characterization of frequent headaches and CDH is limited. METHODS: A Headache Center to characterize headaches in children (3 to 18 years old) was established. Over 34 months, 577 children have been evaluated. With use of a definition of > or =15 headaches per month, 200 (34.6%) children had CDH. RESULTS: The average age at the first headache in these children was 9.3 +/- 3.6 years, whereas the average age at presentation to the Headache Center was 12.5 +/- 3.1 years. Sixty-eight percent were girls, 88% were Caucasian, and 11% were African American. Ninety-two percent clinically had migraine headaches, whereas 60.5% met the International Headache Society migraine criteria. The pain was pulsatile in 79%, 63.5% had nausea with or without vomiting, and 59.5% had photophobia and phonophobia. Three subcategories emerged, with 37% having frequent headaches but not daily, 43.5% having episodic daily headaches, and 19.5% having a continuous headache. CONCLUSION: The features of CDH in children most closely match those of migraine. A clear division of these children using frequency identifies three groups: frequent headaches (15 to 29), daily intermittent, and daily continuous. The daily continuous group is the most unique; however, the nature of these headaches continues to remain migrainous.

Depression and functional disability in chronic pediatric pain.

OBJECTIVES: The primary aim of this study was to describe pain characteristics, coping strategies, depression, and functional disability in children and adolescents with chronic pain and to examine potential factors that are associated with functional disability in a pediatric pain population. The secondary aim of this study was to compare functional disability in two chronic pain conditions: localized musculoskeletal pain and chronic daily headaches. SUBJECTS: The participants in this study were 73 pediatric pain patients with a variety of chronic pain conditions. Subjects in the second part of the study were a subset of patients (N = 44) from the pain clinic sample with chronic localized musculoskeletal pain and a subset of patients (N = 38) from the headache center of the same hospital who had chronic daily headaches. DESIGN: Patients completed self-report measures of pain intensity, depression, coping strategies, coping efficacy, and functional disability. RESULTS: Results indicated that chronic pain had a substantial impact on the children's lives and that depression was strongly associated with functional disability. Maladaptive coping was correlated with depression and disability; however, maladaptive coping was not independently associated with functional disability. A comparison between the two groups found significant differences in pain intensity and functional disability. The localized musculoskeletal pain group reported higher levels of disability and more difficulty coping than the chronic daily headache group. CONCLUSIONS: The implications for treatment of chronic pain in children are discussed with an emphasis on greater attention to developmental issues and their relation to coping, emotional functioning, and disability in pediatric pain. Further research examining differences in coping and disability between different pediatric pain groups is also warranted.

Effectiveness of amitriptyline in the prophylactic management of childhood headaches.

OBJECTIVE: To study the effectiveness of a standardized dose of amitriptyline, 1 mg/kg, for childhood headaches. BACKGROUND: Amitriptyline has been shown to be effective for the prophylaxis of migraine in adults. Studies in children, however, have been quite limited. In adults, the suggested effective dose range is 10 to 150 mg. In children, a standardized dosage is often not used, resulting in a dosage range in clinical practice that often varies from a very low dose to a dose equivalent to that used in adults. METHODS: Children with more than three headaches per month were treated with amitriptyline, slowly increasing the dose to 1 mg/kg per day. The frequency, severity, and duration of their headaches were initially evaluated and subsequently measured at each follow-up evaluation. Two hundred seventy-nine children had headaches occurring frequently enough to indicate prophylactic treatment. Of these children, 192 (68.8%) were treated with amitriptyline. The average age at presentation was 12.0 (+/- 3.0) years. The ratio of boys to girls was 1:1.74. The average frequency of headaches was 17.1 (+/- 10.1) days per month. The average severity was 6.84 (+/- 1.67) on a 10-point pain scale. The average duration was 11.5 (+/- 15.0) hours. The most frequent diagnoses using International Headache Society criteria were migraine (60.6%), migraine with aura (7.9%), and tension-type headache (10.4%). Of these children, 146 have been seen for at least one follow-up examination, occurring on average 67.3 (+/- 32.3) days after beginning prophylactic treatment. RESULTS: A total of 84.2% of the children reported an overall perception of being better, while 11.6% reported being the same. The frequency of headaches improved to 9.2 (+/- 10.0) days per month. The average severity was reduced to 5.1 (+/- 2.1), and the average duration was reduced to 6.3 (+/- 11.1) hours. If daily or continuous headaches were excluded, the improvements were more marked. Minimal side effects were reported from these children and their families. Long-term evaluation (156 to 415 days) showed continued sustained improvement. CONCLUSIONS: Amitriptyline is an effective prophylactic medication for children with frequent headaches. A standardized dosing regimen results in a significant number of children responding with minimal side effects. The children are able to tolerate this dosing scheme and demonstrate good adherence to a dosing schedule of once a day.

Diagnosis of migraine in children attending a pediatric headache clinic.

The International Headache Society (IHS) criteria for migraine are not sufficient to diagnose migraine in children. Specifically, the duration and localization of the headache are different in children and adults with migraine. This study compared the formal IHS criteria with pediatric-amended IHS criteria and IHS criteria with the duration factor removed in children younger than 18 years. In addition, the older criteria by Vahlquist and by Prensky and Sommer were also compared. Finally, clinical diagnosis of migraine was compared with IHS criteria with the duration factor removed. The study showed that many children with a shorter duration headache have migraine and also that a number of children with a very long duration of headaches still fit the diagnosis of migraine. Unilateral headache is quite uncommon. The majority of children with migraine complained of bilateral headaches. It is concluded that the IHS criteria for pediatric migraine should be revised. We suggest making the duration factor a minor criteria for migraine in children or to exclude headaches lasting longer than 72 hours only in children younger than 15 years.

Characterization of the substance P (NK-1) receptor in tunicamycin-treated transfected cells using a photoaffinity analogue of substance P.

Chinese hamster ovary cells expressing the N-glycosylated substance P (NK-1) receptor were treated with the glycosylation inhibitor tunicamycin and photolabeled with 125I-Bolton-Hunter-p-benzoyl-L-phenylalanine8-substance P. Two radioactive proteins of M(r) 80,000 and 46,000, representing the glycosylated and nonglycosylated substance P (NK-1) receptor, respectively, were observed. The IC50 for the inhibition of photolabeling of both receptor forms was 0.3 +/- 0.1 nM for substance P and 30 +/- 5 nM for neurokinin A (substance K). Thus, glycosylation of the substance P (NK-1) receptor has no detectable effect on the affinity of the substance P (NK-1) receptor for substance P or neurokinin A (substance K).

Crystallization and preliminary crystallographic studies of Saccharomyces cerevisiae alcohol dehydrogenase I.

The cytoplasmic yeast alcohol dehydrogenase I crystallized at 5 degrees C as hexagonal plates or short columns in the presence of NAD+ and 2,2,2-trifluoroethanol, in sodium N-tris(hydroxymethyl)methyl-3-aminopropanesulfonate buffer at pH 8.2 to 8.6, using polyethylene glycol 4000 as precipitant. X-ray diffraction data to 3.2 A resolution show that the crystals are hexagonal in space group P622 with unit cell dimensions a = b = 147.9 A, c = 69.1 A. There is one subunit of the tetrameric enzyme per asymmetric unit, giving a packing density of 2.9 A3/Da.

Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses.

Stably transfected Chinese hamster ovary cells expressing either the substance P receptor or neurokinin A receptor were constructed, isolated, and characterized. Equilibrium ligand binding studies performed on whole cells demonstrated that cell lines expressing either of these receptors contained a single class of high-affinity binding sites with an apparent KD of 0.16 nM for the substance P receptor and an apparent KD of 2.1 nM for the neurokinin A receptor. The higher affinity of substance P for its receptor was accounted for by both a greater association rate constant and a lesser dissociation rate constant. The time course and extent of ligand-stimulated inositol 1,4,5-trisphosphate mass increases in both cell lines were similar and displayed rapid and transient kinetics. Ligand-stimulated cyclic AMP accumulation was also apparent in the cell lines, although the time course and magnitude of the responses were substantially different, with the neurokinin A receptor mediating a greater and more prolonged response. These studies establish the presence of functional substance P receptors and neurokinin A receptors in the stably transfected cell lines and provide evidence for agonist-dependent differential stimulation of second messenger responses.

Structure, functions, and mechanisms of substance P receptor action.

Substance P is a member of a family of structurally related peptides, called tachykinins, that are involved in the regulation of many biologic processes. Diversity in the generation of multiple tachykinin peptides arises due to multiple genes encoding these peptides as well as by mechanisms of alternative RNA processing and differential posttranslational processing. The multiple peptides are neurotransmitters and/or neuromodulator substances, and they bring about their actions mainly by activating three primary types of receptors, NK-1, NK-2, and NK-3. The pharmacology and tissue locations of these receptor sites are discussed, as is their involvement in certain biologic responses. These three receptor sites have been molecularly characterized by cDNA cloning and functional expression, and all are members of the superfamily of receptors coupled to G-regulatory proteins. Second messenger systems established to be activated by tachykinin receptor stimulation include the hydrolysis of inositol containing phospholipids by a phospholipase C mechanism. The role of substance P in neurogenic inflammation and plasma extravasation is briefly discussed. The generation of new research tools recently in the tachykinin field should allow for a detailed examination of the mechanisms of peptide action, including a focus on receptor structure-function relations and regulation of receptor sensitivity.